I. SYNTHESIS OF ETHER LINKED ANALOGS AND SAR STUDIES OF ANNONACEOUS ACETOGENINS II. ASYMMETRIC ELECTROPHILIC HALOCYCLIZATION REACTIONS By Atefeh Garzan A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY CHEMISTRY 2012 ABSTRACT I. SYNTHESIS OF ETHER LINKED ANALOGS AND SAR STUDIES OF ANNONACEOUS ACETOGENINS II. ASYMMETRIC ELECTROPHILIC HALOCYCLIZATION REACTIONS By Atefeh Garzan This dissertation discusses the synthesis of ether linked analogs of annonaceous acetogenins. Utilization of ether linkages will enable rapid synthesis of a library of acetogenins with a variety of groups flanking the right and left side of the bis-adjacent THF core, which will be used for future SAR studies of acetogenins. An efficient method for regio- and stereoselective double cyclization of polyhydroxylated systems to form bis-adjacent THF rings with ether linked is developed. Several elegant reports of asymmetric halogenation of alkenes and alkynes followed by intra or inter molecular attack of a nucleophile have appeared in the literature in the last decade. We have recently disclosed catalytic asymmetric routes to chlorolactones, chlorooxazolines, and chlorooxazines. Further studies have shown the feasibility for the cyclization of carbamates to yield chlorooxazolidinone. We have observed a remarkable solvent effect that essentially reverses the chirality of the product chlorooxazolidinone with the same chiral catalyst. The results of this study along with kinetic investigations that suggest enthalpy-entropy compensation as the origin of the chirality switch are discussed in this dissertation. To My Beloved Parents iii ACKNOWLEDGEMENTS An undertaking such as a dissertation is not completed with out the support of many people. My first debt of gratitude must go to my advisor, Prof. Babak Borhan. I would like to gratefully and sincerely thank him for his guidance, understanding, patience, and most importantly, his friendship during my graduate studies. His mentorship was paramount in providing a well rounded experience consistent my long-term career goals. He encouraged me to not only grow as an experimentalist and a chemist but also as an instructor and an independent thinker. For everything you have done for me, Babak, I thank you. I would also like to thank Profs. Wulff, Jackson, and Smith for serving on my committee at various times along with the advice they have provided over the years. The friends I have in the group and in the department have been a great source of support. I would especially like to thank Chrysoula and Arvind for their help, support and friendly advice through out my education. Additionally, I am very grateful for the friendship of all of the members of Borhan’s research group. I would also like to thank all my friends, who were with me and support me in all walks of my life. Most importantly, none of this would have been possible without the patience of my parents who have given me the love and support throughout my life. I am also very grateful to my sisters Mahshid and Maral. iv TABLE OF CONTENTS LIST OF TABLES.......................................................................................................vii LIST OF FIGURES......................................................................................................ix LIST OF SCHEMES ...................................................................................................xii KEY TO SYMBOLS AND ABBREVIATIONS.......................................................xvii Chapter I DEVELOPMENT OF AN EFFICIENT METHOD TO SYNTHESIZE A LIBRARY OF ETHER LINKED ANALOGS OF ANNAONACEOUS ACETOGENINS I.1. Introduction.........................................................................................................1 I.1.1. Structure and classification ...........................................................................2 I.1.2. Biological activity.........................................................................................5 I.1.2.1. In vitro and in vivo cytotoxicity results ...............................................5 I.1.2.2. Cytotoxic and antitumor mechanisms .................................................6 I.1.3. Structure-activity relationship studies........................................................... 10 I.1.4. Mucoxin ...................................................................................................... 20 I.1.4.1. Previous total synthesis of the proposed structure of Mucoxin .......... 21 I.1.4.2. Retrosynthetic analysis..................................................................... 22 I.1.4.3. Total synthesis of the proposed structure of Mucoxin ....................... 23 I.1.4.4. Comparison of spectral data of the synthetic and natural Mucoxin.... 29 I.1.4.5. The strategy towards structure elucidation of Mucoxin..................... 31 I.1.4.6. Synthetic pathway and library synthesis of representative truncated structures of Mucoxin....................................................................... 35 I.1.4.7. Biological evaluation of Mucoxin and analogs ................................. 41 I.1.4.7.1. Red blood cell hemolysis ................................................... 43 I.1.5. Library design of ether linked analogs of acetogenins .................................. 44 I.2. Bis-epoxide ring opening pathway..................................................................... 48 I.3. Sp3-Sp2 cross coupling reactions to synthesize triene intermediate..................... 53 I.4. Sulfone couplin ................................................................................................. 63 I.5. Total synthesis of the center THF core............................................................... 67 I.6. Etherification of bis-adjacent THF core ............................................................. 70 I.7. General pathway for the synthesis of different analog of center THF core.......... 74 I.8. Summary........................................................................................................... 79 I.8. Experimental section ......................................................................................... 80 I.9. References....................................................................................................... 142 v Chapter II ASYMMETRIC ORGANOCATALYTIC HALOCYCLIZATION REACTIONS II.1. Introduction..................................................................................................... 152 II.1.1. Asymmetric halogenation of olefins: stoichiometric methods.................... 153 II.1.2. Asymmetric halogenation of olefins: catalytic methods............................. 157 II.2. A catalytic asymmetric chlorocyclization of unsaturated amides..................... 165 II.3. Evaluation of other reactions with (DHQD)2PHAL catalyst system................ 172 II.3.1. Synthesis of asymmetric cyclic sulfates by halocyclization ................. 180 II.4. Experimental section ...................................................................................... 185 II.5. References...................................................................................................... 215 Chapter III SOLVENT-DEPENDENT ENANTIODIVERGENT CHLOROCYCLIZATION OF UNSATURATED CARBAMATES III.1. Introduction .................................................................................................. 220 III.2. Solvent screen for the chlorocyclization reaction of unsaturated carbamates.. 223 III.3. Halogen screen for the chlorocyclization reaction of unsaturated carbamates 227 III.4. The effect of carbamate structure on enantioselectivity of chlorocyclization reaction of unsaturated carbamates................................................................ 229 III.5. Eyring plot analyses ...................................................................................... 232 III.6. Additive optimization experiments................................................................ 245 III.7. Catalyst and additive loading screening in n-PrOH........................................ 249 III.8. Substrate scope for enantiodivergent chlorocyclization reaction .................... 251 III.9. Experimental section..................................................................................... 258 III.10. References .................................................................................................. 280 Chapter IV SULFUR YLIDE-MEDIATED CHEMISTRY IV.1. Introduction .................................................................................................. 283 IV.1.1. The ylide-mediated homologative ring expansion of 2,3-epoxy-ols ... 285 IV.2. The use of alternate ylides for extension of THF rings formation .................. 290 IV.2.1. Method development for ylide-mediated ring expansion.................... 391 IV.3. Experimental section..................................................................................... 299 IV.4. References .................................................................................................. 308 vi LIST OF TABLES Table I-1: Cytotoxicity against two human cancer cell lines of acetogenins and their polyether mimics ......................................................................................................... 12 Table I-2: Inhibition of mitochondrial complex I by natural acetogenins and synthetic analogs with various terminal functional groups ........................................... 14 Table I-3: Cytotoxic activity of squamocin and its derivatives ..................................... 17 Table I-4: Inhibitory potency of squamocin and its derivatives ...................................... 18 Table I-5: Comparison of NMR resonances between natural and synthetic Mucoxin ...... 30 Table I-6: 1 H NMR comparison of truncated structure V-47 and synthesized mucoxin V-2 ........................................................................................................................... 33 Table I-7: Chemical shift differences between the truncated analogues and the reported chemical shifts for mucoxin (NMR spectra recorded in CDCl3) ....................... 39 Table I-8: 1H- and 13C-NMR comparison of ttcTTT and cccTTT truncated analogs and cccTTT full length acetogenin with naturally isolated Mucoxin ............................... 40 Table I-9: Cytotoxicity and Complex I Inhibition of Mucoxin Analogs ........................ 40 Table I-10: Experiments for etherification reactions ...................................................... 72 Table I-11: Etherification reactions of I-144 ........................................................................ 74 Table II-1: Chlorocyclization of 1,1-disubstituted olefin substrates ............................ 166 Table II-2: Chlorocyclizaion of trans-disubstituted olefin substrates............................ 167 Table II-3: Solvent screen of chlorocyclization of aliphatic olefin .............................. 169 Table II-4: Solvent screen of chlorocyclization of aliphatic olefin................................ 170 Table II-5: Chlorocyclization of aliphatic olefin substrates ..............................................171 vii Table II-6: Reaction of imidate II-79 with different halogen sources and temperature ................................................................................................................. 175 Table II-7: Solvent screen for chloroarylation of II-85 ............................................... 178 Table II-8: Halogen source screening ......................................................................... 179 Table II-9: Solvent screening for chlorocylization of II-87 .......................................... 182 Table II-10: Substrate scope of for chlorocylization reaction ....................................... 183 Table III-1: Aprotic solvent screen for chloroyclization reaction ................................ 225 Table III-2: Protic solvent screen for chlorocyclization reaction ................................. 226 Table III-3: Halogen source screening ....................................................................... 228 Table III-4: The effect of carbamate structure on enantioselectivity ........................... 232 Table III-5: The effect of temperature on the chlorocyclization reaction of carbamate III-15 ......................................................................................................... 235 Table III-6: Differential enthalpy, entropy and Gibbs free energy for the chlorocyclization reaction .......................................................................................... 240 Table III-7: The effect of temperature on the chlorocyclization reaction of carbamate III-7 ........................................................................................................... 241 Table III-8: Acid additives loading screening in n-PrOH ............................................. 246 Table III-9: Screening of different benzoic acid ......................................................... 247 Table III-10: Screen of additives loading in CHCl3-Hexane ....................................... 249 Table III-11: Catalyst and additive loading screening in n-PrOH ................................. 250 Table III-12: Substrate scope for enantiodivergent chlorocyclization reaction ................. 254 Table IV-1: Sulfonium and base loadings study ......................................................... 295 viii LIST OF FIGURES Figure I-1: The first isolated acetogenin, uvaricin ..........................................................1 Figure I-2: General structure of acetogenins ..................................................................2 Figure I-3: Core units for classification of Annonaceous acetogenins .............................3 Figure I-4: Examples of both classical and nonclassical acetogenins ..............................4 Figure I-5: Model for the active conformation of acetogenins interacting with complex I in the mitochondrial membrane proposed by McLaughlin, Shimada, and coworkers .................................................................................................................................. 7 Figure I-6: Two common complex I inhibitors piericidin A and rotenone ...................... 10 Figure I-7: Structure of bullatacin ................................................................................ 11 Figure I-8: Mitochondrial complex I inhibitory activity of various acetogenins ............ 13 Figure I-9: Examples of natural and Δlac-acetogenins and their IC50 values ................ 15 Figure I-10: Variation of the length of spacer and tail of acetogenin analogs ................ 16 Figure I-11: Variation of the length of alkyl chains in Δlac-acetogenins ....................... 18 Figure I-12: Comparison of inhibition between acetogenin analogs and their OH-removed derivatives .............................................................................................. 19 Figure I-13: Proposed structure of mucoxin ................................................................. 21 Figure I-14: Examples of natural and Δlac-acetogenins and their IC50 values ............... 22 Figure I-15: Retrosynthetic analysis for preparation of mucoxin .................................. 23 Figure I-16: C36 Epimer of synthesized mucoxin I-23................................................... 29 Figure I-17: Structure of synthetic mucoxin and proposed structure of mucoxin .......... 29 ix Figure I-18: 64 possible diastereomers of mucoxin ...................................................... 31 Figure I-19: ttcETT Diastereomer of mucoxin .............................................................. 32 Figure I-20: New synthetic strategy to construct different diastereomers of Mucoxin..... 34 Figure I-21: Structure of synthesized truncated diastereomers of mucoxin ................... 37 Figure I-22: RBC Hemolysis for mucoxin and its analogs (D: DMSO, C: Cell, W: Water) ......................................................................................................................... 43 Figure I-23: Ether linked analogs of bis-adjacent THF acetogenins .............................. 44 Figure I-24: Ether linked analogs of bis-adjacent THF acetogenins................................ 45 Figure I-25: Modular synthesis of acetogenin analogs with bis-adjacent THF core ........ 45 Figure I-26: Retro-synthesis of triene ........................................................................... 53 Figure I-27: Retro-synthesis of sulfone coupling .......................................................... 63 Figure I-28: Silyl migration product under basic conditions ......................................... 69 Figure I-29: Retro-synthetic analysis for ether linkage analog of bis-adjacent THF core I-146...................................................................................................................... 72 Figure II-1: a) Generalized halocyclization reaction, b) Recently developed catalytic enantioselective chlorolactonization reaction and c) chlorocyclization of unsaturated amides......................................................................................................................... 172 Figure II-2: Synthesis of cyclic sulfates by bromocyclization ..................................... 180 Figure II-3: 4-Substituted sulfate substrate ................................................................. 182 Figure III-1: Catalyzed enantiodivergent Mannich-type reactions with various aromatic N-Boc imines ................................................................................................ 221 Figure III-2: The (DHQD)2PHAL mediated halolactonization ........................................222 x Figure III-3: The (DHQD)2PHAL mediated halocyclization of unsaturated amides ..... 222 Figure III-4: Stereoselectivity and thermodynamic parameters: a graphic representation of the Eyring equation .................................................................................233 Figure III-5: Energy diagrams in the chlorocyclization reaction; (a) (S)-Selective reactions. (b) (R)-Selective reactions ........................................................................... 234 Figure III-6: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions in n-PrOH ..............................................................................238 Figure III-7: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions in CHCl3-Hexane ............................................................ 239 Figure III-8: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions of carbamate III-17 in n-PrOH.......................................... 243 Figure III-9: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions of carbamate III-17 in CHCl3-Hexane ................................244 Figure III-10: Structure of (DHQD)2PHAL in chloroform and methanol based on the NMR ROESY studies .......................................................................................... 245 Figure III-11: Carbamate substrates ........................................................................... 251 Figure IV-1: First literature example of sulfur ylides ................................................. 283 Figure IV-2: Desired bis-functionalized ylides............................................................. 292 Figure IV-3: Other possible products ......................................................................... 296 Figure IV-4: Some literature examples for 1,3- dioxolane and 1,3-dioxane .................. 297 xi LIST OF SCHEMES Scheme I-1: Synthesis of 2,3,5-trisubstituted THF I-39 ................................................. 24 Scheme I-2: Synthesis of triol intermediate I-27 ............................................................ 25 Scheme I-3: Synthesis of bis-THF iodide I-44 ............................................................... 26 Scheme I-4: Completion of the total synthesis of the proposed structure of Mucoxin..... 28 Scheme I-5: Retrosynthetic strategy used to synthesize the proposed structure of mucoxin ...................................................................................................................... 36 Scheme I-6: Proposed synthetic plan to form bis-adjacent THF segments .................... 47 Scheme I-7: Robbins synthesis of chiral non-racemic vicinal diol ................................ 48 Scheme I-8: Aromatic and aliphatic Grignard reagent in bis-epoxide ring–opening ....... 48 Scheme I-9: Synthesis of non-C2-symmetirc adjacent diols reactions ............................ 49 Scheme I-10: Preparation of different classes of acetogenins ....................................... 49 Scheme I-11: Synthesis of chiral bis-epoxide 62............................................................ 50 Scheme I-12: Synthesis of allylic bromide I-73 ............................................................. 51 Scheme I-13: Bis-epoxide ring-opening reaction by using Grignard reagent .................. 52 Scheme I-14: Different method for bis-epoxide ring-opening reaction ........................... 52 Scheme I-15: Attempts for synthesis of diiodoethylene ................................................ 54 Scheme I-16: Synthesis of homo-allylic iodide I-80....................................................... 54 Scheme I-17: Synthesis of triene .................................................................................. 55 Scheme I-18: SAD reaction of triene ........................................................................... 55 Scheme I-19: Synthesis of homo-allylic iodide I-86....................................................... 56 xii Scheme I-20: Synthesis of vinyl iodide I-88 .................................................................. 56 Scheme I-21: Synthesis of di-TBDPS protected of triene............................................... 57 Scheme I-22: SAD reaction of I-92 ............................................................................... 58 Scheme I-23: Synthesis of homo-allylic iodide I-97 ..................................................... 58 Scheme I-24: Attempts for Negishi reaction of I-97 with vinyl iodide I-98.................... 59 Scheme I-25: Synthesis of I-101.................................................................................... 60 Scheme I-26: Attempts for Suzuki reaction .................................................................. 60 Scheme I-27: Attempts for Suzuki reaction .................................................................. 61 Scheme I-28: Synthesis of diene I-104 .......................................................................... 61 Scheme I-29: Synthesis of Suzuki coupling ................................................................. 62 Scheme I-30: Synthesis of sulfone I-110 ....................................................................... 64 Scheme I-31: Synthesis of I-113.................................................................................... 64 Scheme I-32: Attempts for sulfone coupling ................................................................ 65 Scheme I-33: Synthesis of diiodide I-114 and attempts for sulfone coupling ................ 65 Scheme I-34: Synthesis of alkyl iodide I-116 ............................................................... 66 Scheme I-35: Attempts for sulfone coupling ................................................................ 66 Scheme I-36: Synthesis of abunsaturated ester I-121 ..................................................... 67 Scheme I-37: Synthesis of alcohol I-127........................................................................ 68 Scheme I-38: Synthesis of desired THF core I-135........................................................ 69 Scheme I-39: Conversion of primary alcohol to iodide ................................................ 70 xiii Scheme I-40: Attempts for conversion of primary alcohol I-136 to mesylate ............... 70 Scheme I-41: Synthesis of alcohol I-139........................................................................ 71 Scheme I-42: Synthesis of MOM-protected bis-adjacent THF core I-144 ...................... 73 Scheme I-43: Synthesis of alkyl iodide I-158 ................................................................. 76 Scheme I-44: Coupling of iodide I-161 with I-159 ...................................................... 77 Scheme I-45: Synthesis of bis-THF core I-169 .............................................................. 78 Scheme I-46: Synthesis of bis-THF core I-169 .............................................................. 79 Scheme II-1: Catalytic asymmetric halogenation of carbonyl, dicarbonyl and olefins .. 152 Scheme II-2: Early work on asymmetric halocyclization reactions ............................. 154 Scheme II-3: Amines catalyze iodolactonization in low ee ......................................... 155 Scheme II-4: Enantioselective fluorodesilylation of allyl silne ................................... 155 Scheme II-5: Quinine/Selectfluor mediated asymmetric semipinacol rearrangement.... 156 Scheme II-6: Enantioselective fluorocyclization ........................................................ 156 Scheme II-7: C2-symmetric sulfide can induced asymmetry in chlorination reaction ... 157 Scheme II-8: Mechanistic work on racemization of bromonium ions ......................... 158 Scheme II-9: Iodolactonization catalyzed by chiral quaternary ammonium salt .......... 159 Scheme II-10: Catalytic enantioselective chlorolactonization ..................................... 160 Scheme II-11: Jacobsen’s catalytic asymmetric iodolactonization reaction ................ 161 Scheme II-12: Catalytic enantioselective bromolactonization ..................................... 162 Scheme II-13: Catalytic enantioselective bromocyclizations ...................................... 163 Scheme II-14: Counterion controlled asymmetric opening of meso-halonium ions ..... 164 xiv Scheme II-15: Enantioselective bromolactonization of conjugated (Z)-enyne ............. 165 Scheme II-16: Chlorocyclization of aliphatic olefin in TFE ......................................... 168 Scheme II-17: Chlorocyclization of aliphatic olefin in CHCl3 ...................................... 168 Scheme II-18: Synthesis of the benzoate-amide II-68 .................................................. 173 Scheme II-19: Synthesis of the imidate II-71 ....................................................................173 Scheme II-20: Reaction of imidate II-71 with NBS and DCDMH .............................. 174 Scheme II-21: Reaction of imidate II-76 with NBS and DCDMH .............................. 176 Scheme II-22: Lewis acid catalyzed intramolecular haloarylation of alkenes using N-halosuccinimide (NXS) as the halogen source ........................................................ 176 Scheme II-23: Synthesis of alkene II-85. ..................................................................... 177 Scheme II-24: Racemic intramolecular haloarylation of alkene II-85........................... 177 Scheme II-25: Racemic chlorocyclization of sulfate II-87 ........................................... 181 Scheme III-1: Synthesis of carbamate III-4 ................................................................. 223 Scheme III-2: Synthesis of carbamate III-7 ................................................................ .229 Scheme III-3: Attempts to make desired dimethylphenyl carbamate .............................229 Scheme III-4: Attempts to make desired dimethylphenyl carbamate .......................... 230 Scheme III-5: Synthesis of carbamate III-13 ............................................................... 230 Scheme III-6: Test reaction for Eyring plot analyses.................................................... 233 Scheme III-7: Synthesis of carbamate substrates ........................................................ 252 Scheme III-8: Synthesis of carbamate III-22 and III-25 ............................................ 253 Scheme III-9: The test reaction of carbamate III-26 and carbonate III-27 and III-28 .. 256 xv Scheme IV-1: The ylide-mediated ring expansion of epoxides and aziridines ............. 284 Scheme IV-2: Transformation of 2,3-epoxy-1-ols to 2,3,5-trisubstituted tetrahydrofurans ........................................................................................................ 285 Scheme IV-3: An ylide-mediated homologative ring expansion relay of epoxy alcohol IV-4 to IV-8.................................................................................................... 286 Scheme IV-4: Synthesis of 2,3-disubstituted THF rings ............................................. 288 Scheme IV-5: Synthesis of 2,3-disubstituted THF rings IV-16 .................................... 289 Scheme IV-6: Synthesis of 2,3,5-trisubstituted THF rings IV-18 ....................................290 Scheme IV-7: Proposed synthesis of 2,3,5-trisubstituted THF rings ........................... 291 Scheme IV-8: Attempt for synthesis of bis-functionalized ylides ............................... 292 Scheme IV-9: Synthesis of bis-functionalized ylides IV-39 and IV-40 ........................ 293 Scheme IV-10: Attempts for oxidation of sulfonium IV-39 and IV-40 ...................... 293 Scheme IV-11: Reaction of epoxy alcohol IV-41 with sulfonium IV-39. ..................... 294 Scheme IV-12: Substrate scope .................................................................................. 296 Scheme IV-13: Proposed mechanism ......................................................................... 298 xvi KEY TO SYMBOLS AND ABBREVIATIONS Å angstrom Ac acetyl AcOH acetic acid acac acetoacetate Ar aryl aq. aqueous Bn benzyl CH2Cl2 dichloromethane CI chemical ionization CSA camphorsulfonic acid Cy cyclohexyl δ chemical shift (parts per million) D dextro (denotes configurational (R)-(+)-glyceraldehyde) DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diasteromeric excess DEAD diethyl azodicarboxylate DET diethyl tartrate DI deionized DIAD diisopropyl azodicarboxylate xvii relationship with DIBAL-H diisobutylaluminum hydride DIPT diisopropyl tartrate DMAP 4-(dimethylamino)pyridine DMDO dimethyl dioxirane DMF N,N-dimethylformamide DMP dess-martin periodinane DMSO dimethyl sulfoxide dr diastereomeric ratio ECCD exciton coupled circular dichroim ED50 Effective Dose to 50 percent ee enantiomeric excess EI electric ionization equiv. equivalent(s) Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol FAB fast atom bombardment g gram(s) GC gas chromatography h hour(s) HMPA hexamethyl phosphoramide xviii HRMS high resolution mass spectrometry HWE Horners-Wadsworth-Emmons reaction Hz Hertz i PrOH isopropyl alcohol IR infrared spectrum J coupling constant KHMDS potassium bis(trimethylsilyl)amide L levo (denotes configurational (S)-(-)-glyceraldehyde) LAH lithium aluminum hydride LDA lithium diisopropylamine LiHMDS lithium bis(trimethylsilyl)amide M molar (concentration) mCPBA 4-chloroperbenzoic acid MeCN acetonitrile MeOH methanol Mes mesityl mL milliliter mmol millimole Ms methane sulfonate MS mass spectrometry xix relationship with NaHMDS sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect OAc acetate OTf trifluoromethanesulfonate OsO4 osmium tetroxide PCC pyridinium p-toluenesulfonic acid Ph phenyl PMB p-methoxybenzyl PPTS pyridinium para-toluenesulfonate pTSA p-toluenesulfonic acid R rectus (Cahn-Ingold-Prelog system) RT room temperature S sinister (Cahn-Ingold-Prelog system) SAD Sharpless asymmetric dihydroxylation SAE Sharpless asymmetric epoxidation TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBA-OX tetra-n-butylammonium peroxymonosulfate TBHP t-butyl hydroperoxide xx TBS t-butyldimethylsilyl TBSOTf t-butyldimethylsilyl trifluoromethanesulfonate TES triethylsilyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran THP tetrahydropyran TMS trimethylsilyl TMSCl trimethylsilyl chloride TMEDA tetramethylethylenediamine TsOH p-toluenesulfonic acid xxi CHAPTER I Development of an Efficient Method to Synthesize a Library of Ether Linked Analogs of Annonaceous Acetogenins I.1 Introduction Annonaceous acetogenins are a series of natural products isolated from the plant family Annonaceae, whose members include edible fruits such as cherimoya and custard 1-9 apple that are widely distributed in tropical and sub-tropical regions. Annonaceous acetogenins can be found in the seeds, leaves, twigs, barks, and root of the plants. They are found to have potent and diverse biological effects such as cytotoxic, antitumor, antimalarial, pesticidal, and insecticidal activities. 1-8 Before the early 1980’s, phytochemical studies of the plant family Annonaceae mainly focused on the isolation of numerous secondary metabolites including isoquinoline alkaloids, polyphenols, carbohydrates, lipids, proteins, aromatic compounds, essential oils and terpenes. 10 In 1982, Cole and coworkers isolated and characterized the first acetogenin, uvaricin, from the roots of Uvaria accuminata (a member of the O OH O O O OH Figure I-1: The first isolated acetogenin, uvaricin 1 Annonaceae family) (Figure I-1). 11 It contains a set of bis-adjacent tetrahydrofuran (THF) rings flanked by two hydroxyl groups and a terminal unsaturated lactone ring, which is connected to the THF moiety through an unbranched alkyl chain. Uvaricin was demonstrated to have antitumor properties with in vivo PS system (P-338 lymphocytic leukemia in mice). 11, 12 It exhibited an activity of 157% test/control (T/C) at 1.4 mg/kg in the PS test system. Activity in the PS system is defined as an increase in the survival of treated animals over that of controls resulting in a T/C ≥ 125%. 12 Since uvaricin, during the past quarter century, more than 400 related compounds have been isolated by preparative HPLC, countercurrent chromatography, or chromatography on silica gel. Research in the field of Annonaceous acetogenins dealing with the isolation, structural elucidation, semi-synthesis or total synthesis, mechanism of the cytotoxic action, and structure-activity relationship studies has been growing rapidly. 5, 7, 9 I.1.1 Structure and Classification Annonaceous acetogenins share a common skeleton characterized by an unbranched C32 or C34 fatty acid ending in an α,β-unsaturated γ-lactone (Figure I-2). 2, 7, 9 Several oxygenated functional groups, such as tetrahydrofuran (THF), tetrahydropyran (THP), O OH 32/34 m O O OH OH 2 n 4 Figure I-2: General structure of acetogenins 2 O 35/37 Adjacent bis-THF acetogenins R OH O O Non-adjacent bis-THF acetogenins OH O OH OH R = OH, H O O O O Non THF-ring acetogenins OH OH Non-classical (THP) acetogenins R (R) O R = -(CH2)-, epoxide, ketone, -CH-OH R = OH, H Types of Terminal lactone rings R1 O HO R2 O R1 = OH, H R2 = OH, H O O O O O O O O ring hydroxylated ketolactone H3CO R OH O O O R = OH, H O Figure I-3: Core units for classification of Annonaceous acetogenins epoxide, hydroxyl, and ketone could be present in the structure, as well as double and triple bonds. There is a variety of stereoisomers of the center THF cores, however, all the isolated compounds have S configuration of the chiral center in the γ-lactone ring. The classification of acetogenins is based on the structural characteristics shown in Figure 3 I-3. 2, 5, 7 McLaughlin classified all these congeners based on the number and the arrangement of the THF rings including mono-THF, adjacent bis-THF, non-adjacent OH O 12 9 OH 10 OH OH 9 O 4 O O OH O 4 OH O 10-hydroxyasimicin (I-3) (adjacent bis-THF) OH 9 5 OH O 11 OH OH O 7 O OH O O O 5 O OH trilobalicin (I-4) (non-adjacent bis-THF) OH O O 8 OH HO goniocin (I-5) (tri-THF) O OH O OH O 11 OH 4 O O OH (2,4-cis- and trans)-xylomaticinones (I-2) O O sabadelin (I-1) (non-THF) O O OH O 7 O mucocin (I-6) (nonclassical THP) OH O 16 O O OH O 5 O OH reported mucoxin (I-8) (nonclassical hydroxylated THF) O muconin (I-7) (nonclassical THP) Figure I-4: Examples of both classical and nonclassical acetogenins bis-THF, tri-THF, non-THF ring, THP ring, and hydroxylated THF ring, followed by sub-classification of the γ-lactone, substituted γ-lactone, or ketolactone variations. 5, 7 Generally, all acetogenins belong to two broad groups: 1) Classical acetogenins, which involve acetogenins comprising none to three THF units along with a terminal γ-lactone; 2) Nonclassical acetogenins, which include acetogenins containing a THP ring or 4 hydroxylated THF ring along with a terminal γ-lactone. Figure I-4 shows some examples of both classical and nonclassical acetogenins. Compounds I-1 to I-5 are classical acetogenins with none to three THF units. 1, 13-16 If there are no THF units in the structure, epoxide or double bonds are the most common sub-units such as sababelin I-1, which is a mono-epoxy olefinic acetogenin. 13 Mucocin I-6 is the first nonclassical acetogenin to be reported that bears a hydroxylated THP ring along with a non-adjacent THF ring. muconin I-7, pyranicin, 19 18 17 More examples of this class are which contains a nonhydroxylated THP ring adjacent to another THF ring, the first mono-THP ring acetogenin, and jimenezin, 20 containing a hydroxylated THP ring adjacent to a THF ring. Mucoxin I-8 is the first nonclassical acetogenin containing a hydroxylated THF ring. 14 goniotriocin and donnaienin. 18 Two other examples are 21 I.1.2 Biological Activity Annonaceous acetogenins have several interesting and potent biological activities, including antibacterial, antimalarial, in vivo antitumor, parasiticidal, and pesticidal effects. 1-6 cytotoxic In addition, in recent studies, acetogenins are found to show promising properties against multi drug resistant (MDR) tumor cells and pesticide-resistant insects. I.1.2.1 In Vitro and In Vivo Cytotoxicity Results Annonaceous acetogenins have been always judged as promising candidates for future generation of drugs against the current chemotherapy-resistant tumors. The first 5 isolated acetogenin, uvaricin, was announced as a new antitumor compound. 11 Many studies have established the cytotoxic potency of acetogenins for several human tumor -12 cell lines. For example, asimocin and bullanin have shown ED50 values of ~10 µg/mL against A-549 (lung), MCF-7 (breast), and HT-29 (colon) human cancer cell lines, much -4 lower than adriamycin (~10 use. 22 -2 to ~10 µg/mL), an anticancer drug currently in clinical Moreover, a series of acetogenins show greater cytotoxic effects against cancerous over noncancerous cells. 23 Although extensive and comprehensive animal testing has not been conducted, acetogenins have shown promising in vivo results. Uvaricin showed in vivo activity against 3PS (murine lymphocytic leukemia) (157% T/C at 1.4 mg/kg), 11 and the rollinones (147% T/C at 1.4 mg/kg) and asimicin (124% T/C at 25 µg/kg) were active in the same assay. 8 Bullatacin was 300 times more potent than paclitaxel against L1210 (murine leukemia) in normal mice (effective at only 50 µg/kg) 24 and against X-5563 5 plasma cell myeloma grafts in normal mice (67% tumor inhibition at 50 µg/kg). The latter data has led to further research to elucidate structure-activity relationships. I.1.2.2 Cytotoxic and Antitumor Mechanisms Members of Annonaceous acetogenins family are the most potent inhibitors of nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase that reside in complex I, which is a membrane-bound protein of the mitochondrial electron transport system and the ubiquinono-linked NADH oxidase in the plasma membranes of cancerous 6 cells. 1, 5, 7, 24, 25-27 In 1991, Weiss and coworkers reported that the mitochondrial complex I was the target enzyme for acetogenins. Nowadays, they are considered to be one of the most powerful groups of complex I inhibitors. 28-30 NADH:ubiquinone oxidoreductase is the largest and most complicated of the protein 1 complexes in the inner mitochondrial membrane. Complex I plays an important role in the electron-transfer from NADH to ubiquinone and in the maintenance of the bioenergetic function of the cell by driving the ATP synthesis from the mitochondrial reduced equivalents produced in the central metabolic oxidative pathways. 1, 7 As part of the respiratory chain, as well as in the cytoplasmic membrane bacteria, complex I has been implicated in a variety of neurodegenerative diseases such as Parkinson’s disease, maturity onset diabetes, stroke-like episodes and Huntington’s disease. 31-33 Further Figure I-5: Model for the active conformation of acetogenins interacting with complex I in the mitochondrial membrane proposed by McLaughlin, Shimada, and coworkers For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this dissertation 7 study of these diseases and their medical treatment requires a deeper understanding of the genetics, the structure and the function of this enzyme. Inhibitors of complex I such as acetogenins are important and useful for the elucidation of the structure and mechanism of this enzyme. Although the precise mode of complexation of acetogenins and complex I, as well as their mechanism of selective cytotoxicity, and the factors that modulate the efficacy against cancer cells are not known, some generally accepted suggestions are summarized below. One popular hypothesis, proposed by McLaughlin, Shimada, and coworkers, suggests that the conformation of acetogenins in membranes is strongly related to cytotoxicity. 5, 31 They determined positions of both the THF and lactone ring within 1 liposomal membranes by H NMR and nOe spectroscopy and found that an asimicin-type acetogenin can be in either a sickle-shaped or a U-shaped conformations, depending on the length of the alkyl chain between the THF rings and the lactone ring. The model of this hypothesis is shown in Figure I-5. 34-36 Here the THF rings with flanking hydroxyl group work as a hydrophilic anchor on the mitochondrial membrane. The position of the THF ring-anchor along the acetogenin chain determines the depth of the lactone functional group, which then directly acts with the protein receptor site, perhaps, mimicking the quinone ring of ubiquinone. The functional lactone group reaches complex I by lateral diffusion in the membrane. The THF rings, acting as an anchor in the lipid bilayer, may enhance the bioactivity by restricting the location, conformation, and orientation of the functional lactone moiety by interacting with the head group of the 8 phospholipids. In addition, Miyoshi and coworkers did a mechanistic and structure activity study against submitochondrial particles by using 22 representative acetogenins. 34 They also studied the three-dimensional structure of the bis-THF rings of the different possible stereoisomers optimized by quantum chemical calculations (MNDO-AM1). 34 Their results helped them to propose that the stereochemistry surrounding the THF rings is much less important for activity at the enzymatic level than previously believed, while acetogenins act as potent inhibitors only when the γ-lactone and the THF rings are directly linked by an alkyl spacer with optimal length. Moreover, even though acetogenins are not ionophoric in living cells, the ion complexation ability studies of acetogenins showed that they could form complexes with 2+ Ca 2+ or Mg , which adopted different structures from the free molecules. 37, 38 These secondary structures may be seen as the active conformations of the molecules when they interact with the binding sites on the cell membranes. Binding affinity, metal cation selectivity, and ligand assembly highly depend on the stereochemistry of the coordination sites and the nature of the alkyl side chains. Although the relationship between binding properties of acetogenins and their biological activity is not clear, these ion complexation ability studies could help to investigate the details of the mode of action as well as the application of developing new antitumor agents. Since NADH:ubiquinone 2+ oxidoreductase is an iron dependent cluster enzyme, the investigation of Fe and FeS-acetogenin complexation in aqueous media are suggested by Mclaughlin and 9 coworkers. 5 I.1.3 Structure-Activity Relationship Studies Although Annonaceous acetogenins are thought to inhibit complex I in mitochondrial electron transport systems, there is no direct experimental evidence to verify the exact mode of action with the target proteins. In addition, acetogenins have few structural similarities as compared to ordinary complex I inhibitors such as piericidin A and rotenone (Figure I-6). characteristics H3CO H3CO as Thus, there is interest in studying their unusual structural well CH3 N OH 39 as the strong CH3 CH3 CH3 CH3 inhibitory H3CO properties acetogenins. OCH3 H CH3 O OH of H O O O CH3 H3C Figure I-6: Two common complex I inhibitors piericidin A and rotenone piericidin A rotenone Structure-activity relationship (SAR) studies are also important to elucidate the mode of inhibition of complex I. Even though there is no comprehensive SAR study of acetogenins, several groups have initiated some systematic studies based on their specific interest on particular structures. In 1999, Mclaughlin, Alali, and Liu summarized the previous SAR study 5 based on naturally isolated acetogenins in their review, which suggested the following generalizations: 1) Comparing the potent activity, the general order of different acetogenin classes in order of decreasing inhibitory activity is: adjacent bis-THF > 10 non-adjacent bis-THF > mono-THF > non-THF acetogenins. The THP ring has no effect on activity. The C-35 acetogenins are more potent than the C-37 compounds when their structural features are identical. 2) The terminal γ-lactone ring is crucial for activity. Ketolactone acetogenins are usually less active than those having an α, β-unsaturated γ-lactone. 3) The alkyl chain between the OH-flanked THF and the γ-lactone is critical to potency. 4) Neither the 4-OH group nor the 10-OH group is essential for activity. 5) Three hydroxyl groups (two flanking the THF units and one in the hydrocarbon chain) are important for the potency. A ketone instead of a hydroxyl group normally reduced the activity. Spacer OH O HO O O THF Ring Moiety with Flanking OH Groups Lactone Moiety O HO Tail Figure I-7: Structure of bullatacin Since then, Miyoshi et al., Figadère, et al., 57, 58 35, 36, 40-46 Poupon et al., 59, 61 Yao and Wu et al., 47-54 Duval and Lewin et al., Cortes et al., 62, 63 30, 55, 56 64 and Koert et al. have published different SAR studies of acetogenins. Some of their results are in accordance with the previous observation while some are in conflict with it. 11 Table I-1: Cytotoxicity against two human cancer cell lines of acetogenins and their polyether mimics OH HO O O O (10 RS)-corossolin (I-9) OH O O O I-10 O O HO OH HO O O O bullatacin (I-11) OH O O I-12 O O O O O HO a IG % concentration (µM) for HL-60 100 10 1 for K562 100 10 1 (10 RS)-corossolin I-9 compound I-10 63 56 5 10 2 0 100 50 0 31 18 0 bullatacin I-11 73 7 0 53 39 27 compound I-12 100 65 21 55 25 22 a IG: Inhibithion of Growth Generally, for a SAR study, there are four parts of the acetogenin structure which need to be considered: the lactone moiety, the spacer (the alkyl chain connect lactone moiety to the THF cores), the THF ring moiety with flanking hydroxyl groups, and the tail (the long alkyl chain in the end). Figure I-7 shows one example, bis-THF acetogenin isolated from Annona bullata, bullatacin, which is one of the most potent inhibitors of 12 complex I. 35 All the SAR studies are focused on the relationship of activities and variation of these four domains of the structures. The conclusion based on the most recent SAR studies could be summarized as following: 1) The number of THF rings, the hydroxyl groups in the hydrocarbon chains and the stereochemistry around the THF rings as well as the flanking hydroxyl groups are not essential structural factors for potent activity. Miyoshi, Makabe, and coworkers synthesized a series of diastereomers of natural products and test their bioactivities. 44-46 The inhibitory activity of these acetogenins on complex I shows the comparable IC50 OH HO O HO OH O a OH HO O O IC50= 1.4 nM O O HO murisolin (15R, 16R, 19R, 20R) 16,19-cis -murisolin (15R, 16R, 19S, 20S) HO HO IC50= 1.8 nMa O O O O HO IC50= 1.3nM O HO murisolin A (15R, 16R, 19R, 20S) IC50= 2.6 nM O cis -solamin IC50 value (nM); bullatacin IC50 = 0.8 nM. Figure I-8: Mitochondrial complex I inhibitory activity of various acetogenins 13 Table I-2: Inhibition of mitochondrial complex I by natural acetogenins and synthetic analogs with various terminal functional groups X HO O O OH HO Compound Complex I Inhibition IC50 (nM) Group X NADH oxidase 0.9 1.3 --- 8.0 --- 1.7 0.9 3.3 2.0 3.3 2.3 O squamocin NADH-DB oxidoreductase 9.2 O H2N O β-aminosquamocin O quinone analog of squamocin O OMe OMe O benzimidazole squamocin N N H quinoxalinone squamocin O H N N n-butylester O O squamocin 14 value (examples shows in Figure I-8 46 ). In addition, Yao, Wu, and coworkers found that polyether mimics of acetogenins can lead to remarkable cytotoxicity against human tumor cells (Table I-1). 40-52, 54 Both of the synthetic polyether mimics I-10 and I-12 have comparable cytotoxicity with similar-size natural acetogenins. These experiments indicate that the THF moiety is not a necessary structural feature for bioactivity. OH HO O O O O O IC50= 0.9 nMa IC50= 0.8 nM O O HO HO bullatacin (I-11) lead compound (I-13) HO HO O O O O IC50= 1.6nM IC50= 0.9 nM O HO a O HO O HO The IC50 value (nM) is the molar concentration Figure I-9: Examples of natural and Δlac-acetogenins and their IC50 values 2) The terminal γ-lactone ring could be helpful for the high activity of acetogenins, but it is not a necessary functionality. There are reports of acetogenins with other terminal functional groups such as quinones, benzenes, 45 59 or photoaffinity groups 64 heterocycles, 61, 63 substituted that are still potent inhibitors of complex I. Table 15 13-C spacer 11-C tail HO O O O O 13-C spacer 11-C tail HO 11-C tail O O O 1.2a O 1.7a O O HO HO analog I-16 10-C spacer 10-C tail HO O O a 13-C spacer 11-C tail HO O HO IC50 O n = 1 (5-C spacer) 14 n = 3 (7-C spacer) 1.6 n = 12 (16-C spacer) 13 n = 15 (19-C spacer) 271 HO lead compound (I-13) O n O 0.8a O HO O HO analog I-17 13-C spacer 2-C tail HO O O O O O O O O 1.9a analog I-18 HO 3.1a analog I-19 The IC50 value (nM) of inhibition for mitochondrial complex I. Figure I-10: Variation of the length of spacer and tail of acetogenin analogs I-2 shows that both natural acetogenins and synthetic analogs with various terminal functional groups have comparable value for complex I inhibition. Miyoshi and coworkers also reported that acetogenin analogs possessing two alkyl or aryl chains without a γ-lactone ring, named Δlac-acetogenins; could still retain similar 16 bioactivity (Figure I-9). 41, 43, 45 3) The lengths of both spacer and tail are important structural factors for obtaining high activity. Generally, acetogenins act as potent inhibitors only when the THF moiety and the γ-lactone ring are directly linked by an appropriate alkyl spacer (the optimal length of the spacer for inhibition is approximately 13 carbon atoms). 64, 65-67, 45 However, the spacer portion is not affected by steric congestion when multiple bonds are introduced into different regions of the spacer (Figure I-10, analog I-16 and I-17). 42 The appropriate length of the hydrophobic tail is preferable for activity, but is not as important as the spacer (Figure I-10, analog I-18 and I-19). Table I-3: Cytotoxic activity of squamocin and its derivatives R R R O O Compound Group R squamocin -OH tritosyl squamocin -OTs trimesyl squamocin -OMs triazido squamocin triamino squamocin a O O a KB EC50 (µM) 1.6 × 10 -5 < 1.3 × 10 1.5 × 10 -1 -2 -N3 < 1.4 × 10 -NH2 2.4 × 10 -1 -2 Human epidermoid carcinoma cell lines. These effects are more significant in Δlac-acetogenin analogs (Figure I-11). 41-43, 45 4) The presence of free hydroxyl groups flanking the THF moiety is important t elicit 17 HO O HO n n = 1 (6-C chain): 4500 a n = 4 (9-C chain): 45 O n = 6 (11-C chain): 1.6 n = 8 (13-C chain): 9.0 HO a O n = 0: n = 1: n = 5: n = 9: O HO n C-11 chain 280 45 3.2 1.6 n The IC50 value (nM) of inhibition for mitochondrial complex I. Figure I-11: Variation of the length of alkyl chains in Δlac-acetogenins potent activity. Generally, protection of the free hydroxyl groups such as the transformation of the secondary alcohols into acetates or mesylates could lead to Table I-4: Inhibitory potency of squamocin and its derivatives Compound IC50 (nM) Group R squamocin -OH 0.59 ± 0.07 NADH:DB oxidoreductase 0.77 ± 0.15 trimesyl squamocin -OMs 14.1 ± 1.6 2037 ± 28 triacyl squamocin -OAc 5.0 ± 1.3 2936 ± 564 NADH oxidase significant loss of cytotoxicity (>1000 times, examples in Table I-3) as well as inhibitory potency (Table I-4), 57, 62 while some of these derivatives could retain comparable enzymatic inhibition (such as acetate, examples in Table I-4). 55, 62 Removal of one of the two hydroxyl groups around the THF moiety resulted in a slight, but noticable, loss of activity (Figure I-12, analog I-20). Removal of both hydroxyl groups led to further decreased inhibitory potency of complex I (Figure I-12, analog I-21). 18 41 HO O O 1.6a O O HO HO !lac-acetogenin I-14 analog I-20 O O 0.8a O O 85a O O a O O HO HO 14a lead compound (I-13) analog I-21 The IC50 value (nM) of inhibition for mitochondrial complex I. Figure I-12: Comparison of inhibition In summary, some of the previous results of SAR studies match with the proposed model of active conformation of acetogenins interacting with complex I. Since THF rings with flanking hydroxyl groups only work as a hydrophilic anchor, the stereochemistry in this region should have no effect. The presence of free hydroxyl groups in this region could help to interact with mitochondrial membrane, thus it is important to the activity. Moreover, in the proposed model, the length of spacer is very important because it leads the lactone ring to complex I. The SAR studies also showed that the length of the spacers had effect on the activity. However, some of the results conflict with the proposed model. Since lactone ring acts with the protein receptor site, the presence of lactone ring should be important. In SAR studies, Δlac-acetogenins without terminal functional groups were found to maintain good activity. In addition, besides the length of spacer, the length of 19 tail also has effect on the activity, which suggests that the shape of the whole molecule requires considaration. The SAR studies provide some useful information in helping to understand the inhibitory mechanism of acetogenins against their protein targets, mitochondrial NADH ubiquinone oxidoreductase and plasma membrane NADH oxidase. It would also be helpful to explore acetogenins and their analogs as chemotherapeutic, pesticidal, and antimicrobial agents. However, since there are some conflicts between the SAR studies and the proposed mode of action, further SAR studies of acetogenins need to be carried. I.1.4 Mucoxin As described before, generally, Annonaceous acetogenins belong to two broad groups. Classical acetogenins contain none to three 2,5-disubstitued tetrahydrofuran (THF) units 64 along with a terminal γ-lactone, such as uvaricin and bullatacin. 65 Nonclassical acetogenins contain tetrahydropyran (THP) or hydroxylated THF rings and/or the normal 2,5-disubstituted THF rings along with a terminal γ-lactone. Examples of such are mucocin, which is the first reported nonclassical acetogenin that bears a hydroxylated THP ring with a non-adjacent THF ring, adjacent to another THF ring. 67 66 and muconin, which contains a THP ring More recently, these THP-containing nonclassical acetogenins have drawn the attention of synthetic chemists due to their novel structural features and biological activities. 68-73 Until 2006, however, there were no synthetic studies on the hydroxylated THF-containing nonclassical acetogenins. Mucoxin (Figure I-13), the first hydroxylated 20 THF-containing nonclassical acetogenin was isolated by McLaughlin and coworkers in 1996 from the bioactive leaf extracts of Rollinia mucosa. previously reported to possess hydroxylated THF rings, OH 34 17 I-22 mucoxin 74 67 however their structures were threo O trans cis [Four acetogenins were O 14 OH 37 OH 8 trans O 1 O Figure I-13: Proposed structure of mucoxin 75 proved erroneous and have been corrected. ] Mucoxin exhibited potent and selective in vitro cytotoxicity against MCF-7 cells (breast cancer) in a panel of six human solid tumor cell lines. 67 -3 It has an ED50 value of 3.7 × 10 µg/mL, which is more potent than -2 adriamycin (ED50 = 1.0 × 10 µg/mL). However, further biological studies were limited because only 1.8 mg of mucoxin was isolated from the natural sources. For the same reason, the absolute stereochemistry of mucoxin was not determined. Its novel structural features as well as its interesting bioactivity led us to study the total synthesis of mucoxin. I.1. 4.1 Previous Total Synthesis of the Proposed Structure of Mucoxin Structurally, mucoxin contains a 3-hydroxylated-2,3,5-trisubstituted THF ring adjacent to a 2,5-disubstituted THF ring along with a γ-lactone moiety bound through a 6-carbon linker (Figure I-14). There are eight chiral centers in the molecule. Although no attempts were made to determine the absolute stereochemistry of the C8-C17 region, 21 the absolute configuration at C36 was assigned as S based on the observation that over 400 natural isolated acetogenins possess S configuration in the butenolide moiety. OH 17 O O 14 OH 76, 77 36 OH O 8 O Figure I-14: Synthetic target (mucoxin) Therefore, we chose the enantiomer represented in Figure I-14 as the synthetic target and completed the first total synthesis of the proposed structure of mucoxin in 2006. 78 I.1.4.2 Retrosynthetic Analysis The general scheme involves the construction of the polycyclic ether moiety bearing some functional group handles, as well as the terminal butenolide group, followed by the coupling of these two parts via the appropriate linker. Our retrosynthesis for mucoxin was 78 also based on this sequence and is outlined in Figure I-15. We planned to connect the terminal γ-lactone ring I-25, which could be prepared from the commercially available chiral epoxide I-26, with the bis-THF moiety I-24 via an alkylation reaction. The 2,5-disubstituted THF ring was formed using our 1,2,n-triol cyclization methodology from intermediate I-27. 79 The two adjacent THF cores were coupled via a 1,2-chelation-controlled addition of the Grignard reagent derived from iodide I-29, with THF aldehyde I-28. The 2,3,5-trisubstituted THF I-28 would be accessed using our Lewis acid-catalyzed, thiophenyl group-directed epoxide ring-opening of bis-protected epoxydiol I-30, 80, 81 which could be derived from the commercially available alkynyl 22 OH 16 I-23 OTBS O 16 O OH O O OH alkylation reaction OBn OTBS O OTBS Lewis acid mediatedPhS 1,2,n-triol cyclization I-24 OH OTBS O 16 I-27 OTBS O 16 I-28 O OH OBn Me O OH OTBS H I-26 chelation-controlled nucleophilic addition CHO I Wittig Reaction OTES 16 HO 4 O H I-32 Ph3P O I-33 H OBn I-29 OTBS O O I-25 OH SPh O OTES I-30 I-31 Figure I-15: Retrosynthetic analysis for preparation of mucoxin alcohol I-31. Homoallylic iodide I-29 could also be derived from diol I-32 and ylide I-33 via the Wittig reaction. I.1.4.3 Total Synthesis of the Proposed Structure of Mucoxin The total synthesis of the proposed structure of mucoxin was completed by our group in 2006, 78 utilizing the previously described methodology. The synthesis of the 23 2,3,5-trisubstitued THF core of mucoxin is shown in Scheme I-1. Alkylation of the lithium acetylide derived from TBS-protected commercially available 3-butynol I-31 1. TBSCl, imid. 2. n-BuLi / CH3(CH2)16I THF / HMPA OH 3. TBAF 53% (3 steps) I-31 OPMB 16 I-35 16 2. TESCl / TEA 83% (2 steps) >99% ee CHO OTES I-37 16 1. Ph3PCHCO2Et OTES I-30 OTES I-38 OH SPh BF3•OEt2 O 13 16 56% OPMB 1. DDQ 2. PhI(OAc)2 / TEMPO OTES I-36 OTES 16 2. DIBAL-H 81% (2 steps) OTES O 16 2. PMBCl / NaH 79% (2 steps) I-34 OTES 1. AD-mix-! OTES 16 1. LAH / diglyme OH 120 oC 75% (2 steps) 1. D-(-)-DIPT OH Ti(OiPr)4 / tBuOOH 2. (PhS)2 / Bu3P 62% (2 steps) 99% de SPh OH I-39 Scheme I-1: Synthesis of 2,3,5-trisubstituted THF I-39 gave the homopropargylic TBS ether, which after TBS deprotection forms homopropargylic alcohol I-34. LAH reduction of the triple bond and PMB protection of the alcohol provided the E-homoallylic PMB ether I-35. Sharpless asymmetric 82 dihydroxylation of I-35 afforded the corresponding diol in excellent yield and enantioselectivity (92% yield and >99% ee). Silyl protection of the diol and PMB 24 deprotection of the terminal alcohol followed by TEMPO catalyzed oxidation gave aldehyde I-37, which could undergo Wittig olefination and subsequent DIBAL-H 83 reduction to form the allylic alcohol I-38. Sharpless asymmetric epoxidation of the allylic alcohol V-31 provided the desired epoxy diol in excellent diastereoselectivity 1 (>99:1, by H NMR) and good yield (73%) under optimized conditions. After converting HO 4 OH I-32 1. NaH / BnBr 2. PCC 3. KHMDS HO I-40 Ph3P OHBr 53% (3 steps) OTBS O 16 O 1.MsCl / TEA 2. NaI / Acetone 3. tBuLi / MgBr2•OEt2 Li CHO OTBS I-28 TBSO OBn OBn I-41 85%, >20:1 dr TBSO OH 4 16 OBn AD-mix-! 88%, 5:1 dr O OH 16 OTBS I-27 OTBS I-42 OH OH OBn 5 Scheme I-2: Synthesis of triol intermediate I-27 the epoxy alcohol to the required epoxysulfide precursor I-30, the neighboring group-assisted cyclization reaction under our standard conditions led to the formation of the desired 2,3,5-trisubstituted THF diol I-39 in 56% yield, which could be cleanly separated from a 20% yield of an inseparable mixture of other isomeric cyclic diols. Optimization attempts by changing solvents, concentration, temperature, and acid 25 promoters were unsuccessful. However, this was still a good method to form intermediate I-39 because of the efficient separation of the byproducts and the ability to scale-up the reaction. To obtain a matched SAE product, D-(-)-DIPT needed to be used to set the stereochemistry of the epoxide I-30. Compared with the required stereochemistry of the THF product I-39, the stereochemistry of C13 had to be retained, which led to the choice for the thiophenyl group as the neighboring directing-group. The following step was to couple the trisubstituted THF ring with the functional group before constructing the disubstituted THF ring (Scheme I-2). The free hydroxyl TBSO OH O OH 16 OTBS I-27 OH TBSO 1. K2CO3, MeOH 1. MeC(OMe)3 TBSO OBn PPTS 5 16 2. BF3•OEt2 98% O 2. TBSOTf 92% (2 steps) 16 TBSO OTBS I 5 O 16 O O OTBS OBn 5 O O OAc OBn 5 OTBS I-43 1. H2, Pd / C 2. PPh3, I2 68% (2 steps) OTBS I-24 OTBS I-44 Scheme I-3: Synthesis of bis-THF iodide I-44 groups of compound I-39 were protected as TBS ethers, and the product was subjected to Pummerer rearrangement 84, 85 conditions, providing the desired aldehyde I-28 in good yield. Synthesis of the organolithium reagent I-41 was accomplished in a concise process, which involved the monobenzylation of commercially available 1,6-hexanediol I-32, 26 PCC oxidation, the Z-selective Wittig olefination by in situ TMS protection / deprotection of the ylide’s hydroxyl group, 86, 87 iodination via SN2 displacement, and a lithium-halogen exchange with tBuLi. After transmetalation with freshly prepared MgBr2•OEt2 at -95 °C, 88, 89 the Grignard reagent was formed and treated with aldehyde I-28, which was precoordinated with freshly prepared MgBr2•OEt2 at -40 °C. This optimized procedure gave the desired chelation-controlled addition product I-42 in good yield and excellent diastereoselectivity. The subsequent Sharpless asymmetric 82 dihydroxylation using AD-mix-α proceeded through attacking the olefin from the si face to form isomer I-27. Generally, during the SAD reaction, the stereoselctivity for Z-olefins is lower than for E-olefins, yielding the desired triol in a 5:1 diastereomeric ratio. Next, we focused on constructing the disubstituted THF ring (Scheme I-3). Treatment of I-27 with trimethyl orthoacetate and 10 mol% PPTS followed by addition of catalytic amount of BF3•OEt2 led to the desired 2,5-disubsituted THF ring in 98% yield as a single diastereomer via our 1,2,n-triol cyclization pathway. After converting the acyl group to the silyl group, benzyl-deprotection of I-24 via hydrogenation was followed by iodination to afford the bis-THF iodide I-44. The final stages of the total synthesis are shown in Scheme I-4. α-Phenylthio-γlactone I-25 was prepared by White’s procedure from commercially available thiophenyl acetic acid and chiral epoxide. 90 The coupling of iodide I-44 and α-phenylthio-γ-lactone I-25 was achieved by LDA-mediated α-alkylation in a THF/HMPA (4:1) mixture. 27 Treatment with mCPBA followed by the thermal syn-elimination of the sulfoxide gave the terminal γ-lactone I-45, which upon global deprotection using HF•py furnished the target molecule I-23, in high purity after HPLC isolation. TBSO O O 16 O PhS O 1. I-25, LDA 2. mCPBA I-25 then toluene, reflux 83% (2 steps) OTBS I 5 OTBS I-44 TBSO O O OTBS 5 16 OTBS I-45 OH O O O O HF•Py 75% OH O 16 O OH I-23 proposed structure of mucoxin Scheme I-4: Completion of the total synthesis of the proposed structure of mucoxin The proposed structure of the natural acetogenin, mucoxin, was synthesized in 32 steps and 26 steps along the longest linear sequence. The synthesis contains two regioand stereoselective THF ring-forming methods developed by our group. The 2,3,5-trisubstituted THF ring (C13-C17) group-assisted epoxydiol cyclization, 80, 81 was constructed using neighboring and the 2,5-disubstituted THF ring (C8-C12) was constructed using a one-pot 1,2,n-triol cyclization strategy. 79 The absolute 83 stereochemistries in I-23 were established via Sharpless asymmetric epoxidation 28 and dihydroxylation, 82 as well as the chelation-controlled addition. I.1.4.4 Comparison of Spectral Data of the Synthetic and Natural Mucoxin OH OH O O I-46 epimer of I-23 O O OH Figure I-16: C36 Epimer of synthesized mucoxin I-23 Although the synthesis of the proposed structure of mucoxin was accomplished, both 1 the H and the 13 C NMR spectra of the synthetic material did not match the published spectra of the natural sample. The major differences were in the adjacent bis-THF region chelation control established SAD established by Mosher analysis by Mosher analysis OH O 12 O OH O 16 SAD established by ECCD and Mosher OH O SAE established by nOe and correlation I-23 synthesized mucoxin OH threo O O OH O 16 trans OH trans O cis I-22 proposed structure of mucoxin Figure I-17: Structure of synthetic mucoxin and proposed structure of mucoxin (C8-C17) (Table I-16). 67, 78 In particular, H10, H11, H14, H15, and H17 exhibited differences of greater than 0.1 ppm as compared to the published spectra of the natural 29 Table I-5: Comparison of NMR resonances between natural and synthetic mucoxin OH O O OH O O OH Proton / Carbon I-23 Natural Mucoxin Δδ (I-23–natural) (ppm) H8 H9 H10 H11 H12 H13 H14 H15 3.41 3.96 1.69, 2.02 2.02, 2.13 4.35 3.80 4.44 1.84, 2.02 3.42 3.95 1.91, 2.05 1.91, 2.05 4.31 3.71 4.32 1.91, 2.35 -0.01 +0.01 -0.22, -0.03 +0.11, +0.08 +0.04 +0.09 +0.12 +0.07, -0.33 H16 4.09 4.04 +0.05 H17 C8 C9 C12 C13 C14 C15 3.41 73.6 84.1 79.3 83.3 74.7 39.0 3.53 73.6 83.4 78.9 83.5 72.8 38.0 -0.12 0.0 +0.7 +0.4 -0.2 +1.9 +1.0 C16 C17 81.6 74.3 79.9 73.7 +1.7 +0.6 mucoxin, while C14, C15, and C16 exhibited differences of greater than 1.0 ppm. In order to determine whether or not chiral carbon C36 has any effect on the spectra, the epimer I-46 (Figure I-16) was synthesized using the epimer of α-phenylthio-γ-lactone 30 1 I-25. H and 13 C NMR spectra of epimer I-46 were found to be identical with those of I-23, which supported our hypothesis that configuration of C36 is not the reason for the difference between the synthetic and natural mucoxin. Based on what was previously mentioned, we still believed that C36 should have the S configuration. Based on the latter description, a summary of the stereochemical assignments is shown in Figure I-17. We reason that all the configurations in the C8-C17 region of the synthesized mucoxin I-23 are identical to the proposed relative stereochemistry of natural mucoxin. 67 1 Therefore, the disagreement in both H and 13 C NMR must be due to the misassignments of the natural sample. I.1.4.5 The Strategy towards Structure Elucidation of Mucoxin 67 We re-examined McLaughlin’s structural assignment of mucoxin in order to find the possible reasons for the discrepancies in the NMR spectra between our synthetic and the natural mucoxin. The published 2D-COSY and HRMS fragmentation of the tri-TMS cccEEE ctcETE ttcTTT cttEEE tctTEE cccTTE tttETT cccEET cccTEE tccEEE ttcTTE ctcTEE cctTTE cctTET cccTET ttcEEE tctETE tctEET tccEET tccTTE tttTEE tttTTT cttTTE cttTET ctcTET cccTTT cctTTT cctTEE cccETE cttETT ctcETT tttETE tttEET tccETT tctETT ttcEET tccTTT ttcTET tttTET tttTTE ctcTTT cttTTT cttTEE cctEEE cctETT cccETT ctcEET cttEET cttETE ttcETT tttEEE tccETE tccTET tctTET tctTTE ttcTEE ctcTTE cctEET cctETE tccTEE ttcETE ctcEEE tctTTT tctEEE Figure I-18: 64 possible diastereomers of mucoxin derivative of the natural mucoxin suggested that the proposed structure of mucoxin is constitutionally correct. Therefore, the differences in NMR spectra are most likely due to the misassignments of the stereochemistry of the natural sample. We have performed 31 modeling studies which indicated other possibilities for the stereochemical assignments.91 Using molecular mechanics (MMFF94 force field), conformational searches and energy minimizations of different diastereomers were carried out. It was found that a 3 Hz coupling constant may be maintained for H13 in both H12-H13 threo and erythro relationship. Thus, the possibility of the erythro relationship between two THF rings could not be ruled out only based on the observed coupling constant for H13 in McLaughlin’s assignment. 91 Previous studies demonstrated that the configuration at C36 does not influence the NMR spectra of the molecule. Hence we took into account the remaining seven stereogenic centers (C8, C9, C12, C13, C14, C16, and C17) in calculating the total 7 number of possible diastereomers of mucoxin. There are in all 128 (2 ) possible stereoisomers including all the enantiomers. Since a pair of enantiomers has identical NMR spectra, we only considered the diastereomers for spectral comparison. Figure I-18 indicates all the possible 64 diastereomers of mucoxin, which were encoded in the Erythro ThreoThreo OH O O OH OH trans trans cis O O Figure I-19: ttcETT Diastereomer of mucoxin following manner: c or t is used to denote cis or trans relationship between C16-C13, C14-C13, and C12-C9; E or T is used to denote erythro or threo relationship between 32 C17-C16, C13-C12, and C9-C8. For example, ttcETT diastereomer of mucoxin refers to trans-relationship between C16-C13 and C14-C13, cis-relationship between C12-C9, erythro-relationship between C17-C16, and threo- relationship between C13-C12 and C9-C8 (Figure I-19). 1 Table I-6: H NMR comparison of truncated structure V-47 and synthesized mucoxin V-2 OH 16 O O OH OH 4 OBn 16 O OH I-47 Proton O OH O 4 O OH I-23 I-47 I-23 Δδ (I-47 – I-23) (ppm) 8 3.41 3.41 0.00 9 3.95 3.96 -0.01 10 1.71, 2.01 1.69, 2.02 +0.02, -0.01 11 2.01, 2.12 2.02, 2.13 -0.01, -0.01 12 4.33 4.35 -0.02 13 3.80 3.80 0.00 14 4.43 4.44 -0.01 15 1.83, 2.01 1.84, 2.02 -0.01, -0.01 16 4.09 4.09 0.00 17 3.41 3.41 0.00 33 Of all the 64 diastereomers, we synthesized a focused library of a few representative molecules to construct a database of their NMR spectra. Because C36 chiral center in the terminal γ-lactone ring has no effect on the NMR spectra of the bis-THF region (C8-C17) of mucoxin, it is possible to evaluate truncated structures containing only the bis-THF core and the hydrocarbon tail without the terminal lactone ring instead of preparing the fully assembled molecule for NMR evaluation. Thus prior to the library synthesis of the representative diastereomers of mucoxin we synthesized compound I-47, the truncated structure of the synthesized mucoxin I-23, and 1 1 compared their H NMR spectra (Table I-6). The H NMR chemical shifts in the C8-C17 Differentiation of Protecting Groups Followed by Stereochemistry Inversion (Selective Deprotection / Protection) OP1 O O OP3 OBn OP2 OP1 O OH OH OBn OP2 OH Stereochemistry Inversion before Cyclization (Mitsunobu Inversion) Figure I-20: New synthetic strategy to construct different diastereomers of mucoxin region of mucoxin analogs I-47 and I-23 differ only by 0.02 ppm or less, which shows that both of these molecules have identical NMR spectra in the bis-THF (C8-C17) region. 34 This enabled us to use the simpler truncated structures instead of the fully assembled molecule in the studies to determine the real structure of mucoxin, which could expedite the library synthesis of representative diastereomers. 78 The methods utilized in the total synthesis of the proposed structure of mucoxin were designed so that its stereoisomers could be prepared in a straightforward pathway. Since the absolute stereochemistries in both the THF rings and the flanking hydroxyl groups, except C12, were set from SAD and SAE reactions with the appropriate olefin precursors, the complementary diastereomers could be accessed simply by the choice of the opposite olefin geometry and chiral reagents. Thus the regio- and stereoselective cyclization methods could prepare several isomeric hydroxylated THF rings from a common epoxydiol or triol intermediate. In addition, the stereochemistry of C12 could be varied using Mitsunobu inversion following the chelation-controlled nucleophilic addition. Finally, once the adjacent bis-THF core was constructed, three hydroxyl groups (hydroxyl groups in C8, C14, and C17) could be distinguished via a selective deprotection / protection strategy. Each of these chiral centers (C8, C14, or C17) could then be inverted by simple techniques such as oxidation/reduction or Mitsunobu inversion (Figure I-20). I.1.4.6 Synthetic Pathway and Library Synthesis of Representative Truncated Structures of Mucoxin Scheme I-5 summarizes the strategies utilized to establish the stereogenic centers in I-23. The stereochemistries of C17-C16 and C9-C8 were established via Sharpless 35 asymmetric dihydroxylation, while the stereochemistry of C14-C13 originates from Sharpless asymmetric epoxidation. 78 The stereochemistry at C12 was arrived at via chelation controlled addition of an organometallic reagent with an incipient aldehyde. The trisubstituted tetrahydrofuran ring in I-28 was closed regioselectively with the aid of O OH OH O CH3(CH2)16 TBSO O O CH3(CH2)16 5 H3C(H2C)16 H3C(H2C)16 TESO CH3(CH2)16 OTBS I-28 OTES I-44 TBSO CHO O OTBS I 5 OTBS OH I-23 proposed structure of mucoxin OTBS O O O I-27 1,2,n-triol cyclization OH OH O OTBS OH OBn 5 TBSO PMBO (CH2)16CH3 SPh I-30 I-35 I-48 Scheme I-5: Retrosynthetic strategy used to synthesize the proposed structure of mucoxin. the thiophenyl directed epoxydiol cyclization, 80 furnished through the 1,2,n-triol cyclization. while the disubstituted ring in I-44 was 79 Inspection of the synthetic strategy indicates the ease by which stereogenic changes to the molecule can be accomplished. These could be either through changes in the ligands used for symmetric induction or by inversion of stereochemistry of the three hydroxyl groups present in the target molecule. It should be noted, however, that the stereochemistry of each diastereomer was rigorously 36 OH OH O O OH OBn 5 16 OH O 16 OH A tctTTT same as 1 OH O O OH OH OBn 5 O O O OH OH OBn 5 OH O 16 O OH OBn 5 O OH OH OBn 5 16 O 16 O OH O OBn 5 16 OH I cctETT O OBn 5 OH H tttTTT O OH O 16 OH G cctTTE O OBn 5 OH OH 16 OH O OH F tttTET OH E cttTTT O OBn 5 OH D tctTET 16 OH O 16 OH C tctETT OH OBn 5 OH B tctTTE OH 16 O OH J cctTET OH OH OBn 5 O 16 O OH OBn 5 OH OH K cctTTT L tccTET Figure I-21: Structure of synthesized truncated diastereomers of mucoxin 92 confirmed by a battery of 1D and 2D NMR experiments. Upon completion of the syntheses and inspection of the 1H and 13C NMR data, none 37 of the spectra from 12 isomers A-L (Figure I-21) fully matched the spectra obtained for natural mucoxin.92 In order to efficiently compare the data for each of the isomers with natural mucoxin, the deviations of 1H and 13C NMR chemical shift between the truncated structures and the reported natural mucoxin are tabulated in Table I-7. Considering the analysis of the truncated analogues of mucoxin: C8-C9 threo, C16-C17 threo, C14-C16 cis, C12-C13 threo, the field of isomeric possibilities is narrowed from 64 total diastereomeric choices to only 4. These isomers are highlighted in blue in Figure I-18. As luck would have it, two of the four possibilities (H and K) were synthesized as part of the 12 diastereomers chosen for spectral analysis, thus further narrowing the field to the remaining 2 isomers (ttcTTT M and cccTTT N, see Figure I-18, bold and italicized). Both of the latter truncated isomers were synthesized, and gratifyingly, the cccTTT analogue N was found to be a perfect match (Table I-8). Further verification of this was obtained via the synthesis of the full-length cccTTT molecule, which produced identical 1H and 13C NMR spectra as compared to reported mucoxin. It is noteworthy that upon spectroscopic analysis of the additional two truncated structures ttcTTT (M) and cccTTT (N), the four trends derived from the original 12 diastereomers also fit these structures. In the final analysis, our results indicate that the original trans stereochemical relationship for both rings (C9-C12 and C13-C16) is the source of error in the structure determination (trans stereochemistry of the ring substituents was assumed from lack of NOE). This clearly demonstrates the fallibility of using negative NOE results to assign relative stereochemistries, especially in five membered rings (pseudo axial and pseudo 38 equatorial disposition of substituents) if both cis and trans isomers are not available for comparative analysis. These problems are not isolated in structure determination, but also Table I-7: Chemical shift differences between the truncated analogues and the reported chemical shifts for mucoxin (NMR spectra recorded in CDCl3) OH OH O O 16 OBn 5 I-49 OH Δδ = δ (ppm) truncated analog – δ (ppm) reported mucoxin H/ A B -0.0 1 +0. 40 C D E F G H I J K L +0. 03 +0. 1 -0.0 1 +0. 2 -0.2 0 -0.0 2 -0.0 5 +0. 16 -0.0 5 -0.0 2 -0.2 --- 0.0 0 +2. 1 -0.0 2 C H 8 C -0.2 -2.1 H 9 C H 10 H H 11 H H 12 C H 13 0.0 +0. 0 05 +0. +0. 5 4 -0.2 -0.1 0 0 -0.0 -0.1 5 5 +0. -0.0 10 1 +0. +0. 07 08 +0. +0. 02 09 +0. +0. 1 2 +0. +0. 09 06 C -0.4 -0.2 -0.0 -0.0 1 2 +0. 0.0 2 -0.0 -0.1 3 0 +0. -0.2 5 -0.2 -0.2 7 -0.0 -0.0 4 2 +0. -0.0 02 7 +0. +0. 07 16 -0.0 -0.0 2 9 +0. -1.1 2 +0. 0.0 16 0 +0. +0. 6 5 -0.0 -0.0 +0. -0.0 -0.0 -0.0 3 5 44 5 1 2 +0. +0. +0. 0.0 -2.3 --3 3 3 -0.1 -0.1 +0. -0.1 -0.0 -0.1 1 2 02 8 9 2 +0. 0.0 -0.3 -0.2 -0.1 --1 -0.2 -0.2 -0.0 -0.2 -0.2 -0.2 0 5 4 7 8 1 -0.0 -0.0 -0.1 -0.0 -0.1 -0.0 6 6 8 9 1 4 +0. -0.0 -0.0 +0. +0. -0.0 08 9 9 05 05 1 -0.0 +0. +0. -0.0 +0. +0. 6 03 15 9 14 12 -0.2 -0.4 -0.0 -0.3 -0.1 -0.0 4 8 2 6 9 8 +0. +1. +0. +0. -0.2 --3 3 3 8 +0. +0. -0.0 +0. -0.1 -0.1 05 02 5 15 4 2 +3. +4. +2. +5. +2. --5 6 3 7 6 39 ---0.1 6 ---0.1 7 -0.1 2 +0. 02 +0. 08 -0.1 3 --- pose a challenge to synthetic organic chemists in assigning stereochemistry of synthetic products. The data also point to the fact that empirical results can be of great value in 1 Table I-8: H- and 13 C-NMR comparison of ttcTTT and cccTTT truncated analogs and cccTTT full length acetogenin with naturally isolated mucoxin OH OH O O OBn 5 16 OH 16 OH cccTTT OH O O OH ttcTTT N O OH OH O OBn 5 O 16 M O OH cccTTT 5 I-50 ttcTTT M (truncated) cccTTT N cccTTT (I-50) Δδ H Δδ C Δδ H Δδ C Δδ H Δδ C C/H (truncated) +0.9 0.00 8 -0.05 -0.1 0.00 +0.1 9 -0.09 -0.8 -0.02 +0.1 0.00 +0.1 +0.02, 10 -0.07, -0.10 --0.00, 0.00 ----+0.01 +0.02, 11 0.04, -0.10 --0.00, 0.00 ----+0.01 12 -0.31 +0.8 0.00 0.0 0.00 0.0 13 +0.17 +5.1 +0.03 +0.2 +0.04 +0.2 14 -0.05 +1.2 -0.01 +0.1 0.00 +0.1 15 -0.07, +0.09 -0.1 0.00, 0.00 +0.8a +0.02, 0.00 +0.8a 16 +0.04 +1.7 0.00 +0.2 +0.01 +0.2 17 -0.01 +1.0 0.00 +0.1 +0.01 -0.2 a The reported deviation is based on tabulated data from the original isolation and characterization report, however, close inspection of the original NMR spectrum suggests that the listed data for C15 was transcribed incorrectly by ~1 ppm, and in actuality the deviation between the NMR of cccTTT and the original data is less than 0.2 ppm. stereochemical assignments since they can be used as a guide and/or secondary verification for structural elucidations. 92 40 I.1.4.7 Biological Evaluation of Mucoxin and Analogs In the original report of mucoxin’s discovery and structural elucidation, biological activity against a panel of six cancer cell lines was reported. As tabulated in Table I-9, mucoxin appeared to have significant activity against a number of cancer cell lines, however most significantly, MCF-7 breast carcinoma and A-549 lung cancer showed the best responses intoxicity assays. 18 We have tested the cytotoxicity of both the compound with the proposed structure of mucoxin (I-23) and the corrected structure (I-50) against a large panel of cancer cell lines (Table I-9). In comparison with the data obtained from the initial report of mucoxin’s discovery, our assays do not replicate the high activity observed for A-549 and MCF-7 cell lines, although both I-23 and I-50 retain higher activity in comparison to adriamycin. The synthesis of the enantiomer of I-50 (ent-I-50) was pursued, since the original disclosure did not propose the absolute stereochemistry of mucoxin, nor did it report chiroptical spectroscopic data (such as CD or [α]D values). It should be noted that ent-I-50 is in fact a diastereomer of I-50 since the absolute stereochemistry at C35 was retained as S (common to all acetogenins). Although we had hoped that comparison of the biological data obtained for ent- I-50 and I-50 might lead to the prediction for the correct absolute stereochemistry, as evident from the data in Table I-9, this was not possible. Both I-50 and ent-I-50 lead to similar cytotoxic activities across the panel of cancer cells. Mucoxin analogs do display a reasonably potent cytotoxic activity against all of the nine cancer cell lines tested in Table 10. Most importantly, they retain their potency against the adriamycin resistant cell line 41 (NCI-Adr). The C35 epimer of I-23 (epi-I-23) was also synthesized to investigate its effect, however, in comparison to I-23, one must conclude that the absolute stereochemistry of C35 does not influence cytotoxicity to a large extent. As discussed above, the inhibition of mitochondrial complex I is the generally accepted mode of action for acetogenins. Nonetheless, few studies of acetogenins compare the cytotoxic activity of the molecules with Complex I inhibition potency. Examining the cytotoxicity of I-23, epi-I-23, I-50, and ent-I-50, it is clear that for each cell line the variation in activity is no greater than 4 fold and in most cases is within 50% of each other. Surprisingly, complex I inhibition results tabulated in Table I-9 suggest that I-23 and epi-I-23 with minimal activity (compared to rotenone, a standard complex I inhibitor) must follow a different mode of action as compared to I-50 and ent-I-50, which exhibit potent complex I inhibition (more than rotenone). This is a surprising result since it indicates a clear structure/activity relationship, which is not realized through cytotoxic analyses, but is clearly evident via enzymatic activity assays. It points to the fact that acetogenin bioactivity must be analyzed through targeted biological assays, and might suggest a reason for some of the reported discrepancies in the literature with respect to the levels of apoptotic and necrotic activity of acetogenins. Although we are in no position at this time to suggest alternate targets besides complex I, it clearly points to the need for supplementing cytotoxicity data with complex I inhibition to investigate the relationship (or lack thereof) between the two. Currently, we are investigating other targets besides complex I for the observed cytotoxicity of I-23 and epi-I-23. 42 I.1.4.7.1 Red Blood Cell Hemolysis The red blood cell (RBC) is one of the most studied membrane systems and is therefore used as a model to describe many membrane-solvent-solute interactions. A red blood cell placed into a hypotonic solution of nonpenetrating molecules (i.e., a solution with lower concentration of solute and a higher concentration of solvent than the cell, for example, water) will rapidly swell and hemolyse, as the water molecules influx by osmosis from higher to lower concentration. Conversely, a red blood cell placed into a hypertonic solution of nonpenetrating molecules (i.e., a solution with higher concentration of solute and lower concentration of solvent than the cell, for example, salt water) will rapidly shrink and crenate, as water molecules efflux by osmosis from a Figure I-22: RBC Hemolysis for mucoxin and its analogs (D: DMSO, C: Cell, W: Water) higher to a lower concentration. Further, a red blood cell placed into an isotonic solution of nonpenetrating molecules (i.e., a solution with the same concentration of solute and 43 solvent as the cell, for example, saline solution) will neither swell nor shrink because the osmotic influx and efflux of water is in equilibrium in the absence of a concentration gradient. The amount of time that it takes for hemolysis or crenation to occur is directly related to the rate of osmosis across the cellmembrane. Therefore, hemolysis can be used to determine the hypertonic, hypotonic and isotonic concentrations of particular nonpenetrating solutes and the hemolysis time can be used as an index of the rate of osmosis. 93 The Red Blood Cell (RBC) hemolysis for all molecules that is shown in Table I-9 was studied and no significant hemolytic activity was detected, suggesting a target based mode of action and not cellular membrane disruption as the cause for biological activity (Figure I-22). I.1.5 Library Design of Ether-Linkage Analogs of Acetogenins OH O O OH OH O bullatacin OH OH O O OH O bullanin O O Figure I-23: Ether linked analogs of bis-adjacent THF acetogenins Encouraged by the results of the initial structure-activity relationship (SAR) studies on mucoxin and its analogs, and in order to further understand the mechanism and the exact mode of action of acetogenins, more SAR studies were necessary. Since the 44 OH R1 O O O OH O R2 R1 and R2 can be a variety of groups Figure I-24: Ether linked analogs of bis-adjacent THF acetogenins bis-adjacent THF acetogenins are the most active members of the acetogenin family such 35 as bullatacin (one of the most potent inhibitors of complex I) and bullanin (having much lower ED50 values against a panel of some human cancer cell lines than OAc P1O O O LG OAc OP2 selective removal of P2 I-51 OAc P1O O O LG OAc selective O removal of P1 I-52 remove Ac OAc O O O OAc O I-53 Figure I-25: Modular synthesis of acetogenin analogs with bis-adjacent THF core adriamycin, an anticancer drug currently in clinical use) 22 (Figure I-23), we decided to use the bis-THF motif as the core for further SARs. In order to obtain a large library of acetogenin analogs in the SAR studies, an established methodology on how to quickly and efficiently assemble a series of compounds is very important. Our new plan for SAR investigations is focused on the use of ether linked analogs of acetogenins (Figure I-24). Utilization of ether linkages will enable rapid synthesis of a large library of acetogenins with a variety of groups flanking the right and left side of the 45 bis-THF core. After constructing bis-adjacent THF core I-51, each protecting group (P1 and P2) can be removed selectively and the desired side chain can be installed through a simple Williamson etherification to afford compound I-52 and I-53 (Figure I-25). In theory, there is no limitation for the choice of the side chains, which could lead to a large library of bis-adjacent THF acetogenin analogs that can be evaluated rapidly for their bioactivities. For example, a variety of hydrophobic tails as well as the spacers with terminal butenolide moiety can be installed with different lengths by using electrophiles I-54 and I-55 (Figure I-25). The butenolide functionality can be changed to other groups that could interfere with electron transport in complex I, such as substituted benzenes (I-56) and quinones. Membrane-binding elements such as phosphate esters (I-57) and steroidal compounds (I-58) can also be attached to the tail or instead of the butenolide moiety. Also, by coupling two or more acetogenin skeletons, dimer, trimer or oligomeric acetogenins can be formed (I-59). In addition, fluorescent molecules can be attached for sub-cellular localization experiments (I-60) and photoaffinity groups can be attached for photoaffinity labeling experiements (I-61). The attractive feature of this strategy is that all these compounds can be synthesized easily, and therefore SAR information can be obtained quickly. To implement the latter strategy, the development of the methodology to synthesize bis-adjacent THF segments needs considerable attention. Several stereospecific synthetic approaches to bis-adjacent THF segments have been developed successfully. Our alternative methodology is based on the Lewis acid mediated one-pot 46 regio- and stereoselective cyclization of 1,2,n-triols developed in our group in 2005. Using Sharpless asymmetric dihydroxylation (SAD) 82 79 to control the absolute stereochemistry, 2,5-disubstituted THF rings could be formed in excellent yield. This PO PO OP double-SAD * * R1 I-62 R2 R1 * * HO OH OP * * * HO R2 * OH I-63 OAc OAc double 1,2,n-triol O * * O cyclization R1 * * * * R2 I-64 Scheme I-6: Proposed synthetic plan to form bis-adjacent THF segments methodology was successfully used in the total synthesis of mucoxin and its analogs. 92 78, The advantages of the 1,2,n-triol cyclization are that reaction conditions are mild and the reaction is fast. Generally the reaction is complete within 30 min at room temperature. Also the experimental procedure is operationally facile as compared to other methodologies such as metal-mediated oxidative cyclizations. The question was whether or not this transformation could lead to the formation of a bis-THF moiety in one step. Our proposed synthetic plan is shown in Scheme I-6. After preparing intermediate I-62 containing two double bonds, double SAD reactions can provide tetra-ol I-63 stereospecifically in one step. The following double 1,2,n-triol cyclization mediated by a Lewis acid can afford the desired bis-adjacent THF segment I-64 in one simple step. By varying the stereochemistry of the two double bonds and using different SAD chiral 47 reagents, different diastereomers can be formed efficiently. This one-pot regio- and stereoselective double cyclization of polyhydroxylated systems provides a good alternative pathway to form bis-adjacent THF segments. I.2 Bis-Epoxide Ring-Opening Pathway O O PhMgBr, CuI HO OH 88 % yield Ph Ph Scheme I-7: Robbins synthesis of chiral non-racemic vicinal diol Epoxide ring-opening reaction is an efficient route to prepare chiral secondary alcohols since many good methodologies to prepare chiral epoxides such as Sharpless O O HO ArMgX, CuI OH Ar Ar Ar = p-MeOC6H4, 93% yield Ar = o-MeOC6H4, 68% yield O MgBr , CuI O HO OH 91% yield Scheme I-8: Aromatic and aliphatic Grignard reagent in bis-epoxide asymmetric epoxidation, 83 ring-opening reactions Jacobsen’s epoxidation, 9a and Shi epoxidation 94b well developed. Different organometallic reagents such as organolithium, organocuprate, 97 and organoaluminum reagents 96 Grignard, 96 were successfully used in the ring-opening reaction of chiral epoxides to form secondary alcohols. 48 95 are already O O HO R1M O HO R 2M OH R1 R1 R2 . Scheme I-9: Synthesis of non-C2-symmetirc adjacent diols reactions In 1999, Robbins and coworkers reported the synthesis of chiral non-racemic vicinal diols (Scheme I-7), which provided an efficient route to prepare chiral vicinal diols. 100 99, Later on, different nucleophilic reagents were used, following the same strategy, to open the chiral bis-epoxide. For example, de March and coworkers reported the synthesis OAc HO P1O OH OP2 1. SAD OAc O O O O O P1O O OP2 2. cyclization P1O HO OP2 HO P1O OH OAc 1. SAD OH OP2 P1O OAc OP2 2. cyclization OAc 1. SAD 2. cyclization P1O OP2 AcO Scheme I-10: Preparation of different classes of acetogenins 101 of enantiomerically pure monoketals of p-benzoquinone and Clive and coworkers found that aliphatic Grignard reagents could undergo the same ring-opening reaction to 102 give the desired chiral vicinal diols (Scheme I-8). The bis-epoxide ring-opening pathway provides an efficient method to prepare chiral vicinal diols with a variety of side functional groups. Thus, in order to prepare our 49 diene precursors, we just need to prepare the corresponding organometallic reagents. If only 1 equiv. of organometallic nucleophile (R1M) is used epoxyalcohol could be formed, which could be subjected to a second ring-opening reaction using a different organometallic nucleophile (R2M) to afford the non-C2-symmetric adjacent diol (Scheme I-9). The ability to change R1 and R2 groups leads to quick access to different classes of acetogenins (Scheme I-10). For example, if both R1 and R2 are allylic organometallic nucleophiles, diol 53 would be formed after the two-step ring-opening reactions, which then leads to the formation of the bis-adjacent THF acetogenins with two different (CH3O)2C(CH3)2 MeO2C CO2H MeOH O OH cyclohexane, p-TsOH 74% yield HO2C HO CO2Me O LiAlH4 Et2O, reflux 55% yield I-65 CH2OH 1. CH3SO2Cl, Py. HOH2C O O 2. p-TsOH, EtOH, H2O 84% yield MsOH2C CH2OMs HO OH I-67 I-66 KOH O O Et2O, H2O 88% yield I-68 Scheme I-11: Synthesis of chiral bis-epoxide 62 terminal protecting groups. If R1 is allylic and R2 is a homoallylic organometallic nucleophile, diol would be formed from which the non-classical THF-THP acetogenin 50 would be obtained. If R1 is vinyl and R2 is an allylic organometallic nucleophile, diol is anticipated and the hydroxylated THF acetogenin would be accessed. Synthesis of chiral bis-epoxide I-68 was carried out from the commercially available L-tartaric acid. L-tartaric acid was protected by 2,2-dimethoxylpropane in methanol to give I-65 in 74% yield. Reduction of the dimethyl ester with LiAlH4, followed by mesyl protection and acetonide group deprotection afforded diol I-67. Base-mediated cyclization furnished the (S,S)-1,2,3,4-diepoxybutane I-68 (Scheme I-11). HO OH NaH, BnBr BnO TBAI, THF, reflux 68% yield CHO Ph3PCHCO2Et BnO I-70 BnO 78% yield OH I-72 OH I-69 (COCl)2, DMSO 86% yield CO2Et BnO DIBAL-H 85% yield I-71 1. MsCl, Et3N 2. LiBr, DMF 75% yield Br BnO I-73 Scheme I-12: Synthesis of allylic bromide I-73 In order to synthesize bis-adjacent THF acetogenin analogs, allylic organometallic reagents are used in the epoxide ring-opening reactions. The following study was to prepare the desired allyl bromide containing a trans-olefin. Mono-benzylation of 1,3-propanediol with NaH and benzyl bromide at refluxing conditions provided the desired alcohol I-69 in 68% yield. Swern oxidation followed by Wittig reaction provided trans-olefin I-71 as a single isomer, which was subjected to DIBAL-H reduction to give 51 allylic alcohol I-72. The terminal hydroxyl group was converted to a good leaving group followed by SN2 displacement with lithium bromide to provide allylic bromide I-73 (Scheme I-12). Br BnO O BnO I-73 O OBn HO Mg, CuI I-68 OH I-74 Scheme I-13: Bis-epoxide ring-opening reaction by using Grignard reagent Attempts to perform the bis-epoxide ring-opening reaction with Grignard reagent generated in situ in different solvents such as THF and Et2O under reflux condition did not give any desired diol product I-74. The starting material was recovered based on the crude NMR of the reaction (Scheme I-13). Br BnO I-73 BnO n-Bu3SnH CuCN, n-BuLi 84% yield SnBu3 I-75 SnBu3 I-75 BnO n-BuLi O BnO OBn HO O I-68 OH I-74 Scheme I-14: Different method for bis-epoxide ring-opening reaction With the failure of the Grignard approach, we next turned to organolithium reagents. Since allylic bromide is not as efficient in the halogen-lithium exchange, the corresponding allyltin was prepared by using tri-butyltin hydride. The reaction proceeded 52 smoothly in good yield. Treatment of compound I-75 with n-butyl lithium should provide the desired organolithium reagent, which could then be coupled with the diepoxide. But, even after more than 24 h, there was still no desired product. After failing in situ generation of lithium reagent, we tried to first prepare the organolithium reagent. Allyltin I-75 was treated with n-butyl lithium and after 24 h no desired product was obtained. Considering that this reaction failed, it seemed that the problem was due to the generation of the organolithium reagent (Scheme I-14). 3 2 I.3 Sp -Sp Cross Coupling Reactions to Synthesize Triene Intermediate P1O OAc ! !O ! OAc O!! ! OH OP OH P1O OP2 OP2 OH OP OH P1O P1 O OP2 X + P2O X + X X Figure I-26: Retro-synthesis of triene With the failure of the bis epoxide opening, we next turned to develop another simple and efficient method to achieve the bis-THF core in a stereocontrolled fashion (Figure I-26). We had seen an example in the literature where the exact same substrate was used (where the terminal carbons are the ethyl esters) and the Sharpless Asymmetric Dihydroxylation (SAD) was achieved selectively at the central double bond. 103 Our goal was to synthesize the triene and vary the oxidation state of the terminal carbons (free 53 hydroxyls, protected hydroxyls, or esters) and see if we could get selective dihydroxylation of the central double bond (using SAD). If we could get selective dihydroxylation, then the next step would be to develop an efficient methodology to synthesize the triene. EtO2C H I(coll)2PF6 CO2Et CH2Cl2 H I2, alumina petrolium ether 5% yield I I I-76 I I I-76 Scheme I-15: Attempts for synthesis of diiodoethylene The synthesis of the central fragment was started using two different approaches. The first approach began by iodination of ethylene dicarboxylic acid that is failed. The second method was bubbling acetylene gas into a solution of alumina and iodine (Scheme I-15). CO2H HO2C MeOH, H2SO4 91% yield CO2Me MeO2C I-77 LiAlH4, THF 87 % yield NaH, BnBr HO OH I-78 PPh3, I2 imidazole BnO OH I-79 CH3CN, Et2O 67% yield TBAI, THF, reflux 52% yield BnO I I-80 Scheme I-16: Synthesis of homo-allylic iodide I-80 54 The synthesis of side chain started by esterification of trans-hydromuconic acid followed by LAH reduction. Mono-benzylation of I-78 with NaH and benzyl bromide at refluxing conditions provided the desired alcohol I-79 in 52% yield. Iodination reaction of I-79 afforded I-80 in good yield (Scheme I-16). BnO I Zn, THF BnO ZnI I-80 I I I-76 I-81 Cl2Pd(dppf), THF 72% yield OBn BnO I-82 Scheme I-17: Synthesis of triene The next attempt to synthesize the triene required zinc activation of the iodinated side fragment I-81 to couple with diiodoethylene and two side fragments together using OBn BnO AD-mix ! 30% yield I-82 OH OH OH OBn BnO OH OBn BnO OH I-83 OH Na, NH3, THF 67% yield I-82 OH HO AD-mix ! I-84 mixture of products Scheme I-18: SAD reaction of triene 55 palladium (Scheme I-17). The subsequent Sharpless Asymmetric Dihydroxylation (SAD) using AD-mix-β proceeded I-83 in 30% yield as the major product without showing any regio- and enantio-selectively. With the failure of the selective SAD reaction, we next deprotected benzyl group of I-82 to afford diol I-84. SAD reaction of diol I-84 gave a mixture of different products (Scheme I-18). HO OH I-78 DHP, p-TsOH•H2O CH2Cl2, rt, 58% yield THPO OH I-85 PPh3, I2 imidazole CH3CN, Et2O 84% yield THPO I I-86 Scheme I-19: Synthesis of homo-allylic iodide I-86 With the failure of selective SAD reaction, we next turned to change the alcohol protective group to a bulkier one such as TBDPS and closer to the sides of the double bond (by removing one methylene) to see if a selective SAD reaction of middle double bond. For this purpose we change our pathway to avoid the low yield in synthesis of diiodoethylene I-76. Our methodology for this synthesis is described in the following. We started with mono-THP protection and iodination of diol I-78 to provide the desired central fragment I-86, which was then coupled with vinyl iodide I-88 (Scheme I-19). 56 Hydrozirconation of propargyl alcohol with Cp2ZrCl2/DIBAL-H and iodination provided the desired product I-87 in 85% yield. TBDPS protection of the free alcohol I-87 gave the desired vinyliodide I-88 in excellent yield (Scheme I-20). 3 2 Then, synthesis of the desired triene by sp -sp cross-coupling reaction was considered. For this purpose, Negishi coupling could be used to form the desired carbon-carbon bond. Thus, homoallylic iodide I-86 and vinyliodide I-88 was converted to the corresponding diene I-89 under Negishi condition followed by THP deprotection, iodination and another Negishi coupling with I-88 (Scheme I-21). THPO Cp2ZrCl2, DIBAL-H OH I2, THF, 85% yield I I + I OH TBDPSCl t-BuLi, ZnBr2 imidazole PdCl2(dppf) I OTBDPS OTBDPSDMF, rt, 80% yield I-87 I-88 Et2O, THF I-86 I-88 -78 ºC-rt, I-88 Scheme I-20: Synthesis of vinyl iodide 92% yield THPO OTBDPS I-89 HCl, THF 92% yield PPh3, I2 imidazole CH3CN, Et2O 80% yield I OTBDPS I-91 TBDPSO HO OTBDPS I-90 I-88, t-BuLi, ZnBr2 PdCl2(dppf) Et2O, THF -78 ºC-rt, 78% yield OTBDPS I-92 Scheme I-21: Synthesis of di-TBDPS protected of triene At this point, Sharpless Asymmetric Dihydroxylation (SAD) 82 of the middle double bond, with TBDPS protected alcohols also failed (Scheme 22). However, Sharpless 57 Asymmetric Dihydroxylation (SAD) 82 was achieved selectively at the central double 103 bond where there is an ester on both ends of triene. TBDPSO OTBDPS AD-mix ! mixture of products I-92 Scheme I-22: SAD reaction of I-92 Therefore, the future work for the synthesis of the triene can be based on having two different esters on both ends of the triene. To accomplish this, we tried to make the mCPBA K2HPO4 O CH2Cl2, H2O I-93 rt, 68% yield CHO OHC I-94 H5IO4, CH2Cl2 H2O, 4 ºC 83% yield NaBH4 MeOH, rt 78% yield HO I-95 OH DHP, p-TsOH•H2O CH2Cl2, rt, 56% OTHP HO I-96 yield PPh3, I2, imidazole CH3CN, Et2O I 80% yield I-97 OTHP Scheme I-23: Synthesis of homo-allylic iodide I-97 cis-isomer of I-86 by the following method. Mono-epoxidation of 1,4-cyclohexadiene provided 68% yield of the desired product I-93. Next, oxidation of epoxide to dialdehyde was considered followed by reduction with NaBH4. After reducing the dialdehyde to the 58 diol, mono-protection of diol I-95 proceeded smoothly. Iodination of alcohol led to the homo-allylic alcohol I-97 (Scheme I-23). I OH I-87 pivCl, pyridine CH2Cl2, rt, 81% yield I Opiv I-98 Scheme I-23: Piv protection of I-87 For synthesis of desired vinyl iodide, Piv protection of I-87 was applied (Scheme I-23). Negishi conditions were applied for coupling of homo-allylic iodide I-97 and vinyl t-BuLi, ZnBr2 I I-97 OTHP Et2O, THF -78 ºC-rt I-98 PdCl2(dppf) THF, rt + I-99 OTHP BrZn I Opiv OTHP I-98 t-BuLi, ZnBr2 I I-97 OTHP Et2O, THF -78 ºC-rt I-98 Pd(PPH3)4 THF, rt BrZn + I-99 OTHP I OTHP Opiv I-98 Scheme I-24: Attempts for Negishi reaction of I-97 with vinyl iodide I-98 iodide I-98 in the presence of PdCl2(dppf) as a catalyst. The result did not show any desired coupling product and gave compound I-99 that was the result of protonation of alkyl zinc bromide which presumably occurred in the work up. Changing of the catalyst 59 to Pd(PPh3)4 did not change the results, yielding I-99 again as the product (Scheme I-24). With the failure of above Negishi coupling, we next turned to the Suzuki coupling of 2 vinyl iodide I-98. Sp -Sp coupling of THP protected propargyl alcohol I-100 and vinyl bromide should provide the desired central fragment I-101, which could then be coupled with vinyl iodide I-98 (Scheme I-25). OH DHP, p-TsOH•H2O CH2Cl2, rt, 78% OTHP I-100 CuI, i-PrNH2 OTHP+ I-100 Br Pd(PPh3)2Cl2 THPO THF, rt, 61% I-101 Scheme I-25: Synthesis of I-101 As shown in Scheme I-26, Suzuki coupling of vinyl iodide I-100 and I-101 in the presence of 9-BBN and PdCl2(dppf) as a catalyst failed and starting material was 9-BBN, PdCl2(dppf) THPO + I I-101 Opiv I-100 Cs2CO3, AsPh3 recovered SM DMF, THF, rt or reflux 9-BBN(dimer) THPO I-101 + I Opiv I-100 Pd(PPh3)4, K3PO4 dioxane, THF rt or reflux Scheme I-26: Attempts for Suzuki reaction 60 recovered SM recovered. Changing the boron source to 9-BBN (dimer) and Pd(PPh3)4 as a catalyst, also failed and starting material was again recovered (Scheme I-26). 9-BBN, PdCl2(dppf) THPO O + I Cs2CO3, AsPh3 O DMF, THF, rt or reflux I-101 9-BBN(dimer) O THPO + I recovered SM Pd(PPh3)4, K3PO4 recovered SM dioxane, THF rt or reflux O I-101 Scheme I-27: Attempts for Suzuki reaction The piv protecting group in vinyl iodide I-100 was changed to other groups to further explores the Suzuki reaction. We used commercially available (E)-ethyl 3-iodoacrylate to have an ester vinyl iodide instead of a reverse ester. Suzuki coupling reaction was attempted under different conditions (Scheme I-27). Neither 9-BBN with PdCl2(dppf) nor 9-BBN (dimer) with Pd(PPh3)4 gave any product. In 1997, Zaidlewics and coworker O n-BuLi, i-PrNH2 HO THF, -10 ºC-rt, O HO I-102 quantative yield DHP, p-TsOH•H2O HO I-103 CH2Cl2, rt, 90% yield LAH, Et2O reflux, 84% yield THPO I-104 Scheme I-28: Synthesis of diene I-104 61 reported the monohydroboration of conjugated dienes with catecholborane catalyzed by 104 nickel(II) chloride with good selectivity and yield. To use the same conditions, conjugated diene I-104 was prepared in three steps starting with a conjugated acid ((2E,4E)-hexa-2,4-dienoic acid) which was deconjugated by kinetic protonation of its extended enolate. LAH reduction of acid I-102 and THP O Catecholborane THPO I-104 + O I NiCl2(dppe) PdCl2(dppf) THPO OEt I-105 (13% yield) + Cs2CO3, AsPh3 THPO THF, rt O 70% yield O Catecholborane NiCl2(dppe) THPO I-104 + O I O THPO PdCl2(dppf) OEt I-105(30% yield) Cs2CO3, AsPh3 + O BO THF, reflux THPO I-106 (52% yield) Scheme I-29: Synthesis of Suzuki coupling protection provided diene I-104 in 90% yield (Scheme I-28). The coupling reaction was attempted under the same reported condition. The reaction at room temparature was attempted and we isolated the desired coupled product in 13% yield, with 70% of diene I-104 isolated as well. Isolation of starting material, suggests that the problem of low yield resides with hydroboration step. This reaction under reflux condition proceeded to 62 yield 30% of desired product I-105 and 52% of hyroboration product I-106 was isolated without any trace of diene I-104 (Scheme I-29). The latter result indicates that the hydroboration problem was solved by refluxing the reaction, however, the coupling step is still problematic. I.4 Sulfone Coupling The sulfone-stabilized carbanion is an efficient nucleophile to couple with alkyl or allyl halides in carbon-carbon bond forming reactions. P1O OAc OAc O * * O * * * * P1 O 105 Since, attempts to perform the OH P1 O OP2 OP ! ! OP2 ! ! OH OP OH ! ! OP ! ! OH P1O OP2 SO2Ph OP X + OP ! ! X OP + PhO2S OP2 Figure I-27: Retro-synthesis of sulfone coupling 3 2 carbon-carbon bond formation by sp -sp coupling failed, we next turned to coupling of sulfone with alkyl halide. Our retro-synthesis is outlined in Figure I-27. The protected alcohol was established in the middle before coupling, since we knew the SAD reaction of the triene is not selective for the center double bond. 63 Our studies began with the synthesis of sulfone I-110. 1,3-Propandiol was treated with sodium hydride and benzyl bromide to give mono-protected alcohol I-107 in 87% 1. (COCl)2, DMSO HO BnBr, NaH, TBAI OH BnO THF, 87% yield O BnO I-107 DIBAL-H, Et2O OEt OH quantitative yield 94% yield 2. O 89% yield BnO I-108 OEt Ph3P OH I-109 1. MsCl, Et3N, CH2Cl2 2. PhSO2Na, DMF BnO SO2Ph I-110 66% yield Scheme I-30: Synthesis of sulfone I-110 yield. The following Swern oxidation and Wittig olefination afford compound I-108. The ester group was successfully reduced under DIBAL-H condition and the sulfonation of alcohol I-109 occurred uneventually (Scheme I-30). MeO2C HO CO2Me 2,2-dimethoxy propane MeO2C p-TsOH, CH2Cl2 OH CO2Me O O 71% yield I-111 LAH, Et2O HOH2C 96% yield O CH2OH p-TsCl, Pyridine TsOH2C 76% yield O I-112 O I-113 Scheme I-31: Synthesis of I-113 64 CH2OTs O Next, the synthesis of the mid-section was carried out. Since selective SAD reaction of triene failed, we started our synthesis with L-dimethyl tartrate with the stereochemistry of the center diol in place. Acetonide protection of L-dimethyl tartrate under acidic condition followed by LAH reduction gave I-112 in 96% yield. The corresponding diol was activated as a tosyl group as it is a good leaving group for sulfone coupling (Scheme I-31). TsOH2C SO2Ph+ O BnO I-110 CH2OTs n-BuLi, HMPA, THF no reaction O I-113 Scheme I-32: Attempts for sulfone coupling The coupling between sulfone I-110 and I-113 was tried in basic condition by using n-BuLi as the base in the presence of HMPA. There was no reaction even after 24 h, both starting materials were recovered (Scheme I-32). The major problem in the failed sulfone coupling reaction is due to the tosyl TsOH2C O CH2OTs NaI, acetone IH2C 87% yield O O I-113 I-110 O I-114 IH2C SO2Ph+ O BnO CH2I CH2I n-BuLi, HMPA, THF degraded O I-114 Scheme I-33: Synthesis of diiodide I-114 and attempts for sulfone coupling 65 protecting groups of I-113. So, to solve this problem, we converted the tosyl protected alcohols in I-113 to the corresponding diiodide to have a better leaving group for the coupling (Scheme I-33). After treating sulfone I-110 with diiodide I-114, the reaction is degraded and none of the starting materials were isolated (Scheme I-33). The failure of the coupling reaction might be the result of having two iodides in I-114. We synthesized mono iodide compound to be sure that the substrate has just one reactive HOH2C O CH2OH BnBr, NaH BnOH2C THF, 63% yield O I-112 O CH2OH O I-115 1. p-TsOH, Py. BnOH2C 2. NaI, CH3CN O CH2I O 91% yield I-116 Scheme I-34: Synthesis of alkyl iodide I-116 site. Diol I-112 was monobenzylated, followed by iodination of the tosyl protected alcohol to provide the desired iodide I-116 in 91% yield (Scheme I-34). BnOH2C SO2Ph+ O BnO I-110 CH2I n-BuLi, HMPA, THF 3 unknown products O I-116 Scheme I-35: Attempts for sulfone coupling The coupling reaction of sulfone I-110 with I-116 led to the production of three unknown products (Scheme I-35). 66 I.5 Total Synthesis of the Center THF Core At this point, we decided to synthesze one of the center THF cores with two different alcohol protecting group on the two ends of the core to minimized problems with etherification in future steps. For this purpose, we started our synthesis with 1. n-BuLi, HMPA, THF OH DHP, CH2Cl2 HCl, rt 67% yield I-117 I Cl OTHP 2. HCl, reflux, 90% yield H2, Lindlar Cat. Cl HO MeOH, 91% yield HO I-118 (COCl)2, DMSO NEt3, CH2Cl2 87% yield O H I-120 Cl I-119 PPh3 CO2Et Cl THF, reflux 80% yield O Cl OEt I-121 Scheme I-36: Synthesis of α,β−unsaturated ester I-121 4-pentyn-1-ol shown in Scheme I-36. THP protection of 4-pentyn-1-ol gave the THP ether I-117, which after coupling with commercially available 1-chloro-3-iodopropane, and subsequent THP deprotection yielded alcohol I-118. Lindlar hydrogenation of the triple bond and Swern oxidation of the alcohol provided the cis-aldehyde I-120. Wittig olefination of I-120 afforded the corresponding α,β−unsaturated ester I-121 in good yield (80% yield). DIBAL reduction of the ester and Sharpless Asymmetric Epoxidation (SAE) 83 of the side double bond provided the desired epoxide in excellent enantioselectivity (98% ee). 67 TBDPS protection of alcohol I-123 gave I-124, which upon Finkelstein reaction, subsequent, nucleophilic attack of acetate, and hydrolysis provided I-127 (Scheme I-37). PCC reduction and Wittig olefination of alcohol I-127 provided the desired DIBAL-H, Et2O I-121 Cl 0 ºC, 77% yield HO D-DET, Ti(i-PrO)4 O O OEt I-122 TBDPSCl, Et3N Cl t-BuOOH, CH2Cl2 HO -20 ºC 72% yiled, 98% ee I-123 DMAP, CH2Cl2 92% yield NaI, acetone O TBDPSO Cl Cl reflux, 98% yield TBDPSO I-124 AcOH, AgNO3 I I-125 K2CO3, MeOH O 50 ºC, 93% yield TBDPSO O OAc H2O, 89% yield I-126 O OH TBDPSO I-127 Scheme I-37: Synthesis of alcohol I-127 α,β−unsaturated ester I-129 in moderate yield (68%). After converting the ester I-129 to 83 the required allyl alcohol I-130, the SAE reaction led to the formation of the desired diepoxide I-131 in 75% yield (97% ee), which could be cleanly separated from a 10% recovery of starting material. Benzylation of the alcohol and Sharpless Asymmetric 68 Dihydroxylation (SAD) 82 106 gave I-133, which was treated with trifluoroacetic acid to produce the THF core I-134 (Scheme I-38). Next, we protected the free diol with an acetate group to have the desired THF core for the etherification reactions. PCC, CH2Cl2 O TBDPSO I-127 EtO2C PPh3 THF, reflux 68% yield O OH 73% yield TBDPSO O H I-128 DIBAL-H, Et2O O TBDPSO I-129 0 ºC, 40% yield O EtO L-DET, Ti(i-PrO)4 O TBDPSO I-130 NaH, BnBr THF, 90% yield TBDPSO HO O t-BuOOH, CH2Cl2 OH TBDPSO O O I-132 AD-mix ! 87% yield, 95% ee OBn OH O TFA, CH2Cl2 TBDPSO 80% yield OBn TBDPSO OAc TBDPSO O O I-134 I-133 AcCl, Pyridine O OAc OBn DMAP, 80% yield I-135 Scheme I-38: Synthesis of desired THF core I-135 69 OH I-131 OH O O O OH OBn I.6 Etherification of Bis-Adjacent THF Core Our goal is to develop a quick and efficient pathway to synthesize the bis-adjacent THF core with different stereochemistries for providing a possibility for the library synthesis of ether linked analogs of acetogenins. However, before we run the library OAc TBDPSO O O OAc OBn H2 TBDPSO OAc O O OAc OH Pd/C I-136 I-135 PPh3, imidazole S.M. decomposed I2, toluene, rt Scheme I-39: Conversion of primary alcohol to iodide synthesis and install different functional groups to either side of the bis-adjacent THF core, it is important to optimize the conditions for the etherification reaction. For this purpose, we made bis THF ring I-135 to optimize the etherification reaction. The first OAc TBDPSO O O OAc OH MsCl, Et3N CH2Cl2, 0 ºC I-136 SM decomposed Scheme I-40: Attempts for conversion of primary alcohol I-136 to mesylate idea for the etherification reaction was to convert the terminal hydroxyl group after deprotection in the bis-adjacent THF core to a good leaving group such as an iodide. Then the subsequent SN2 displacement using different nucleophiles could install different functional groups in both sides of the bis-THF core. However, the conversion of hydroxyl 70 OAc TBDPSO O OAc O OH TBDPSO OBn K2CO3 O OH OBn I-137 I-135 TBSCl, Et3N, THF O TBDPSO OTBS O O OTBS OBn 77% yield H2, Pd/C 82% yield I-138 TBDPSO OTBS O O OTBS OH I-139 Scheme I-41: Synthesis of alcohol I-139 groups to iodides in substrate I-136, which was formed via hydrogenolysis of the benzyl groups in intermediate I-135, was not successful and the messy crude NMR showed that the starting material decomposed under these conditions (Scheme I-39). The mesylation of alcohol I-136 using triethylamine and mesyl chloride in dichloromethane was not successful also and the starting material decomposed. The reason can be the instability of the acyl groups under basic condition (Scheme I-40). An alternate way for the etherification was to use the bis-adjacent THF core as the nucleophile in the etherification reaction. Since acyl groups are not stable under basic conditions, the protecting groups were changed and the alcohols were protected as TBS ethers (Scheme I-41). Some of the experiments and the results for the etherification reactions are summarized in Table I-10. 71 OTBS O TBDPSO O OH OTBS I-142 Figure I-28: Silyl migration product under basic conditions With sodium hydride as the base, for the substrates I-140 and I-141 no desired products were obtained (Table I-10, entries 1 and 3). Instead, silyl migration of 1,2-diols under basic conditions occurred, which gave the secondary free alcohols as the product Table I-10: Experiments for etherification reactions OR TBDPSO O O OR OH conditionsTBDPSO OR O O OR O I 7 I-140 OMs or 7 I-141 Entry R Reagents 1 TBS I-140 2 TBS I-140 3 TBS I-141 K2CO3 NaH 4 Ac I-140 5 Ac I-141 NaH Temperature Solvent 7 Results THF I-142 acetone I-142 + SM 0 ºC to RT THF I-142 NaH 0 ºC to RT THF S.M. decomposed NaH 0 ºC to RT THF 0 ºC to RT reflux S.M. decomposed (Figure I-28). However, after changing the TBS groups to acyl groups, the same conditions decomposed the starting material (Table I-10, entries 4 and 5). Potassium 72 carbonate in refluxing acetone could not promote the reaction; after overnight stirring only I-142 along with some starting material were isolated (Table I-10, entry 2). It seems that the major problem in the failed etherification reactions is due to the protecting groups on the secondary alcohols. It is possible that the steric bulk of the protecting group on the secondary alcohols can hinder the etherification of the neighboring primary alcohol. In addition, silyl groups are not good under basic etherification conditions because they preferred to migrate from the secondary alcohols to primary alcohols. Therefore, a less hindered protecting group such as methoxy methyl (MOM) was chosen to prevent these problems. The synthesis of new bis-adjacent THF substrate I-144 was achieved via MOM protection of intermediate I-137, followed by debenzylation via hydrogenolysis in excellent yield over two steps (Scheme I-42). OH TBDPSO O O I-137 OH H2, Pd/C 86% yield TBDPSO OBn Hunig's base MOMCl TBDPSO OMOM O O OMOM OBn I-143 OMOM O OMOM O OH I-144 Scheme I-42: Synthesis of MOM-protected bis-adjacent THF core I-144 Treatment of intermediate I-144 under etherification conditions provided the desired product in low yield (Table I-11). Increasing the amount of sodium hydride and mesylate improved the yield of the etherification (Table I-11, entry 2). DMF was a better solvent under the same conditions. By changing the reactant from mesylate to iodide the yield dropped to 28% (Table I-11, entry 4). 73 At this point, it seemed that the major problem in the etherification reactions was having the protected secondary alcohols neighboring the primary alcohols (the reaction side). For solving this problem, we thought it is better to have primary alcohol one carbon further away from the protected secondary alcohol to avoid any silyl migration and low conversions. Table I-11: Etherification reactions of I-144 OMOM OMOM OMOM OMOM O O TBDPSO OH reagents TBDPSO O O O 7 conditions I-144 I-145 Entry NaH Mesylate or Iodide Solvent Temperature Yield (%) 1 2 3.0 equiv 3.0 equiv 8.0 equiv OMs 7 THF 0 ºC to reflux 32 4.0 equiv THF 0 ºC to reflux 36 4.0 equiv DMF 0 ºC to 50 ºC 40 I-141 3 8.0 equiv 4.0 I.7 General Pathway for the Synthesis of Different Analog of Center THF Core 4 8.0 equiv DMF 28 0 ºC to 50 ºC equiv of the ether linked analog of the central THF The general pathway for the synthesis core is outlined in Figure I-29. We planned to connect the two sides with the center moiety via alkyne coupling. The bis THF rings would be formed using our 1,2,n-triol cyclization methodology from intermediate I-147. 79 The tetraol I-147 could be derived from the SAD reaction82 of I-148 after reducing the triple bonds to cis or trans double 74 P1O OAc AcO !O ! ! O ! ! ! I-146 P1 O P2O P1 O OP3 I-149 + OP ! ! I OP I-150 + OP3 OH !! OH OP OH !! !! OP OH I-147 OP3 PO OP ! ! P1O I-148 OP3 I-151 Figure I-29: Retro-synthetic analysis for eher linkage analog of bis-adjacent THF core I-146 bonds. The dialkyne I-148 would be accessed by alkyne coupling with alkyl iodide I-150 derived from the commercially available 1,4-butanediol. Homoallylic protected alcohols I-149 and I-151 could also be derived from protection of 3-butyn-1-ol. The synthesis of one derivative of alkyl iodide I-150 is shown in Scheme I-43. Mono TBDPS-protection of commercially available 1,4-butanediol gave the alcohol I-152, which after Swern oxidation yielded the aldehyde I-153. Reaction of I-153 with monoethyl malonate under basic condition provided the trans ester I-154. Sharpless 82 asymmetric dihydroxylation of I-154 afforded the corresponding lactone in excellent yield and enantioselectivity (80% yield and >99% ee). LAH reduction and iodination of the primary alcohol gave I-157, which was protected as TES ethers to form iodide I-158. PMB protected homopropargyl alcohol I-159 was synthesized and subjected to iodide 75 OH TBDPSCl, imidazole HO CH2Cl2, 57% yield OH TBDPSO I-152 EtO (COCl)2, DMSO, Et3N TBDPSO CH2Cl2, 85% yield CHO I-153 OEt AD-mix ! 80% yield I-154 O 98% ee TBDPSO OH LAH, THF 78% yield OH TBDPSO OH I-156 OH TBDPSO I-157 OH OH O I-154 O Et3N, 84% yield OH TBDPSO O I-155 O I2, PPh3, CH3CN Et2O, 68% yield OTES I TESCl, Et3N TBDPSO THF, 87% yield I OTES I-158 Scheme I-43: Synthesis of alkyl iodide I-158 I-158 in a coupling reaction. Iodide I-158 decomposed under coupling conditions and no desired product was obtained. The lack of success was probably due to the instability of the TES groups under basic conditions. After converting the TES protecting groups to acetonide I-160, followed by iodination, the coupling reaction provided the desired product in 78% yield (Scheme I-44). The final stages of the synthesis of the bis THF core are shown in Scheme I-45. Deprotection of the TBDPS group followed by iodination of free alcohol provided iodide I-164. The coupling of iodide I-164 and MEM protected homopropargyl alcohol I-165 was promoted with n-butyllithium in a THF/HMPA mixture. Hydrogenation with Lindlar catalyst followed by the Sharpless asymmetric 76 OH 69% yield OH I-156 O I2, PPh3, CH3CN Et2O,70% yield O O OH Acetone, p-TsOH TBDPSO TBDPSO O I-161 TBDPSO O I-160 OH OPMB I-159 n-BuLi, HMPA I THF, 78% yield O TBDPSO I-162 OPMB Scheme I-44: Coupling of iodide I-161 with I-159 82 dihydroxylation gave the desired tetraol I-168. Construction of the bis THF unit was 79 achieved via the 1,2,n-triol cyclization mediated with BF3•OEt2 (Scheme I-45) in low yield (35% and >90% dr), producing three other undetermined products as well. One hypothesis for why this reaction only affords low yield was that the acetonide protecting group could not be successfully deprotected before cyclization in the presence of BF3•Et2O as a Lewis acid, thus cyclization of I-168 did not occur. In order to solve this problem, we changed the acetonide protecting group to TES. The newly formed 82 compound I-171 was subjected to the Sharpless asymmetric dihydroxylation 79 1,2,n-triol cyclization and to provide the desired bis THF rings in 56% yield, along with two other undetermined products (Scheme I-46). 77 O O O O TBAF, THF I2, PPh3, Et2O 76% yield HO TBDPSO CH3CN, 72% yield I-162 I-163 OPMB O O OPMB O OMEM I-165 n-BuLi, HMPA THF, 77% yield I I-164 OPMB O I-166 H2, Lindlar's cat. quinoline EtOH, 98% yield MEMO O OPMB O AD-mix ! MEMO O OPMB MEMO OPMB HO I-167 AcO BF3•Et2O, CH2Cl2 CH3C(OMe)3 35% yield >90% dr O O O MEMO OH OAc HO I-168 OPMB I-169 Scheme I-45: Synthesis of bis-THF core I-169 78 OH O MEMO O TMSOTf, CH2Cl2 OPMB 76% yield MEMO I-167 TESCl, Et3N OTES MEMO OTES OPMB AcO CH3C(OMe)3MEMO 56% yield O O MEMO OH OPMB I-170 TESO AD-mix! I-171 BF3•Et2O HO HO OH OTES HO I-172 OH OPMB OAc OPMB I-169 >90% dr Scheme I-46: Synthesis of bis-THF core I-169 I.8 Summary In conclusion, desymmetrization and etherification of the bis-adjacent THF core can be used to make ether linked analogs of acetogenins. Scheme I-46 depicts our strategy towards the synthesis of THF core. Utilization of ether linkages will enable the rapid synthesis of a library of acetogenin analogs with a variety of groups flanking the left and right side of the bis-adjacent THF core, which is very useful for the SAR study of acetogenins. 79 I.9 Experimental Section Commercially available starting materials were obtained from Aldrich or Fluka and were used without further purification. Unless otherwise mentioned, solvents were purified as follows: tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/benzophenone; methylene chloride (CH2Cl2) and toluene (PhCH3) was dried over calcium hydride (CaH2) and freshly distilled prior to use; DMF, DMSO, Et3N, and HMPA were distilled from CaH2 and stored over 4 Å molecular sieves. 4 Å molecular sieves were dried at 160 ºC under vacuum prior to use. All of the spectral data for known compounds either match those reported by Aldrich or by comparison to the literature report. 1 H NMR spectra were measured at 300, 500 or 600 MHz on a Varian Gemini-300, a Varian VXR-500 or Varian Inova-600 instrument respectively. Chemical shifts are reported relative to residual solvent (δ 7.24 ppm for CDCl3). 13 C NMR spectra were measured at 75 MHz on a Varian Gemini-300, at 125 MHz on a Varian VXR-500 or 150 MHz on a Varian Inova-600 instrument. Chemical shifts are reported relative to the central line of CDCl3 (δ 77.0 ppm). High resolution mass spectra were measured at the Michigan State University, Mass Spectrometry Laboratory. Optical rotations were measured on a Perkin-Elmer polarimeter (model 341) using a 1 mL capacity quartz cell with a 10 cm path length. Analytical thin layer chromatography (TLC) was performed using pre-coated silica 80 gel 60 F254 plates. Compounds were visualized with UV light, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH. Column chromatographic purifications were performed using Silicycle 40-60 Å, 30-75 µm silica gel. All compounds purified by chromatography were sufficiently pure for use in further experiments. GC analysis was performed using HP (6890 series) GC system equipped with an Altech SE-54, 30 m × 320 µm × 0.25 µm column. 107 (4R,5R)-Dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate In a 1-L, one-necked, round-bottomed flask fitted with a reflux condenser and a large magnetic stirring bar under argon, a mixture of L-tartaric acid (101 g, 0.673 mol), 2,2-dimethoxypropane (190 mL, 161 g, 1.54 mol), methanol (40 mL), and p-toluenesulfonic acid monohydrate (0.4 g, 2.1 mmol) is warmed on a steam bath with occasional swirling until a dark-red homogeneous solution is obtained. Additional 2,2-dimethoxypropane (95 mL, 80.5 g, 0.77 mol) and cyclohexane (450 mL) are added and the flask is fitted with a 30-cm Vigreux column and a variable reflux distilling head. The mixture is heated to reflux with internal stirring and the acetone–cyclohexane and methanol–cyclohexane azeotropes are slowly removed. Additional 2,2-dimethoxypropane (6 mL, 5.1 g, 49 mmol) is then added and the mixture heated under reflux for 15 min. After the mixture has cooled to room temperature, anhydrous potassium carbonate (1 g, 7.2 mmol) is added and the mixture is stirred until the reddish color has abated. Volatile material is removed under reduced pressure (water aspirator) and the residue is 81 fractionally distilled under vacuum to afford the product I-65 as pale-yellow oil, (108 g, 74% yield). 1 Data for I-65: H NMR (300 MHz, CDCl3) δ 5.42 (2H, s), 4.20 (6H, s), 1.32 (6H, s); 13 C NMR (75 MHz, CDCl3) δ170.0, 113.8, 76.9, 52.7, 26.2. ((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol 108 In a dry, 2-L, three-necked, round-bottomed flask equipped with a 500-mL pressure-equalized addition funnel, a reflux condenser, a thermometer, and a large magnetic stirring bar is suspended lithium aluminum hydride (36 g, 0.95 mol) in diethyl ether (600 mL) under argon. The mixture is stirred and heated to reflux for 30 min. Heating is discontinued while a solution of I-65 (123 g, 0.564 mol) in diethyl ether (300 mL) is added dropwise over 2 h. Heating is then resumed and the mixture is refluxed for an additional 3 h. The mixture is cooled to 0–5 ºC and cautiously treated with water (36 mL), 4 N sodium hydroxide solution (36 mL), and water (112 mL). The mixture is then stirred at room temperature until the gray color of unquenched lithium aluminum hydride has completely disappeared. The mixture is filtered on a Büchner funnel and the inorganic precipitate is extracted with ether in a Soxhlet apparatus. The combined ethereal extracts are dried over anhydrous magnesium sulfate and filtered, and volatile material is removed under reduced pressure (water aspirator). The residue is fractionally distilled under vacuum to afford the product I-66 as colorless oil (50 g, 55% yield). 1 Data for I-66: H NMR (300 MHz, CDCl3) δ 4.42-4.48 (2H, m), 3.80-3.83 (4H, m), 2.10 82 (2H, br.), 1.35 (6H, s); 13 C NMR (75 MHz, CDCl3) δ109.3, 78.3, 62.1, 27.0. 109 (2S,3S)-2,3-Dihydroxybutane-1,4-diyl dimethanesulfonate 1. A dry, 1-L, round-bottomed flask equipped with a magnetic stirring bar, vacuum adapter, rubber septum, and a nitrogen line is charged with 2,3-o-isopropylidene -L-threitol (25.0 g, 0.154 mol), pumped under high vacuum for 10 min, and a nitrogen atmosphere is introduced. Methylene chloride (308 mL) and pyridine (37.4 mL, 0.462 mol) are added, and the stirred solution is cooled to 0 ºC with an ice-water bath. methanesulfonyl chloride (29.8 mL, 0.385 mol) is added dropwise via a 50-mL glass syringe over a period of 10 min. After an additional 30 min, the ice-water bath is removed, and the stirred solution is allowed to warm to room temperature. After an additional 6 h a precipitate forms (pyridinium chloride); 300 mL of an aqueous saturated solution of sodium bicarbonate (NaHCO3) is added slowly, dissolving the precipitate. The solution is stirred for an additional 30 min and then transferred to a 1-L separatory funnel. The layers are separated, and the aqueous layer is extracted with methylene chloride (3 × 100 mL). The organic layers are combined, dried with anhydrous sodium sulfate, and the drying agent is removed by filtration. The solvent is removed by rotary evaporation to give a tan solid that can be used as such or recrystallized from 1:1 chloroform-diethyl ether to give the product as a crystalline white solid, 2. A 1-L, one-necked, round-bottomed flask equipped with a heating mantle, magnetic stirring bar, and a reflux condenser is charged with 2,3-o-isopropylidene-L-threitol 1,4-bismethanesulfonate (40 g, 0.126 mol), 95% ethanol (250 mL) and methanesulfonic 83 acid (0.204 mL, 3.14 mmol), and brought to a gentle reflux. The solution is refluxed for 10 h and then cooled to 0 °C with an icewater bath resulting in the formation of crystals. The crystals are collected by suction filtration, washed with cold ethanol (2 x 50 mL) and diethyl ether (2 x 50 mL), and dried in a vacuum desiccator at 60 ºC under full vacuum for 4 h to give the product as white crystals (36.0 g, 84% yield). 1 Data for I-67: H NMR (300 MHz, CDCl3) δ 4.25-4.20 (4H, m), 3.85-3.83 (2H, m), 3.25 (6H, s), 2.08 (2H, br.); 13 C NMR (75 MHz, CDCl3) δ 70.9, 68.4, 36.4. 110 (2S,2'S)-2,2'-Bioxirane A 250-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar, nitrogen line, and a 125-mL pressure-equalizing addition funnel is charged with L-threitol 1,4-bismethanesulfonate (25.0 g, 0.0898 moles) and diethyl ether (180 mL). The mixture is stirred vigorously to form a suspension, and a solution of potassium hydroxide (11.6 g, 0.207 mol) in water (35 mL) is added dropwise via the addition funnel over a period of 15 min. The clear mixture is stirred for an additional 45 min at room temperature, and the ether layer is decanted. The aqueous layer is transferred to a 500-mL separatory funnel and extracted with methylene chloride (3 x 50 mL). The combined ether and methylene chloride extracts are dried with anhydrous sodium sulfate, the sodium sulfate is removed by filtration, and the solution is concentrated to approximately 50 mL total volume by rotary evaporation. The concentrate is fractionally distilled through a 13-cm Vigreux distillation column at atmospheric pressure to give the product as a clear oil (6.8 g, 88% yield). 84 1 Data for I-68: H NMR (300 MHz, CDCl3) δ 2.90-2.85 (2H, m), 2.42-2.39 (4H, m); 13 C NMR (75 MHz, CDCl3) δ 44.5, 50.42. 3-(Benzyloxy)propan-1-ol111 To a slurry of NaH (6.1 g, 152.4 mmol) in THF (277 mL), propane-1,3-diol (10 mL, 138.55 mmol) was added at 0 ºC and stirred for 1 h while warming to rt. Benzyl bromide (17.3 mL, 145.48 mmol) was the added drop wise followed by TBAI (2.56 g, 6.93 mmol). The reaction was heated to 60 ºC for 15 h. After cooling to room temperature H2O (100 mL) was carefully added. The layers were separated, aqueous layer was extracted with Et2O (3 x 50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Monobenzyl ether I-69 was obtained as pale yellow oil (15.6, 68% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for monobenzyl ether I-69: H NMR (500 MHz, CDCl3) δ 7.37-7.30 (5H, m), 4.53 (2H, s), 3.77 (2H, t, J = 6.0 Hz), 3.66 (2H, t, J = 6.0 Hz), 2.05 (1H, br), 1.89-1.86 (2H, quin, J = 6.0 Hz); 13 C NMR (75 MHz, CDCl3) δ 137.9, 128.4, 127.7, 127.6, 73.2, 69.0, 61.5, 31.9. 3-(Benzyloxy)propanal 112 To a slurry of Oxalyl dichloride (8.7 mL, 99.9 mmol) in CH2Cl2 (250 mL) at -78 ºC, a solution of DMSO (14.2 mL, 199.8 mmol) in CH2Cl2 (83 mL) was added drop wise. After 5 min. alcohol I-69 (13.82 g, 83.25 mmol) in CH2Cl2 (83 mL) was added drop wise and after 15 min. triethyl amine (58 mL, 416.25 mmol) was added. The solution 85 stirred for 5 min and then at rt H2O (100 mL) were added. The layers were separated, aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined organic layers after drying (MgSO4) were concentrated. The product was concentrated and the crude brown oily material was purified by flash column chromatography (10% EtOAc in hexanes) to afford aldehyde I-70 as a pale yellow oil (11.74 g, 86% yield). 1 Data for aldehyde I-70: H NMR (300 MHz, CDCl3) δ 9.82 (1H, t, J = 1.7 Hz), 7.38-7.27 (5H, m), 4.55 (2H, s), 3.83 (2H, t, J = 6.0 Hz), 2.73-2.71 (2H, td, J = 6.0, 1.9 Hz); 13 C NMR (75 MHz, CDCl3) δ 201.1, 137.8, 128.4, 127.8, 127.7, 73.2, 63.8, 43.8. 113 (E)-Ethyl 5-(benzyloxy)pent-2-enoate A solution of aldehyde I-70 (6.45 g, 39.33 mmol) and (carbethoxymethylene) triphenylphosphorane (27.37 g, 78.66 mmol) in THF (450 mL) was heated to reflux for 16 h. After cooling the solution to rt, the solvent was evaporated and the crude product was purified by column chromatography (5% EtOAc in hexanes) to afford α, β-unsaturated trans-ester I-71 as a colorless oil (7.18 g, 78% yield). 1 Data for I-71: H NMR (300 MHz, CDCl3) δ 7.39-7.30 (5H, m), 7.00-6.90 (1H, m), 5.96 (1H, dd, J = 15.6, 1.3 Hz), 4.46 (2H, s), 4.24-4.19 (2H, q, J = 7.1 Hz), 3.64-3.60 (2H, m), 2.54-2.56 (2H, q, J = 6.6 Hz), 1.32 (3H, t, J = 7.1 Hz); 13 C NMR (75 MHz, CDCl3) δ 166.3, 145.5, 138.0, 128.3, 127.8, 127.6, 122.8, 72.9, 68.2, 60.1, 32.5, 14.2. (E)-5-(Benzyloxy)pent-2-en-1-ol 114 To a cold (0 ºC) solution of ester I-71 (3.63 g, 15.51 mmol) in diethyl ether (135 mL), 86 DIBAL-H (46.54 mmol, 18.61 mL of 2.5 M solution in toluene) was added under N2. After stirring for 1 h. at the same temperature, saturated potassium-sodium tartrate solution (157 mL) was added and the mixture was brought to rt. Et2O (162 mL), H2O (32.5 mL) and glycerol (7.5 mL) were added and the resultant heterogeneous mixture was stirred overnight. The two layers were then separated and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (MgSO4), concentrated and the crude product after chromatographic purification (30% EtOAc in hexanes) afforded allylic alcohol I-72 as a colorless oil (2.53 g, 85% yield). 1 Data for allylic alcohol I-72: H NMR (300 MHz, CDCl3) δ 7.38-7.37 (5H, m), 5.74 (2H, m), 4.55 (2H, s), 4.10-4.11 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 2.40 (2H, m), 2.00(1H, br); 13 C NMR (75 MHz, CDCl3) δ 138.1, 130.8, 129.0, 128.2, 127.5, 127.4, 72.9, 69.6, 63.5, 32.7. 115 (E)-(((5-Bromopent-3-en-1-yl)oxy)methyl)benzene A solution of allylic alcohol I-72 (2.31 g, 12.03 mmol) in CH2Cl2 (50 mL) was cooled to 0 ºC. To this, mesyl chloride (2.8 mL, 36.09 mmol) and triethyl amine (5.9 mL) were added and stirring was continued at the same temperature for 30 min. The reaction was quenched with H2O (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL) and combined organic layers were concentrated. The residue was taken up in DMF (50 mL) and cooled to 0 ºC. Lithium bromide (0.9 mL, 36.09 mmol) was added dropwise and allowed to stir at room temperature for 5 h. The reaction was treated with 1 M HCl 87 solution. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL). Chromatographic purification (5% EtOAc in hexanes) of the crude product obtained by concentration of the organic portion afforded I-73 (2.29 g, 75% yield). 1 Data for I-73: H NMR (300 MHz, CDCl3) δ 7.39-7.37 (5H, m), 5.82-5.65 (2H, m), 4.55 (2H, s), 4.09-4.06 (2H, m), 3.58-3.54 (2H, t, J = 6.6 Hz), 2.44-2.42 (2H, q, J = 6.3 Hz); 13 C NMR (75 MHz, CDCl3) δ 138.2, 132.7, 128.4, 128.1, 127.6, 127.5, 72.9, 69.1, 33.1, 32.5. (E)-(5-(Benzyloxy)pent-2-en-1-yl)tributylstannane To a cooled (−78 ºC) and stirred suspension of CuCN (40 mg, 0.451 mmol) in dry THF (1 mL) a solution of butyllithium in hexane (0.361 mL, 0.902 mmol) was added and the mixture was stirred for 10 min. To a slightly yellow solution of resulting organocuprate, tri-n-butyltin hydride (0.239 mL, 0.902 mmol) was added by a syringe at −78 ºC and stirred for more 10 min. A solution of allyl bromide (0.1 g, 0.392 mmol) in 0.5 mL of dry THF was added by a syringe to a solution of tributyltin cuprate in THF and o the mixture was stirred at -78 C for 5 min. The mixture was diluted with ether (15 mL), aqueous saturated ammonium chloride (5 mL) was added and the mixture was stirred for 30 min at rt. Organic layer was separated, washed with water, dried and concentrated and the crude product was isolated by column chromatography (hexane–diethyl ether, 95:5 and then hexane–ethyl acetate, 15:1) to yield I-75 in 80% yield (0.15 g). 1 Data for I-75: H NMR (300 MHz, CDCl3) δ 7.39-7.38 (5H, m), 5.82-5.65 (2H, m), 4.56 (2H, s), 3.54-3.49 (2H, t, J = 6.5 Hz), 2.44-2.42 (2H, q, J = 6.3 Hz), 2.22-2.19 (2H, m), 88 1.65-1.63 (6H, m), 1.52-1.50 (6H, m), 1.35-1.32 (6H, m), 0.94-0.91 (9H, m); 13 C NMR (75 MHz, CDCl3) δ 139.0, 129.3, 128.5, 128.1, 127.7, 127.6, 76.2, 73.1, 29.3, 27.5, 32.3, 17.9, 14.5, 9.3. 116 (E)-1,2-Diiodoethene Petroleum ether (40 mL of 35-60 ºC), iodine (7.40 g, 29.2 mmol), and alumina (25 g of Brockman I, basic) were combined. In a separate flask, calcium carbide (excess) and distilled water (excess) were added to liberate acetylene gas which was cooled in a trap filled with dry ice/acetone, and then bubbled into the reaction flask. The gas was bubbled for 120 minutes (30 minutes extra time). The reaction was then capped and stirred at room temperature overnight. In the morning, chloroform (50 mL) was added and the rxn contents were extracted using sodium metabisulfite (2 x 50 mL of a 10% aqueous solution), dried using brine (2 x 20 mL), and dried over anhydrous potassium carbonate. The solution was then filtered and concentrated (0.40 g, 5% yield). 1 Data for diiodoethylene I-76: H NMR (300 MHz, CDCl3) δ 7.43 (2H, m). 117 (E)-Dimethyl hex-3-enedioate Concentrated sulfuric acid (5.0 mL, 94 mmol) was added to a stirred suspension of trans-hydromuconic acid (30.0 g, 208 mmol) in MeOH (150 mL) and the reaction mixture refluxed under a nitrogen atmosphere for 21 h. The mixture was then allowed to cool to room temperature, and the solvent was evaporated in vacuo. The resulting residue was diluted with Et2O (80 mL) and washed successively with a saturated aqueous 89 solution of NH4Cl (2 x 33 mL), a saturated aqueous solution of NaHCO3 (2 x 33 mL), and brine (1 x 33 mL). The combined aqueous washings were extracted with Et2O (33 mL), and the combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title diester (32.5 g, 91% yield). 1 Data for diester I-77: H NMR (300 MHz, CDCl3) δ 5.72 (2H, m), 3.71 (6H, s), 3.12 (4H, d, J= 5.7 Hz); 13 C NMR (75 MHz, CDCl3) δ 171.9, 125.9, 51.8. (E)-Hex-3-ene-1,6-diol 118 To a stirred solution of 3 (15.9 g, 92.4 mmol) in anhydrous THF (60 mL) was added LiAlH4 in THF (2.0 M, 60.0 mL, 120.1 mmol) dropwise at 0 ºC. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 19 h. The reaction was quenched at 0 ºC by the successive dropwise addition of H2O (4 mL), aqueous solution of NaOH (4 M, 4 mL) and H2O (12 mL). The salt formed was filtered and washed thoroughly with THF, and the filtrate dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title diol (9.3 g, 87% yield). 1 Data for diol I-78: H NMR (300 MHz, CDCl3) δ 5.56 (2H, m), 3.68 (4H, m), 2.33 (4H, m), 1.68 (2H, s); 13 C NMR (75 MHz, CDCl3) δ 129.6, 61.7, 36.0. (E)-6-(Benzyloxy)hex-3-en-1-ol 119 To a suspension of NaH (416 mg, 10.4 mmol, 1.1 equiv) in THF (200 mL) and DMSO (44 mL), diol 4 (4.33 g, 9.45 mmol, 1.0 equiv) in THF (120 mL) was added and stirred for 0.5 h. Benzyl bromide (1.25 mL, 10.4 mmol) in THF (120 mL) was added drop wise followed by TBAI (1.75 g, 4.73 mmol). The reaction was refluxed for 15 h. 90 After cooling to room temperature H2O (200 mL) was carefully added. The layers were separated, aqueous layer was extracted with Et2O (3 x 100 mL) and the combined organic layers after drying (MgSO4) were concentrated. Mono-benzyl ether I-79 was obtained (1.01 g, 52% yield). 1 Data for mono-benzyl ether I-79: H NMR (300 MHz, CDCl3) δ 7.29-7.41 (5H, m), 5.74-5.59 (2H, m), 4.54 (2H, s), 4.16-4.14 (4H, m), 3.63 (2H, m), 3.53 (2H, m), 2.28-2.32 (4H, m), 2.07 (2H, s); 13 C NMR (75 MHz, CDCl3) δ 138.3, 130.0, 128.3, 128.1, 127.6, 127.5, 72.8, 69.8, 61.8, 36.0, 33.0. (E)-(((6-Iodohex-3-en-1-yl)oxy)methyl)benzene To a stirred solution of I-79 (2.0 g, 9.4 mmol), triphenylphosphine (5.0 g, 19.0 mmol) and imidazole (1.3 g, 19.0 mmol) in dry CH3CN/Et2O 1:2 (16.7:33.3 mL) at 0 ºC was added I2 (4.8 g, 19.0 mmol) in portions. The reaction mixture was left to stir at room temperature for 1 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 20% EtOAc–hexanes to give I-80 (2.0 g, 67% yield). 1 Data for I-80: H NMR (300 MHz, CDCl3) δ 7.29-7.39 (5H, m), 5.74-5.59 (2H, m), 4.56 (2H, s), 3.56 (2H, m), 3.20 (2H, m), 2.62 (2H, m), 2.38 (2H, m); 13 C NMR (75 MHz, CDCl3) δ138.3, 130.1, 128.2, 128.1, 127.8, 127.6, 72.8, 69.9, 36.2, 33.1, 5.5. 91 (3E,7E,11E)-1,14-Bis(benzyloxy)tetradeca-3,7,11-triene 1,2-Dibromoethane (10 µL, 5 mol%) in THF (1 mL) was added to zinc dust (200 mg, 1.17 mmol) and the suspension was refluxed for 30 min. Upon cooling the mixture to rt, TMSCl (8.5 µL, 3 mol%) and I-80 (0.2 g, 0.56 mmol) in THF (2 mL) were added and the mixture was heated at 40 ºC for 20 h after which CG analysis indicated complete consumption of I-80. The suspension was then allowed to settle at room temperature. A solution of I-78 (78 mg, 0.28 mmol) and Cl2Pd(dppf)(CH2Cl2) (11 mg, 0.015 mmol) in THF (1 mL) were added and the reaction was completed within 2 h at rt. The reaction mixture was quenched with H2O (1 mL) and extracted with Et2O. The combined organic layer was dried over MgSO4 and evaporated. The crude oil was purified by flash chromatography (hexane) to give the title compound (0.16 g, 72% yield). 1 Data for I-82: H NMR (300 MHz, CDCl3) δ 7.27-7.33 (10H, m), 5.34-5.58 (6H, m), 4.48 (4H, s), 3.00-3.50 (4H, m), 2.23-2.33 (4H, m), 1.96-2.02 (8H, m); 13 C NMR (75 MHz, CDCl3) δ 138.5, 134.9, 128.3, 127.8, 127.7, 127.5, 126.8, 126.3, 71.9, 71.0, 29.9, 29.5. (3R,4R,7R,8R,11R,12R)-1,14-Bis(benzyloxy)tetradecane-3,4,7,8,11,12-hexaol AD-mix-β (89 mg) was dissolved in 1:1 tBuOH:H2O (1 mL). To this clear, orange solution, methane sulfonamide (6 mg, 0.064 mmol) and potassium osmate (0.2 mg, 0.00064 mmol) was added and stirred until all the solids dissolved. The solution was then cooled to 0 ºC upon which triene I-82 (26 mg, 0.64 mmol) was added in one portion. The reaction was vigorously stirred for 24 h after which solid sodium sulfite (95 mg) was 92 added at the same temperature. The mixture was warmed to room temperature and stirring was continued for 45 min. EtOAc (10 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (4×10 mL), combined organic layers were dried over anhydrous Na2SO4, concentrated and the crude product was purified by column chromatography (50% EtOAc in hexanes to pure EtOAc) to yield I-83 (97 mg, 30% yield). 1 Data for tetraol I-83: H NMR (300 MHz, CDCl3) δ 7.24-7.34 (10H, m), 4.51 (4H, s), 3.63-3.71 (6H, m), 3.23 (2H, m), 3.15 (2H, m), 1.77-1.78 (4H, m), 1.45-1.57 (8H, m); 13 C NMR (125 MHz, CDCl3) δ 137.7, 128.5, 127.9, 127.7, 75.7, 73.7, 72.8, 72.6, 72.3, 31.5, 30.8, 26.6. (3E,7E,11E)-Tetradeca-3,7,11-triene-1,14-diol A solution of I-82 (0.36 g, 0.90 mmol) in THF (4 mL) was cooled to -78 ºC and liquid ammonia (10 mL) was added. An adequate amount of sodium was added in small pieces. After stirring for 45 min at 33 ºC, excess metal was consumed by careful addition of aq. NH4Cl (sat.). The resulting mixture was allowed to warm to room temperature, stirred for 2 h and then extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous MgSO4. Filtration and concentration in vacuo afforded the crude product, which was purified by a flash column chromatography (30% EtOAc in hexane) to give I-84 (0.13 g, 67% yield). 1 Data for diol I-84: H NMR (300 MHz, CDCl3) δ 5.36-5.60 (6H, m), 3.41-3.55 (4H, m), 93 2.25-2.36 (4H, m), 1.95-2.01 (8H, m); 13 C NMR (125 MHz, CDCl3) δ 133.4, 128.9, 127.5, 63.8, 31.3, 29.9, 29.3. (E)-6-((Tetrahydro-2H-pyran-2-yl)oxy)hex-3-en-1-ol 120 To a solution of DHP (0.53 mL, 5.85 mmol) and diol I-78 (0.68 g, 5.85 mmol) in CH2Cl2 (3 mL), p-TsOH.H2O (0.011 g, 0.058 mmol) was added and stirred for 4 h. H2O (100 mL) was added. The layers were separated, aqueous layer was extracted with Et2O (3×50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Mono-THP ether I-85 was obtained as pale yellow oil (0.67 g, 58% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-85: H NMR (300 MHz, CDCl3) δ 5.47-5.54 (2H, m), 4.54-4.56 (1H, m), 3.85-3.70-3.75 (2H, m), 3.57-3.63 (2H, m), 3.38-3.49 (2H, m), 2.22-2.34 (4H, m), 1.51-1.72 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 130.1, 128.1, 98.8, 66.9, 62.4, 61.7, 35.9, 33.0, 30.6, 25.4, 19.6. (E)-2-((6-Iodohex-3-en-1-yl)oxy)tetrahydro-2H-pyran 120 To a stirred solution of I-85 (0.37 g, 1.85 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and imidazole (0.25 g, 3.70 mmol) in dry CH3CN/Et2O 1:2 (5:8 mL) at 0 ºC was added I2 (0.47 g, 1.85 mmol) in portions. The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 2% EtOAc–hexanes to give I-86 (0.48 g, 84% yield). 94 1 Data for I-86: H NMR (300 MHz, CDCl3) δ 5.45-5.52 (2H, m), 4.56-4.57 (1H, m), 3.72-3.75 (2H, m), 3.40-3.45 (2H, m), 3.09-3.14 (2H, m), 2.52-2.55 (2H, m), 2.28-2.30 (2H, m), 1.49-1.72 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 130.3, 129.6, 98.7, 66.9, 62.3, 36.7, 32.9, 30.7, 25.4, 19.6, 5.7. (E)-3-Iodoprop-2-en-1-ol 121 To a solution of Cp2ZrCl2 (5.90 g, 20.31 mmol) in THF (76 mL) at 0 ºC, DIBAL-H (7.45 mL, 18.62 mmol) was added in dark and let to stir for 30 min. at 0 ºC. In another flask, propargyl alcohol (1.00 mL, 16.93 mmol) was added to DIBAL-H (8.10 mL, 20.31 mmol) solution and stir at 0 ºC for 30 min. This solution was transferred to a zirconium hydride solution by cannula. After stiring 2 h. at rt, a solution of iodine (6.50 g, 25.39 o mmol) in THF (16 mL) was added drop wise to the reaction at -78 C. After 30 min. HCl (1 mL) was added and the aqueous layer was extracted with Et2O (3×100 mL) and the combined organic layers after drying (MgSO4) were concentrated. The product was concentrated and the crude brown oily material was purified by flash column chromatography (20% EtOAc in hexanes) to afford I-87 as a pale yellow oil (2.63 g, 85% yield). 1 Data for I-87: H NMR (300 MHz, CDCl3) δ 6.70-6.77 (1H, m), 6.41-6.47 (1H, m), 4.13-4.17 (2H, m), 2.39 (2H, s); 13 C NMR (75 MHz, CDCl3) δ 144.6, 77.8, 65.1. 122 (E)-tert-Butyl((3-iodoallyl)oxy)diphenylsilane To a solution of the alcohol I-87 (2.25 g, 12.23 mmol) in DMF (34 mL), imidazole (4.16 g, 61.15 mmol) was added followed by t-butyl diphenylsilyl chloride (3.18 mL, 95 12.23 mmol) at room temperature. The reaction was stirred under N2 for 14 h after which time it was quenched by adding water (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL) to afford a crude oil which was purified by column chromatography (2% EtOAc in hexanes) providing the protected I-88 (4.12 g, 80% yield). 1 Data for I-88: H NMR (300 MHz, CDCl3) δ 7.68-7.7 (4H, m), 7.42-7.48 (6H, m), 6.61 (1H, m), 6.40 (1H, m), 4.15 (2H, m), 1.1 (9H, s); 13 C NMR (75 MHz, CDCl3) δ 144.3, 135.8, 133.6, 130.0, 128.0, 77.9, 65.6, 28.3, 19.4. tert-Butyldiphenyl(((2E,6E)-9-((tetrahydro-2H-pyran-2-yl)oxy)nona-2,6-dien-1-yl)ox y)silane To a solution of I-88 (12.7 g, 30.0 mmol) in Et2O (30 mL) was added dropwise at -78 ºC a 1.7 M solution of t-BuLi (18.8 mL, 32.0 mmol) in pentane via syringe. After stirring for 30 min at -78 ºC, a solution of flame dried ZnBr2 (6.8 g, 30.0 mmol) in THF was transferred via cannula into the reaction mixture which was then warm to 0 ºC. A solution of I-86 (6.2 g, 20.0 mmol) and PdCl2(dppf)(CH2 Cl2) (326 mg, 0.4 mmol) in THF (30 mL) were added and the reaction was completed in 2 h at rt. The reaction mixture was quenched with H2O (50 mL) and extracted with Et2O. The combined organic layers were dried over anhydrous Na2SO 4 and evaporated, the crude oil was purified by flash column chromatography (hexanes) to give the title I-89 (8.8 g, 92% yield). 1 Data for I-89: H NMR (300 MHz, CDCl3) δ 7.64-7.68 (4H, m), 7.32-7.45 (6H, m), 5.65-5.82 (4H, m), 4.57 (1H, m), 4.18-4.21 (2H, m), 3.73-3.76 (2H, m), 3.40-3.45 (2H, m), 2.06-2.10 (6H, m), 1.49-1.72 (6H, m), 1.04 (9H, m). 96 (3E,7E)-9-((tert-Butyldiphenylsilyl)oxy)nona-3,7-dien-1-ol A solution of I-89 (16.2 g, 33.9 mmol) and 3M aq. HCI (22.6 mL, 67.8 mrnol) in THF (125 mL) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and basified with 2M aq. KOH (until pH=10). The aq. solution was extracted with EtOAc (3x50 rnL) and the organic phases were combined, dried over K2CO3, filtered and concentrated in vacuo to afford a yellow oil which slowly crystallised. Flash chromatography (30% EtOAc in hexanes) yielded I-90 (12.3 g, 92% yield). 1 Data for I-90: H NMR (300 MHz, CDCl3) δ 7.64-7.68 (4H, m), 7.33-7.45 (6H, m), 5.65-5.82 (4H, m), 4.26-4.28 (2H, m), 3.72-3.75 (2H, m), 2.05-2.13 (6H, m), 1.51 (1H, br. s), 1.04 (9H, m). tert-Butyl(((2E,6E)-9-iodonona-2,6-dien-1-yl)oxy)diphenylsilane To a stirred solution of I-90 (0.73 g, 1.85 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and imidazole (0.25 g, 3.70 mmol) in dry CH3CN/Et2O 1:2 (5:8 mL) at 0 ºC was added I2 (0.47 g, 1.85 mmol) in portions. The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 2% EtOAc–hexanes to give I-91 (0.74 g, 80% yield). 1 Data for I-91: H NMR (300 MHz, CDCl3) δ 7.64-7.68 (4H, m), 7.33-7.45 (6H, m), 5.66-5.80 (4H, m), 4.26-4.28 (2H, m), 3.16-3.20 (2H, m), 2.05-2.20 (6H, m), 1.03 (9H, m). 97 (6E,10E,14E)-2,2,19,19-Tetramethyl-3,3,18,18-tetraphenyl-4,17-dioxa-3,18-disilaicos a-6,10,14-triene To a solution of I-88 (1.5 g, 3.0 mmol) in Et2O (3 mL) was added dropwise at -78 ºC a 1.7 M solution of t-BuLi (1.9 mL, 3.2 mmol) in pentane via syringe. After stirring for 30 min at -78 ºC, a solution of flame dried ZnBr2 (0.7 g, 3.0 mmol) in THF was transferred via cannula into the reaction mixture which was then warm to 0 ºC. A sulution of I-91 (0.6 g, 2.0 mmol) and PdCl2(dppf)(CH2Cl2) (3.26 mg, 0.04 mmol) in THF (3 mL) were added and the reaction was completed in 2 h at rt. The reaction mixture was quenched with H 2 O (5 mL) and extracted with Et2O. The combined organic layers were dried over Na2 SO 4 and evaporated, the crude oil was purified by flash column chromatography (hexanes) to give the title I-92 (0.10 g, 78% yield). 1 Data for I-92: H NMR (300 MHz, CDCl3) δ 7.73 (8H, m), 7.44-7.45 (12H, m), 5.48-5.79 (6H, m), 4.20 (4H, m), 2.02-2.12 (8H, m), 1.10 (18H, m). 117 7-Oxabicyclo[4.1.0]hept-3-ene To a solution of 1,4-cyclohexadiene (5.00 g, 62.40 mmol) in H2O (3 mL) and CH2Cl2 (450 mL) was added mCPBA (10.55 g, 61.15 mmol) and K2HPO4 (13.95 g, 61.15 mmol) and stirring was continued at rt for 18 h. The reaction was quenched with H2O (50 mL) and washed with NaHCO3 (sat.), Na2SO3 (5%), NaHCO3 (sat.), H2O and brine. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL) and combined organic layers were concentrated to afforded I-93 (4.07 g, 68% yield). 98 1 Data for I-93: H NMR (300 MHz, CDCl3) δ 5.42 (2H, m), 3.22 (2H, m) , 2.45-2.52 (4H, m); 13 C NMR (125 MHz, CDCl3) δ 121.5, 50.8, 24.9. 123 (Z)-Hex-3-enedial Into CH2Cl2 (10 mL) and H2O (50 mL) were added under stirring sequentially I-93 (2.50 g, 26.00 mmol), followed by H5IO6 (5.87 g, 25.74 mmol). After stirring for 3.5 h. o at 0 C, brine (50 mL) was added to the residue. The aqueous layer was extracted with EtOAc (3 x 50 mL) and washed with Na2SO3 (sat.). to afford crude oil which was purified by column chromatography (5% EtOAc in hexanes) providing I-94 (2.41 g, 83% yield). 1 Data for I-94: H NMR (300 MHz, CDCl3) δ 9.67 (2H, s), 5.89 (2H, m), 3.18-3.21 (4H, m); 13 C NMR (75 MHz, CDCl3) δ 198.3, 123.5, 42.4. (Z)-Hex-3-ene-1,6-diol 117 To a solution of I-94 (2.41 mL, 21.49 mmol) in MeOH (107 mL) at 0 ºC, NaBH4 (2.44 g, 64.48 mmol) was added and stirred for 4 h. at rt. NH4Cl (sat.) (100 mL) was added. The layers were separated, aqueous layer was extracted with Et2O (3×50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Diol I-95 was obtained (1.94 g, 78% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-95: H NMR (300 MHz, CDCl3) δ 5.60 (2H, m), 3.69-3.71 (4H, m), 2.38-2.39 (4H, m); 13 C NMR (125 MHz, CDCl3) δ 128.7, 61.5, 30.4. 99 (Z)-6-((Tetrahydro-2H-pyran-2-yl)oxy)hex-3-en-1-ol 120 To a solution of DHP (0.53 mL, 5.85 mmol) and diol (0.68 g, 5.85 mmol) in CH2Cl2 (3 mL), p-TsOH.H2O (0.011 g, 0.058 mmol) was added and stirred for 4 h. H2O (100 mL) was added. The layers were separated, aqueous layer was extracted with Et2O (3×50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Mono-THP ether I-96 was obtained as pale yellow oil (0.65 g, 56% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-96: H NMR (300 MHz, CDCl3) δ 5.50-5.57 (2H, m), 4.56-4.57 (1H, m), 3.77-3.83 (2H, m), 3.59-3.65 (2H, m), 3.39-3.49 (2H, m), 2.30-2.39 (2H, m), 2.34-2.36 (2H, m), 1.95-1.99 (1H, s), 1.49-1.67 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 129.5, 127.5, 98.8, 66.7, 62.2, 61.9, 30.6, 30.5, 27.9, 25.3, 19.5. (Z)-2-((6-Iodohex-3-en-1-yl)oxy)tetrahydro-2H-pyran 124 To a stirred solution of I-96 (0.37 g, 1.85 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and imidazole (0.25 g, 3.70 mmol) in dry CH3CN/Et2O 1:2 (5:8 mL) at 0 ºC was added I2 (0.47 g, 1.85 mmol) in portions. The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 2% EtOAc–hexanes to give I-97 (0.46 g, 80% yield). 100 1 Data for I-97: H NMR (300 MHz, CDCl3) δ 5.51-5.58 (2H, m), 4.62-4.63 (1H, m), 3.78-3.90 (2H, m), 3.46-3.51 (2H, m), 3.16-3.20 (2H, d, J= 14.4 Hz), 2.59-2.61 (2H, m), 2.34-2.36 (2H, m), 1.55-1.74 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 129.3, 127.6, 98.7, 66.8, 62.1, 36.0, 32.1, 30.7, 25.4, 19.6, 5.6. 2-(Prop-2-yn-1-yloxy)tetrahydro-2H-pyran 125 To a solution of DHP (0.53 mL, 5.85 mmol) and propargyl alcohol (0.33 g, 5.85 mmol) in CH2Cl2 (3 mL), p-TsOH.H2O (0.011 g, 0.058 mmol) was added and stirred for 4 h. H2O (100 mL) was added. The layers were separated, aqueous layer was extracted with Et2O (3 x 50 mL) and the combined organic layers after drying (MgSO4) were concentrated. THP ether I-100 was obtained as pale yellow oil (0.64 g, 78% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-100: H NMR (300 MHz, CDCl3) δ 4.85-4.87 (1H, t, J= 3.3 Hz), 4.28-4.31 (2H, dd, J= 4.5 Hz, 2.4), 3.87 (1H, m), 3.59 (1H, m), 2.45 (1H, t, J= 2.4 Hz), 1.57-1.81 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 96.7, 79.7, 73.9, 61.9, 53.9, 30.1, 25.2, 18.9. 2-(Pent-4-en-2-yn-1-yloxy)tetrahydro-2H-pyran A mixture of Pd(PPh3)2Cl2 (34 mg, 0.048 mmol) and CuI (57 mg, 0.3 mmol) were dissolved in i-PrNH2:THF (7.5 mL) under argon. After cooling to –10 ºC, I-100 (2.1 g, 15 mmol) and vinyl bromide (20 mL, 1.0 M in THF, 20 mmol) were added. The reaction mixture was kept stirring at rt for 20 h. The reaction mixture was poured into H2O, and extracted with Et2O. The organic phase was washed with HCl (1 M), dried with MgSO4 and concentrated to give crude compound. The crude was purified by column 101 chromatography (hexanes) over silica gel to give pure product I-101 as colorless oil (1.5 g, 61%yield). 1 Data for I-101: H NMR (300 MHz, CDCl3) δ 5.81-5.90 (1H, m), 5.66-5.71 (1H, m), 5.51-5.54 (1H, m), 4.86 (1H, m), 4.48, (2H, m), 3.84-3.91 (1H, m), 3.54-3.59 (1H, m), 1.43-1.91 (6H, m); 13 C NMR (75 MHz, CDCl3) δ127.5, 116.5, 96.8, 87.8, 84.4, 60.2, 51.5. 30.2, 25.5, 18.9. 125 (E)-3-Iodoallyl pivalate To a solution of the alcohol I-87 (0.50 g, 2.71 mmol) in CH2Cl2 (25 mL) at 0 ºC, pyridine (0.88 mL, 10.84 mmol) was added followed by PivCl (0.67 mL, 5.43 mmol). The reaction was stirred under N2 for 3 h at rt and then the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexanes) providing I-98 (0.58 g, 81% yield). 1 Data for I-98: H NMR (300 MHz, CDCl3) δ 6.59-6.64 (1H, m), 6.41-6.45 (1H, m), 4.44-4.46 (2H, d, J= 4.5 Hz), 1.19 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 178.3, 135.1, 76.5, 61.0, 38.9, 27.3. (E)-Hexa-3,5-dienoic acid 126 Isopropylamine (2.26 g, 38.3 mmol) in THF (40 mL) was stirred under N2 in a dry ice-acetone bath. Added dropwise was n-butyllithium in hexanes (20.1 mL, 38.3 mmol, 1.9 M in hexanes). The resulting slightly yellow solution was stirred at this temperature for 40 min. The conjugated acid (3.6 g, 32.14 mmol) in THF (15 mL) was added 102 dropwise over 1 h. The temperature did not rise past -10 ºC during addition. Stirring was continued for 3 h. The orange enolate solution was warmed to rt and poured into H2O (75 mL) and separated. The aqueous layer was washed with (1 x 50 mL) of ether, and the aqueous layer was then acidified to pH 3 with 3 M HCl. Extraction with ether (4 x 50 mL) and drying (MgSO4) gave after removal of solvent in vacuo (3.6 g, quantitative yield) of 1 the deconjugated acid. Data for I-102: H NMR (300 MHz, CDCl3) δ 6 6.46 (1H, dd, J = 10.7, 14.9 Hz), 6.14 (1H, d, J = 6.3 Hz), 5.63 (1H, dd, J = 7.2, 14.9 Hz), 5.19 (1H, dd, J = 6.3, 10.7 Hz), 4.92 (2H, s), 3.73 (2H, m) 3.55 (2H, m), 3.38 (3H, s), 3.15 (2H, d, J = 7.2 Hz); 13 CNMR (75 MHz, CDCl3) δ 177.44, 143.58, 127.03, 121.71,108.09, 95.86, 71.81, 67.74, 59.25, 38.29. (E)-Hexa-3,5-dien-1-ol 127 A solution of I-102 (0.63 g, 5.64 mmol) in diethyl ether (3 mL) is added dropwise over 2 h to a suspended lithium aluminum hydride (0.36 g, 9.50 mmol) in diethyl ether (6 mL) under argon. The mixture is refluxed for an additional 3 h. The mixture is cooled to 0–5 ºC and cautiously treated with water (0.4 mL), 4 N sodium hydroxide solution (0.4 mL), and water (1 mL). The mixture is then stirred at room temperature until the gray color of unquenched lithium aluminum hydride has completely disappeared. The mixture is filtered on a Büchner funnel and the inorganic precipitate is extracted with ether in a Soxhlet apparatus. The combined ethereal extracts are dried over anhydrous magnesium sulfate and filtered, and volatile material is removed under reduced pressure (water aspirator). The residue is fractionally distilled under vacuum to afford the product I-103 103 as colorless oil (0.46 g, 84% yield). 1 Data for I-103: H NMR (300 MHz, CDCl3) δ 6.33 (1H, ddd, J = 16.8, 10.4, 10.4 Hz), 6.16 (1H, dd, J = 15.2, 10.4 Hz), 5.68 (1H, dt, J = 15.2, 7.2 Hz), 5.14 (1H, d, J =16.8 Hz), 5.02 (1H, d, J = 10.0 Hz), 3.69 (2H, t, J = 6.4 Hz), 2.36 (2H, dt, J = 6.4, 6.4 Hz), 1.50 (1H, br s); 13 C NMR (75 MHz, CDCl3) δ 136.8, 133.7, 130.6, 115.9, 61.9, 35.9. (E)-2-(Hexa-3,5-dien-1-yloxy)tetrahydro-2H-pyran To a solution of DHP (0.53 mL, 5.85 mmol) and alcohol I-103 (0.57 g, 5.85 mmol) in CH2Cl2 (3 mL), p-TsOH•H2O (0.011 g, 0.058 mmol) was added and stirred for 4 h. H2O (100 mL) was added. The layers were separated, aqueous layer was extracted with Et2O (3 x 50 mL) and the combined organic layers after drying (MgSO4) were concentrated. THP ether I-104 was obtained as pale yellow oil (0.95 g, 90% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-104: H NMR (300 MHz, CDCl3) δ 6.35 (1H, ddd, J = 16.8, 10.4, 10.4 Hz), 6.17 (1H, dd, J = 15.2, 10.4 Hz), 5.66 (1H, dt, J = 15.2, 7.2 Hz), 5.14 (1H, d, J =16.8 Hz), 5.02 (1H, d, J = 10.0 Hz), 4.85-4.86 (1H, t, J= 3.3 Hz), 3.85 (2H, m), 3.75 (2H, t, J = 6.4 Hz), 2.37 (2H, dt, J = 6.4, 6.4 Hz), 1.57-1.81 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 136.8, 133.7, 130.6, 115.9, 97.1, 61.9, 54.1, 35.9, 30.2, 25.3, 19.0. 3-(Benzyloxy)propan-1-ol 111 To a slurry of NaH (6.1 g, 152.4 mmol) in THF (277 mL), propane-1,3-diol (10 mL, 138.55 mmol) was added at 0 ºC and stirred for 1 h while warming to rt. Benzyl bromide (17.3 mL, 145.48 mmol) was the added drop wise followed by TBAI (2.56 g, 6.93 mmol). 104 The reaction was heated to 60 ºC for 15 h. After cooling to room temperature H2O (100 mL) was carefully added. The layers were separated, aqueous layer was extracted with Et2O (3 x 50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Monobenzyl ether 6 was obtained as pale yellow oil (20 g, 87% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for monobenzyl ether I-107: H NMR (500 MHz, CDCl3) δ 7.37-7.30 (5H, m), 4.53 (2H, s), 3.77 (2H, t, J = 6.0 Hz), 3.66 (2H, t, J = 6.0 Hz), 2.05 (1H, br), 1.89-1.86 (2H, quin, J = 6.0 Hz); 13 C NMR (75 MHz, CDCl3) δ 137.8, 128.0, 127.5, 127.4, 72.9, 68.8, 61.1, 32.1. 113 (E)-Ethyl 5-(benzyloxy)pent-2-enoate 1. To a slurry of oxalyl chloride (8.7 mL, 99.9 mmol) in CH2Cl2 (250 mL) at -78 ºC, a solution of DMSO (14.2 mL, 199.8 mmol) in CH2Cl2 (83 mL) was added drop wise. After 5 min alcohol I-107 (13.82 g, 83.25 mmol) in CH2Cl2 (83 mL) was added drop wise and after 15 min triethyl amine (58 mL, 416.25 mmol) was added. The solution stirred for 5 min and then at rt H2O (100 mL) was added. The layers were separated, aqueous layer was extracted with CH2Cl2 (3×100 mL) and the combined organic layers after drying (MgSO4) were concentrated. The crude brown oily material was purified by flash column chromatography (10% EtOAc in hexanes) to afford aldehyde (94% yield) as a pale yellow oil. 2. A solution of aldehyde (6.45 g, 39.33 mmol) and (carbethoxymetylene) triphenylphosphorane (27.37 g, 78.66 mmol) in THF (450 mL) was heated to reflux for 105 16 h. After cooling the solution to rt, the solvent was evaporated and the crude product was purified by column chromatography (5% EtOAc in hexanes) to afford α, β-unsaturated trans-ester I-108 as a colorless oil (17.33 g, 89% yield). 1 Data for α, β-unsaturated trans-ester I-108: H NMR (300 MHz, CDCl3) δ 7.39-7.30 (5H, m), 7.00-6.90 (1H, m), 5.96 (1H, dd, J = 15.6, 1.3 Hz), 4.46 (2H, s), 4.24-4.19 (2H, q, J = 7.1 Hz), 3.64-3.60 (2H, m), 2.54-2.56 (2H, q, J = 6.6 Hz), 1.32 (3H, t, J = 7.1 Hz); 13 C NMR (75 MHz, CDCl3) δ 166.3, 145.5, 138.0, 128.3, 127.8, 127.6, 122.8, 72.9, 68.2, 60.1, 32.5, 14.2. (E)-5-(Benzyloxy)pent-2-en-1-ol 114 To a cold (0 ºC) solution of ester I-108 (3.63 g, 15.51 mmol) in diethyl ether (135 mL), DIBAL-H (46.54 mmol, 18.61 mL of 2.5 M solution in toluene) was added under N2. After stirring for 1 h. at the same temperature, saturated potassium-sodium tartrate solution (157 mL) was added and the mixture was brought to rt. Et2O (162 mL), H2O (32.5 mL) and glycerol (7.5 mL) were added and the resultant heterogeneous mixture was stirred overnight. The two layers were then separated and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (MgSO4), concentrated and the crude product after chromatographic purification (30% EtOAc in hexanes) afforded allylic alcohol I-109 as a colorless oil (2.97 g, quantitative yield). 1 Data for allylic alcohol I-109: H NMR (300 MHz, CDCl3) δ 7.38-7.37 (5H, m), 5.74 106 (2H, m), 4.55 (2H, s), 4.10-4.11 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 2.40 (2H, m), 2.00 (1H, br); 13 C NMR (75 MHz, CDCl3) δ 138.3, 131.0, 129.1, 128.3, 127.6, 127.5, 72.9, 69.6, 63.5, 32.6. (E)-((5-(Benzyloxy)pent-2-en-1-yl)sulfonyl)benzene 1. A solution of allylic alcohol I-109 (2.31 g, 12.03 mmol) in CH2Cl2 (50 mL) was cooled to 0 ºC. To this, mesyl chloride (2.8 mL, 36.09 mmol) and triethyl amine (5.9 mL) were added and stirring was continued at the same temperature for 30 min. The reaction was quenched with H2O (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL) and combined organic layers were concentrated. The residue was taken up in DMF (50 mL) and cooled to 0 ºC. Lithium bromide (0.9 mL, 36.09 mmol) was added dropwise and allowed to stir at room temperature for 5 h. The reaction was treated with 1 M HCl solution. The organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL). Chromatographic purification (5% EtOAc in hexanes) of the crude product obtained by concentration of the organic portion afforded the desired product. 2. Into anhydrous DMF (24 mL) were added under stirring sequentially (2.89 g, 17.02 mmol) of mesylated alcohol, followed by sodium benzenesufinate (4.19 g, 25.53 mmol). After stirring for 1 h at 0 ºC, brine (100 mL) was added to the residue. The aqueous layer was extracted with CH2Cl2 (3×50 mL) to afford crude oil which was purified by column chromatography (3% EtOAc in hexanes) providing I-110 (2.50 g, 66% yield). 107 1 Data for I-110: H NMR (300 MHz, CDCl3) δ 7.81-7.84 (2H, m), 7.22-7.62 (7H, m), 7.05-7.07 (1H, m), 5.45-5.58 (2H, m), 4.29 (2H, s), 3.73-3.75 (2H, d, J = 6 Hz), 3.37-3.41 (2H, t, J = 6.3 Hz), 2.27-2.33 (2H, m). 107 (4R,5R)-Dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate In a 1-L, one-necked, round-bottomed flask fitted with a reflux condenser and a large magnetic stirring bar under argon, a mixture of L-tartaric acid (101 g, 0.673 mol), 2,2-dimethoxypropane (190 mL, 161 g, 1.54 mol), methanol (40 mL), and p-toluenesulfonic acid monohydrate (0.4 g, 2.1 mmol) is warmed on a steam bath with occasional swirling until a dark-red homogeneous solution is obtained. Additional 2,2-dimethoxypropane (95 mL, 80.5 g, 0.77 mol) and cyclohexane (450 mL) are added and the flask is fitted with a 30-cm Vigreux column and a variable reflux distilling head. The mixture is heated to reflux with internal stirring and the acetone–cyclohexane and methanol–cyclohexane azeotropes are slowly removed. Additional 2,2-dimethoxypropane (6 mL, 5.1 g, 49 mmol) is then added and the mixture is heated under reflux for 15 min. After the mixture has cooled to room temperature, anhydrous potassium carbonate (1 g, 7.2 mmol) is added and the mixture is stirred until the reddish color has abated. Volatile material is removed under reduced pressure (water aspirator) and the residue is fractionally distilled under vacuum to afford the product I-111 as pale-yellow oil, (104 g, 71% yield). Data for I-111: 1H NMR (300 MHz, CDCl3) δ 5.42 (2H, s), 4.20 (6H, s), 1.32 (6H, s); 13C NMR (75 MHz, CDCl3) δ 170.0, 113.8, 76.9, 52.7, 26.2. 108 ((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol 108 In a dry, 2-L, three-necked, round-bottomed flask equipped with a 500-mL pressure-equalized addition funnel, a reflux condenser, a thermometer, and a large magnetic stirring bar is suspended lithium aluminum hydride (36 g, 0.95 mol) in diethyl ether (600 mL) under argon. The mixture is stirred and heated to reflux for 30 min. Heating is discontinued while a solution of I-111 (123 g, 0.564 mol) in diethyl ether (300 mL) is added dropwise over 2 h. Heating is then resumed and the mixture is refluxed for an additional 3 h. The mixture is cooled to 0–5 ºC and cautiously treated with water (36 mL), 4 N sodium hydroxide solution (36 mL), and water (112 mL). The mixture is then stirred at room temperature until the gray color of unquenched lithium aluminum hydride has completely disappeared. The mixture is filtered on a Büchner funnel and the inorganic precipitate is extracted with ether in a Soxhlet apparatus. The combined ethereal extracts are dried over anhydrous magnesium sulfate and filtered, and volatile material is removed under reduced pressure (water aspirator). The residue is fractionally distilled under vacuum to afford the product I-112 as colorless oil (87 g, 96% yield). 1 Data for I-112: H NMR (300 MHz, CDCl3) δ 4.42-4.48 (2H, m), 3.80-3.83 (4H, m), 2.10 (2H, br.), 1.35 (6H, s); 13 C NMR (75 MHz, CDCl3) δ 109.3, 78.3, 62.1, 27.0. ((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)-bis(4-methylbenzenesul fonate) 128 A dry, 1-L, round-bottomed flask equipped with a magnetic stirring bar, vacuum adapter, rubber septum, and a nitrogen line is charged with 2,3-o-isopropylidene 109 -L-threitol (25.0 g, 0.154 mol), pumped under high vacuum for 10 min, and a nitrogen atmosphere is introduced. Methylene chloride (308 mL) and pyridine (37.4 mL, 0.462 mol) are added, and the stirred solution is cooled to 0 ºC with an ice-water bath. p-Tosyl chloride (73.1 g, 0.385 mol) is added dropwise via a 50-mL glass syringe over a period of 10 min. After an additional 30 min, the ice-water bath is removed, and the stirred solution is allowed to warm to room temperature. After an additional 6 h a precipitate forms (pyridinium chloride); 300 mL of an aqueous saturated solution of sodium bicarbonate (NaHCO3) is added slowly, dissolving the precipitate. The solution is stirred for a further 30 min and then transferred to a 1-L separatory funnel. The layers are separated, and the aqueous layer is extracted with methylene chloride (3 x 100 mL). The organic layers are combined, dried with anhydrous sodium sulfate, and the drying agent is removed by filtration. The solvent is removed by rotary evaporation to give a tan solid that can be used as such or recrystallized from 1:1 chloroform-diethyl ether to give the product as a crystalline white solid (55.0 g, 76% yield). 1 Data for I-113: H NMR (300 MHz, CDCl3) δ 7.33–7.81 (8H, m), 4.10 (4H, m), 4.01 (2H, m), 2.46 (6H, s), 1.29 (6H, s); 13 C NMR (75 MHz, CDCl3) δ 145.4, 132.1, 130.1, 128.1, 110.9, 75.1, 68.5, 26.8, 22.8. 129 (4R,5R)-4,5-Bis(iodomethyl)-2,2-dimethyl-1,3-dioxolane To a stirred solution of I-113 (5.95 g, 12.67 mol), in acetone (30 mL) was added NaI (11.40 g, 76.05 mol). The reaction mixture was left to stir at room temperature for 12 h. 110 The mixture was diluted with water and Et2O. The aqueous layer was extracted with Et2O (3 x 50 mL) to afford I-114 (4.20 g, 87% yield). 1 Data for I-114: H NMR (300 MHz, CDCl3) δ 3.82 (2H, m), 3.36 (4H, s), 1.44 (6H, s); 13 CNMR (CDCl3) δ 109.8, 79.7, 27.4, 6.2. ((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol 130 To a slurry of NaH (6.1 g, 152.4 mmol) in THF (277 mL), diol I-112 (22.44 g, 138.55 mmol) was added at 0 ºC and stirred for 1 h while warming to rt. Benzyl bromide (17.3 mL, 145.48 mmol) was the added drop wise followed by TBAI (2.56 g, 6.93 mmol). The reaction was heated to 60 ºC for 15 h. After cooling to room temperature H2O (100 mL) was carefully added. The layers were separated, aqueous layer was extracted with Et2O (3×50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Monobenzyl ether I-115 was obtained as pale yellow oil (22.0 g, 63% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-115: H NMR (300 MHz, CDCl3) δ 7.25 (5H, m), 4.52 (2H, s), 3.99 (1H, m), 3.88 (1H, m), 3.63 (3H, m), 3.49 (1H, dd, J = 9.9, 5.5 Hz), 2.15 (1H, br s), 1.35 (6H, s); 13 C NMR (75 MHz, CDCl3) δ 27.1, 62.6, 70.6, 73.9, 76.8, 79.9, 109.5, 128.0, 128.1, 128.7, 137.8. 131 (4S,5R)-4-((Benzyloxy)methyl)-5-(iodomethyl)-2,2-dimethyl-1,3-dioxolane 1. A dry, 1-L, round-bottomed flask equipped with a magnetic stirring bar, vacuum adapter, rubber septum, and a nitrogen line is charged with I-115 (38.9 g, 0.154 mol), 111 pumped under high vacuum for 10 min, and a nitrogen atmosphere is introduced. CH2Cl2 (308 mL) and pyridine (37.4 mL, 0.462 mol) are added, and the stirred solution is cooled to 0 ºC with an ice-water bath. p-Tosyl chloride (73.1 g, 0.385 mol) is added dropwise via a 50-mL glass syringe over a period of 10 min. After an additional 30 min, the ice-water bath is removed, and the stirred solution is allowed to warm to room temperature. After an additional 6 h a precipitate forms (pyridinium chloride); 300 mL of an aqueous saturated solution of sodium bicarbonate (NaHCO3) is added slowly, dissolving the precipitate. The solution is stirred for a further 30 min and then transferred to a 1-L separatory funnel. The layers are separated, and the aqueous layer is extracted with methylene chloride (3 x 100 mL). The organic layers are combined, dried with anhydrous sodium sulfate, and the drying agent is removed by filtration. The solvent is removed by rotary evaporation to give the product. 2. To a stirred solution of tosylated alcohol (5.14 g, 12.67 mol), in acetonitrile (30 mL) was added NaI (11.40 g, 76.05 mol). The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with water and Et2O. The aqueous layer was extracted with Et2O (3 x 50 mL). I-116 (50.7 g, 91% yield) was obtained after chromatographic purification (10% EtOAc in hexanes). 1 Data for I-116: H NMR (300 MHz, CDCl3) δ 7.38-7.25 (5H, m), 4.58 (2H, s), 3.96 (1H, dt, J = 7.2, 4.8 Hz), 3.86 (1H, dt, J = 7.5, 5.4 Hz), 3.65 (1H, d, J = 1.8 Hz), 3.64 (1H, d, J = 1.5 Hz), 3.34 (1H, dd, J = 10.8, 5.1 Hz), 3.24 (1H, dd, J = 10.8, 5.1 Hz), 1.46 (3H, s), 1.41 (3H, s); 13 C NMR (75 MHz, CDCl3) δ 137.6, 128.3, 127.6, 127.5, 109.6, 79.9, 73.4, 112 70.3, 30.8, 27.2, 27.1, 6.3. 2-(Pent-4-yn-1-yloxy)tetrahydro-2H-pyran 13 To a stirred solution of 5-hydroxypentynol (4.5 g, 53.5 mmol) in CH2CI2 (100 mL) at 0 ºC under an argon atmosphere was added DHP (4.9 mL, 53.6 mmol). A few drops of concentrated HCl were added to catalyze the reaction. The reaction was allowed to slowly return to rt and stir overnight. Water was added and the organic layer was separated from the aqueous fraction. The aqueous fraction was extracted three times with CH2Cl2. The combined organic material was washed with saturated brine then dried over anhydrous MgSO4. The solvent was removed by rotary evaporation to give the product in 67% yield (6.0 g). 1 Data for I-117: H NMR (300 MHz, CDCl3) δ 4.52-4.58 (1H, m), 3.72-3.85 (2H, m), 3.35-3.48 (2H, m), 2.20-2.28 (2H, m), 1.87 (1H, s), 1.68-1.78 (2H, t), 1.40-1.65 (6H, m); 13 C NMR (75 MHz, CDCl3) δ 98.7, 83.8, 68.3, 65.7, 62.0, 30.6, 28.6, 25.4, 19.4, 15.2. 8-Chlorooct-4-yn-1-ol 133 A solution composed of 5-tetrahydropyranyl-l-pentyne I-117 (7.9 g, 47.0 mmol) in THF (80 mL) was placed under an argon atmosphere at 0 ºC. To this solution n-BuLi (24.7 mL, 47.0 mmol, 1.9 M in hexanes) were added dropwise. The mixture was stirred for five minutes, followed by addition of HMPA (7.8 mL). The temperature was allowed to slowly warm to rt and stirring was continued for 30 min. The reaction was chilled to -78 ºC and 1,3-chloroiodopropane (5.5 mL, 51.2 mmol) was added. The reaction was allowed to slowly reach rt and to stir for 24 hours. Water was used to quench the reaction, 113 followed by extraction of the aqueous layer three times with hexane. The combined organic extracts were washed with saturated brine and then saturated sodium bicarbonate. The organic extracts were dried over MgSO4 and solvent was removed via rotary evaporation to give the crude product. The crude product was placed in THF / HCl (1:l, 25 mL, 5% aq.). solution and heated to reflux for 8 hours. After the reaction had cooled to rt, the THF was removed by rotary evaporation, and the water solution was extracted three times with diethyl ether. The extracts were dried over MgSO4, and the solvent was removed via rotary evaporation to give product I-118 in 90% yield (6.7 g). 1 Data for I-118: H NMR (300 MHz, CDCl3) δ 3.70-3.76 (2H, m), 3.60-3.64 (2H, m), 2.23-2.35 (4H, m), 1.86-1.93 (2H, m), 1.70-1.76 (2H, m), 1.42-1.51 (1H, m); 13 C NMR (75 MHz, CDCl3) δ 80.5, 78.9, 62.0, 43.7, 31.8, 31.7, 16.2, 15.4. (Z)-8-Chlorooct-4-en-1-ol The titled compound I-119 was prepared by hydrogenation of I-118 (9.6 g, 60 mmol) in dry methanol (30 mL) in the presence of Lindlar catalyst (1.03 g) under 1 atm of H2 at room temperature. The reaction mixture was filtered with suction through a pad of celite. The filter cake was washed several times with diethyl ether. This mixture was concentrated and alcohol I-119 was obtained as a pale yellow oil (8.8 g, 91% yield) after chromatographic purification (30% EtOAc in hexanes). 1 Data for I-119: H NMR (300 MHz, CDCl3) δ 5.34-5.41 (2H, m), 3.60-3.63 (2H, m), 3.48-3.53 (2H, d, J = 6.6 Hz), 2.08-2.19 (4H, m), 1.79-1.87 (2H, m), 1.58-1.65 (2H, m); 114 13 C NMR (75 MHz, CDCl3) δ 131.0, 128.8, 62.8, 44.9, 32.9, 32.7, 24.7, 23.9. (Z)-8-Chlorooct-4-enal To a slurry of oxalyl chloride (8.7 mL, 99.9 mmol) in CH2Cl2 (250 mL) at -78 ºC, a solution of DMSO (14.2 mL, 199.8 mmol) in CH2Cl2 (83 mL) was added drop wise. After 5 min alcohol I-119 (13.49 g, 83.25 mmol) in CH2Cl2 (83 mL) was added drop wise and after 15 min triethyl amine (58 mL, 416.25 mmol) was added. The solution stirred for 5 min and then at rt H2O (100 mL) were added. The layers were separated, the aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined organic layers after drying (MgSO4) were concentrated. The product was concentrated and the crude brown oily material was purified by flash column chromatography (10% EtOAc in hexanes) to afford aldehyde (11.59 g, 87% yield). 1 Data for I-120: H NMR (300 MHz, CDCl3) δ 9.74 (1H, s), 5.32-5.42 (2H, m), 3.48-3.52 (2H, t, J = 6.6 Hz), 1.78-2-51 (8H, m); 13 C NMR (75 MHz, CDCl3) δ 202.4, 129.7, 129.3, 44.8, 44.1, 32.5, 24.6, 20.4. (2E,6Z)-Ethyl 10-chlorodeca-2,6-dienoate A solution of aldehyde (6.29 g, 39.33 mmol) and (carbethoxymethylene) triphenylphosphorane (27.37 g, 78.66 mmol) in THF (450 mL) was heated to reflux for 16 h. After cooling the solution to rt, the solvent was evaporated and the crude product was purified by column chromatography (5% EtOAc in hexanes) to afford I-121 as a colorless oil (7.23 g, 80% yield). 115 1 Data for I-121: H NMR (300 MHz, CDCl3) δ 6.89-6.95 (1H, m), 5.77-5.83 (1H, d, J = 14.1 Hz), 5.33-5.40 (2H, m), 4.12-4.19 (2H, m), 3.48-3.52 (2H, m), 2.12-2.24 (6H, m), 1.77-1.84 (2H, m), 1.23-1.28 (3H, t, J = 6.9 Hz); 13 C NMR (75 MHz, CDCl3) δ 166.0, 148.3, 129.5, 128.9, 121.7, 60.1, 44.3, 32.2, 32.1, 25.7, 24.3, 14.2. (2E,6Z)-10-Chlorodeca-2,6-dien-1-ol To a cold (0 ºC) solution of ester I-121 (3.57 g, 15.51 mmol) in diethyl ether (135 mL), DIBAL-H (46.54 mmol, 18.61 mL of 2.5 M solution in toluene) was added under N2. After stirring for 1 h. at the same temperature, saturated potassium-sodium tartrate solution (157 mL) was added and the mixture was brought to rt. Et2O (162 mL), H2O (32.5 mL) and glycerol (7.5 mL) were added and the resultant heterogeneous mixture was stirred overnight. The two layers were then separated and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (MgSO4), concentrated and the crude product after chromatographic purification (30% EtOAc in hexanes) afforded allylic alcohol I-122 as a colorless oil (2.24 g, 77% yield). 1 Data for I-122: H NMR (500 MHz, CDCl3) δ 5.62-5.71 (2H, m), 5.31-5.42 (2H, m), 4.06-4.10 (2H, m), 3.50-3.53 (2H, m), 2.09-2.20 (6H, m), 1.78-1.83 (2H, m); 13 C NMR (75 MHz, CDCl3) δ 129.5, 128.9, 122.2, 121.7, 64.9, 44.3, 32.2, 32.1, 25.7, 24.3. ((2R,3R)-3-((Z)-7-Chlorohept-3-en-1-yl)oxiran-2-yl)methanol A two necked round bottom flask charged with 4 Å mol. sieves (0.8 g) and CH2Cl2 (7 mL) was cooled to -20 ºC. To this, Ti(OiPr)4 (0.38 mL, 1.29 mmol) and a CH2Cl2 116 soltution of D-(-)-DET (0.27 ml, 1.55 mmol in 6 mL CH2Cl2) were added in that order and stirred at the same temperature under N2 for 30 min. After cooling the complex to -30 ºC, tBuOOH (0.6 mL of 3.1 M solution in toluene, 2.19 mmol) was added dropwise and the mixture was stirred for another 45 min. A solution of allylic alcohol I-122 (0.24 g, 1.29 mmol) in CH2Cl2 (5 mL) was added via a syringe pump over 45 min. The reaction was warmed to -20 ºC, stirred for 2 h and then quenched by adding saturated Na2SO4 and Na2SO3 solutions (1.2 mL each). Et2O (5 mL) was added and the resultant yellow mixture was vigorously stirred at rt for 4 h. The yellow gelatinous mass was further diluted with Et2O (30 mL), celite was added and the mixture was filtered through a pad of celite. The filter cake was washed with Et2O (ca. 60 mL) until it turned dry and granular. The filtrate was concentrated and epoxy alcohol I-123 was isolated in 72% yield (0.19 g) after purification by column chromatography (5% EtOAc in hexanes). 1 Data for epoxy alcohol I-123: H NMR (500 MHz, CDCl3) δ 5.32-5.45 (2H, m), 3.86-3.88 (1H, m), 3.56-3.60 (1H, m), 3.48-3.50 (2H, m), 2.91-2.95 (2H, m), 2.17-2.21 (4H, m), 1.77-1.83 (2H, m), 1.59-1.63 (2H, m). tert-Butyl(((2R,3R)-3-((Z)-7-chlorohept-3-en-1-yl)oxiran-2-yl)methoxy)diphenylsilan e To a solution of the alcohol I-23 (2.52 g, 12.23 mmol) in CH2Cl2 (34 mL), triethyl amine (2.06 mL, 14.68 mmol) and DMAP (0.6 g, 4.89 mmol) was added followed by t-butyl diphenylsilyl chloride (3.18 mL, 12.23 mmol) at room temperature. The reaction 117 was stirred under N2 for 14 h after which time was quenched by adding water (100 mL). The aqueous layer was extracted with CH2Cl2 (3 x 100 mL) to afford crude oil which was purified by column chromatography (2% EtOAc in hexanes) providing the protected I-124 (4.97 g, 92% yield). 1 Data for I-124: H NMR (300 MHz, CDCl3) δ 7.65-7.68 (4H, m), 7.34-7.42 (6H, m), 5.35-5.41 (2H, m), 3.72-3.76 (2H, dd, J = 4.5, 3.6), 3.48-3.52 (2H, t, J = 6.6 Hz), 2.89-2.90 (1H, m), 2.79-2.80 (1H, m), 2.14-2.20 (4H, m), 1.78-1.82 (2H, m), 1.57-1.61 (2H, m), 1.04 (9H, s). tert-Butyl(((2R,3R)-3-((Z)-7-iodohept-3-en-1-yl)oxiran-2-yl)methoxy)diphenylsilane To a stirred solution of I-124 (5.60 g, 12.67 mol), in acetone (30 mL) was added NaI (11.40 g, 76.05 mol). The reaction mixture was reflux for 12 h. The mixture was diluted with water and Et2O. The aqueous layer was extracted with Et2O (3×50 mL). to afford I-125 was obtained (6.63 g, 87% yield) after chromatographic purification (10% EtOAc in hexanes). 1 Data for I-125: H NMR (300 MHz, CDCl3) δ 7.64-7.67 (4H, m), 7.35-7.42 (6H, m), 5.33-5.41 (2H, m), 3.72-3.76 (2H, dd, J = 4.5, 3.6), 3.13-3.18 (2H, t, J = 6.9 Hz), 2.88-2.91 (1H, m), 2.77-2.82 (1H, m), 2.10-2.22 (4H, m), 1.80-1.89 (2H, m), 1.54-1.61 (2H, m), 1.03 (9H, s). (Z)-7-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)hept-4-en-1-yl acetate To a stirred solution of I-125 (6.76 g, 12.67 mol), in acetic acid (30 mL) was added 118 AgNO3 (6.46 g, 38.01 mol). The reaction mixture was heated to 50 ºC for 4 h. The mixture was filtered through a celite pad and the solventwas removed under reduced pressure. The crude product after chromatographic purification (5% EtOAc in hexanes) afforded I-126 as a colorless oil (5.49 g, 93% yield). 1 Data for I-126: H NMR (300 MHz, CDCl3) δ 7.66-7.67 (4H, m), 7.34-7.43 (6H, m), 5.35-5.39 (2H, m), 4.01-4.05 (2H, t, J = 6.6 Hz), 3.71-3.76 (2H, dd, J = 4.5, 3.6), 2.88-2.89 (1H, m), 2.77-2.79 (1H, m), 2.11-2.16 (4H, m), 2.02 (3H, s), 1.53-1.68 (4H, m), 1.03 (9H, s). (Z)-7-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)hept-4-en-1-ol To a stirred solution of I-126 (11.05 g, 23.70 mol), in MeOH (258 mL) and water (24 mL) was added K2CO3 (6.88 g, 29.77 mol). The reaction mixture was stirred at rt for 12 h. The mixture was diluted with water. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL) and the solvent was removed under reduced pressure. The crude product after chromatographic purification (30% EtOAc in hexanes) afforded I-127 as a colorless oil (8.94 g, 89% yield). 1 Data for I-127: H NMR (300 MHz, CDCl3) δ 7.64-7.70 (4H, m), 7.34-7.41 (6H, m), 5.37-5.41 (2H, m), 3.71-3.75 (2H, dd, J = 4.5, 3.6), 3.58-3.63 (2H, m), 2.88-2.89 (1H, m), 2.78-2.80 (1H, m), 2.09-2.19 (4H, m), 1.56-1.64 (4H, m), 1.03 (9H, s). (Z)-7-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)hept-4-enal To a slurry of PCC (1.99 g, 9.23 mmol) in CH2Cl2 (20 mL), a solution of alcohol 119 I-127 (2.61 g, 6.16 mmol) in CH2Cl2 (5 mL) was added at room temperature under N2 with vigorous stirring. After 2 h, anhydrous Et2O (30 mL) was added and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated and the crude brown oily material was purified by flash column chromatography (10% EtOAc in hexanes) to afford aldehyde I-128 as a pale yellow oil (1.90 g, 73% yield). 1 Data for aldehyde I-128: H NMR (300 MHz, CDCl3) δ 9.73 (1H, s), 7.64-7.67 (4H, m), 7.37-7.42 (6H, m), 5.37-5.40 (2H, m), 3.71-3.76 (2H, dd, J = 4.5, 3.6), 2.88-2.89 (1H, m), 2.78-2.79 (1H, m), 2.14-2.49 (6H, m), 1.56-1.58 (2H, m), 1.03 (9H, s). (2E,6Z)-Ethyl-9-((2R,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)nona-2, 6-dienoate A solution of aldehyde I-128 (16.60 g, 39.33 mmol) and (carbethoxymethylene) triphenylphosphorane (27.37 g, 78.66 mmol) in THF (450 mL) was heated to reflux for 16 h. After cooling the solution to rt, the solvent was evaporated and the crude product was purified by column chromatography (5% EtOAc in hexanes) to afford I-129 as a colorless oil (13.16 g, 68% yield). 1 Data for I-129: H NMR (500 MHz, CDCl3) δ 7.65-7.70 (4H, m), 7.36-7.40 (6H, m), 6.91-6.94 (1H, m), 5.79-5.82 (1H, d, J = 15.5 Hz), 5.36-5.40 (2H, m), 4.14-4.18 (2H, m), 3.69-3.77 (2H, m), 2.88-2.89 (1H, m), 2.77-2.79 (1H, m), 2.14-2.23 (6H, m), 1.56-1.59 (2H, m), 1.25-1.27 (3H, t, J = 7.0 Hz), 1.03 (9H, s). 120 (2E,6Z)-9-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)nona-2,6-dien -1-ol To a cold (0 ºC) solution of ester I-129 (7.63 g, 15.51 mmol) in diethyl ether (135 mL), DIBAL-H (46.54 mmol, 18.61 mL of 2.5 M solution in toluene) was added under N2. After stirring for 1 h. at the same temperature, saturated potassium-sodium tartrate solution (157 mL) was added and the mixture was brought to rt. Et2O (162 mL), H2O (32.5 mL) and glycerol (7.5 mL) were added and the resultant heterogeneous mixture was stirred overnight. The two layers were then separated and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (MgSO4), concentrated and the crude product after chromatographic purification (30% EtOAc in hexanes) afforded allylic alcohol I-130 as a colorless oil (2.79 g, 40% yield). 1 Data for allylic alcohol I-130: H NMR (300 MHz, CDCl3) δ 7.64-7.68 (4H, m), 7.35-7.42 (6H, m), 6.63-6.65 (2H, m), 5.36-5.90 (2H, m), 4.09-4.12 (2H, m), 3.72-3.76 (2H, dd, J = 4.5, 3.6), 2.88-2.89 (1H, m), 2.78-2.79 (1H, m), 2.10-2.19 (6H, m), 1.52-1.56 (2H, m), 1.03 (9H, s). ((2S,3S)-3-((Z)-6-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)hex-3en-1-yl)oxiran-2-yl)methanol A two necked round bottom flask charged with 4 Å mol. sieves (0.8 g) and CH2Cl2 i (7 mL) was cooled to -20 ºC. To this, Ti(O Pr)4 (0.38 mL, 1.29 mmol) and a CH2Cl2 soltution of L-(-)-DET (0.27 ml, 1.55 mmol in 6 mL CH2Cl2) were added in that order 121 and stirred at the same temperature under N2 for 30 min. After cooling the complex to -30 ºC, tBuOOH (0.6 mL, 3.1 M solution in toluene, 2.19 mmol) was added dropwise and the mixture was stirred for another 45 min. A solution of allylic alcohol I-130 (0.58 g, 1.29 mmol) in CH2Cl2 (5 mL) was added via a syringe pump over 45 min. The reaction was warmed to -20 ºC, stirred for 2 h and then quenched by adding saturated Na2SO4 and Na2SO3 solutions (1.2 mL each). Et2O (5 mL) was added and the resultant yellow mixture was vigorously stirred at rt for 4 h. The yellow gelatinous mass was further diluted with Et2O (30 mL), celite was added and the mixture was filtered through a pad of celite. The filter cake was washed with Et2O (ca. 60 mL) until it turned dry and granular. The filtrate was concentrated and epoxy alcohol I-131 was isolated in 75% yield (0.45 g) after purification by column chromatography (5% EtOAc in hexanes). 1 Data for epoxy alcohol I-123: H NMR (300 MHz, CDCl3) δ 7.65-7.67 (4H, m), 7.35-7.42 (6H, m), 5.40 (2H, m), 3.71-3.76 (4H, m), 2.78-2.90 (4H, m), 2.16-2.18 (4H, m), 1.56-1.65 (4H, m), 1.03 (9H, s). (((2R,3R)-3-((Z)-6-((2S,3S)-3-((Benzyloxy)methyl)oxiran-2-yl)hex-3-en-1-yl)oxiran-2yl)methoxy)(tert-butyl)diphenylsilane To a slurry of NaH (6.1 g, 152.4 mmol) in THF (277 mL), I-131 (64.56 g, 138.55 mmol) was added at 0 ºC and stirred for 1 h while warming to rt. Benzyl bromide (17.3 mL, 145.48 mmol) was the added drop wise followed by TBAI (2.56 g, 6.93 mmol). The reaction was heated to 60 ºC for 15 h. After cooling to room temperature H2O (100 mL) 122 was carefully added. The layers were separated, aqueous layer was extracted with Et2O (3 x 50 mL) and the combined organic layers after drying (MgSO4) were concentrated. Benzyl ether I-132 was obtained as pale yellow oil (69.33 g, 90% yield) after chromatographic purification (5% EtOAc in hexanes). 1 Data for monobenzyl ether I-132: H NMR (300 MHz, CDCl3) δ7.64-7.67 (4H, m), 7.29-7.45 (11H, m), 5.39 (2H, m), 4.50 (2H, s), 3.69-3.74 (2H, dd, J = 4.5, 3.6), 3.21-3.26 (2H, dd, J = 3.3, 3.0 Hz), 2.76-2.91 (4H, m), 2.15 (4H, m), 1.55-1.58 (4H, m), 1.03 (9H, s). (3S,4R)-1-((2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl)-6-((2S,3S)-3(hydroxymethyl)oxiran-2-yl)hexane-3,4-diol AD-mix-α (89 mg) was dissolved in 1:1 tBuOH:H2O (1 mL). To this clear, orange solution, methane sulfonamide (6 mg, 0.064 mmol) and potassium osmate (0.2 mg, 0.00064 mmol) was added and stirred until all the solids dissolved. The solution was then cooled to 0 ºC upon which I-132 (0.36 g, 0.64 mmol) was added in one portion. The reaction was vigorously stirred for 24 h after which solid sodium sulfite (95 mg) was then added at the same temperature. The mixture was warmed to room temperature and stirring was continued for 45 min. EtOAc (10 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (4 x 10 mL), combined organic layers were dried over Na2SO4, concentrated and the crude product was purified by column chromatography (50% EtOAc in hexanes to pure EtOAc) to yield I-133 (0.30 g, 87% yield). 123 1 Data for diol I-133: H NMR (300 MHz, CDCl3) δ 7.66-7.68 (4H, m), 7.30-7.43 (11H, m), 4.53 (2H, s), 3.87-3.93 (2H, m), 3.57-3.65 (4H, m), 2.90-2.94 (4H, m), 1.54-1.77 (8H, m), 1.03 (9H, s). (S)-2-(Benzyloxy)-1-((2R,2'S,5S,5'R)-5'-((R)-2-((tert-butyldiphenylsilyl)oxy)-1-hydro xyethyl)octahydro-[2,2'-bifuran]-5-yl)ethanol CH2Cl2 (3.0 mL) and TFA (0.16 g, 1.45 mmol) were added dropwise to a solution of I-133 (1.50 g, 2.54 mmol) in CH2Cl2 (8.0 mL) at 0 ºC, and the mixture was stirred at rt for 5 h. The mixture was diluted with CH2Cl2, successively washed with saturated aqueous NaHCO3, water, brine, and then dried over Na2SO4. Filtration and evaporation of the solvents afforded the crude mixture, which was chromatographed on a silica gel column (50% EtOAc in hexanes) to give I-134 (1.20 g, 80% yield) as a yellow solid. 1 Data for I-134: H NMR (500 MHz, CDCl3) δ 7.66-7.68 (4H, m), 7.30-7.40 (11 H, m), 4.43-4.57 (2H, m), 3.81-4.04 (6H, m), 3.30-3.59 (4H, m), 1.84-1.95 (6H, m), 1.55-1.62 (2H, m), 0.97 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 138.3, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 82.0, 80.3, 79.7, 73.3, 73.2, 73.1, 72.9, 71.7, 71.6, 71.5, 28.6, 28.4, 26.9, 26.2, 25.9, 18.1, 14.1. (S)-1-((2R,2'S,5S,5'R)-5'-((R)-1-Acetoxy-2-((tert-butyldiphenylsilyl)oxy)ethyl)octahy dro-[2,2'-bifuran]-5-yl)-2-(benzyloxy)ethyl acetate To a solution of I-134 (1.60g, 2.71 mmol) in CH2Cl2 (25 mL) at 0 ºC, pyridine (0.88 mL, 10.84 mmol) and DMAP (0.3 g, 0.27 mmol) was added followed by AcCl (0.39 mL, 124 5.43 mmol). The reaction was stirred under N2 for 3 h at rt and then removed solvent. The crude product was purified by column chromatography (30% EtOAc in hexanes) providing I-135 (1.46 g, 80% yield). 1 Data for I-135: H NMR (500 MHz, CDCl3) δ 7.65-7.69 (4H, m), 7.32-7.43 (11 H, m), 4.45-4.56 (2H, m), 3.82-4.05 (6H, m), 3.33-3.60 (4H, m), 2.06 (3H, s), 2.02 (3H, s), 1.86-1.97 (6H, m), 1.52-1.63 (2H, m), 1.02 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 170.8, 170.5, 138.3, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 82.0, 80.2, 79.7, 73.4, 73.2, 73.1, 72.7, 71.7, 71.5, 71.5, 28.5, 28.4, 26.9, 26.2, 25.9, 21.1, 21.0, 18.1, 14.1. (S)-1-((2R,2'S,5S,5'R)-5'-((R)-1-Acetoxy-2-((tert-butyldiphenylsilyl)oxy)ethyl)octahy dro-[2,2'-bifuran]-5-yl)-2-hydroxyethyl acetate i I-135 (0.27 g, 0.40 mmol) was dissolved in 1 : 1 EtOAc : PrOH (5 mL). To this solution, 10% Pd-C (105 mg) was added and the mixture was stirred vigorously under H2 (1 atm). The hydrogenolysis was complete in 3 h after which the reaction was filtered through a celite pad. The filtrated was concentrated and the crude product was purified by flash column chromatography (30% EtOAc in hexanes) to furnish diol I-136 in 72% yield (0.16 g). 1 Data for diol I-136: H NMR (500 MHz, CDCl3) δ 7.64-7.69 (4H, m), 7.32-7.45 (6 H, m), 3.82-4.05 (6H, m), 3.35-3.63 (4H, m), 2.05 (3H, s), 2.03 (3H, s), 1.86-1.97 (6H, m), 1.52-1.63 (2H, m), 1.02 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 170.6, 170.4, 138.4, 138.2, 128.3, 128.2, 128.1, 127.5, 127.4, 82.3, 80.5, 79.5, 73.3, 73.2, 72.9, 71.8, 71.6, 125 71.5, 28.8, 28.4, 26.9, 26.3, 25.9, 21.1, 21.0, 18.5, 14.3. (S)-2-(Benzyloxy)-1-((2R,2'S,5S,5'R)-5'-((R)-2-((tert-butyldiphenylsilyl)oxy)-1-hydro xyethyl)octahydro-[2,2'-bifuran]-5-yl)ethanol Bis-adjacent THF acetate I-135 (0.52 g, 0.78 mmol) was dissolved in MeOH (8 mL). Solid K2CO3 was added to this solution and the heterogeneous mixture was stirred vigorously at room temperature for 15 h. The reaction was then diluted with CH2Cl2 (10 mL) and washed with NaHCO3 (10 mL) and H2O (10 mL). The aqueous layers were mixed and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, the solvents were evaporated and the crude product was purified by flash column chromatography (50% EtOAc in hexanes). Bis-THF diol I-137 was obtained in 67% yield (0.20 g). 1 Data for bis-THF diol I-137: H NMR (500 MHz, CDCl3) δ 7.66-7.68 (4H, m), 7.30-7.40 (11 H, m), 4.46-4.57 (2H, m), 3.81-4.04 (6H, m), 3.30-3.59 (4H, m), 1.84-1.95 (6H, m), 1.55-1.62 (2H, m), 0.97 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 138.3, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 82.0, 80.3, 79.7, 73.3, 73.2, 73.1, 72.9, 71.7, 71.6, 71.5, 28.6, 28.4, 26.9, 26.2, 25.9, 18.1, 14.1. (R)-5-((2S,2'R,5R,5'S)-5'-((S)-2-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)ethyl)oct ahydro-[2,2'-bifuran]-5-yl)-2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disila decane To a 0 ºC solution of bis-THF diol I-137 (0.33 g, 0.56 mmol) in THF (11 mL), triethylamine (0.21 mL, 1.51 mmol) and TBSCl (0.21 g, 1.40 mmol) were added in that 126 order. After 30 min at the same temperature, saturated NaHCO3 solution (10 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×15 mL), combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford a crude oil. Upon purification of the oil by column chromatography (10% EtOAc in hexanes), bis-TBS ether I-138 was obtained in 77% yield (0.35 g). 1 Data for bis-TBS ether I-138: H NMR (500 MHz, CDCl3) δ 7.65-7.69 (4H, m), 7.30-7.40 (11 H, m), 4.45-4.57 (2H, m), 3.81-4.04 (6H, m), 3.59-3.30 (4H, m), 1.84-1.95 (6H, m), 1.57-1.62 (2H, m), 0.99 (9H, s), 0.87 (9H, s), 0.85 (9H, s), 0.07 (3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.04 (3H, s); 13 C NMR (125 MHz, CDCl3) δ 138.3, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 82.0, 80.3, 79.7, 73.3, 73.2, 73.1, 72.9, 71.7, 71.6, 71.5, 28.6, 28.4, 28.3, 26.9, 26.2, 25.9, 18.1, 17.9, 14.1,-4.9, -4.8, -4.5, -4.4. (S)-2-((tert-Butyldimethylsilyl)oxy)-2-((2R,2'S,5S,5'R)-5'-((R)-2,2,3,3,9,9-hexamethyl8,8-diphenyl-4,7-dioxa-3,8-disiladecan-5-yl)octahydro-[2,2'-bifuran]-5-yl)ethanol i I-138 (0.33 g, 0.40 mmol) was dissolved in 1 : 1 EtOAc : PrOH (5 mL). To this solution, 10% Pd-C (105 mg) was added and the mixture was stirred vigorously under H2 (1 atm). The hydrogenolysis was complete in 3 h after which the reaction was filtered through a celite pad. The filtrated was concentrated and the crude product was purified by flash column chromatography (30% EtOAc in hexanes) to furnish diol I-139 in 82% yield (0.24 g). 127 1 Data for diol I-139: H NMR (500 MHz, CDCl3) δ 7.66-7.70 (4H, m), 7.32-7.44 (6 H, m), 3.85-4.00 (6H, m), 3.58-3.31 (4H, m), 1.85-1.91 (6H, m), 1.58-1.63 (2H, m), 1.00 (9H, s), 0.89 (9H, s), 0.85 (9H, s), 0.08 (3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.04 (3H, s); 13 C NMR (125 MHz, CDCl3) δ 138.4, 138.2, 128.3, 128.2, 128.1, 128.0, 127.8, 127.5, 127.4, 82.0, 80.3, 79.7, 73.3, 73.2, 73.0, 71.7, 71.6, 71.5, 28.5, 28.4, 28.3, 26.9, 26.2, 25.7, 18.1, 17.9, 14.1,-4.9, -4.8, -4.5, -4.4. (R)-5-((2S,2'R,5R,5'S)-5'-((S)-2-(Benzyloxy)-1-(methoxymethoxy)ethyl)octahydro-[2, 2'-bifuran]-5-yl)-9,9-dimethyl-8,8-diphenyl-2,4,7-trioxa-8-siladecane To a solution of diol I-137 (0.16g, 0.28 mmol) in dichloromethane (3 mL), DMAP (13.7 mg, 0.11 mmol), Hünig’s base (0.59 mL, 3.36 mmol), methoxylmethyl chloride (0.13 mL, 1.68 mmol), and TBAI (41.4 mg, 0.11 mmol) were added in that order. The reaction was stirred at room temperature overnight. Sat. ammonium chloride solution (10 mL) was added to quench the reaction and the layers were separated. The aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified via fast column chromatography (30% EtOAc in hexanes) to yield the desired fully protected diol I-143 in 97% yield (0.18 g). 1 Data for di-MOM ether I-143: H NMR (500 MHz, CDCl3) δ 7.65-7.69 (4H, m), 7.32-7.40 (11 H, m), 4.91-4.94 (4H, m), 4.46-4.57 (2H, m), 3.80-4.00 (6H, m), 3.35-3.56 (4H, m), 3.05 (3H, s), 3.00 (3H, s), 1.85-1.96 (6H, m), 1.55-1.60 (2H, m), 0.98 (9H, s); 128 13 C NMR (125 MHz, CDCl3) δ 138.3, 138.2, 138.0, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 82.0, 81.9, 81.7, 80.3, 79.7, 73.3, 73.2, 73.1, 72.9, 71.7, 71.6, 71.5, 68.3, 68.1, 28.6, 28.4, 26.9, 26.2, 25.9, 18.1, 14.1. (S)-2-((2R,2'S,5S,5'R)-5'-((R)-9,9-Dimethyl-8,8-diphenyl-2,4,7-trioxa-8-siladecan-5-y l)octahydro-[2,2'-bifuran]-5-yl)-2-(methoxymethoxy)ethanol i I-143 (0.18 g, 0.27 mmol) was dissolved in 1 : 1 EtOAc : PrOH (5 mL). To this solution, 10% Pd-C (71 mg) was added and the mixture was stirred vigorously under H2 (1 atm). The hydrogenolysis was complete in 3 h after which the reaction was filtered through a celite pad. The filtrated was concentrated and the crude product was purified by flash column chromatography (80% EtOAc in hexanes to pure EtOAc) to furnish diol I-144 in 86% yield (0.13 g). 1 Data for I-144: H NMR (500 MHz, CDCl3) δ 7.66-7.69 (4H, m), 7.35-7.43 (5 H, m), 4.92-4.95 (4H, m), 3.80-4.02 (6H, m), 3.35-3.53 (4H, m), 3.06 (3H, s), 3.02 (3H, s), 1.86-1.97 (6H, m), 1.55-1.61 (2H, m), 0.97 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 138.2, 138.0, 128.3, 128.2, 128.0, 127.8, 127.5, 127.4, 127.3, 82.0, 81.9, 81.7, 80.3, 79.7, 73.2, 73.1, 72.9, 71.7, 71.6, 71.5, 68.3, 68.1, 28.6, 28.4, 26.9, 26.2, 25.9, 18.1, 14.1. 4-((tert-Butyldiphenylsilyl)oxy)butan-1-ol 134 To a solution of l,4-butanediol (15.00 g, 166.00 mmol) in CH2Cl2 (30 ml) containing imidazole (11.29 g, 166.00 mmol) was added dropwise tert- butylchlorodiphenylsilane (15.0 ml, 57.30 mmol) under argon at room temperature. The solution was stirred at room temperature for 18 h, concentrated in vacuo, and the residue was purified by flash 129 chromatography (Hex-EtOAc, 30%) to give alcohol I-152 (10.58 g, 57% yield) as a clear oil. 1 Data for I-152: H NMR (300 MHz, CDCl3) δ 7.26–7.69 (10H, m), 3.70 (2H, t, J = 5.68 Hz), 3.63 (2H, t, J = 5.84 Hz), 2.04 (1H, s), 1.63–1.71 (4H, m), 1.05 (9H, s); 13 C NMR (75 MHz, CDC13) δ 136.0, 134.0, 130.1, 128.1, 64.4, 63.3, 30.3, 29.7, 27.2, 19.6. 4-((tert-Butyldiphenylsilyl)oxy)butanal 135 A solution of oxalyl chloride (4.7 ml, 54.1 mmol) in CH2Cl2 (85 mL) was treated with a solution of DMSO (6.5 mL, 91.5 mmol) in CH2Cl2 (5 mL) at –78 ºC under argon in 10 min. After 15 min at −78 ºC, alcohol I-152 (13.66 g, 41.6 mmol) in CH2Cl2 (34 mL) was added in 5 min. After 15 min at –78 ºC, triethylamine (29 mL, 208 mmol) was added in 15 min, and the mixture was allowed to warm up to room temperature. The reaction mixture was treated with water (150 mL) and extracted with CH2Cl2 (2 x 100 mL). The organic extracts were washed with saturated aqueous NaCl (100 mL), and dried over MgSO4. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (Hex-EtOAc, 10%) to give aldehyde I-153 (11.52 g, 85% yield) as an oil. 1 Data for I-153: H NMR (500 MHz, CDCl3) δ 9.79 (1H, d, J = 1.68 Hz), 7.66–7.35 (10H, m), 3.69 (2H, t, J = 5.97 Hz), 2.55 (2H, dt, J = 7.17, 1.65 Hz), 1.89 (2H, tt, J = 7.08, 6.02 Hz), 1.04 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 203.0, 135.9, 134.0, 130.1, 128.1, 63.3, 41.2, 27.2, 25.6, 19.6. (E)-Ethyl 6-((tert-butyldiphenylsilyl)oxy)hex-3-enoate 130 A mixture of I-153 (13.51 g, 41.4 mmol), monoethyl malonate (6.60 g, 50.0 mmol) and Et3N (7.0 mL, 50.2 mmol) was heated at 90 ºC overnight. After addition of ice (100 mL), 2 N HCl (50 mL), and EtOAc (100 mL), the mixture was extracted with EtOAc (2x 100 mL). The organic extracts were washed with saturated aqueous NaCl (100 mL), and dried over MgSO4. After removal of the solvent under reduced pressure, purification of the residue by flash chromatography (Hex-EtOAc, 10%) gave ester I-154 (13.77 g, 84% 1 yield). Data for I-154: H NMR (300 MHz, CDCl3) δ 7.67–7.64 (4H, m), 7.42–7.25 (6H, m), 5.59–5.55 (2H, m), 3.69 (2H, t, J = 6.5 Hz), 3.67 (3H, s), 3.03 (2H, d, J = 4.9 Hz), 2.25 (2H, m), 1.04 (9H, s); 13 C NMR (75 MHz, CDCl3) δ 172.8, 136.0, 134.3, 131.6, 130.0, 128.0, 124.0, 63.9, 52.1, 38.4, 36.3, 27.2, 19.6. (4R,5R)-5-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-4-hydroxydihydrofuran-2(3H)-one Ester I-155 (6.70 g, 17.5 mmol) was added to a mixture of AD-mix-β (25 g, 1.4 g/mmol of I-155) and methanesulfonamide (1.67g, 17.5 mmol) in t-BuOH (88 mL) and water (88 mL) at 0 ºC. The solution was stirred at 0 ºC for 20 h. After addition of saturated aqueous Na2S2O3 (100 mL), the mixture was extracted with EtOAc. The extracts were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Hex-EtOAc, 2:1) to yield lactone I-155 (5.37 g, 80% yield, 98% ee) as a clear oil. 20 Data for I-155: [α]D 1 +27 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.67–7.41 (10H, m), 4.59 (1H, qui, J = 2.90 Hz), 4.50 (1H, qui, J = 4.61 Hz), 3.86 (1H, dt, J =10.79, 3.95 Hz), 3.69 (1H, dt, J = 10.73, 2.25 Hz), 3.55 (1H, t, J = 1.86 Hz), 2.83 (1H, ddd, J = 131 17.83, 5.73, 1.38 Hz), 2.63 (1H, d, J = 17.79 Hz), 2.30 (1H, m), 2.10 (1H, ddt, J = 14.60, 4.81, 2.09 Hz), 1.07 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 175.7, 135.9, 135.9, 132.5, 132.3, 130.6, 128.4, 84.1, 69.1, 60.8, 38.5, 31.1, 27.2, 19.4. (3R,4R)-6-((tert-Butyldiphenylsilyl)oxy)hexane-1,3,4-triol A solution of lactone I-155 (6.3 g, 16.5 mmol) in THF (35 mL) was slowly added to a suspension of LiAlH4 (626 mg, 16.5 mmol) in THF (35 mL) at –78 ºC. The reaction mixture was warmed to room temperature, and after 30 min, treated with diluted H2SO4 (3 wt. %, 58mL) at 0 ºC. The mixture was extracted with EtOAc (4 x 100 mL). The combined organic extracts were dried over MgSO4. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography (Hex-EtOAc, 50%) to yield triol I-156 (5.0 g, 78% yield) as a clear oil. 20 Data for I-156: [α]D 1 -1.9 (c 1.0, CHCl3); H NMR (500 MHz, 300 CDCl3) δ 7.68–7.37 (10H, m), 3.91–3.72 (6H, m), 3.73 (1H, br. s), 3.13 (1H, d, J = 4.32), 2.70 (1H, br. s), 1.88–1.65 (4H, m), 1.06 (9H, s); 13 C NMR (125 MHz, CDCl3) δ 135.94, 135.91, 133.23, 133.14, 130.34, 130.36, 130.33, 128.25, 74.48, 74.44, 63.18, 61.37, 35.54, 35.28, 27.21, 19.43. (3R,4R)-1-((tert-Butyldiphenylsilyl)oxy)-6-iodohexane-3,4-diol To a stirred solution of I-156 (0.72 g, 1.85 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and imidazole (0.25 g, 3.70 mmol) in dry CH3CN/Et2O 1:2 (5:8 mL) at 0 ºC was added I2 (0.47 g, 1.85 mmol) in portions. The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with pentane/ether (4:1) and filtered 132 through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 30% EtOAc–hexanes to give I-157 (0.62 g, 68% yield). 1 Data for I-157: H NMR (300 MHz, CDCl3) δ 7.64-7.66 (4H, d, J = 6.6 Hz), 7.36-7.46 (6H, m), 3.69-3.89 (4H, m), 3.18-3.30 (2H, m), 1.95-2.10 (2H, m), 1.65-1.84 (2H, m), 1.03 (9H, s). (7R,8R)-10,10-Diethyl-8-(2-iodoethyl)-2,2-dimethyl-3,3-diphenyl-7-((triethylsilyl)oxy )-4,9-dioxa-3,10-disiladodecane To a solution of the diol I-157 (0.5 g, 1.0 mmol) in THF (9.5 mL) triethyl amine (3.5 mL) was added followed by triethylsilyl chloride (0.67 mL, 4.0 mmol) and DMAP (49 mg, 0.4 mmol) at ambient temperature. The reaction was stirred under N2 for 5 h after which time it was quenched by adding saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with 1: 5 EtOAC : hexanes (3 x 10 mL) to afford crude oil which was purified by column chromatography (1% EtOAc in hexanes) providing the fully protected diol I-158 (0.6 g, 87% yield) as a colorless oil. 1 Data for diol I-158: H NMR (300 MHz, CDCl3) δ7.63-7.66 (4H, d, J = 6.6 Hz), 7.35-7.45 (6H, m), 3.68-3.88 (4H, m), 3.18-3.28 (2H, m), 1.97-2.11 (2H, m), 1.68-1.80 (2H, m), 1.03 (9H, s), 0.96-0.99 (18H, m), 0.59-0.62 (12H, m). 2-((4R,5R)-5-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)et hanol p-Toluenesulfonic acid (p-TsOH, 0.19 g, 0.89 mmol) was added as one portion to the 133 solution of diol I-156 (2.83 g, 8.9 mmol) and acetone (100 mL). Hot oven dried 4 Å molecular sieves (1.2 g) was also added and the mixed slurry was stirred at room temperature overnight. The slurry was then filtered through a celite pad and washed with EtOAc (4 x 60 mL). The combined organic layers were drided over Na2SO4 and concentrated under reduced pressure. Purification via column chromatography (30% EtOAc-hexanes) yielded the protected diol I-160 in 69% yield (2.62 g). 1 Data for I-160: H NMR (300 MHz, CDCl3) δ 7.63-7.66 (4H, d, J = 6.6 Hz), 7.33-7.43 (6H, m), 3.68-3.89 (6H, m), 1.58-1.83 (4H, m), 1.37 (3H, s), 1.34 (3H, s), 1.03 (9H, s). tert-Butyl(2-((4R,5R)-5-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)diphenyl silane To a stirred solution of I-160 (0.79 g, 1.85 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and imidazole (0.25 g, 3.70 mmol) in dry CH3CN/Et2O 1:2 (5:8 mL) at 0 ºC was added I2 (0.47 g, 1.85 mmol) in portions. The reaction mixture was left to stir at room temperature for 12 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 10% EtOAc–hexanes to give I-161 (0.69 g, 70% yield). 1 Data for I-161: H NMR (300 MHz, CDCl3) δ 7.64-7.67 (4H, d, J = 6.6 Hz), 7.34-7.42 (6H, m), 3.66-3.87 (4H, m), 3.18-3.30 (2H, m), 1.99-2.15 (2H, m), 1.73-1.79 (2H, m), 1.34 (6H, s), 1.04 (9H, s). 134 tert-Butyl(2-((4R,5R)-5-(6-((4-methoxybenzyl)oxy)hex-3-yn-1-yl)-2,2-dimethyl-1,3-di oxolan-4-yl)ethoxy)diphenylsilane To a solution of I-159 (2.12 g, 11.15 mmol) in THF (98 mL), n-BuLi (1.6 M solution in THF, 7.00 mL, 11.15 mmol) was added at -78 ºC. After stirring for 10 min, I-161 (5.00 g, 9.29 mmol) in HMPA (6.5 mL) was added and the mixture was stirred for 12 h at 0 ºC. Saturated NH4Cl (aq.) solution (100 mL) was added to quench the reaction. EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and the solvent was evaporated to afford a crude product. Purification by column chromatography (5% EtOAc in hexanes) gave I-162 in 78% yield (4.34 g). 1 Data for I-162: H NMR (600 MHz, CDCl3) δ 7.65-7.66 (4H, d, J = 6.0 Hz), 7.34-7.41 (8H, m), 6.84-6.86 (2H, d, J = 8.4 Hz), 4.45 (2H, s), 3.79-3.83 (2H, m), 3.77 (3H, s), 3.69-3.70 (2H, m), 3.49-3.51 (2H, t, J = 7.2 Hz), 2.24-2.44 (4H, m), 1.67-1.79 (4H, m), 1.33 (3H, s), 1.32 (3H, s), 0.95 (9H, s). 2-((4R,5R)-5-(6-((4-Methoxybenzyl)oxy)hex-3-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-y l)ethanol To a solution of di-TBDPS ether I-162 (0.021 g, 0.035 mmol) in THF (2 mL), TBAF (1.0 M solution in THF, 35 µL, 0.035 mmol) was added at room temperature. After stirring for 16 h at room temperature, saturated NH4Cl (aq.) solution (5 mL) was added to quench the reaction. EtOAc (5 mL) were added and the layers were separated. The aqueous layers were extracted with EtOAc (3 x 8 mL). The organic layers were combined, 135 dried over anhydrous Na2SO4, and the solvent was evaporated to afford a crude product. Purification by column chromatography (80% EtOAc in hexanes to pure EtOAc) gave I-163 (10 mg) in 76% yield. 1 Data for I-163: H NMR (300 MHz, CDCl3) δ 7.23-7.26 (2H, m), 6.84-6.87 (2H, m), 4.45 (2H, s), 3.75-3.81 (7H, m), 3.48-3.52 (2H, t, J = 6.9 Hz), 2.28-2.45 (4H, m), 1.67-1.82 (4H, m), 1.37 (3H, s), 1.36 (3H, s). (4R,5R)-4-(2-Iodoethyl)-5-(6-((4-methoxybenzyl)oxy)hex-3-yn-1-yl)-2,2-dimethyl-1,3 -dioxolane To a stirred solution of I-163 (4.4 g, 9.4 mmol), triphenylphosphine (5.0 g, 19.0 mmol) and imidazole (1.3 g, 19.0 mmol) in dry CH3CN/Et2O 1:2 (16.7:33.3 mL) at 0 ºC was added I2 (4.8 g, 19.0 mmol) in portions. The reaction mixture was left to stir at room temperature for 1 h. The mixture was diluted with pentane/ether (4:1) and filtered through a silica plug. The colorless filtrate was dried and concentrated in vacuo and the residue was chromatographed on silica eluting with hexanes, then 10% EtOAc–hexanes to give I-164 (3.2 g, 72% yield). 1 Data for I-164: H NMR (300 MHz, CDCl3) δ 7.23-7.26 (2H, m), 6.84-6.87 (2H, m), 4.46 (2H, s), 3.79 (3H, s), 3.53-3.75 (2H, m), 3.48-3.53 (2H, t, J = 7.2 Hz), 3.19-3.30 (2H, m), 2.40-2.46 (4H, m), 2.02-2.06 (2H, m), 1.67-1.74 (2H, m), 1.35 (6H, s). (4R,5R)-4-(6-((4-Methoxybenzyl)oxy)hex-3-yn-1-yl)-5-(6-((2-methoxyethoxy)methox y)hex-3-yn-1-yl)-2,2-dimethyl-1,3-dioxolane To a solution of I-165 (0.18 g, 1.11 mmol) in THF (10 mL), n-BuLi (1.6 M solution 136 in THF, 0.70 mL, 1.11 mmol) was added at -78 ºC. After stirring for 10 min, I-164 (0.44 g, 0.93 mmol) in HMPA (0.6 mL) was added and the mixture was stirred for 12 h at 0 ºC. Saturated NH4Cl (aq.) solution (10 mL) was added to quench the reaction. EtOAc (5 mL) were added and the layers were separated. The aqueous layers were extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried over anhydrous Na2SO4, and the solvent was evaporated to afford a crude product. Purification by column chromatography (5% EtOAc in hexanes) gave I-166 in 77% yield (0.36 g). 1 Data for I-166: H NMR (300 MHz, CDCl3) δ 7.23-7.26 (2H, m), 6.84-6.87 (2H, m), 4.72 (2H, s), 4.46 (2H, s), 3.78 (3H, s), 3.50-3.72 (10H, m), 3.38 (3H, s), 2.27-2.45 (8H, m), 1.69-1.71 (4H, m), 1.34 (6H, s). (4R,5R)-4-((Z)-6-((4-Methoxybenzyl)oxy)hex-3-en-1-yl)-5-((Z)-6-((2-methoxyethoxy) methoxy)hex-3-en-1-yl)-2,2-dimethyl-1,3-dioxolane The titled compound I-167 was prepared by hydrogenation of I-166 (0.3 g, 0.6 mmol) in dry ethanol (0.3 mL) in the presence of Lindlar catalyst (0.01 g) under 1 atm of H2 at room temperature. The reaction mixture was filtered with suction through a pad of celite. The filter cake was washed several times with diethyl ether. This mixture was concentrated and I-167 was obtained as pale yellow oil (0.3 g, 98% yield) after chromatographic purification (10% EtOAc in hexanes). 1 Data for I-167: H NMR (600 MHz, CDCl3) δ 7.23-7.24 (2H, d, J = 6.6 Hz), 6.84-6.86 (2H, d, J = 6.6 Hz), 5.38-5.46 (4H, m), 4.69 (2H, s), 4.42 (2H, s), 3.77 (3H, s), 3.66-3.67 (2H, m), 3.52-3.59 (6H, m), 3.41-3.43 (2H, t, J = 7.2 Hz), 3.37 (3H, s), 2.31-2.36 (4H, 137 m), 2.11-2.22 (4H, m), 1.53-1.59 (4H, m), 1.34 (6H, s). (3S,4R)-1-((4R,5R)-5-((3R,4S)-3,4-Dihydroxy-6-((2-methoxyethoxy)methoxy)hexyl)-2 ,2-dimethyl-1,3-dioxolan-4-yl)-6-((4-methoxybenzyl)oxy)hexane-3,4-diol Compound I-167 (0.67 g, 1.75 mmol) was added to a mixture of AD-mix-α (2.5 g, 1.4 g/mmol of I-167) and methanesulfonamide (0.17g, 1.75 mmol) in t-BuOH (9 mL) and water (9 mL) at 0 ºC. The solution was stirred at 0 ºC for 20 h. After addition of saturated aqueous Na2S2O3 (10 mL), the mixture was extracted with EtOAc. The extracts were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Hex-EtOAc, 2:1) to yield I-168 (0.72 g, 72% yield) as a white solid. 1 Data for I-168: H NMR (600 MHz, CDCl3) δ 7.20-7.22 (2H, d, J = 8.4 Hz), 6.84-6.85 (2H, d, J = 8.4 Hz), 4.68 (2H, s), 4.43 (2H, s), 3.77 (3H, s), 3.54-3.71 (14H, m), 3.37 (3H, s), 1.49-1.82 (12H, m), 1.34 (6H, s). (S)-1-((2R,2'R,5S,5'R)-5'-((R)-1-Acetoxy-3-((4-methoxybenzyl)oxy)propyl)octahydro -[2,2'-bifuran]-5-yl)-3-((2-methoxyethoxy)methoxy)propyl acetate Trimethylortho acetate (31 µL, 0.24 mmol) was added to a solution of tetraol I-168 (57.4 mg, 0.1 mmol) and in CH2Cl2 (3 mL) at rt. After complete consumption of the tetraol (ca. 20 min, as judged by TLC), BF3•OEt2 (8 µL, 0.06 mmol) was rapidly added to the reaction. After 30 min, the reaction was slowly poured into saturated NaHCO3 solution (5 mL) and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). 138 Combined organic layers were dried (anhydrous Na2SO4), concentrated under reduced pressure and the crude product was purified by flash column chromatography (40% EtOAc in hexanes to 60% EtOAc in hexanes) to furnish bis-THF acetate mixture I-169 (the mixture of diastereomers) (20 mg, 35% yield) as a clear oil. 1 Data for I-169: H NMR (500 MHz, CDCl3) δ 7.22-7.27 (2H, m), 6.82-6.87 (2H, m), 4.66 (2H, s), 4.45 (2H, s), 3.81-4.04 (6H, m), 3.79 (3H, s), 3.46 (3H, s), 3.62-3.30 (8H, m), 2.28 (3H, s), 2.25 (3H, s), 1.84-2.10 (12H, m). (10Z,14R,15R,18Z)-23-(4-Methoxyphenyl)-2,5,7,22-tetraoxatricosa-10,18-diene-14,15 -diol To a stirred, ice-cold solution of I-167 (0.05 g, 0.10 mmol) in anhydrous CH 2Cl2 (1 mL) under an inert atmosphere was added TMSOTf (0.04 g, 0.20 mmol). The resulting solution was stirred at the same temperature for the specified time (TLC monitoring), followed by quenching the reaction by addition of a saturated aqueous NaHCO 3 solution. After stirring the mixture for 5 min, the organic layer was separated and the aqueous layer was saturated with solid NaCl and extracted with CH2 Cl2 (three times). The combined organic layers were dried over anhydrous Na2 SO4 . Concentration of the solvent under reduced pressure and column chromatographic purification of the residue (40% EtOAc in hexanes to 60% EtOAc in hexanes) provided the pure I-170 (35 mg, 76% yield). 1 Data for I-170: H NMR (600 MHz, CDCl3) δ 7.23-7.25 (2H, d, J = 6.6 Hz), 6.85-6.87 (2H, d, J = 6.6 Hz), 5.39-5.46 (4H, m), 4.69 (2H, s), 4.41 (2H, s), 3.78 (3H, s), 3.66-3.68 (2H, m), 3.52-3.60 (6H, m), 3.42-3.45 (2H, t, J = 7.2 Hz), 3.38 (3H, s), 2.31-2.36 (4H, 139 m), 2.11-2.23 (4H, m), 1.54-1.58 (4H, m);. (14R,15R,Z)-17,17-Diethyl-15-((Z)-6-((4-methoxybenzyl)oxy)hex-3-en-1-yl)-14-((triet hylsilyl)oxy)-2,5,7,16-tetraoxa-17-silanonadec-10-ene To a solution of the diol I-170 (0.05 g, 0.10 mmol) in THF (1 mL) triethyl amine (0.35 mL) was added followed by triethylsilyl chloride (0.07 mL, 0.4 mmol) and DMAP (4.9 mg, 0.04 mmol) at ambient temperature. The reaction was stirred under N2 for 5 h after which time it was quenched by adding saturated NaHCO3 solution (1 mL). The aqueous layer was extracted with 1:5 EtOAC:hexanes (3 x 1 mL) to afford a crude oil which was purified by column chromatography (5% EtOAc in hexanes) providing the fully protected diol I-171 (52 mg, 78%) as a colorless oil. 1 Data for I-171: H NMR (600 MHz, CDCl3) δ 7.23-7.25 (2H, d, J = 6.6 Hz), 6.85-6.87 (2H, d, J = 6.6 Hz), 5.40-5.45 (4H, m), 4.68 (2H, s), 4.42 (2H, s), 3.75 (3H, s), 3.65-3.68 (2H, m), 3.50-3.59 (6H, m), 3.42-3.45 (2H, t, J = 7.2 Hz), 3.39 (3H, s), 2.31-2.34 (4H, m), 2.11-2.22 (4H, m), 1.54-1.59 (4H, m), 0.91-0.98 (18H, m), 0.56-0.63 (12H, m). (10S,11R,14R,15R,18S,19R)-23-(4-Methoxyphenyl)-14,15-bis((triethylsilyl)oxy)-2,5,7, 22-tetraoxatricosane-10,11,18,19-tetrao Compound I-171 (0.08 g, 0.18 mmol) was added to a mixture of AD-mix-α (0.25 g, 1.4 g/mmol of I-171) and methanesulfonamide (0.02g, 0.17 mmol) in t-BuOH (1 mL) and water (1 mL) at 0 ºC. The solution was stirred at 0 ºC for 20 h. After addition of saturated aqueous Na2S2O3 (1 mL), the mixture was extracted with EtOAc. The extracts were dried over MgSO4, and the solvent was removed under reduced pressure. The 140 residue was purified by flash chromatography (Hex-EtOAc, 2:1) to yield I-172 (0.11 g, 80% yield) as a white solid. 1 Data for I-172: H NMR (600 MHz, CDCl3) δ 7.20-7.24 (2H, d, J = 8.4 Hz), 6.86-6.87 (2H, d, J = 8.4 Hz), 4.67 (2H, s), 4.42 (2H, s), 3.77 (3H, s), 3.54-3.73 (14H, m), 3.38 (3H, s), 1.51-1.83 (12H, m), 0.92-0.97 (18H, m), 0.56-0.62 (12H, m). 141 I.10 References 142 REFERENCES 1. Zafra-Polo, M. C.; Gonzalez, M. C.; Estornell, E.; Sahpaz, S.; Cortes, D. Phytochemistry 1996, 42, 253-271. 2. Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. 3. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275 - 306. 4. Cavé, A.; Figadère, B.; Laurens, A.; Cortes, D., In Progress in the Chemistry of Organic Natural Products, Herz, W.; Kirby, G.; Moore, R. E.; Seglich, W.; Tamm, C., Eds. Springer-Verlag: Wien, 1997; Vol. 70, p 81. 5. Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. 6. Tormo, J. R.; Gallardo, T.; González, M. C.; Bermejo, A.; Cabedo, N.; Andreu, I.; Estornell, E. Curr. Top. Phytochem. 1999, 2, 69. 7. Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269-303. 8. Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278. 9. Maezaki, N.; Kojima, N.; Tanaka, T. Synlett 2006, 993-1003. 10. Leboeuf, M.; Cave, A.; Bhaumik, P. K.; Mukherjee, B.; Mukherjee, R. Phytochemistry 1980, 21, 2783-2813. 11. Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J. Org. Chem. 1982, 47, 3151-3153. 12. Geran, R. I.; Greenberg, N. H.; MacDonald, M. N.; Schumacher, A. M.; Abbott, B. J. Cancer Chemother. Rep. 1972, 3, 9. 13. Gleye, C.; Laurens, A.; Laprevote, O.; Serani, L.; Hocquemiller, R. Phytochemistry 1999, 52, 1403-1408. 14. Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 31-34. 143 15. He, K.; Shi, G.; Zhao, G. X.; Zeng, L.; Ye, Q.; Schwedler, J. T.; Wood, K. V.; McLaughlin, J. L. J. Nat. Prod. 1996, 59, 1029-1034. 16. He, K.; Zhao, G.-X.; Shi, G.; Zeng, L.; Chao, J.-F.; McLaughlin, J. L. Bioorg. Med. Chem. 1997, 5, 501-506. 17. Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-m.; Zhao, G.-x.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995, 117, 10409-10410. 18. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988-7989. 19. Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron 1998, 54, 5833-5844. 20. Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419-421. 21. Jiang, Z.; Chen, R. Y.; Chen, Y.; Yu, D. Q. J. Nat. Prod. 1998, 61, 86-88. 22. Marshall, J. A.; Hinkle, K. W.; Hagedorn, C. E. Isr. J. Chem. 1997, 37, 97-107. 23. Oberlies, N. H.; Jones, J. L.; Corbett, T. H.; Fotopoulos, S. S.; McLaughlin, J. L. Cancer Lett. 1995, 96, 55-62. 24. Ahammadsahib, K. I.; Hollingworth, R. M.; McGovren, J. P.; Hui, Y. H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113-1120. 25. Londershausen, M.; Leicht, W.; Lieb, F.; Moeschler, H.; Weiss, H. Pestic. Sci. 1991, 33, 427. 26. Lewis, M. A.; Arnason, J. T.; Philogene, B. J. R.; Rupprecht, J. K.; McLaughlin, J. L. Pestic. Biochem. Physiol. 1993, 45, 15-23. 27. James Morre, D.; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin, J. L. Life Sci. 1994, 56, 343-348. 28. Degli Esposti, M.; Ghelli, A.; Ratta, M.; Cortes, D.; Estornell, E. Biochem. J. 1994, 301, 161-167. 29. Carmen GonzAlez, M.; Tormo, J.; Bermejo, A.; Carmen Zafra-polo, M.; Estornell, E.; Cortes, D. Bioorg. Med. Chem. Lett. 1997, 7, 1113-1118. 144 30. Gallardo, T.; Saez, J.; Granados, H.; Tormo, J. R.; Velez, I. D.; Brun, N.; Torres, B.; Cortes, D. J. Nat. Prod. 1998, 61, 1001-1005. 31. Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin, J. L. Biochemistry 1998, 37, 854-866. 32. Weiss, H.; Friedrich, T.; Hofhaus, G.; Preis, D. Eur. J. Biochem. 1991, 197, 563-576. 33. Singer, T. P.; Ramsay, R. R., In Molecular Mechanisms in Bioenergetics, Ernster, L., Ed. Elsevier: Amsterdam, 1992; p 145. 34. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura, H.; McLaughlin, J. L. Biochim. Biophys. Acta 1998, 1365, 443-452. 35. Konno, H.; Hiura, N.; Makabe, H.; Abe, M.; Miyoshi, H. Bioorg. Med. Chem. Lett. 2004, 14, 629-632. 36. Kuwabara, K.; Takada, M.; Iwata, J.; Tatsumoto, K.; Sakamoto, K.; Iwamura, H.; Miyoshi, H. Eur. J. Biochem. 2000, 267, 2538-2546. 37. Peyrat, J. F.; Mahuteau, J.; Figadere, B.; Cave, A. J. Org. Chem. 1997, 62, 4811-4815. 38. Sasaki, S.; Maruta, K.; Naito, H.; Maemura, R.; Kawahara, E.; Maeda, M. Tetrahedron 1998, 54, 2401-2410. 39. Okun, J. G.; Lummen, P.; Brandt, U. J. Biol. Chem. 1999, 274, 2625-2630. 40. Motoyama, T.; Yabunaka, H.; Miyoshi, H. Bioorg. Med. Chem. Lett. 2002, 12, 2089-2092. 41. Hamada, T.; Ichimaru, N.; Abe, M.; Fujita, D.; Kenmochi, A.; Nishioka, T.; Zwicker, K.; Brandt, U.; Miyoshi, H. Biochemistry 2004, 43, 3651-3658. 42. Abe, M.; Murai, M.; Ichimaru, N.; Kenmochi, A.; Yoshida, T.; Kubo, A.; Kimura, Y.; Moroda, A.; Makabe, H.; Nishioka, T.; Miyoshi, H. Biochemistry 2005, 44, 14898-14906. 43. Ichimaru, N.; Abe, M.; Murai, M.; Senoh, M.; Nishioka, T.; Miyoshi, H. Bioorg. 145 Med. Chem. Lett. 2006, 16, 3555-3558. 44. Makabe, H.; Kimura, Y.; Higuchi, M.; Konno, H.; Murai, M.; Miyoshi, H. Bioorg. Med. Chem. 2006, 14, 3119-3130. 45. Ichimaru, N.; Yoshinaga, N.; Nishioka, T.; Miyoshi, H. Tetrahedron 2007, 63, 1127-1139. 46. Hattori, Y.; Kimura, Y.; Moroda, A.; Konno, H.; Abe, M.; Miyoshi, H.; Goto, T.; Makabe, H. Chem. Asian J. 2006, 1, 894-904. 47. Yao, Z. J.; Wu, H. P.; Wu, Y. L. J. Med. Chem. 2000, 43, 2484-2487. 48. Zeng, B. B.; Wu, Y. K.; Yu, Q.; Wu, Y. L.; Li, Y.; Chen, X. G. Angew. Chem. Int. Ed. 2000, 39, 1934-1937. 49. Zeng, B. B.; Wu, Y. K.; Jiang, S.; Yu, Q.; Yao, Z. J.; Liu, Z. H.; Li, H. Y.; Li, Y.; Chen, X. G.; Wu, Y. L. Chem. Eur. J. 2003, 9, 282-290. 50. Jiang, S.; Liu, Z. H.; Sheng, G.; Zeng, B. B.; Cheng, X. G.; Wu, Y. L.; Yao, Z. J. J. Org. Chem. 2002, 67, 3404-3408. 51. Jiang, S.; Li, Y.; Chen, X. G.; Hu, T. S.; Wu, Y. L.; Yao, Z. J. Angew. Chem. Int. Ed. 2004, 43, 329-334. 52. Huang, G. R.; Jiang, S.; Wu, Y. L.; Yao, Z. J.; Wu, J. R. Chembiochem 2003, 4, 1216-1221. 53. Hai-Xia Liu, G.-R. H. H.-M. Z. S. J. J.-R. W. Z.-J. Y. Chembiochem 2007, 8, 172-177. 54. Liu, H.-X.; Huang, G.-R.; Zhang, H.-M.; Jiang, S.; Wu, J.-R.; Yao, Z.-J. Chembiochem 2007, 8, 172-177. 55. Gallardo, T.; Zafra-Polo, M. C.; Tormo, J. R.; Gonzalez, M. C.; Franck, X.; Estornell, E.; Cortes, D. J. Med. Chem. 2000, 43, 4793-4800. 56. Tormo, J. R.; Estornell, E.; Gallardo, T.; Gonzalez, M. C.; Cave, A.; Granell, S.; Cortes, D.; Zafra-Polo, M. C. Bioorg. Med. Chem. Lett. 2001, 11, 681-684. 57. Duret, P.; Hocquemiller, R.; Gantier, J. C.; Figadere, B. Bioorg. Med. Chem. 1999, 146 7, 1821-1826. 58. Queiroz, E. F.; Roblot, F.; Duret, P.; Figadere, B.; Gouyette, A.; Laprevote, O.; Serani, L.; Hocquemiller, R. J. Med. Chem. 2000, 43, 1604-1610. 59. Derbre, S.; Roue, G.; Poupon, E.; Susin, S. A.; Hocquemiller, R. Chembiochem 2005, 6, 979-982. 60. Duval, R. A.; Poupon, E.; Brandt, U.; Hocquemiller, R. Biochim. Biophys. Acta-Bioenergetics 2005, 1709, 191-194. 61. Duval, R. A.; Poupon, E.; Romero, V.; Peris, E.; Lewin, G.; Cortes, D.; Brandt, U.; Hocquemiller, R. Tetrahedron 2006, 62, 6248-6257. 62. Duval, R. A.; Duret, P.; Lewin, G.; Peris, E.; Hocquemiller, R. Bioorg. Med. Chem. 2005, 13, 3773-3781. 63. Duval, R. A.; Lewin, G.; Peris, E.; Chahboune, N.; Garofano, A.; Drose, S.; Cortes, D.; Brandt, U.; Hocquemiller, R. Biochemistry 2006, 45, 2721-2728. 64. Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J. Org. Chem. 1982, 47, 3151-3153. 65. Hui, Y. H.; Rupprecht, J. K.; Liu, Y. M.; Anderson, J. E.; Smith, D. L.; Chang, C. J.; McLaughlin, J. L. J. Nat. Prod. 1989, 52, 463-477. 66. Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-m.; Zhao, G.-x.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995, 117, 10409-10410. 67. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988-7989. 68. Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369-2372. 69. Shunya Takahashi, A. K. T. N. Angew. Chem. Int. Ed. 2002, 41, 4751-4754. 70. Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993-1998. 71. Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. J. Org. Chem. 2005, 7, 2783-2786. 72. Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025-2028. 147 73. Bandur, N. G.; Bruckner, D.; Hoffmann, R. W.; Koert, U. Org. Lett. 2006, 8, 3829-3831. 74. Nonfon, M.; Lieb, F.; Moeschler, H.; Wendisch, D. Phytochemistry 1990, 29, 1951-1954. 75. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275-306. 76. Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. 77. Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269-303. 78. Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416-1429. 79. Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005, 127, 6946-6947. 80. Narayan, R. S.; Sivakumar, M.; Bouhlel, E.; Borhan, B. Org. Lett. 2001, 3, 2489-2492. 81. Sivakumar, M.; Borhan, B. Tetrahedron Lett. 2003, 44, 5547-5551. 82. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547. 83. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. 84. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157-405. 85. Padwa, A.; Gunn, J. D.; Osterhout, M. Synthesis 1997, 1353-1377. 86. Rodefeld, L.; Tochtermann, W. Tetrahedron 1998, 54, 5893-5898. 87. Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P. Tetrahedron 1998, 54, 1529-1562. 88. Koert, U.; Wagner, H.; Pidun, U. Chem. Ber. 1994, 127, 1447-1457. 148 89. Arndt, S.; Emde, U.; Baurle, S.; Friedrich, T.; Grubert, L.; Koert, U. Chem. Eur. J. 2001, 7, 993-1005. 90. White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57, 4991-4998. 91. Narayan, R. S. PhD Thesis, Michigan State University, East Lansing, 2004. 92. Yan, J.; Garzan, A.; Narayan, R. S.; Vasileiou, C.; Borhan, B. Chem. Eur. J. 2010, 16, 13749-13756. 93. Strand, F. L. The Plasma Membrane as a Regulatory Organelle, 1983, Pages 49-67. 94. (a) Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296-2298. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496. 95. Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5245-5253. 96. Suzuki, S.; Fujita, Y.; Kobayashi, Y.; Sato, F. Tetrahedron Lett. 1986, 27, 69-70. 97. Williams, D. R.; Sit, S. Y. J. Am. Chem. Soc. 1984, 106, 2949-2954. 98. Schneider, C. Synthesis 2006, 3919-3944. 99. Devine, P. N.; Oh, T. Tetrahedron Lett. 1991, 32, 883-886. 100. Robbins, M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76. 101. De March, P.; Figueredo, M.; Font, J.; Medrano, J. Tetrahedron 1999, 55, 7907-7914. 102. Clive, D. L. J.; Wickens, P. L.; Sgarbi, P. W. M. J. Org. Chem. 1996, 61, 7426-7437. 103. Marshall, J. A.; Sabatini, J. J. Org. Lett. 2006, 8, 3557-3560. 104. Zaidlewics, M.; Meller, J. Tetrahedron Lett. 1997, 38, 7279-7282. 105. Guha, S. K.; Koo, S. J. Org. Chem. 2005, 70, 9662-9665. 149 106. Motoyama, T.; Yabunaka, H.; Miyoshi, H. Bioorganic & Medicinal Chemistry Letters 2002, 12, 2089–2092. 107. Magee, D. I.; Wu, J.; Silk, P. J.; Mayo, P. D.; Ryall, K. Tetrahedron 2011, 67, 5329-5338. 108. Davoli, P.; Spaggiari, A.; Castagnetti, L.; Prati, F. Organic and Biomolecular Chemistry 2004, 38-47. 109. Brisset, H.; Gourdel, Y.; Pellon, P.; Corre, M. L. Tetrahedron Lett. 1993, 34. 4523-4526. 110. Sangaiah, R.; Christova-Gueorguieva, N. I.; Ranasinghe, A.; Tretyakova, N. Yu.; Gold, A.; Ball, L. M.; Swenberg, J. M. Journal of Labelled Compounds and Radiopharmaceuticals 1997, 39, 731-740. 111. Lin, S.; Deiana, L.; Tseggai, A.; Cordova, A. Eur. J. Org. Chem. 2012, 398-408. 112. Neumaier, J.; Maier, M.E. Synlett 2011, 187-190. 113. Davis, F. A.; Qi, H.; Sundarababu, G. Tetrahedron, 2000, 56, 5303-5310. 114. Dias, L. C.; Oliveira, L. G. Org. Lett. 2004, 6, 2587-2590. 115. Tosatti, P.; Nelson, A.; Marsden, S. P.; Campbell, A. J.; House, D. J. Org. Chem. 2011, 76, 5495-5501. 116. Savitsky; N. Journal of Physical Chemistry 1963, 67, 2754. 117. Ruggles, E. L.; Hondal, R. J.; Deker, P. B. Tetrahedron 2009, 65, 1257-1267 118. Braddock, D. C.; Bhuva, R.; Millan, D. S.; Perez-Fuertes, Y.; Roberts, C. A.; Sheppard, R. N.; Solanki, S.; Stokes, E. S. E.; White, A. J. P. Org. Lett., 2007, 9, 445-448. 119. Madelaine, C.; Ouhamou, N.; Chiaroni, A.; Vedrenne, E.; Grimaud, L.; Six, Y. Tetrahedron 2008, 64, 8878-8898. 120. Eya, B. K.; Otsuka, T.; Kubo, I.; Wood, D. L. Tetrahedron 1990, 46, 2695-2706. 121. Darwish, A.; Chong, J. M. Tetrahedron 2012, 68, 654-658. 150 122. Spino, C.; Tremblay, M. C.; Gobdout, C. Org. Lett. 2004, 6, 2801-2804. 123. Perlman, N.; Albeck, A. Synthetic Communications 2000, 30, 4443-4450. 124. Carvalho, J. F.; Prestwich, G. D. J. Org. Chem. 1984, 49, 1251-1258. 125. Rehbein, J.; Leick, S.; Hiersemann, M. J. Org. Chem. 2009, 74, 1531-1540. 125. Rao, C. B.; Chinnababu, B.; Venkateswarlu, Y. J. Org. Chem. 2009, 74, 8856-8858. 126. Thibonnet, J.; Abarbri, M.; Parrain, J. L.; Duchene, A. Tetrahedron 2003, 59, 4433-4442. 127. Wu, J.; Jiang, X.; Xu, J.; Dai, W. M. Tetrahedron 2011, 67, 179-192. 128. Collins, D. J.; Crosby, I. T. Australian Journal of Chemistry 1998, 51, 1025-1030. 129. Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J. J.; Rokach, J. J. Org. Chem. 1995, 60, 7548-7551. 130. Srihari, P.; Mahankali, B.; Rajendraprasad, K. Tetrahedron Lett. 2012, 53, 56-58. 131. Prasad, K. R.; Swain, B. J. Org. Chem. 2011, 76, 2029-2039. 132. Parsons, S. R.; Hooper, J. F.; Willis, M. C. Org. Lett. 2011, 13, 998-1000. 133. Rees, M. S.; Kuijk, F. J. G. M.; Siakotos, A. N.; Mundy, B. P. Synthetic Communications 1995, 25, 3225-3236. 134. Von Delius, M.; Hauke, F.; Hirsch, A. Eur. J. Org. Chem. 2008, 24, 4109-4119 135. Commandeur, M.; Commandeur, C.; Cossy, J. Org. Lett. 2011, 13, 6018-6021. 151 CHAPTER II Asymmetric Organocatalytic Halocyclization Reactions II.1. Introduction Although the field of asymmetric catalysis has flourished over the last four decades, 1 there are some areas that remain virtually untouched. One of these areas, is electrophilic addition to olefins. Here we discuss methods that accomplish asymmetric halogen addition reactions of olefins. The products of these reactions, chiral nonracemic O O X R R R1 R1 O O R O O R OR2 OR2 R1X R1 R R R1 X Nu R1 Scheme II-1: Catalytic asymmetric halogenation of carbonyl, dicarbonyl and olefins halogenated compounds are the most versatile building blocks in synthesis. Halogen incorporation also alters the physical properties of molecules, including steric and electronic effects that are related to biological activity. 2, 3 Over 4000 halogenated natural products have been discovered; the carbon–halogen bonds are generated in these natural 152 products enzymatically. 2 The catalytic asymmetric α-halogenation of carbonyl and 4, 5, 6 1,3-dicarbonyl compounds (Scheme II-1) has seen recent interest. These reactions can now be accomplished by a different methods. Electrophile-promoted nucleophilic addition reactions to olefins (Scheme II-1) are among the most powerful transformations in organic chemistry. II.1.1 Asymmetric Halogenation of Olefins: Stoichiometric Methods A few examples of asymmetric olefin halogenation have been studied. The most successful approaches to this problem was the use of stoichiometric chiral selenium or mercury reagents prepared by using multistep routes. 7, 8, 9 A few stoichiometric enantioselective halocyclization reactions have been reported, but most results in selectivity are moderate. The few highly effective methods are limited in scope. This is despite the fact that developing an asymmetric halocyclization reaction is a long-standing goal in asymmetric synthesis. 10 There are different examples in the literature that show a “chiral halogen” analogue should be able to transfer to products stereochemically when reacting with prochiral olefins. This reagent-controlled reactions has met with only 11 limited success in halogenation reactions. Grossman and Trupp reported the first reagent-controlled stereoselective halolactonization using a chiral iodonium species, in which the source of asymmetry was the dihydroquinidine–iodine complex II-3. The selectivities of 5-exo iodolactonization of II-1 to II-2 were up to 14% ee (Scheme II-2). 153 1.0 equiv II-6, I2 HO2C I O O II-2, 15% ee CH2Cl2, -78 ºC to rt 92% yield II-1 N AcO I BF4 MeO II-3 N 2 II-4 1.1 equiv II-4 OH II-5 Br BF4 N 2 Br CH2Cl2, -78 ºC O II-6 (2.4% ee) Scheme II-2: Early work on asymmetric halocyclization reactions 12 Cui and Brown also showed that the pyridine complex II-4 could induce the enantioselectivity in the bromocyclization of 4-penten-1-ol II-5 (2.4% ee). Wirth and co-workers showed that the addition of non-racemic chiral primary amines gave higher levels of enantioselectively in iodolactonization reactions (<40 % ee, Scheme II-3). 13 The mixture of ICl as halogen source and II-9 gave the best results with prochiral carboxylic acids II-7. The increase in selectivity of substrates of aryl ring with electron-withdrawing groups is due to the altered geometry of the intermediate iodonium ion, which is less stabilized and more reactive. 13 Reaction of the solid amine–ICl complex with carboxylic acids under solid-state reaction conditions, supports the idea that it is a chiral halogen complex that induces asymmetry during face-selective attack of the double bond. 14 Ester II-10, and amides II-11 can be cyclized under similar reaction without a major drop in enantioselectivity. 154 I II-9 (>100 mol%), ICl R CO2H O ! R CH2Cl2, -78 ºC, 24h II-7 O II-8 NH2 Ph Ph CO2tBu CONHR II-9 II-10 II-11 Scheme II-3: Amines catalyze iodolactonization in low ee In 2003, Gouverneur and co-workers reported that the electrophilic fluorodesilylation with the enantiopure N-fluorocinchona alkaloids provided a highly efficient method for preparation of allylic fluorides with high ee. The (DHQ)2PYR/Selectfluor combination fluorinated cyclic allylsilanes in MeCN to give five and six membered chiral allyl fluorides (Scheme II-4). An asymmetric semipinacol rearrangement of racemic allylic alcohols, also mediated (DHQ)2PYR/ Selectfluor SiMe3 R F nR MeCN, -20 ºC, 24h >95% conversion II-12a R=CH2Ph, n=1 n II-13a (96% ee) II-13b (83% ee) II-12b R=CH2Ph, n=2 Et N N F Cl 2 BF4 Selectfluor N O O N MeO N N Et OMe N (DHQ)2PYR Scheme II-4: Enantioselective fluorodesilylation of allyl silne 155 by a combination of chinchona alkaloids and Selectfluor. 16 Best results were obtained with excess quinine/Selectfluor in MeCN in the presence of an inorganic base. The yields are low, but analysis of recovered starting materialshowed that it was racemic, so kinetic resolution was ruled out as the enantiodetermining step. Electron-donating groups in the ortho or para positions on the migrating aromatic ring were necessary to get better enantioselectivity. The highest reported ee is a naphthyl group (Scheme II-5). OH quinine/Selectfluor (1:1, 1.4 equiv) CHO K2CO3, MeCN rt, 6 days, II-14 45% yield, 82% ee F II-15 Scheme II-5: Quinine/Selectfluor mediated asymmetric semipinacol rearrangement Examples of enantioselective fluorocyclization of alkenes are scarce. Gouverneur and 17 co-workers recently reported the first asymmetric example of enantioselective fluorocyclization. The (DHQ)2PHAL/Selectfluor combination could provide asymmetry Selectfluor Ph HO II-16 (DHQ)2PHAL, NaHCO3 SiiPr2p-Tol MeCN, -20 ºC, 4 days 70% yield F Ph SiiPr2p-Tol O (+)-II-17 (45% ee) Scheme II-6: Enantioselective fluorocyclization in the cyclization of prochiral allyl silane II-16 to produce II-17 (70% yield, 45 % ee) (Scheme II-6). Snyder group developed a number of new racemic reagents for polyene 156 cyclizations. 18 Initial explorations illustrated that C2-symmetrical sulfide derivatives can induce enantioselectivity in the chlorination of olefin II-18 (Scheme II-7). Cl SbCl4 Cl S II-18 Cl CH2Cl2 -78 to -20 ºC, 2h II-19 II-20 (57% yield, 14% ee) Scheme II-7: C2-symmetric sulfide can induced asymmetry in chlorination reaction II.1.2 Asymmetric Halogenation of Olefins: Catalytic Methods There are a few catalytic asymmetric examples for olefin halogenation. Many of these results have been reported in the last few years. Denmark and co-workers, demonstrating the careful mechanistic work of Brown and co-workers, 22 that enantiopure bromonium ions with olefins. 20 20, 21 19 have shown may undergo degenerate halogen-exchange reactions The unreacted alkene is present until the end of the reaction, so the relative rates of racemization and nucleophilic capture must be overcome to achieve a successful catalytic enantioselective bromination. When tosylate II-21 was treated in hexafluoroisopropanol (HFIP) with NaOAc, complete retention of configuration was observed (Scheme II-8). Addition of (E)-4-octene II-23 to the reaction mixture caused a dramatic loss of enantiospecificity, which could not be improved by using a large excess of NaOAc. Substituting n-Bu4NOAc led to enhancement of the enantiospecificity. Chloronium ions, were found to have lower stability than bromonium ions but enantiomeric erosion 157 OTs n-Pr n-Pr HFIP, rt Br II-21 (er=98:2) n-Pr II-21 + n-Pr (er=98:2) II-23 (1.0 equiv) II-21 + (er=98:2) n-Pr n-Pr II-23 (1.0 equiv) OTf n-Pr n-Pr Cl II-24 (er=98:2) II-24 + (er=98:2) OAc NaOAc (2.0 equiv) n-Pr n-Pr Br II-22 (79% yield, er=97:3) NaOAc (2.0 equiv) HFIP, rt II-22 (75% yield, er=62:38) n-Bu4NOAc (5.0 equiv) HFIP, rt II-22 (81% yield, er=95:5) OAc n-Bu4NOAc (2.0 equiv) HFIP, CH2Cl2, rt n-Pr n-Pr Cl II-25 (32% yield, er=98:2) n-Pr n-Bu4NOAc (2.0 equiv) II-25 n-Pr (43% yield, er=98:2) II-23 (1.0 equiv) HFIP, CH2Cl2, rt Scheme II-8: Mechanistic work on racemization of bromonium ions was not observed in conversion of II-24 to II-25 even in the presence of II-23. The inverse relationship between chemical and stereochemical stability is attributed to the relative electronegativity of the halonium ions. The more electronegative chlorine places more positive charge on the carbon atom, and the less electronegative bromine carries more of the positive charge. The bromonium ion is more stable toward elimination and rearrangement, but allows olefin to olefin transfer of bromine by nucleophilic attack by the olefin at bromine, 19 following formation of the olefin π complex. 20 Another mechanistic study by Denmark and co-worker showed that sulfur, selenium, and phosphorus donors can accelerate halocyclization reactions with NBS and 158 N-iodosuccinimide (NIS). 23 In 1979 Julia and co-worker reported addition of chlorine to a variety of alkenes under asymmetric phase-transfer conditions. 24 More recently, chiral quaternary ammonium salts II-27 derived from cinchona alkaloids were found to induce low levels II-27 (0.3 equiv) CH2Cl2, H2O NaHCO3, 0 ºC I I O O Ph II-28 (17% ee) (ratio=56:44) cinchonidine (1.1 equiv) Ph O II26 OH I2, CH2Cl2, 0 ºC, (ratio=0:100) + Ph O O II-29 (28% ee) II-29 (35% ee) Cl HO H N II-27 N Scheme II-9: Iodolactonization catalyzed by chiral quaternary ammonium salt of asymmetry (<35% ee) during iodolactonizations of trans-5-aryl-4-pentenoic acids II-26 (Scheme II-9) under catalytic conditions. cinchonidine provided exclusively II-29. 25 When using stoichiometric alkaloids, 26 Several organocatalytic methods for enantioselective halolactonization of carboxylic 27 acids were reported in 2010. All of these studies use bifunctional catalysts. Our group reported the first catalytic enantioselective chlorolactonization of exocyclic 4-substituted pentenoic acids II-7 mediated by (DHQD)2PHAL or (DHQ)2PHAL and DCDPH (1,3-dichloro-5,5-diphenylhydantoin). When substrates II-7 were allowed to react in 159 CHCl3–Hexane, in the presence of benzoic acid, the corresponding chlorolactones II-30 were obtained with high enantioselectivities (Scheme II-10). Aliphatic substituents led to lower enantioselectivity. experiments suggest a hydantoin/catalyst complex 1 H NMR spectroscopy (II-31 or II-32) imparts enantioselectivity and rate acceleration. Subsequent mechanistic studies indicate the N1 chlorine of the dichlorodiphenyl hydantoin serves as an inductive activator, and the N3 chlorine is delivered to the substrate. (DHQD)2PHAL (0.1 equiv) DCDPH (1.1 equiv) OH R O O O PhCO2H (1.0 equiv) R Cl II-30 (43-90% ee) CHCl3/Hex (1:1), -40 ºC II-7 Et R 28 N Et N H H O Cl N N Cl II-31 O Ph Ph R or MeO N H Cl O N N Cl O II-32 Ph Ph H O N N NN O H MeO (DHQD)2PHAL N Scheme II-10: Catalytic enantioselective chlorolactonization 160 O 15% II-37, II-38 (1-2 equiv) Ph OH I II-34 15% II-37, II-38 (1-2 equiv) OH O O I II-36 Ph I2, (15 mol%), Toluene -80 ºC, 5 days 82% yield, 90% ee O II-35 Ph I2, (15 mol%), Toluene 87% yield, 94% ee II-33 Ph O O CF3 O O F3C N II-37 H N I N H F NPent2 CF3 II-38 O CF3 O O N H N H O F3C N F3C NPent2 I N H O O N H O O N H NPent R 2 I O F F II-39 II-40 Scheme II-11: Jacobsenʼs catalytic asymmetric iodolactonization reaction Jacobsen and co-worker used a aminourea catalyst to achieve enantioselectivity iodolactonization. 29 + Tertiary aminourea complex II-37 combined with an I source gave five and six-membered iodolactones with high enantioselectivity. They used the catalytic I2 in combination with an N-iodoimide, with N-iodo-4-fluorophthalimide II-38. In the case of 5-substituted hexenoic acid derivatives (such as II-33, Scheme II-11), a correlation between the electronic properties 161 of the olefin substituent and enantioselectivity was observed, with electron deficient derivatives undergoing more enantioselective cyclization. Mechanistically, the iodonium ion of hexenoic acid II-33 formed intermediate iodonium ion complex II-40, which keeps a tertiary amino iodoium ion interaction during cyclization. In the case of pentenoic acid II-35, a lower I2 loading was needed. OH R O 10% II-43, NsNH2 NBS (1.2 equiv) O CHCl3:Tol (1:2), -78 ºC O II-7 Ph 10% II-43, NsNH2 NBS (1.2 equiv) CHCl3:Tol (1:2), -78 ºC O OH II-26 MeO R Br II-41 (82-90% ee) Br Ph O O II-42 80% yield, 80% ee S N OMeH O H N II-43 N Scheme II-12: Catalytic enantioselective bromolactonization Catalytic enantioselective bromolactonization of the exocyclic pentenoic acids II-7 can be mediated by cinchonine derived thiocarbamate catalysts II-43 (Scheme II-12). 30 The high levels of enantioselectivity are proposed to be due to the rigid skeleton and bifunctional nature of the catalyst II-43. Structural variation of the catalyst shows that the NH and S of the thiocarbamate are necessary for the high selectivity. The optimized procedure was also found to be applicable to the formation of an enantioenriched 162 O R 10% II-46, DBDMH OH N NH H N Ph N N Ph O II-45 (72-91% ee) Ph Ph O R Toluene, -40 ºC II-44 Br HN II-43 Ph Ph Scheme II-13: Catalytic enantioselective bromocyclizations δ-lactone II-42. Asymmetric bromolactonization catalyzed by a C3-symmetric chiral trisimidazoline 31 II-46 with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) was also recently reported (Scheme II-13). Fujioka and co-workers suggest that a chiral-ion pair between the catalysts and substrate causes enantioselectivity, but they did not rule out the possibility of the catalyst activating the brominating agent. Hennecke and co-workers recently reported a promising organocatalytic approach to 32 haloetherfications by desymmetrization of in situ generated meso halonium ions. The approach is based on selectively opening halonium ions in the presence of a chiral counteranion and aims to circumvent the potentially insufficient stereochemical integrity of halonium ions by alkene-to-alkene transfer. 19, 21 Treatment of symmetrical diol II-47 with chiral phosphoric acid salt II-51a in the presence of electrophilic iodine sources 163 gave enantioenriched II-48 under practical reaction conditions. Enantioselectivities for bromocyclizations can reach up to 67% ee (Scheme II-14). The authors suggest that OH 20% II-51a II-52 (1.2 equiv) HO 20% II-51a NBS (1.2 equiv) HO Ph Ph CH2Cl2, M.S. (4Å) Ph Ph II-49 SiPh3 II-48 (81% yield, 62% ee) O Ph Ph Br OH Ph Ph II-50 (82% yield, 67% ee) O O O O P OX SiPh3 I OH CH2Cl2, M.S. (4Å) II-47 OH O N I II-51a (X=Na) II-51b (X=Li) II-52 Scheme II-14: Counterion controlled asymmetric opening of meso-halonium ions similar levels of enantioselectivity were observed by using sodium salt II-51a or lithium salt II-51b, and also show that the catalyst cannot be acting as a Lewis acid, but can activates the halogenating agent prior to halonium ion generation. The Tang group recently discovered a DABCO-catalyzed syn-selective 1,4-bromolactonization of enynes. This reaction gave axially chiral allenes as the major 33 products and the same group also demonstrated that the catalyst II-55 promotes highly enantioselective bromolactonization of (Z)-enynes II-53 and II-56 to give bromoallenes II-54 and II-57 (Scheme II-15). 34 Reactions with catalysts related to II-55 revealed the importance of the hydrogen bond donating urea, as well as the configuration at the center bearing this group. The quinuclidine nitrogen of the catalyst is also critical for activity 164 and it is proposed that II-55 may both activate the system by deprotonation of the acid and activation of the NBS by hydrogen bonding. X O R OH NBS (1.2 equiv) Cl(CH2)2Cl, rt X O 20 mol% II-55 II-53 R Br O II-54 (62-70% ee) OMe N II-55 NH N R O CO2H O NBS (1.2 equiv) Cl(CH2)2Cl, rt NTs R O Br 20 mol% II-55 O II-56 H O II-57 (98-99% ee) Scheme II-15: Enantioselective bromolactonization of conjugated (Z)-enyne 35 II.2. A Catalytic Asymmetric Chlorocyclization of Unsaturated Amides We have recently reported the catalytic asymmetric chlorolactonization of alkenoic acids.27 We were interested by the possibility of a one-step access to chiral heterocycles such as oxazolines and dihydrooxazines by a catalytic asymmetric halocyclization of unsaturated amides. The conversion of benzamide II-58 to oxazoline II-59 was studied in the presence of (DHQD)2PHAL as the best catalyst candidate affording the desired oxazoline II-59 in 68-98% ee (Table II-1) with DCDPH as the terminal chlorine source. 35 Reactions with other chlorenium sources were marred with poor 165 enantioselectivities and/or poor conversions. Solvent screening process revealed trifluoroethanol (TFE) to be the optimal solvent for the chlorocyclization. The effect of catalyst loading, concentration and temperature was also studied. It was observed that the stereoselectivity of this reaction was not diminished even at a catalyst loading of 2 mol%. Table II-1: Chlorocyclization of 1,1-disubstituted olefin substrates Br H N Ar Br 2 mol% (DHQD)2PHAL 1.1 equiv DCDPH TFE, -30 ºC, 1 h O II-58 O N Cl Ar a Entry Yield (%) 1 Ph 93 3-NO2-Ph 75 68 3 3-OMe-Ph 72 93 4 4-F-Ph 65 87 5 4-Br-Ph 89 84 6 4-Cl-Ph 94 b 98 2 a R II-59 87 ee (%) b Isolated yields after column chromatography. ees were determined by HPLC analysis. It also emerged that a concentration of 0.04 M and a temperature of -30 ºC was optimal. 35 We discovered that the same reaction conditions could be extended to trans-disubstituted and trisubstituted olefin substrates which yielded the corresponding dihydro-4-H-1,3-oxazines (Table II-2). These reactions were more stereoselective and 166 almost all of the substituted phenyl rings evaluated gave 20->99% enantioselectivity. The Table II-2: Chlorocyclizaion of trans-disubstituted olefin substrates 2 mol% (DHQD)2PHAL Ar R2 O 1.1 equiv DCDPH O N N Ar R2 R1 TFE, -30 ºC, 1-2 h R1 II-60 H II-61 Cl 1 Entry R Yield 2 Ar R (%) a ee (%) 1 H 4-Br-Ph 91 99 2 Ph H 4-OMe-Ph 93 >99 3 4-F-Ph H 4-Br-Ph 99 95 4 4-BrPh H 4-Br-Ph 85 93 5 4-CF3-Ph H 4-Br-Ph 94 95 6 4-OMe-Ph H 4-Br-Ph 84 20 7 4-Me-Ph H 4-Br-Ph 93 60 8 2-Me-Ph H 4-Br-Ph 99 87 9 2-Me-Ph H 4-OMe-Ph 64 91 10 a Ph Ph Ph 4-Br-Ph 92 b 86 b Isolated yields after column chromatography. ees were determined by HPLC analysis. 4-Br-Ph was determined as the optimal amide end functionality for the 1,1 and trans disubstituted olefin substrates. Electron deficient aryl rings presented no problems yielding excellent stereoselectivities (Table II-2, entries 2, 3, 5). Electron rich 167 substituents led to significant erosion of stereoselectivity. For example the 4-OMe-Ph substituted amide gave the corresponding product in only 20% ee and 84% isolated yield Br 2 mol% (DHQD)2PHAL O DCDPH (1.1 equiv) N H Br II-62 OTFE O O N TFE, -30 ºC N Cl H + Cl II-63 40% yield, >99% ee II-64 35% yield Scheme II-16: Chlorocyclization of aliphatic olefin in TFE (Table II-2, entry 6). The 4-Me-Ph substituent also gave only moderate levels of stereoinduction affording product in 60% ee (Table II-2, entry 6). The 2-Me-Ph group was better tolerated returning the corresponding product in excellent yield (99%) and good enantioselectivity (87% ee, Table II-2, entry 8). This result indicates that the amide Br O N H 2 mol% (DHQD)2PHAL DCDPH (1.1 equiv) Br O N CHCl3, -30 ºC Cl II-63 II-62 92% yield, 93% ee Scheme II-17: Chlorocyclization of aliphatic olefin in CHCl3 end functionality is an invaluable handle for electronic and steric fine-tuning, allowing for the systematic optimization of the enantioselectivity for a given substrate. Trisubstituted olefin substrate was also compatible with this chemistry (Table II-2, entries 168 Br Table II-3: Solvent screen of chlorocyclization of aliphatic olefin Br 2 mol% (DHQD)2PHAL O DCDPH (1.1 equiv) N H Br O Solvent, -30 ºC Cl II-63 II-62 a Entry Solvent Yield (%) 1 TFE 40 CHCl3 92 93 3 CHCl3-TFE (9:1) 92 87 4 CHCl3-TFE (8:2) 94 79 5 CHCl3-TFE (1:1) 90 b >99 2 a N 53 ee (%) b Isolated yields after column chromatography. ees were determined by HPLC analysis. 10). The absolute stereochemistry of 2-(4-bromophenyl)-5-chloro-6-phenyl-5,6-dihydro4H-1,3-oxazine (Table II-2, entry 1) was verified by X-ray diffraction and was inferred by analogy for other substrates. 35 Substrates with aliphatic olefin substituents were next studied. Substrate II-62 was prepared and evaluated using the standard conditions shown in Table II-2. The main problem for this reaction was the incorporation of TFE as a nucleophile to generate II-64 in 35% yield along with the desired product II-63 in 40% yield and >99% ee (Scheme II-16). To solve this problem, we examined other solvents that cannot participate as 169 Table II-4: Solvent screen of chlorocyclization of aliphatic olefin Br O N H 2 mol% (DHQD)2PHAL DCDPH (1.1 equiv) Br II-62 O Solvent, -30 ºC M.S. 4 Å Cl II-63 a Entry Solvent Yield (%) 1 CHCl3-Hex (1:1) 94 CH3CN-CCl4 (1:1) 87 80 3 1-nitropropane 77 b 64 2 a N >99 ee (%) b Isolated yields after column chromatography. ees were determined by HPLC analysis. nucleophile (Scheme II-17). This reaction proceeded well in CHCl3 and provided the desired product in high yield (92%) and good selectivity (93% ee) albeit with lower selectivity in comparison to TFE. Next, we studied different mixture of CHCl3 and TFE. In all cases the enantioselectivity drop although the yield of the reactions remained good (Table II-3). The enantioselectivity of the reaction in CHCl3-Hex was less selective than CHCl3 (64% ee, Table II-4, entry 1). The selectivity could be further enhanced to 80% ee when CH3CN-CCl4 was utilized as the solvent, however it was still lower than CHCl3 (Table II-4, entry 2). Fortunately, the use of 1-nitropropane in the presence of 4 Å molecular sieves alleviated our problem and the product II-63 was obtained in high yield and high 170 selectivity (>99% ee, Table II-4, entry 3). Likewise, the conformationally more flexible n-pentyl substituent was also well tolerated and returned the corresponding product in excellent yield (90%) and ee (>99% Table II-5: Chlorocyclization of aliphatic olefin substrates Br O R N H 2 mol% (DHQD)2PHAL DCDPH (1.1 equiv) Br 1-nitropropane, -30 ºC M.S. 4 Å R Cl a Entry R Yield (%) 1 Cy 77 n-C5H11 90 >99 3 CH2Cy 80 b >99 2 a N O 88 ee (%) b Isolated yields after column chromatography. ees were determined by HPLC analysis. ee, Table II-5, entry 2). Cy-CH2 substitute also produced the corresponding product in 35 good enantioselectivity (88% ee, Table II-5, entry 3). It is important to note that no regioisomeric 5 membered ring products were detected under the optimized reaction conditions for aliphatic substrates. Also, the absolute stereochemistry of products with aliphatic substituents was the same as that for products with aryl substituents (as verified by X-ray diffraction of II-63). 35 Substrates with Z-olefins did not undergo halocyclization to the desired products presumably due to stereoelectronic constraints 171 a Nu Nu Nu X X X b (DHQD)2PHAL (10 mol%) OH R O c O R2 N R1 H DCDPH (1.1 equiv) O O R3 Benzoic acid (1.0 equiv) R CHCl3:Hex (1:1), -40 ºC Cl up to 90% ee O N H R2 1 R Cl (DHQD)2PHAL (1-2 mol%) DCDPH (1.1 equiv) R3 R3 Solvent, -30 ºC O N Cl up to >99% ee R1 R2 Figure II-1: a) Generalized halocyclization reaction, b) Recently developed catalytic enantioselective chlorolactonization reaction and c) chlorocyclization of unsaturated amides which are well precedented in halolactonization reactions of similar substrates. 36 II.3. Evaluation of Other Reactions With (DHQD)2PHAL Catalyst System Electrophilic halocyclizations of olefins, depicted in general terms in Figure II-1, are common and important reactions in organic chemistry; however controlling the enantioselectivity of these reactions is not trivial. 37, 38 Two challenges in this class of asymmetric transformations are: (1) developing an efficient catalyst system which delivers the halenium to the olefin in an enantioselective fashion and (2) preventing racemization of the resulting chiral halonium, which can be eroded by a process known as olefin to olefin transfer. 19 172 OMe HO OMe NBS, CHCl3, EtOH O PPh3, DEAD, THF O O Ph II-65 O N H O Ph N O Ph Ph II-66 OMe OMe O Br N COPh O Ph OEt O Br NHCOPh PhCOO II-68 II-67 Scheme II-18: Synthesis of the benzoate-amide II-68 The general, mechanism of all halocyclizations involves the formation of a halonium intermediate, which then undergoes attack by an intramolecular nucleophile to create a ring. Based on this mechanism, two different strategies can be used to acquire high enantioselectivity in various halocyclizations. One relies on the chiral delivery of the O OH NH2 + CrO3, H5IO6 Ac2O, CH3CN O Ph 71% yield O N O NsCl, Et3N, DMAP quantative yield Ph O N Ph H II-69 PPh3, DIAD, THF N Ph H allyl alcohol, 70% yield II-70 Ph Ph O II-71 Scheme II-19: Synthesis of the imidate II-71 173 halenium to the olefin, while the other relies on the asymmetric attack of the nucleophile to the halonium. A recent breakthrough in our lab has led to the development of a NBS or DMDCH Ph N O X CHCl3, EtOH O O (DHQD)2PHAL (5 mol%) Ph Ph X + Ph HN Ph N H O X X=Br II-74a O X=Cl II-74b O N COPh Ph OEt X=Br II-72a X=Cl II-72b O O O + Ph OEt 0% ee O X N COPh X=Br II-73a X=Cl II-73b Ph X=Br II-75a X=Cl II-75b Scheme II-20: Reaction of imidate II-71 with NBS and DCDMH catalytic, enantioselective chlorolactonization of chlorocyclization of unsaturated amides (Figure II-2). application of the 35 alkenoic 27, acids 28 and Disscused in this chapter are the (DHQD)2PHAL catalyst system for the development the other asymmetric halocyclization. In 1985, Sammes and Thetford showed that the imidate II-66 with N-bromosuccinimide in chloroform containing ethanol produced the ortho-amide II-67, which was readily hydrolyzed in situ, under acidic conditions, to give the benzoate-amide 39 II-68 (Scheme II-18). We attempted to develop an asymmetric version of this reaction under our catalytic system. For this purpose, imidate II-71 was synthesized in a few steps as is shown in 174 Table II-6: Reaction of imidate II-79 with different halogen sources and temperature O Ph O Ph N Ph H II-70 OH Ph PPh3, DIAD, THF 57% yield Halogen source CHCl3, EtOH (DHQD)2PHAL (5 mol%) 0% ee II-79 O HN Ph Ph O Ph O Ph N O Ph O O X + Ph Ph O X X=Br II-80a O X=Cl II-80b N H Ph X=Br II-81a X=Cl II-81b Entry Halogen source Temperature Conversion (%) II-80:II-81 1 NBS rt 77 1:1 2 NBS -40 ºC 80 1:1 3 DCDMH rt 90 1:1 4 DCDMH -40 ºC 50 1:1.5 5 TCCA rt 90 1:1 6 TCCA -40 ºC 80 1:1 Scheme II-19. Amidation of benzoic acid with benzyl amine, followed by oxidation of the methylene provided II-70. Mitsunobu reaction afforded our desired imidate II-71 in 70% yield. Imidate II-71, under our catalytic system reacted with NBS to provide regioisomers II-74a and II-75a (1:1 ratio) with no apparent enantioselectivity. The lack of regio and enantioselectivity was also observed when DCDMH was used as the chlorionium source (Scheme II-20). The 1,1-disubstituted olefin II-76 was synthesized in hopes of gaining 175 regioselectivity. Suprisingly, the reaction of imidate II-76 with NBS or DCDMH in the presence of (DHQD)2PHAL provided once again a 1:1 regioisomeric mixture of products without enantioselectivity (Scheme II-21). O Ph O OH Ph N Ph H II-70 PPh3, DIAD, THF 68% yield N O Ph Ph Ph O II-76 NBS or DMDCH O CHCl3, EtOH (DHQD)2PHAL (5 mol%) Ph O Ph O HN 0% ee X + Ph Ph O X=Br II-77a X=Cl II-77b O Ph O X N H Ph X=Br II-78a X=Cl II-78b Scheme II-21: Reaction of imidate II-76 with NBS and DCDMH Since addition of phenyl group in C2 was not helpful for improving the regio and enantioselectivity, the trans-substituted imidate was examined. Table II-6 shows the use of a variety of halogen sources and temperature utilized for this reaction. The best result Y Z NXS, Sm(OTf)3 (cat.) R1 R2 II-82 Y = O, NR, CH2 Z = O, 2H X = Br, I Y Y Z R1 + R2 X II-83 Z R1 X R2 II-84 Scheme II-22: Lewis acid catalyzed intramolecular haloarylation of alkenes using N-halosuccinimide (NXS) as the halogen source 176 was obtained when DCDMH at -40 ºC was used to give II-81a:II-81b (1:1.5), in 50% conversion after 24 h (Table II-6, entry 4). No enantioselectivity was observed in any of the examples. The lack of success was probably due to low interaction of substrate and catalyst. In order to develop new asymmetric reaction with (DHQD)2PHAL catalyst, the other halocyclization reactions was examined. Hajra and co-workers in 2005 developed a Lewis acid catalyzed intramolecular haloarylation of alkenes using inexpensive and easily available N-halosuccinimide (NXS) as O O OH PhOH, DCC, DMAP CH2Cl2, 75% yield O II-85 Scheme II-23: Synthesis of alkene II-85 the halogen source. This catalytic process is a regio and stereoselective method and is utilized to synthesize a diverse range of structural motifs, such as chromanones, chromans, quinolones, tetrahydroquinolines and tetralins with halofunctionality (Scheme II-22). 40 O O DCDMH, Cu(OTf)2 (10 mol%) CH3CN, 60% yield O O Cl II-85 II-86 Ph Scheme II-24: Racemic intramolecular haloarylation of alkene II-85 We tested the intramolecular haloarylation reactionwith our catalytic system. The desired olefin was synthesized in one step as shown in Scheme II-23. Initially, the racemic haloarylation of alkene II-85 was examined, in the presence of 177 DCDMH as the halogen source in acetonitrile with copper triflate instead of samarium triflate (the best second catalyst for this reaction), 40 providing the desired product in 60% Table II-7: Solvent screen for chloroarylation of II-85 O O II-85 DCDMH, Cu(OTf)2 (10 mol%) (DHQD)2PHAL (10 mol%) Solvent, -30 ºC Entry Solvent ee (%) 1 CH3CN 2 a O O Cl II-86 Ph Entry Solvent ee (%) 0 6 acetone 0 CHCl3 2 7 THF 0 3 CH2Cl2 0 8 TFE 4 4 DMSO 0 9 CHCl3-Hex a 2 (1:1) 5 a DMF 0 10 1-nitropropane 1 ees were determined by HPLC analysis. yield (Scheme II-24). This reaction in the presence of (DHQD)2PHAL showed no enantioselectivity, so a comprehensive solvent screen was performed in an attempt to drive the enantioselectivity of the reaction higher. Ten different solvents were screened in the test reaction (II-85 to II-86). The range of solvents screened included protic, aprotic, non-polar and polar examples (Table II-7). None of the solvents led to high enantioselectivity of the desired product II-86. TFE retuned the product in 4% ee accounting for the highest selectivity 178 obtained for this reaction (Table II-7, entry 8). We decided to investigate the enantioselectivity of the chlorocyclization reaction in the presence of different hydantoins and other chlorine sources. We investigated three hydantoins with different substituentsat C5 (Table II-8). In the TFE solvent system, going from dichloro-dimethyl hydantoin (4% ee, Table II-8, entry 1) to dichloro-diphenyl hydantoin (Table II-8, entry 2) the selectivity Table II-8: Halogen source screening halogen source O O II-85 Entry Halogen source Cu(OTf)2 (10 mol%) (DHQD)2PHAL (10 mol%) TFE, -30 ºC ee (%) a O O X Ph ee Entry Halogen source (%) 1 DCDMH 4 4 NCS 0 2 DCDPH 4 5 TCCA 0 3 DCDHH 2 6 NBS a 0 a ees were determined by HPLC analysis. remain almost the same. The removal of the C5 substitute on the chlorohydantoin returned II-86 in lowered 2% ee (Table II-8, entry 3). N-Chlorosuccinimide and trichloroisocyanuric acid (TCCA) produced an inferior result (0% ee, entries 4, 5). It is also noteworthy that the transformation in the presence of N-bromosuccimide (NBS) provides the desired product II-86 in racemic mixture (Table II-8, entry 6). 179 II.3.1. Synthesis of Asymmetric Cyclic Sulfates by Halocyclization Cyclic sulfates are versatile electrophiles. 41, 42 They react with a variety of nucleophiles 43 to facilitate the construction of natural products R + OSO3-PyH+ Br and specific functionality, such as O O O S O or R O O O S O R Br aziridines, 44 Br Figure II-2: Synthesis of cyclic sulfates by bromocyclization 45 46, modified sugars, and cyclopropane derivatives. 47 The use of cyclic sulfates was limited by the lack of an efficient method for their synthesis of methods for the oxidation of cyclic sulfite intermediates. 49 48 until the advent Access to cyclic sulfates incorporating a wider range of functional groups would expand applications. Kiessling and co-workers report a new method for cyclic sulfate synthesis (Figure II-2). 50 Via halocyclization reactions, six-membered and larger cyclic sulfate ring systems can be generated; these compounds are difficult to access through cyclic sulfite intermediates. Moreover, a diversity of functional groups can be incorporated into the halocyclization substrates, including those that are incompatible with oxidants needed to convert cyclic sulfites to sulfates. The halocyclization process occurs with predictable regioselectivity, and the resulting products can be selectively modified. Significantly, this approach to cyclic sulfate formation introduces two new stereocenters, which could be used advantageously in organic syntheses (Figure II-2). 50 180 Initial efforts were geared towards establishing a test reaction to screen solvents for the asymmetric induction of cyclic sulfates. Our test substrate II-87 was synthesized in one step from trans-cinnamyl alcohol. A racemic chlorocyclization of corresponding sulfate returned the desired product II-88 in 95% yield (Scheme II-25). An initial screen Ph OH SO3•py. OSO3- PyH+ Ph pyridine 98% yield II-87 Cl OSO3- PyH+ Ph DCDMH, CHCl3 95% yield II-87 Ph O O S O O II-88 Scheme II-25: Racemic chlorocyclization of sulfate II-87 was conducted whereby a number of different solvents were assayed in the test reaction (II-87 to II-88). A control experiment with our catalytic reaction conditions employing 10 mol% of (DHQD)2PHAL at -40 ºC in chloroform (Table II-9, entry 1) returned halosulfate II-88 in 10% ee. Changing the solvent to acetonitrile resulted in a more selective transformation (14% ee, Table II-9, entry 2). Mixture of chloroform-hexanes (1:1) provided II-88 in 20% ee (Table II-9, entry 4). Excitingly, going to more polar and protic solvents such as n-PrOH increased the selectivity up to 93% (Table II-9, entry 5). The major problem for this transformation is the low stability of product II-88, which decomposed after a few hours even stored cold. 181 Table II-9: Solvent screening for chlorocylization of II-87 Cl DCDMH OSO3- PyH+ Ph (DHQD)2PHAL (10 mol%) Ph Solvent, -40 ºC II-87 a Entry yield (%) 1 CHCl3 82 CH3CN 87 14 3 CH2Cl2 75 12 4 CHCl3-Hex 79 20 5 n-PrOH 88 b 10 2 a Solvent ! ! O O S O O II-89 93 ee (%) Isolated yields after column chromatography. b ees were determined by HPLC analysis. Having discovered optimal conditions for the asymmetric chlorosulfonation of II-87, a number of analogous sulfate were prepared and evaluated using the standard conditions described above. In total, three additional 4-substituted sulfates were prepared (Figure OSO3- PyH+ F3C OSO3-PyH+ Ph II-90 II-91 OSO3- PyH+ II-92 Figure II-3: 4-Substituted sulfate substrate 182 II-3). These substrates were readily prepared from their corresponding trans-cinnamyl alcohol with sulfur trioxide pyridine complex. 50 Substrate II-90 was subjected to the chlorocyclization protocol at -40 ºC however no product was obtained after 24 h, presumably as a result of the electron poor nature of the olefin. Increasing the temperature to -20 ºC, 40% conversion was observed in 45% ee. The reaction reached to 100% conversion at 0 ºC but the enantioselectivity decreased to Table II-10: Substrate scope of for chlorocylization reaction Cl DCDMH (DHQD)2PHAL (10 mol%) OSO3- PyH+ n-PrOH, temperature Ar Ar ! ! O O S O O Temperature Entry Substrate Conversion ee (ºC) (%) (%) a 1 -40 0 - 2 II-90 -20 40 45 3 II-90 0 100 10 4 II-91 -40 100 - 5 a II-90 II-92 -40 100 - ees were determined by HPLC analysis. 10% (Table II-10). The cyclized product of substrate II-91 was not stable and after 1 work-up decomposed. From HNMR the main product is the elimination of the cyclic sulfate. The para-methyl substituted substrate II-92 returned chloro cyclized sulfate, base on crude NMR analysis, however it also decomposed after a few minutes. The aryl ring 183 with electron deficient group was the main problem for having low reactivity in low temperature and the enantioselectivity dropped by increasing the temperature. The product of aryl ring with electron deficient groups were not stable. 184 II.4 Experimental Section Commercially available starting materials were obtained from Aldrich or Fluka and were used without further purification. Unless otherwise mentioned, solvents were purified as follows: tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/benzophenone; methylene chloride (CH2Cl2) and toluene (PhCH3) was dried over calcium hydride (CaH2) and freshly distilled prior to use; DMF, DMSO, Et3N, and HMPA were distilled from CaH2 and stored over 4 Å molecular sieves. 4 Å molecular sieves were dried at 160 ºC under vacuum prior to use. All of the spectral data for known compounds either match those reported by Aldrich or by comparison to the literature report. 1 H NMR spectra were measured at 300, 500 or 600 MHz on a Varian Gemini-300, a Varian VXR-500 or Varian Inova-600 instrument respectively. Chemical shifts are reported relative to residual solvent (δ 7.24 ppm for CDCl3). 13 C NMR spectra were measured at 75 MHz on a Varian Gemini-300, at 125 MHz on a Varian VXR-500 or 150 MHz on a Varian Inova-600 instrument. Chemical shifts are reported relative to the central line of CDCl3 (δ 77.0 ppm). High resolution mass spectra were measured at the Michigan State University, Mass Spectrometry Laboratory. Optical rotations were measured on a Perkin-Elmer polarimeter (model 341) using a 1 mL capacity quartz cell with a 10 cm path length in chloroform. Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel 60 F254 185 plates. Compounds were visualized with UV light, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH. Column chromatographic purifications were performed using Silicycle 40-60 Å, 30-75 µm silica gel. All compounds purified by chromatography were sufficiently pure for use in further experiments. GC analysis was performed using HP (6890 series) GC system equipped with an Altech SE-54, 30 m × 320 µm × 0.25 µm column. Enantiomeric excess for all products was judged by HPLC analysis using DAICEL CHIRALPAK OJ-H, OD-H or AS-H columns. α−Phthalimido aryl ketones were synthesized from commercially available α−bromo acetophenones by previously reported methods. 51 1-Phthalimido-2-(4-bromophenyl)-2-ethanone MP: 229 – 233 °C 1 H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 5.4, 3.0 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.74 (dd, J = 5.4, 3.0 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 190.5, 168.2, 134.6, 133.5, 132.7, 132.6, 130.0, 129.8, 124.0, 44.5. 1-Phthalimido-2-(4-chlorophenyl)-2-ethanone 1 H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 2H), 7.88 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 5.07 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 189.9, 167.8, 140.6, 134.3, 134.2, 132.7, 132.2, 129.5, 129.3, 123.6, 44.1. 1-Phthalimido-2-(4-fluorophenyl)-2-ethanone MP: 151 – 152 °C 186 1 H NMR (300 MHz, CDCl3) δ 8.02-7.99 (m, 2H), 7.87-7.85 (m, 2H), 7.73-7.71 (m, 2H), 7.15 (t, J = 8.5 Hz, 2H), 5.07 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 189.9, 168.2, 134.6, 132.6, 131.2, 123.9, 116.7, 116.5, 116.4, 44.4; HRMS: Calcd. for C16H10FNO3: 283.0645; Found: 283.0639. 1-Phthalimido-2-(3-nitrophenyl)-2-ethanone 1 H NMR (500 MHz, CDCl3) δ 8.83 (t, J = 2.0 Hz, 1H), 8.49 (ddd, J = 8.5, 2.0, 1.0 Hz, 1H), 8.32 (ddd, J = 8.5, 1.0, 0.5 Hz, 1H), 7.90 (dd, J = 5.5, 3.0 Hz, 2H), 7.72 – 7.78 (m, 3H), 5.15 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 189.3, 167.6, 135.6, 134.3, 133.6, 132.1, 130.3, 128.3, 123.7, 123.1, 44.3. 1-Phthalimido-2-(3-methoxyphenyl)-2-ethanone 1 H NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 7.58 (td, J = 7.5, 1.5 Hz, 1H), 7.49 (dd, J = 2.5, 1.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.15 (ddd, J = 7.5, 2.5, 1.5 Hz, 1H), 5.09 (s, 2H), 3.84 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 190.9, 167.9, 160.0, 135.7, 134.1, 132.3, 129.9, 123.6, 120.6, 120.5, 112.4, 55.5, 44.3. MePPh3Br (1.07g, 3 mmol, 1.5 equiv) was suspended in anhydrous toluene (10 mL) and cooled in an ice bath. NaHMDS (3 mL of 1.0 M solution in THF, 3 mmol, 1.5 equiv) was added drop wise under N2 and the resulting yellow slurry was stirred for 0.5 h at 0 °C. The reaction vessel was then cooled to -78 °C (dry ice- acetone) and the ketone (2 mmol, 1.0 equiv) was added in a single portion under N2. After a further 10 min. the cooling bath was removed and the reaction was allowed to warm to ambient temperature. 187 A reflux condenser was attached and the reaction was refluxed (bath temp. ~120 °C) for 12-24 h (till reaction was complete by TLC). The reaction was poured into water (100 mL) and extracted with EtOAc (3 x 25 mL). The combined organics were washed sequentially with water (1 x 20 mL) and brine (1 x 20 mL) and then dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude products. Pure products were obtained after column chromatography on silica gel using EtOAc-Hexane gradient elution. 2-(3-Nitrophenyl)-3-phthalimido-1-propene 50% yield (white solid); Rf: 0.43 (30% EtOAc-Hex) (UV, PMA) 1 H NMR (600 MHz, CDCl3) δ 8.34 (t, J = 2.0 Hz, 2H), 8.12 (ddd, J = 8.4, 2.0, 1.0 Hz, 1H), 7.81 – 7.84 (m, 3H), 7.70 (dd, J = 5.4, 2.5 Hz, 2H), 5.56 (s, 1H), 5.34 (t, J = 1.5 Hz, 1H), 4.17 (t, J = 1.5 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 167.8, 148.4, 140.7, 140.2, 134.2, 132.3, 131.8, 129.4, 123.5, 122.9, 121.5, 117.1, 41.1; HRMS: Calcd. for C17H12N2O4: 308.0797; Found: 308.0797. 2-(3-Methoxyphenyl)-3-phthalimido-1-propene 75% (84% brsm) yield (Yellowish solid); Rf: 0.19 (15% EtOAc- Hex) 1 H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 4.5, 3.0 Hz, 2H), 7.69 (dd, J = 4.5, 3.0 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.06 – 7.08 (m, 1H), 7.02 (t, J = 2.5 Hz, 1H), 6.80 – 6.83 (m, 1H), 5.43 (s, 1H), 5.15 (d, J = 1.5 Hz, 1H), 4.67 (t, J = 1.5 Hz, 2H), 3.80 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 167.9, 159.5, 142.3, 139.9, 134.0, 132.0, 129.4, 123.4, 118.9, 188 114.7, 114.2, 113.8, 111.9, 55.3, 41.5; HRMS: Calcd. for C18H15NO3 : 293.1052; Found: 293.1046. 2-(4-Fluorophenyl)-3-phthalimido-1-propene 71% (82% brsm) yield (white solid); Rf: 0.52 (30% EtOAc-Hex) (UV, PMA); MP: 85 – 87 °C 1 H NMR (600 MHz, CDCl3) δ 7.82 (dd, J = 5.4, 3.0 Hz, 2H), 7.69 (dd, J = 5.4, 3.0 Hz, 2 3 2 2 2H), 7.44 (dd, J H-H = 9.0 Hz, J H-F = 5.4 Hz, 2H), 6.99 (dd, J H-H = J H-F = 9.0 Hz, 2H), 5.37 (s, 1H), 5.16 (t, J = 1.5 Hz, 1H), 4.65 (t, J = 1.5 Hz, 2H); 1 13 C NMR (150 MHz, 4 CDCl3) δ 167.9, 162.6 (d, JC-F = 245.6 Hz), 141.6, 134.5 (d, JC-F = 3.5 Hz), 134.0, 3 2 5 131.9, 128.1 (d, JC-F = 6.6 Hz), 123.4, 115.2 (d, JC-F = 21.1 Hz), 114.3 (d, JC-F = 1.1 Hz), 41.5; HRMS: Calcd. for C17H12NO2F: 281.0852, Found: 281.0842. 2-[2-(4-bromophenyl)allyl]isoindoline-1,3-dione 95% Yield (White solid); Rf: 0.32 (20% EtOAc-Hexanes) (UV, PMA) ; MP: 125-128 °C 1 H NMR (300 MHz, CDCl3) δ 7.82 (dd, J = 5.7, 3.0 Hz, 2H), 7.68 (dd, J = 5.7, 3.0 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 5.42 (s, 1H), 5.21 (d, J = 0.9 Hz, 1H), 4.65 (t, J = 0.9 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 190.1, 167.8, 134.2, 133.1, 132.3, 132.2, 129.6, 129.4, 123.6, 44.0; HRMS: Calcd. for C17H12BrNO2: 341.0051; Found: 341.0047. 2-(4-Chlorophenyl)-3-phthalimido-1-propene 77% Yield (White solid); Rf: 0.52 (30% EtOAc-Hexanes) (UV, PMA); MP: 114-119 °C 189 1 H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.67 (dd, J = 5.5, 3.0 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 5.40 (s, 1H), 5.19 (s, 1H), 4.64 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 167.8, 141.5, 136.8, 134.0, 131.9, 128.5, 127.7, 123.3, 114.8, 41.3; HRMS: Calcd. for C17H12NO2 Cl: 297.0557, Found: 297.0558. 3-Phthalimido-2-aryl-1-propene (1 mmol, 1.0 equiv) was dissolved in MeOH (5 mL). NH2NH2•H2O (98 µL, 1.5 mmol, 1.5 equiv) was introduced into the reaction vessel and the resulting suspension was stirred overnight. The reaction was then diluted with water (5 mL) and most of the MeOH was removed by rotary evaporation. Concentrated HCl (1 mL) was added and the resulting suspension was stirred for a further 30 min at ambient temperature. The precipitated solids were filtered and the filter cake was washed with water (2 x 2 mL). The combined filtrates were basified with solid NaOH and extracted with ether (3 x 5 mL) and concentrated to give the crude 2-arylprop-2-en-1-amines which were used in the next reaction without any purification. A solution of amine (9.0 mmol, 1.0 equiv), triethyl amine (1.04 mL, 18.0 mmol, 2.0 equiv) and a catalytic amount of DMAP in DCM (50 mL) was cooled in an ice bath. To it was added p-BrBzCl (2.93 g, 13.5 mmol, 1.5 equiv) drop wise. After the addition was complete, the reaction was allowed to warm to rt. After 2 h, the reaction was diluted with an equal amount of water and extracted with DCM (3 x 25 mL). The combined organics were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product as a yellow solid. It was recrystallized from MeOH to obtain the pure product II-58 that was purified by column chromatography. 190 4-Bromo-N-(2-phenylallyl)benzamide White solid; MP: 157 – 159 °C; Rf: 0.54 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 – 7.30 (m, 1H), 6.13 (br s, 1H), 5.50 (s, 1H), 5.29 (s, 1H), 4.51 (d, J = 5.4 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.4, 144.1, 138.2, 133.2, 131.8, 131.6, 128.6, 128.5, 128.2, 128.0, 126.2, 126.1, 114.3, 43.8; HRMS: Calcd. for C16H14NOBr: 315.0259, Found: 315.0273. 4-Bromo-N-[2-(3-nitrophenyl)allyl]benzamide Brown solid; MP: 124 -125 °C; Rf: 0.33 (30% EtOAc-Hexanes) (UV, I2, anisaldehyde) 1 H NMR (600 MHz, CDCl3) δ 8.32 (t, J = 2.4 Hz, 1H), 8.12 – 8.14 (m, 1H), 7.77 – 7.79 (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 6.23 (br s, 1H), 5.62 (s, 1H), 5.45 (t, J = 1.4 Hz, 1H), 4.54 (d, J = 5.4 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.4, 142.5, 140.0, 132.8, 132.0, 131.9, 129.6, 128.5, 126.5, 122.9, 121.1, 116.6, 43.4; HRMS: Calcd. for C16H13N2O3Br: 360.0110, Found: 360.0127. 4-Bromo-N-[2-(3-methoxyphenyl)allyl]benzamide MP: 128 – 130 °C Rf: 0.21 (30% EtOAc- Hex) (UV, I2, anisaldehyde) 1 H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.02 (qd, J = 7.5, 1.0 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 6.84 (ddd, J = 7.5, 2.5, 1.0 Hz, 1H), 6.16 (br s, 1H), 5.49 (d, J = 0.5 Hz, 1H), 5.28 (d, J = 1.0 Hz, 1H), 191 4.48 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 166.3, 159.8, 144.0, 139.7, 133.2, 131.8, 129.6, 128.5, 126.2, 118.5, 114.5, 113.7, 111.9, 55.3, 43.9; HRMS: Calcd. for C17H16NO2 Br: 345.0365, Found: 345.0352. 4-Bromo-N-[2-(4-fluorophenyl)allyl]benzamide White solid; MP: 155 – 157 °C; Rf: 0.50 (30% EtOAc-Hexanes) (UV, I2, anisaldehyde) 1 H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2), 7.42 (dd, 4 4 J H-H = 8.4 Hz, J H-F = 5.4 Hz, 2H), 7.02 (t, J H-H = J H-F = 8.4 Hz, 2H), 6.10 (br s, 1H), 5.44 (s, 1H), 5.27 (s, 1H), 4.48 (d, J = 5.4 Hz, 2H); 1 13 C NMR (150 MHz, CDCl3) δ 4 162.7 (d, J C-F = 246.6 Hz), 163.5, 143.2, 134.2 (d, J C-F = 3.5 Hz), 133.1, 128.5, 127.8 3 2 (d, J C-F = 8.0 Hz), 126.3, 115.5 (d, J C-F = 21.3 Hz), 114.2, 43.8; HRMS: Calcd. for C16H13NOBrF: 333.0165, Found: 333.0154. 4-Bromo-N-[2-(4-bromophenyl)allyl]benzamide Yellowish solid; MP: 152 – 154 °C; Rf: 0.50 (30% EtOAc-Hexanes) (UV, I2, anisaldehyde) 1 H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.15 (br s, 1H), 5.49 (s, 1H), 5.31 (s, 1H), 4.48 (d, J = 5.4 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 143.2, 137.0, 133.0, 132.1, 131.9, 131.5, 128.5, 127.7, 114.9, 43.6; HRMS: Calcd. for C16H13NOBr2: 392.9364, Found: 392.9376. 192 4-Bromo-N-[2-(4-chlorophenyl)allyl]benzamide White solid; MP: 152 – 154 °C; Rf: 0.50 (30% EtOAc-Hexanes) (UV, I2, anisaldehyde) 1 H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 6.14 (br s, 1H), 5.49 (d, J = 1.2 Hz, 1H), 5.30 (d, J = 0.6 Hz, 1H), 4.48 (dd, J = 6.0, 0.6 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 143.1, 136.5, 133.0, 131.9, 128.8, 128.5, 127.4, 114.8, 43.6; HRMS: Calcd. for C16H13NOBrCl: 348.9869, Found: 348.9865. General procedure for the catalytic asymmetric chlorocyclization of unsaturated amides: DCDPH (35 mg, 0.11 mmol, 1.1 equiv) was suspended in trifluoroethanol (TFE, 2.2 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to -30 °C in an immersion cooler. (DHQD)2PHAL (1.56 mg, 312 µL of a 5 mg/mL solution in TFE, 2 mol%) was then introduced. After stirring vigorously for 10 min, the substrate (0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 °C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes as the eluent. 193 (R)-2-(4-Bromophenyl)-5-(chloromethyl)-5-(3-nitrophenyl)-4,5-dihydrooxazole Colorless film; Rf: 0.28 (30% EtOAc-Hexanes) (UV) 1 H NMR (600 MHz, CDCl3) δ 8.29 (t, J = 1.8 Hz, 1H), 8.21 (ddd, J = 8.4, 2.4, 1.2 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.74 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.59 – 7.61 (m, 2H), 4.52 (d, J = 15.6 Hz, 1H), 4.21 (d, J = 15.6 Hz, 1H), 3.92 (d, J = 12.0 Hz, 1H), 3.87 (d, = 12.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 162.1, 148.5, 143.4, 131.9, 131.2, 130.0, 129.8, 126.7, 125.8, 123.5, 120.4, 87.3, 65.3, 50.3; HRMS: Calcd. for C16H12N2O3ClBr: 393.9720, Found: 393.9704. Resolution of enantiomers: CHIRALCEL OJ-H, 10% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 47.1 min, RT2 = 54.5 min; [α]D = -95.0 (c = 1.0, CHCl3) (R)-2-(4-Bromophenyl)-5-(chloromethyl)-5-(3-methoxyphenyl)-4,5-dihydrooxazole Colorless film; Rf: 0.21 (15% EtOAc- Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.57(d, J = 8.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 6.93 – 6.95 (m, 2H), 6.84 – 6.87 (m, 1H), 4.46 (d, J = 14.5 Hz, 1H), 4.19 (d, J = 14.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 162.2, 159.9, 143.0, 131.7, 130.0, 129.8, 128.5, 126.3, 117.1, 113.1, 111.4, 87.8, 65.0, 55.3, 51.0; HRMS: Calcd. for C17H15NO2ClBr: 378.9975, Found: 378.9994. Resolution of enantiomers : CHIRALCEL AS-H, 5% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 10.7 min, RT2 = 16.6 min; [α]D = -134.0 (c = 1.0, CHCl3) 194 (R)-2-(4-Bromophenyl)-5-(chloromethyl)-5-(4-fluorophenyl)-4,5-dihydrooxazole Colorless oil; Rf: 0.50 (30% EtOAc-Hexanes) (UV) 1 H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.37 3 4 3 3 (dd, J H-H = 9.0 Hz, J H-F = 5.4 Hz, 2H), 7.08 (t, J H-H = J H-F = 9.0 Hz, 2H), 4.46 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.4 Hz, 1H), 3.87 (d, J = 12.0 Hz, 1H), 3.80 (d, J = 1 12.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 162.5 (d, J C-F = 246.0 Hz), 162.2, 137.1 4 3 (d, J C-F = 3.0 Hz), 132.0, 131.8, 129.8, 128.5, 126.8 (d, J C-F = 8.7 Hz), 126.4, 126.2, 2 115.8 (d, J C-F = 21.8 Hz), 87.6, 65.1, 50.8; HRMS: Calcd. for C16H12NOClBrF: 366.9775, Found: 366.9759. Resolution of enantiomers : CHIRALCEL OJ-H, 5% IPA-Hex, 1.0 mL/min, RT1 = 12.5 20 min, RT2 = 23.1 min.; [α]D = -87.8 (c = 1.0, CHCl3) (R)-2,5-Bis(4-bromophenyl)-5-(chloromethyl)-4,5-dihydrooxazole Colorless gum; Rf: 0.53 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 4.45 (d, J = 15.0 Hz, 1H), 4.15 (d, J = 15.0 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.79 (d, J = 12.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 162.2, 140.3, 132.0, 131.8, 129.8, 126.7, 126.5, 126.1, 122.5, 87.6, 65.0, 50.6; HRMS: Calcd. for C16H12NOClBr2: 426.8782, Found: 426.8786. Resolution of enantiomers: CHIRALCEL OJ-H, 5% IPA-Hex, 1.0 mL/min, RT1 = 14.8 20 min, RT2 = 20.5 min; [α]D = -96.7 (c = 1.0, CHCl3) 195 (R)-2-(4-Bromophenyl)-5-(chloromethyl)-5-(4-chlorophenyl)-4,5-dihydrooxazole Yellow gum; Rf: 0.48 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.46 (d, J = 15.0 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.87 (d, J = 12.0 Hz, 1H), 3.80 (d, J = 12.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 162.2, 139.8, 134.4, 131.8, 129.8, 129.0, 128.9, 128.5, 126.4, 126.1, 87.5, 65.0, 50.7; HRMS: Calcd. for C16H12NOCl2Br: 382.9479, Found: 382.9484. Resolution of enantiomers: CHIRALCEL OJ-H, 5% IPA-Hex, 1.0 mL/min, RT1 = 12.9 20 min, RT2 = 18.9 min; [α]D = -58.8 (c = 1.0, CHCl3) Allylic alcohols were synthesized from the corresponding aldehydes or ketones by a HWE reaction followed by DIBAL reduction of the resulting ester (typical yields were ~ 95% for the two steps). The bromination of the allylic alcohols gave the corresponding allyl bromides which were used without purification in the subsequent one pot azide displacement–Staudinger reduction sequence. Allyl bromide (1.0 equiv) dissolved in THF-H2O (4:1) (5 mL/mmol) was treated with 1.1 equivalents of NaN3 at rt. After TLC analysis revealed the complete consumption of starting material (~ 20 min.), 2.0 equivalents of PPh3 was added to the reaction vessel. After 2 h at ambient temperature, the reaction was concentrated to remove most of the THF. The resulting suspension was diluted with aq. HCl and extracted with ether (3x). The aqueous layer was then basified by adding solid KOH and extracted with ether (3x). 196 The combined organics were dried (anhydrous Na2SO4) and concentrated to give the crude amine which was usually pure enough to use in the next step. Typical yield over three steps was 55–60%. The crude amines from the previous step were reacted with the p-benzyl acid chloride using the same protocol as described for the synthesis of II-58 to give the products II-60 which were purified by column chromatography. N-Cinnamyl-4-bromobenzamide White solid; MP: 148 – 150 °C; Rf: 0.50 (30% EtOAc-Hexanes) 1 H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.21 – 7.38 (m, 5H), 6.59 (d, J = 15.9 Hz, 1H), 6.27 (td, J = 15.9, 3.3 Hz, 1H), 6.18 (br s, 1H), 4.22 (dt, J = 4.8, 1.5 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 136.3, 133.2, 132.8, 131.8, 128.6, 128.5, 127.9, 126.4, 126.2, 125.1, 42.2; HRMS: Calcd. for C16H14NOBr: 315.0259, Found: 315.0241. (E)-4-Bromo-N-[3-(4-fluorophenyl)allyl]benzamide Yellowish solid; MP: 164 – 165 °C; Rf: 0.42 (30% EtOAc-Hexanes) 1 H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.32 4 2 3 (dd, J H-H = 8.7 Hz, J H-F = 5.4 Hz, 2H), 6.99 (t, J H-H = J H-F = 8.7 Hz), 6.54 (d, J = 15.3 Hz, 1), 6.13 – 6.23 (m, 2H), 4.21 (dt, J = 6.0, 1.5 Hz, 2H); 1 13 C NMR (150 MHz, 4 CDCl3) δ 166.1, 162.2 (d, J C-F = 245.6 Hz), 133.0, 132.3 (d, J C-F = 3.5 Hz), 131.7, 3 5 2 131.4, 128.3, 127.7 (d, J C-F = 8.5 Hz), 126.1, 124.6 (d, J C-F = 2.2 Hz), 115.4 (d, J 197 C-F = 21.8 Hz), 41.9; HRMS: Calcd. for C16H13 NOBrF: 333.0165, Found: 333.0169. (E)-4-Bromo-N-[3-(4-bromophenyl)allyl]benzamide MP: 170 – 173 °C; Rf: 0.42 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 16.2 Hz, 1H), 6.25 (td, J = 16.2, 6.6 Hz, 1H), 6.20 (br s, 1H), 4.21 (dt, J = 6.6, 1.2 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 135.3, 133.1, 131.9, 131.8, 131.5, 128.5, 127.9, 126.3, 126.0, 121.7, 42.1; HRMS: Calcd. for C16H13NOBr2: 392.9364, Found: 392.9369. (E)-4-Bromo-N-{3-[4-(trifluoromethyl)phenyl]allyl}benzamide MP: 156 – 158 °C; Rf: 0.38 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 15.6 Hz, 1H), 6.36 (td, J = 15.6, 6.6 Hz, 1H), 6.32 (br s, 1H), 4.25 (t, J = 6.0 Hz, 2H); 13 C NMR (75 MHz, CDCl3) δ 2 166.4, 139.8, 133.0, 131.9, 131.6, 131.1, 129.6 (q, J C-F = 32.7 Hz), 128.6, 128.5, 128.0, 3 126.4, 123.7 (q, 1J C-F = 270.9 Hz), 125.5 (q, J C-F = 4.1 Hz), 42.0; HRMS: Calcd. for C17H13NOF3Br: 383.0133, Found: 383.0139. (E)-4-Bromo-N-[3-(4-methoxyphenyl)allyl]benzamide MP: 156 – 158 °C; Rf: 0.38 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 16.2 Hz, 1H), 6.30 (br s, 1H), 6.10 198 (td, J = 16.2, 6.6 Hz, 1H), 4.17 (d, J = 6.4 Hz, 2H), 3.78 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 159.4, 133.3, 132.4, 131.8, 129.1, 128.6, 127.6, 126.1, 122.7, 114.0, 55.3, 42.3; HRMS: Calcd. for C17H16NO2Br: 345.0364, Found: 345.0382. (E)-4-Bromo-N-(3-p-tolylallyl)benzamide MP: 136 – 138 °C; Rf: 0.47 (30% EtOAc-Hexanes) 1 H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 6.53 (d, J = 16.0 Hz, 1H), 6.27 (br s, 1H), 6.19 (td, J = 16.0, 6.0 Hz, 1H), 4.19 (dt, J = 6.0, 1.5 Hz, 2H), 2.31 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 166.3, 137.7, 133.6, 133.3, 132.7, 131.8, 129.3, 128.6, 126.3, 126.2, 124.0, 42.3, 21.2; HRMS: Calcd. for C17H16NOBr: 329.0415, Found: 329.0414. (E)-4-Bromo-N-(3-o-tolylallyl)benzamide MP: 130 – 132 °C; Rf: 0.50 (30% EtOAc-Hexanes) 1 H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.40 – 7.42 (m, 1H), 7.11 – 7.15 (m, 3H), 6.81 (d, J = 15.6 Hz, 1H), 6.19 (br s, 1H), 6.14 (td, J = 15.6, 6.0 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 2.33 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 166.3, 135.4, 135.3, 133.3, 131.8, 130.8, 130.3, 128.5, 127.8, 126.3, 126.2, 126.1, 125.7, 42.5, 19.8; HRMS: Calcd. for C17H16NOBr: 329.0415, Found: 329.0399. 4-Bromo-N-(3,3-diphenylallyl)benzamide MP: 191 – 192 °C; Rf: 0.63 (30% EtOAc-Hexanes) 1 H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.31 – 7.41 (m, 3H), 7.18 – 7.30 (m, 7H), 6.16 (t, J = 6.9 Hz, 1H), 6.09 (br s, 1H), 4.13 (dd, J = 199 6.9, 5.4 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 166.2, 145.1, 141.5, 138.9, 133.3, 131.8, 129.6, 128.5, 128.5, 128.2, 127.7, 127.4, 126.1, 124.0, 39.5; HRMS: Calcd. for C22H18NOBr: 391.0572, Found: 391.0576. (E)-4-Bromo-N-(3-cyclohexylallyl)benzamide MP: 108 – 112 °C; Rf: 0.54 (30% EtOAc-Hexanes) 1 H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 6.03 (br s, 1H), 5.62 (dd, J = 15.5, 6.5 Hz, 1H), 5.43 – 5.49 (m, 1H), 3.98 (t, J = 6.5 Hz, 2H), 1.94 (m, 1H), 1.61 – 1.71 (m, 5H), 1.10 – 1.28 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 166.1, 140.3, 133.5, 131.8, 128.5, 126.0, 122.8, 42.2, 40.4, 32.8, 26.1, 26.0; HRMS: Calcd. for C16H20NOBr: 321.0728, Found: 321.0726. (E)-4-Bromo-N-(oct-2-enyl)benzamide MP: 75 – 76 °C; Rf: 0.54 (30% EtOAc-Hexanes) 1 H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.34 (br s, 1H), 5.62 – 5.67 (m, 1H), 5.45 – 5.51 (m, 1H), 3.95 (dt, J = 6.0, 1.0 Hz, 2H), 1.96 – 2.00 (m, 2H), 1.21 – 1.36 (m, 6H), 0.85 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 166.2, 134.4, 133.4, 131.7, 128.5, 125.9, 125.1, 42.1, 32.2, 31.3, 28.7, 22.4, 13.9; HRMS: Calcd. for C15H20NOBr: 309.0728, Found: 309.0735. (E)-4-Bromo-N-(4-cyclohexylbut-2-enyl)benzamide Waxy solid; Rf: 0.45 (20% EtOAc- Hex) 1 H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 6.02 (br s, 1H), 5.63 – 5.69 (m, 1H), 5.46 – 5.52 (m, 1H), 3.99 (dt, J = 6.0, 1.0 Hz, 2H), 1.92 (t, 200 J = 6.5 Hz, 2H), 1.61 – 1.68 (m, 5H), 1.07 – 1.32 (m, 4H), 0.83 – 0.90 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 166.2, 133.5, 133.2, 131.8, 128.5, 126.2, 126.0, 42.1, 40.2, 37.7, 33.1, 26.5, 26.3; HRMS: Calcd. for C17H22NOBr: 335.0885, Found: 335.0866. General procedure for the catalytic asymmetric chlorocyclization of unsaturated amides: DCDPH (35 mg, 0.11 mmol, 1.1 equiv) was suspended in trifluoroethanol (TFE, 2.2 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to -30 °C in an immersion cooler. (DHQD)2PHAL (1.56 mg, 312 µL of a 5 mg/mL solution in TFE or 1-nitropropane (in the presence of molecular sieves), 2 mol%) was then introduced. After stirring vigorously for 10 min, the substrate (0.10 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at -30 °C till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes as the eluent. (5S, 6R)-2-(4-Bromophenyl)-5-chloro-6-phenyl-5,6-dihydro-4H-1,3-oxazine Colorless needles; MP: 93 – 95 °C; Rf: 0.50 (15% EtOAc-Hexanes) 1 H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.34 – 7.42 (m, 5H), 5.21 (d, J = 7.2 Hz, 1H), 4.19 (dt, J = 7.5, 4.8 Hz, 1H), 3.95 (dd, J = 17.1, 201 4.8 Hz, 1H), 3.75 (ddd, J = 17.1, 7.5, 0.9 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 154.4, 137.0, 131.5, 131.4, 129.1, 128.9, 128.7, 126.7, 125.6, 80.7, 53.8, 49.8; HRMS: Calcd. for C16H13NOBrCl: 348.9869, Found: 348.9853. Resolution of enantiomers: CHIRALCEL AS-H, 3% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 6.7 min, RT2 = 10.7 min; [α]D = -17.8 (c = 0.50, CHCl3) (5S,6R)-2-(4-Methoxyphenyl)-5-chloro-6-phenyl-5,6-dihydro-4H-1,3-oxazine White solid; MP: 98 – 100 °C; Rf: 0.25 (20% EtOAc-Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 9.0 Hz, 2H), 7.36 – 7.41 (m, 5H), 6.87 (d, J = 9.0 Hz, 2H), 5.23 (d, J = 8.0 Hz, 1H), 4.21 (dt, J = 8.0, 4.5 Hz, 1H), 3.93 (dd, J = 16.5, 4.5 Hz, 1H), 3.82 (s, 3H), 3.76 (dd, J = 16.5, 8.0 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 162.1, 156.2, 137.0, 129.2, 129.1, 128.7, 127.8, 126.7, 113.6, 80.9, 55.4, 55.3, 49.4; HRMS: Calcd. for C16H13NOBrCl: 348.9869, Found: 348.9853. Resolution of enantiomers: CHIRALCEL AS-H, 4% IPA-Hexane, 0.7 mL/min, 254 nm, 20 RT1 = 16.7 min, RT2 = 22.5 min; [α]D = -45.9 (c = 1.0, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-(4-fluorophenyl)-5,6-dihydro-4H-1,3-oxazine White film; Rf: 0.54 (15% EtOAc- Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 2 3 2 2 (dd, JH-H = 8.5 Hz, JF-H = 5.0 Hz, 2H), 7.11 (t, JH-H = JF-H = 8.5 Hz, 2H), 5.15 (d, J = 8.5 Hz, 1H), 4.13 (dt, J = 8.5, 5.0 Hz, 1H), 3.98 (dd, J = 17.5, 5.0 Hz, 1H), 3.75 (dd, 202 J = 17.5, 8.5 Hz, 1H); 13 1 C NMR (150 MHz, CDCl3) δ 163.1 (d, JC-F = 247.1 Hz), 154.4, 4 3 132.7 (d, JC-F = 2.9 Hz), 131.4, 131.3, 128.9, 128.7 ( JC-F = 8.7 Hz), 125.7, 115.7 2 ( JC-F = 21.8 Hz), 80.2, 53.8, 50.3; HRMS: Calcd. for C16H12NOBrClF: 366.9775, Found: 366.9767. Resolution of enantiomers: CHIRALCEL AS-H, 5% IPA-Hexane, 1.0 mL/min, 250 nm, 20 RT1 = 7.0 min, RT2 = 9.3 min; [α]D = -29.4 (c = 1.0, CHCl3) (5S,6R)-2,6-Bis(4-bromophenyl)-5-chloro-5,6-dihydro-4H-1,3-oxazine Colorless film; Rf: 0.50 (15% EtOAc- Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 5.13 (d, J = 8.0 Hz, 1H), 4.11 (dt, J = 8.0, 4.5 Hz, 1H), 3.97 (dd, J = 17.5, 5.0 Hz, 1H), 3.75 (dd, J = 17.5, 8.0 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 154.3, 135.9, 131.9, 131.4, 131.3, 128.9, 128.6, 125.8, 123.3, 80.2, 53.6, 50.2; HRMS: Calcd. for C16H12NOBr2Cl: 426.8974, Found: 426.8982. Resolution of enantiomers: CHIRALCEL AS-H, 5% IPA-Hexane, 1.0 mL/min, 250 nm, 20 RT1 = 6.4 min, RT2 = 8.6 min; [α]D = -9.6 (c = 1.0, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-[4-(trifluoromethyl)phenyl]-5,6-dihydro-4H1,3-oxazine White film; Rf: 0.48 (15% EtOAc – Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.49 – 7.53 (m, 4H), 5.22 (d, J = 8.5 Hz, 1H), 4.14 (dt, J = 8.5, 5.0 Hz, 1H), 3.99 (dd, J = 17.5 203 Hz, 5.0 Hz, 1H), 3.77 (dd, J = 17.5, 8.5 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 154.1, 2 3 140.7, 131.5, 131.4 (q, JC-F = 32.5 Hz), 131.2, 128.9, 127.4, 125.9, 125.8 (q, JC-F = 3.8 Hz), 123.7 (q, 1 JC-F = 270.9 Hz), 80.1, 53.5, 50.3; HRMS: Calcd. for C17H12NOF3BrCl: 416.9743, Found: 416.9721. Resolution of enantiomers: CHIRALCEL AS-H, 3% IPA-Hexane, 0.8 mL/min, 254 nm, 20 RT1 = 7.2 min, RT2 = 9.1 min; [α]D = -30.7 (c = 1.0, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-(4-methoxyphenyl)-5,6-dihydro-4H-1,3-oxazi ne Colorless film; Rf: 0.44 (15% EtOAc – Hex) (UV) 1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 5.14 (d, J = 8.1 Hz, 1H), 4.16 (dt, J = 8.1, 4.8 Hz, 1H), 3.97 (dd, J = 17.1, 4.8 Hz, 1H), 3.82 (s, 3H), 3.74 (dd, J = 17.1, 8.1 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 160.2, 154.6, 131.6, 131.3, 129.0, 128.9, 128.2, 125.6, 114.1, 80.5, 55.3, 54.0, 50.2; HRMS: Calcd. for C17H15NO2BrCl: 378.9975, Found: 378.9982. Resolution of enantiomers: CHIRALCEL AS-H, 3% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 8.5 min, RT2 = 12.3 min; [α]D = +4.7 (c = 0.75, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-p-tolyl-5,6-dihydro-4H-1,3-oxazine Colorless film; Rf: 0.56 (15% EtOAc- Hex) (UV) 1 H NMR (600 MHz, CDCl3) δ7.80 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 5.17 (d, J = 7.8 Hz, 1H), 4.18 (dt, J = 7.8, 4.8 204 Hz, 1H), 3.96 (dd, J = 17.4, 4.8 Hz, 1H), 3.74 (dd, J = 17.4, 7.8 Hz, 1H), 2.37 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 154.5, 139.1, 134.1, 131.6, 131.4, 129.4, 128.9, 126.7, 125.6, 80.7, 53.9, 50.0, 21.2; HRMS: Calcd. for C17H15NOBrCl: 363.0026, Found: 363.0037. Resolution of enantiomers: CHIRALCEL AS-H, 3% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 5.7 min, RT2 = 7.4 min; [α]D = -4.3 (c = 1.0, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-o-tolyl-5,6-dihydro-4H-1,3-oxazine Colorless film; Rf: 0.54 (15% EtOAc- Hex) (UV) 1 H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.20 – 7.30 (m, 4H), 5.49 (d, J = 8.2 Hz, 1H), 4.25 (dt, J = 8.2, 4.8 Hz, 1H), 3.99 (dd, J = 17.1, 4.8 Hz, 1H), 3.78 (dd, J = 17.1, 8.2 Hz, 1H), 2.44 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 154.7, 136.1, 135.3, 132.0, 131.6, 131.4, 131.2, 130.8, 129.0, 128.9, 126.6, 126.0, 125.6, 77.6, 53.2, 49.9, 19.4; HRMS: Calcd. for C17H15NOBrCl: 363.0026, Found: 363.0032. Resolution of enantiomers: CHIRALCEL OJ-H, 3% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 9.7 min, RT2 = 11.7 min; [α]D = +7.2 (c = 0.9, CHCl3) (5S,6R)-5-Chloro-2-(4-methoxyphenyl)-6-o-tolyl-5,6-dihydro-4H-1,3-oxazine Yellowish solid; MP: 87 – 90 °C 1 H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 9.0 Hz, 2H), 7.23 – 7.29 (m, 5H), 6.88 (d, J = 9.0 Hz, 2H), 5.53 (d, J = 7.0 Hz, 1H), 4.27 (dt, J = 7.0, 5.0 Hz, 1H), 3.99 (dd, J = 17.0, 5.0 Hz, 1H), 3.78 – 3.83 (m, 4H), 2.45 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 161.8, 155.3, 136.1, 135.6, 130.8, 129.0, 128.8, 125.5, 126.2, 125.1, 113.4, 77.4, 55.3, 53.6, 50.0, 205 19.4; HRMS: Calcd. for C18H18ClNO2: 315.1026, Found: 315.1030. Resolution of enantiomers: CHIRALCEL OD-H, 1% IPA-Hexane, 0.8 mL/min, 250 nm, 20 RT1 = 25.8 min, RT2 = 27.7 min; [α]D = -1.7 (c = 1.0, CHCl3) (S)-2-(4-Bromophenyl)-5-chloro-6,6-diphenyl-5,6-dihydro-4H-1,3-oxazine White film; Rf: 0.35 (15% EtOAc- Hex) (UV) 1 H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.35 – 7.39 (m, 4H), 7.20 – 7.30 (m, 6H), 5.19 (dd, J = 3.8, 2.0 Hz, 1H), 3.89 (dd, J = 18.0, 2.0 Hz, 1H), 3.75 (dd, J = 18.0, 3.8 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 153.5, 131.6, 129.2, 128.9, 128.4, 128.2, 127.8, 125.2, 124.5, 56.1, 49.4; HRMS: Calcd. for C22H17NOBrCl: 425.0182, Found: 425.0166. Resolution of enantiomers: CHIRALCEL AS-H, 5% IPA-Hexane, 1.0 mL/min, 254 nm, 20 RT1 = 8.3 min, RT2 = 14.8 min; [α]D = +44.7 (c = 0.50, CHCl3) (5S, 6R)-2-(4-Bromophenyl)-5-chloro-6-cyclohexyl-5,6-dihydro-4H-1,3-oxazine White solid; Rf: 0.33 (15% EtOAc- Hex) (UV, PMA) 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 4.12 – 4.17 (m, 1H), 4.02 (dd, J = 8.0, 4.0 Hz, 1H), 3.94 (dd, J = 16.5, 4.0 Hz, 1H), 3.63 (dd, J = 16.5, 8.0 Hz, 1H), 1.85-1.95 (m, 1H), 1.60-1.84 (m, 6H), 1.22 – 1.45 (m, 4H); 13 C NMR (150 MHz, CDCl3) δ 154.7, 131.9, 131.4, 128.8, 126.9, 125.4, 82.4, 50.5, 50.2, 38.5, 29.7, 29.5, 26.3, 26.2, 25.8, 25.7; HRMS: Calcd. for C16H19NOBrCl: 355.0339, Found: 355.0333. Resolution of enantiomers: CHIRALCEL AS-H, 1% IPA-Hexane, 1 mL/min, RT1 = 5.5 206 20 min; RT2 = 7.8 min; [α]D = +50.3 (c = 0.50, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-pentyl-5,6-dihydro-4H-1,3-oxazine Colorless liquid; Rf: 0.63 (15% EtOAc- Hex) (UV, PMA) 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 4.17 (dt, J = 8.5, 3.0 Hz, 1H), 3.91 – 3.97 (m, 2H), 3.62 (dd, J = 10.0, 18.5 Hz, 1H), 1.87 – 2.03 (m, 1H), 1.65 – 1.71 (m, 1H), 1.31 – 1.37 (m, 3H), 1.24 – 1.27 (m, 3H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 165.6, 133.6, 131.3, 128.8, 126.1, 125.6, 125.4, 78.7, 52.8, 50.6, 32.3, 31.5, 24.3, 22.5, 14.0; HRMS: Calcd. for C15H19NOBrCl: 343.0339, Found: 343.0319. Resolution of enantiomers: CHIRALCEL OD-H, 100% Hexane, 1 mL/min, RT1 = 52.1 20 min; RT2 = 62.2 min; [α]D = +33.9 (c = 0.50, CHCl3) (5S,6R)-2-(4-Bromophenyl)-5-chloro-6-(cyclohexylmethyl)-5,6-dihydro-4H-1,3-oxazi ne Colorless oil ; Rf: 0.66 (20% EtOAc- Hex) 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.26–4.30 (m, 1H), 3.89-3.97 (m, 2H), 3.63 (dd, J = 16.8, 7.8 Hz, 1H), 1.81-1.86 (m, 2H), 1.61-1.74 (m, 6H), 1.55-1.59 (m, 1H), 1.15-1.33 (m, 3H), 0.93-1.07 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 154.2, 131.9, 131.4, 128.8, 125.4, 76.7, 53.4, 50.3, 40.2, 34.1, 33.8, 32.4, 26.4, 26.2, 26.1; HRMS: Calcd. for C17H21NOBrCl: 369.0495, Found: 369.0487. Resolution of enantiomers: CHIRALCEL OD-H, 100% Hexane, 1 mL/min, RT1 = 30.0 207 20 min; RT2 = 48.5 min; [α]D = +69.9 (c = 1.0, CHCl3) To a stirred solution of the benzoic acid (1.22 g, 10 mmol) in CH3CN (100 mL) was added Et3N (2.81 mL, 20 mmol), DMAP (0.24 g, 2 mmol), and NsCl (2.21 g, 10 mmol). After being stirred for 20 min, benzyl amine (1.18 g, 11 mmol) in CH3CN (30 mL) was added under ice bath and stirring was continued for 30 min at room temperature. After evaporation of the solvent, the residue was extracted with CH2Cl2 (2 x 50 ml). The extract was washed with saturated NaHCO3 (50 mL), water (50 mL), dried (MgSO4) and concentrated. The crude product was chromatographed on a short silica gel column with ethyl acetate as eluent to give II-69 in quantitative yield (2.11 g). Colourless solid, MP: 118–120 ºC 1 H NMR (CDCl3, 600 MHz) δ 7.36–7.32 (m, 2H), 7.32–7.22 (m, 6H), 7.19–7.15 (d, J = 7.1, 2H), 5.79 (br s, 1H), 4.41 (d, J = 5.8, 2H), 3.63 (s, 2H); 13 C NMR (CDCl3, 150 MHz) δ 171.1, 138.2, 134.9, 129.6, 129.2, 128.8, 127.61, 127.56, 127.55, 43.9, 43.7. A mixture of H5IO6 (6.90g, 30 mmol) and CrO3 (25 mg, 5 mol%) in acetonitrile (70 mL) was stirred at room temperature for 30 min, then acetic anhydride (3.1 g, 30 mmol) was added. The resulting mixture was cooled to 0 °C. The amide II-69 (1.05 g, 5 mmol) was added in one portion. After the reaction was complete (monitored by TLC), the reaction mixture was quenched by addition of ice-water (70 g), extracted with EtOAc (2 x 70 mL), washed respectively with sat. NaHCO3 solution (80 mL), sat. Na2S2O3 solution (80 mL) and brine (80 mL). The organic portion was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash 208 chromatography (SiO2, hexanes: EtOAc = 6 : 1) to give pure II-70 in 71% yield (0.80 g). White solid, MP: 146–148 ºC 1 H NMR (500 MHz, CDCl3) δ 7.42–7.50 (m, 4 H), 7.53–7.60 (m, 2 H), 7.83–7.89 (m, 4 H), 9.49 (br. s, 1 H); 13 C NMR (125 MHz, CDCl3) δ 128.3, 128.9, 133.2, 133.7, 167.1. Diisopropyl azodicarboxylate (0.6 mL, 4.9 mmol) was added dropwise to a precooled (0 ºC) solution of dibenzamide (1.0 g, 4.4 mmol), Ph3 P (1.3 g, 4.9 mmol), allyl alcohol (0.25 g, 4.4 mmol), and THF (20 mL). The resulting mixture was maintained for 1 h at 0 ºC and then allowed to warm to rt. After 2 h, the reaction was concentrated, and the residue was purified by flash chromatography (20:1 hexane-EtOAc) to afford II-71 (70% yield, 0.8 g) as colorless oil. 1 H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6Hz, 2H), 7.40 (t, J = 7.3Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 5.58 (m, 1H), 5.25 (1H, dd, J = 10.4, 1.7 Hz), 5.36 (1H, dd, J = 17.4, 1.7 Hz), 4.91 (d, J = 7.1 Hz, 2H); 13 C NMR (125 MHz, CDCl3) 176.0, 158.4, 134.8, 134.2, 132.7, 131.5, 130.6, 129.4, 128.5, 128.4, 128.2, 117.1, 64.9. General procedure: Halogen source (0.11 mmol) was suspended in CHCl3-EtOH (2:1, 2.2 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to appropriate temperature. (DHQD)2PHAL (3.90 mg, 312 µL of a 5 mg/mL solution in CHCl3 (in the presence of molecular sieves), 5 mol%) was then introduced. After stirring vigorously for 10 min, the substrate (0.10 mmol) was added in a single portion. The vial was capped and the stirring was continued at appropriate temperature 209 till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes as the eluent. 1 H NMR (300 MHz, CDCl3) δ 8.04-8.10 (m, 4H), 7.21-7.60 (m, 6H), 4.69 (dd, J = 4.7 and 11.3 Hz, 1 H), 4.41 (dd, J = 5.9 and 11.3 Hz, 1 H), 4.08 (m, 1H), 3.60-3.74 (m, 2H); 13 CNMR (125 MHz, CHCl3) δ 167.8, 167.5, 133.8, 133.5, 131.8, 129.8, 129.3, 128.6, 128.5, 127.0, 63.1, 51.2, 33.2. 1 H NMR (300 MHz, CDCl3) δ 7.97-8.05 (m, 4H), 7.46-7.58 (m, 6H), 4.68 (dd, J = 4.7 and 11.3 Hz, 1 H), 4.38 (dd, J = 6.0 and 11.3 Hz, 1 H), 4.10 (m, 1H), 3.65-3.70 (m, 2H); 13 CNMR (125 MHz, CHCl3) δ 171.1, 168.4, 133.9, 133.3, 131.6, 130.0, 129.2, 128.9, 128.4, 127.1, 63.2, 51.5, 45.8. 1 H NMR (300 MHz, CDCl3) δ 8.05-8.08 (m, 4H), 7.22-7.55 (m, 6H), 4.60 (dd, J = 4.8 and 11.0 Hz, 1 H), 4.41 (dd, J = 6.1 and 11.0 Hz, 1 H), 4.07-4.19 (m, 1H), 3.62-3.70 (m, 2H); 13 CNMR (125 MHz, CHCl3) δ 167.5, 167.3, 133.9, 133.5, 131.9, 129.7, 129.0, 128.3, 128.1, 127.0, 63.3, 55.5, 48.6. 1 H NMR (300 MHz, CDCl3) δ 7.98-8.05 (m, 4H), 7.48-7.60 (m, 6H), 4.65 (dd, J = 4.8 and 11.1 Hz, 1 H), 4.35 (dd, J = 6.2 and 11.1 Hz, 1 H), 4.11-4.15 (m, 1H), 3.66-3.74 (m, 2H); 13 CNMR (125 MHz, CHCl3) δ 171.2, 168.6, 134.0, 133.5, 131.8, 130.5, 129.4, 210 129.2, 128.4, 127.1, 63.4, 57.0, 51.9. A 500-mL, one-necked flask was charged with cinnamic acid (2.96 g, 20.00 mmol), 20 mL of dry dichloromethane, benzyl alcohol (6.48 g, 60.00 mmol), and 4-dimethylaminopyridine (0.2 g, 16.00 mmol). The solution was stirred and cooled in an ice bath to 0 ºC, and dicyclohexylcarbodiimide (4.56 g, 22 mmol) was added over a 5 min period. After 5 min at 0 ºC the ice bath was removed and the dark-brown reaction mixture was stirred for 3 h at room temperature. The dicyclohexylurea that had precipitated was removed by filtration through a fritted Büchner funnel, and the filtrate was washed with two portions of 0.5 N hydrochloric acid (5 mL) and two portions of saturated sodium bicarbonate solution (5mL). The organic solution is dried over anhydrous sodium sulfate and concentrated with a rotary evaporator. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes (10%) as the eluent in 75% yield (3.57 g). 1 H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 16.0 Hz, 1H), 7.54-7.36 (m, 10H), 6.49 (d, J = 16.0 Hz, 1H), 5.27 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 166.7, 145.1, 136.1, 134.4, 130.2, 128.8, 128.5, 128.2, 128.1, 128.0, 117.9, 66.3. General procedure: Halogen source (0.11 mmol) was suspended in TFE (2.2 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to -30 ºC. (DHQD)2PHAL (7.80 mg, 10 mol%) was then introduced along with Cu(OTf)2 (3.61 mg, 10 mol%). After stirring vigorously for 10 min, the substrate (0.10 mmol) was added 211 in a single portion. The vial was capped and the stirring was continued at -30 ºC till the reaction was complete (TLC). The reaction was quenched by the addition of 10% aq. Na2SO3 (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexanes as the eluent. 1 H NMR (300 MHz, CDCl3) δ 7.08−7.68 (m, 9H), 4.59 (d, J = 2.2 Hz, 1H), 4.40 (d, J = 2.2 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 164.2, 122.3, 121.8, 128.8, 128.7, 123.6, 123.4, 116.8, 52.5, 40.1. 1 H NMR (300 MHz, CDCl3) δ 7.06−7.66 (m, 9H), 4.88 (d, J = 2.2 Hz, 1H), 4.73 (d, J = 2.2 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 164.1, 122.5, 121.5, 128.9, 128.7, 123.5, 123.3, 117.4, 45.8, 40.5. General procedure for the formation pyridinium sulfates: The alcohol (1.0 equiv) was dissolved in freshly distilled pyridine to generate a 0.1 M solution. Sulfur-trioxide pyridine (SO3•Py) complex (1.25 equiv) was then added, and the resulting mixture was stirred at rt for 1 h. The excess SO3•Py then was quenched with a small amount of freshly distilled methanol. The resulting solution was concentrated under reduced pressure. (Note: avoid heating above 30 ºC, as decomposition of the product pyridinium sulfate can occur). The resulting crude oil was then purified by flash chromatography to afford the sulfate salt (CH2Cl2-MeOH 4:1). 212 1 H NMR (600 MHz, CDCl3) δ 8.70 (m, 2H), 8.31 (brs, 1H), 7.21-7.46 (m, 8H), 6.65 (d, J = 16.2 Hz, 1H), 6.34-6.37 (m, 1H), 4.78 (d, J = 5.4 Hz, 2H). 1 H NMR (300 MHz, CDCl3) δ 8.70 (m, 2H), 7.98-8.03 (m, 2H), 7.40-7.62 (m, 6H), 6.64-6.69 (d, J = 15.3 Hz, 1H), 6.39-6.48 (m, 1H), 4.77 (d, J = 5.7 Hz, 2H). General procedure: DCDMH (10 mg, 0.041 mmol, 1.1 equiv) was suspended in n-PrOH (1.4 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to the appropriate temperature. (DHQD)2PHAL (3.0 mg, 10 mol%) was then introduced. After stirring vigorously for 10 min, the substrate (0.037 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at the appropriate temperature until the reaction was complete (TLC). The reaction was quenched by the addition of H2O (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexane (20-50%) as the eluent. 1 H NMR (600 MHz, CDCl3) δ 7.29-7.41 (m, 5H), 5.97 (d, J = 10.8 Hz, 1H), 4.79-4.83 (t, J = 12.0 Hz, 1H), 4.69-4.71 (dd, J = 4.8, 4.8 Hz, 1H), 4.47-4.52 (ddd, J = 12.0, 4.8, 4.8 Hz, 1H). 1 H NMR (300 MHz, CDCl3) δ 7.35-7.68 (m, 9H), 5.65-5.68 (d, J = 10.5 Hz, 1H), 4.68-4.85 (ddd, J = 11.4, 4.8, 4.8 Hz, 2H), 4.33-4.42 (ddd, J = 10.5, 4.8, 4.8 Hz, 1H). 1 H NMR (300 MHz, CDCl3) δ 7.71-7.74 (m, 2H), 7.56-7.59 (m, 2H), 5.65-5.69 (d, J = 213 10.2 Hz, 1H), 4.68-4.81 (ddd, J = 11.4, 4.8, 4.8 Hz, 2H), 4.23-4.32 (ddd, J = 10.2, 4.8, 4.8 Hz, 1H). 214 II.5 References 215 REFERENCES 1. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis, Springer, Berlin, New York, 1999. 2. Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364–3378. 3. Butler, A.; Sandy, M. Nature 2009, 460, 848–854. 4. Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005–2012. 5. Oestreich, M. Angew. Chem. 2005, 117, 2376–2379; Angew. Chem. Int. Ed. 2005, 44, 2324–2327. 6. Lee, E.C.; McCauley, K.M.; Fu, G.C. Angew. Chem. 2007, 119, 995–997; Angew. Chem. Int. Ed. 2007, 46, 977–979. 7. Okamoto, K.; Nishibayashi, Y.; Uemura, S.; Toshimitsu, A. Angew. Chem. 2005, 117, 3654–3657; Angew. Chem. Int. Ed. 2005, 44, 3588–3591. 8. Wirth, T. Angew. Chem. 1995, 107, 1872–1873; Angew. Chem. Int. Ed. Engl. 1995, 34, 1726–1728. 9. Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684–4685. 10. Baran, P. S.; Maimone, T. J. Nature 2007, 445, 826–827. 11. Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233–1237. 12. Cui, X. L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653–5658. 13. Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297–300. 14. Haas, J.; Bissmire, S.; Wirth, T. Chem. Eur. J. 2005, 11, 5777–5785. 15. Greedy, B.; Paris, J. M.; Vidal, T.; Gouverneur, V. Angew. Chem. 2003, 115, 3413–3416 ; Angew. Chem. Int. Ed. 2003, 42, 3291–3294. 16. Wang, M.; Wang, B. M.; Shi, L.; Tu, Y.Q.; Fan, C.A.; Wang, S.H.; Hu, X.D.; Zhang, S. Y. Chem. Commun. 2005, 5580–5582. 216 17. Wilkinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M. C.; Salmon, R.; Gouverneur, V. Angew. Chem. 2009, 121, 7217–7220; Angew. Chem. Int. Ed. 2009, 48, 7083–7086. 18. Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303–14314. 19. Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232–1233. 20. Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137. 21. Neverov, A. A.; Brown, R. S. J. Org. Chem. 1996, 61, 962–968. 22. Braddock, D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.; Redmond, J. M.; White, A. J. P. Chem. Commun. 2009, 1082–1084. 23. Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. USA 2010, 107, 20655–20660. 24. Julia, S.; Ginebreda, A. Tetrahedron Lett. 1979, 20, 2171–2174. 25. Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874–2876. 26. Wang, M.; Gao, L. X.; Yue, W.; Mai, W. P. Synth. Commun. 2004, 34, 1023–1032. 27. Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298–3300. 28. Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608–611. 29. Veitch, G. E.; Jacobsen, E. N. Angew. Chem. 2010, 122, 7490–7493; Angew. Chem. Int. Ed. 2010, 49, 7332–7335. 30. Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y. Y. J. Am. Chem. Soc. 2010, 132, 15474–15476. 31. Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, 217 H. Angew. Chem. 2010, 122, 9360–9363; Angew. Chem. Int. Ed. 2010, 49, 9174–9177. 32. Hennecke, U.; Müller, C. H.; Frçhlich, R. Org. Lett. 2011, 13, 860–863. 33. Zhang, W.; Xu, H. D.; Xu, H.; Tang, W. P. J. Am. Chem. Soc. 2009, 131, 3832–3833. 34. Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664–3665. 35. Jaganathan, A.; Garzan, A.; Whitehead, D.C.; Staples, R; Borhan, B. Angew. Chem. Int. Ed. 2011, 50, 2593. 36. Denmark, S. E.; Burk, M. T. Proc Natl Acad Sci, 2010, 107, 20655. 37. Chen, G. F.; Ma, S. M. Angew. Chem. Int. Ed. 2010, 49, 8306. 38. Castellanos, A.; Fletcher, S. P. Chem. Eur. J. 2011, 17, 5766. 39. Sammes, P. G.; Thetford, D. J. Chem. Soc. Chem. Commun., 1985, 352. 40. Hajra, S.; Maji, B.; Karmakar A. Tetrahedron Lett. 2005, 46, 8599–8603. 41. Lohray, B. B. Synthesis 1992, 1039. 42. Byun, H. S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051. 43. For some examples, see: (a) Machinaga, N.; Kibayashi, C. J. Chem. Soc., Chem. Commun. 1991, 405. (b) Nicolaou, K. C.; Patron, A. P.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M. Chem. Eur. J. 1996, 2, 847. (c) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 39, 2732. (d) Trost, B. M.; Dudash, J.; Hembre, E. J. Chem. Eur. J. 2001, 7, 1619. (e) Waterson, A. G.; Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4305. (f) Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc. 1999, 121, 6100. 44. Tanaka, K. Sulfonic Acids, Esters, Amides and Halides as Synthons; John Wiley & Sons Ltd.: New York, 1991. 45. For some examples, see: (a) van der Klein, P. A. M.; Filemon, W.; Veeneman, G. H.; Van der Marel, G. A.; Van Boom, J. H. J. Carbohydr. Chem. 1992, 11. (b) 218 Maracaurelle, L. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123, 1587. (c) Cohen, S. B.; Halcomb, R. L. Org. Lett. 2001, 3, 405. 46. Bryson, T. A.; Koen, J. J. H.; Roth, G. A. Synlett 1992, 723. 47. Guijarro, D.; Guillena, G.; Mancheno, B.; Yus, M. Tetrahedron 1994, 50, 3427. 48. For some examples, see: (a) Bragg, P. D.; Jones, J. K. N.; Turner, J. C. Can. J. Chem. 1959, 37, 1412. (b) Kaiser, E. T.; Katz, I. R.; Wulfers, T. F. J. Am. Chem. Soc. 1965, 87, 3781. (c) Helferich, B. Chem. Ber. 1921, 54, 1082. (d) Denmark, S. E. J. Org. Chem. 1981, 46, 3144. (e) Latif, F.; Shekhani, M. S.; Voelter, W. J. Chem. Soc., Perkin Trans. 1 1990, 1573. 49. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538. 50. Steinmann, J. G.; Phillips, J. H.; Sanders, W. J.; Kiessling L. L. Org. Lett., 2001, 3, 3557. 51. Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626. 219 CHAPTER III Solvent-Dependent Enantiodivergent Chlorocyclization of Unsaturated Carbamates III.1 Introduction The field of asymmetric organocatalysis has witnessed tremendous advancements 1 over the past decades. The field has matured to the point that a widely diverse array of transformations leading to molecular scaffolds of varying complexities has been developed. A major contributor to these developments has been the equally impressive arsenal of experimental and theoretical tools that have become accessible to synthetic chemists. As a consequence, detailed mechanistic investigations of stereoselective reactions are routinely undertaken to better understand the underlying principles for the origins and erosion of stereoselectivity. 2-4 For example, the determination of the enthalpic and entropic activation parameters has led to a systematic and predictable optimization of both catalyst structure and reaction conditions for many stereoselective transformations. 5-7 Nonetheless, certain aspects of asymmetric catalysis such as enantiodivergent syntheses have not succumbed to a detailed mechanistic investigation. This is attributable, primarily, to the exceptionally rare occurrence of this phenomenon whereby either enantiomer of a desired product can be obtained using the same chiral catalyst. 8-12 Furthermore, numerous reaction variables such as temperature, additives and solvent can contribute to this phenomenon. Of all these parameters, the effect of solvent 220 is perhaps the least predictable given that catalyst conformations and solute solvent interactions may vary significantly in different solvents and these factors will likely play a pivotal role in determining the stereoselectivity. developed an enantiodivergent catalytic 13-17 Sohtome and coworkers have Mannich-type reaction by utilizing conformationally flexible organocatalysts. The simple methodology has a broad aromatic N-Boc imine substrate scope and it enables selective access to both enantiomers of the Mannich adducts using a single chiral organocatalyst in different solvents (Figure III-1). 13 N HN Ar S Ar Boc H + CH2(CO2R)2 m-xylene CO2R CO2R Ar Boc HN MeCN Ar R Boc CO2R CO2R H N H N N N H N H N N Ar H S S (1 mol%) Figure III-1: Catalyzed enantiodivergent Mannich-type reactions with various aromatic N-Boc imines In rare cases where synthetically meaningful enantiodivergent reactions have been developed, they have not been accompanied with an in depth study of the possible sources that contribute to the enantiodivergence. During the course of our studies aimed at developing enantioselective olefin halogenation reactions, 18, 19 we stumbled upon a solvent dependent enantiodivergent reaction. A detailed kinetic analysis of this reaction 221 using Eyring plot analyses 20 has helped us to determine the enthalpic and entropic drivers for the observed solvent dependent enantiodivergence of this reaction. (DHQD)2PHAL (0.1 equiv) DCDPH (1.1 equiv) OH Ar Benzoic Acid (1.0 equiv) O O O Ar Cl CHCl3-Hex (1:1), -40 ºC, 30-180 min 43-90% ee Figure III-2: The (DHQD)2PHAL mediated halolactonization The hitherto overlooked research area of catalytic asymmetric halogenation of olefins has witnessed a renewed interest in recent years. Our group has previously reported a novel organocatalytic asymmetric chlorolactonization that returns chiral chlorolactones R3 R2 O N R1 H R4 1.1 equiv DCDPH 1-2 mol% (DHQD)2PHAL solvent, -30 ºC R4 R4 O Cl R2 N R1 R3 15 examples O N R3 R2 R1Cl 14 examples Figure III-3: The (DHQD)2PHAL mediated halocyclization of unsaturated amides 222 by action of (DHQD)2PHAL and dichloro diphenylhydantoin (DCDPH). This methodology represents the first example of a catalytic, enantioselective halolactonization that proceeds with synthetically useful enantioselectivities (figure III-2). 18 We also have developed a highly stereoselective chlorocyclization of unsaturated amides to chiral heterocycles mediated by catalytic amounts (1–2 mol %) of the commercially available (DHQD)2PHAL. The reaction is operationally simple with no need to resort to strictly anhydrous or inert reaction conditions. The reaction scope is fairly general with regards to the substitution pattern of the olefin. Both aliphatic and aromatic residues on the olefin are well tolerated. (Figure III-3). 19 III.2 Solvent Screen for the Chlorocyclization Reaction of Unsaturated Carbamates CuI OH PhBr, Mg, Et2O Ph Ph 1. NaN3 2. PPh3, 96% yield Ph H N NH2 Ph THF:H2O (4:1) III-2 CBr4, PPh3 III-1 reflux, 87% yield Br OH III-3 CH2Cl2 92% yield (Boc)2O, Et3N CH2Cl2, 89% yield O III-4 O Scheme III-1: Synthesis of carbamate III-4 With the discovery that Cinchona alkaloid based ligands were effective in providing 223 halocyclized product with high enantioselectivities, 18, 19 the conversion of carbamates to oxazolidinones was studied with this catalytic system in different solvents. The synthesis of our test substrate III-4 is shown in Scheme 1II-1. The coupling of bromobenzene and propargyl alcohol was achieved by copper iodide to provide III-1. Bromination of alcohol III-1 followed by azide displacement and hydrolyzation gave the desired amine III-3. Formation of carbamate III-4 was achieved by Boc protection of amine in 89% yield. A comprehensive solvent screen was undertaken in an attempt to drive the enantioselectivity of the reaction higher. Fourteen different non alcoholic solvents were screened in the test reaction (III-4 to III-5). Carbamate III-4 (0.037 mmol) was cyclized in the presence of dichloro-dimethyl hydantoin (DCDMH) as a chlorine source in appropriate solvent (1.4 mL, 0.025 M in substrate) at -40 ºC. A range of solvents were screened including polar and non-polar examples (Table III-1). CH3CN and CHCl3 returned carbamate III-4 in 14 and 22% ee, respectively (Table III-1, entries 2,3). Interestingly, a 1:1 mixture of these solvents with hexane improved enantioselectivities to 27 and 47% ee respectively (Table III-1, entries 4,5). The mixture of CHCl3:hexane (1:1) gave the best selectivity. Other mixture solvents with chloroform including toluene (43% ee, entry 6), cyclohexane (41% ee, entry 8), pentane (40% ee, entry 9), benzene (32% ee, entry 10) and heptane (40% ee, entry 11) were all found to be slightly less selective than mixture of chloroform with hexane. The reaction in pure hexane gives no cyclized product due to low solubility of the substrate and cartalyst in hexane (Table III-1, entry 224 Table III-1: Aprotic solvent screen for chlorocyclization reaction O Ph H N III-4 DCDMH (1.1 equiv) O Cl (DHQD)2PHAL (10 mol%) -40 ºC, solvent O a O NH Ph III-5 a Entry Solvent ee (%) Entry Solvent 1 CH2Cl2 +2 8 CHCl3:Cyclohexane 2 CH3CN +14 9 CHCl3:Pentaneb +40 3 CHCl3 +22 10 CHCl3:benzeneb +32 4 CH3CN:Hexane b +27 11 CHCl3:Heptaneb +40 5 CHCl3:Hexane b +47 12 Hexane - 6 CHCl3:Toluene b +43 13 CH2Cl2:Hexane 7 CH3CN:CCl4 +25 14 acetone a b b ee (%) b b +41 +26 -20 c c ees were determined by GC analysis. 1:1 mixture. ent.III-5 was obtained. 12). Interestingly, the use of polar solvents such as yielded the opposite enantiomer in 20% ee (Table III-1, entry 14), a net change of 67 percentage points! The reason for this dramatic reversal in selectivity was not clear, but led to trials of protic solvents for this reaction. 225 The switch in enantioselectivity was observed in all protic solvents (Table III-2). The best results are obtained when n-PrOH (-74% ee, entry 4), n-BuOH (-61% ee, entry 6), and i-BuOH (-65% ee, entry 7) were used. Trifluoroethanol (TFE) proved to be less Table III-2: Protic solvent screen for chlorocyclization reaction O Ph H N III-4 Entry DCDMH (1.1 equiv) O O Cl (DHQD)2PHAL (10 mol%) -40 ºC, solvent Solvent ee NH O Ph ent. III-5 a a Entry Solvent ee (%) (%) 1 -37 7 i-BuOH -65 2 EtOH -52 8 pentanol -52 3 MeOH -36 9 TFE:EtOH 4 n-PrOH -74 10 TFE:MeOH 5 IPA -50 11 TFE:n-PrOH 6 a Trifluoroethanol n-BuOH -61 12 TFE:IPA b -56 b -49 b -72 b -56 b ees were determined by GC analysis. 1:1 mixture. selective than other alcoholic solvents (-37% ee, Table III-2, entry 1) but when mixed with EtOH (-56% ee, entry 9), MeOH (-49% ee, entry 10), and IPA (-56% ee, entry 12) the selectivity increased except for n-PrOH (-72% ee, entry 11). The reaction achieved highest enantioselectivity for III-5 in CH3Cl:Hexane (+47% ee) and in n-PrOH ent.III-5 (-74% ee). 226 III.3 Halogen Source Screen for the Chlorocyclization Reaction of Unsaturated Carbamates In addition to screening the chlorocyclization reaction in different protic and aprotic solvents, it was also interesting to investigate the enantioselectivity of the chlorocyclization reaction in the presence of different hydantoin and other chloronium sources. We investigated three hydantoins with different substituents in C5 (Table III-3). In CH3Cl:Hexane solvent system, going from dimethyl-dichloro hydantoin (+47% ee, entry 1) to diphenyl-dichloro hydantoin (+46% ee, entry 2), the selectivity remained the same. The removal of the C5 substitution returned III-5 in a substantially lowered +28 ee (Table III-3, entry 3). Similarly, trichloroisocyanuric acid (TCCA) produced an inferior result (+21% ee, entry 4). It is also noteworthy that the transformation in the presence of N-chlorosuccimide (NCS) provides the desired product III-5 in racemic mixture (Table III-3, entry 5). In n-PrOH, the maximum selectivity was observed when dimethyl-dichloro hydantoin (-74% ee, entry 6) was used in the presence of dichloro-dihydro hydantoin selectivity dropes to -70 ee (Table III-3, entry 8). The transformation in the presence of dichloro-diphenyl hydantoin did not proceed to completion after 24 h due to low solubility of DPDCH in n-PrOH (Table III-3, entry 7). TCCA and NCS did not improve the selectivity. Various bromonium sources were also screened for this transformation, but only low levels of stereoinduction were observed in the presence of dibromo-dimethyl hydantoin (-31% ee, entry 11). N-Bromosuccimide (NBS) provides the 227 bromocyclized product in good yield (86%) but no enantioselectivity (Table III-3, entry Table III-3: Halogen source screening O H N Ph O O halogen source (1.1 equiv) (DHQD)2PHAL (10 mol%) solvent, -40 ºC III-4 Entry Cl III-6 Halogen Solvent O Ph X R NH R a O N Cl N O R=Me, DCDMH R=Ph, DCDPH R=H, DCDHH b Yield (%) ee (%) source c DCDMH 95 +47 c DCDPH 98 +46 c DCDHH 78 +28 c TCCA 90 +21 c NCS 57 0 n-PrOH DCDMH 88 -74 7 n-PrOH DCDPH NR - 8 n-PrOH DCDHH 86 -70 9 n-PrOH TCCA 90 -57 10 n-PrOH NCS 51 -67 11 n-PrOH DBDMH 90 -31 12 n-PrOH NBS 86 0 1 2 CHCl3: Hexane 3 CHCl3: Hexane 4 CHCl3: Hexane 5 CHCl3: Hexane 6 a CHCl3: Hexane b d d d d d Isolated yields after column chromatography. ees were determined by c d GC analysis. 1:1 mixture. ent.III-6 was obtained. 228 12). The investigation of alternative chlorine sources failed to provide a more selective transformation than the initially optimized (DCDMH) chlorine source. III.4 The Effect of Carbamate Structure on Enantioselectivity of Chlorocyclization Reaction of Unsaturated Carbamates Ph III-3 NH2 BnOCOCl,Pyridine CH2Cl2, 77% yield Ph H N Ph O III-7 O Scheme III-2: Synthesis of carbamate III-7 In an effort to further improve the stereoselectivity of this transformation, different carbamates were studied in the two optimized solvent systems. We tried to synthesize carbamates with more bulky group than t-butyl like dimethylphenyl and less bulky group such as benzyl. The synthesis of III-7 by protection of amine III-3 is outlined in Scheme III-2. Ph OH triphosgene pyridine Ph Et2O, benzene 86% yield NH2 Ph III-3 Ph NH2 O Cl O III-8 III-8, Et3N (1.2 equiv) no reaction DMAP, THF III-8, Et3N (5.0 equiv) DMAP, THF, 52% III-3 O Ph N H III-9 O Ph Scheme III-3: Attempts to make desired dimethylphenyl carbamate 229 The first attempt to synthesize dimethylphenyl carbamate started with formation of corresponding chloroformate III-8 in 86% yield. The reaction of amine III-3 with in the presence of Et3N (1.2 equiv) was failed and starting material was isolated. The reaction proceeded to provide enamine III-9 as a major product in 52% yield by increasing the amount of the Et3N to 5.0 equivalents (Scheme III-3). Ph OH + Ph O Cl Ph NH2 III-3 O OH + Ph O2 N O O 83% yield O Ph pyridine, CH2Cl2 III-10, Et3N (1.2-5.0 equiv) no reaction DMAP, THF Cl Et3N, DMAP, THF Ph O 82% yield NH2 Ph III-3 Ph O III-10 III-11, Et3N (1.2-5.0 equiv) O O O III-11 NO2 no reaction DMAP, THF Scheme III-4: Attempts to make desired dimethylphenyl carbamate Next, the reaction of amine III-3 with carbonate III-10 instead of chloroformate was studied. The desired carbonate III-10 was synthesized as shown in Scheme III-4. NH2 Ph III-3 triphosgene, Et3N Ph CH2Cl2, 85% yield III-12 O H N NaH, THF H N O Ph Ph 2-phenylpropan-2-ol III-13 O 57% yield Scheme III-5: Synthesis of carbamate III-13 230 Cl However, the reaction of amine III-3 in the presence of different equiv (1.2-5.0) of triethyl amine did not provide any product and, instead starting material was isolated (Scheme III-4). One problem could be the low activity of carbonate III-10, so carbonate III-11 with a nitro group in para position was prepared. Unfortunately, the reaction failed once again yielding the isolated starting material for the reaction of amine III-3 with carbonate III-11 (Scheme III-4). Finally, the desired carbamte III-13 was synthesized from carbamic chloride III-12 and 2-phenylpropan-2-ol in the presence of sodium hydride (Scheme III-5). The chlorocyclization of carbamtes (III-4, III-13, III-7) under optimized condition was studied. Modulation of the t-butyl group to benzyl or dimethyl phenyl did not affect the stereoselectivity of the reaction in n-PrOH (Table 4, entries 4-6). Conversely, the stereoselectivity diminished in the CHCl3-Hexane solvent system (Table 4, entries 1-3). Contrasting trends in the enantioselectivity were observed as a function of carbamate structure in the two different solvent systems. This observation is likely an indication of different modes of catalyst-substrate interaction in different solvents. 231 Table III-4: The effect of carbamate structure on enantioselectivity O H N Ph O DCDMH, (DHQD)2PHAL (10 mol%) R Cl Solvent, -40 !C O Ph III-14 A H N A: Ph O III-4 Ph O H N O Ph III-4 CHCl3: Hexane 2 III-13 CHCl3: Hexane 3 III-7 CHCl3: Hexane 4 III-4 5 6 a Solvent 1 a Carbamate Ph H N O Ph III-7 O III-13 O Entry NH O b Yield (%) ee (%) c 95 +47 c 78 +25 c 80 +13 n-PrOH 88 -74 III-13 n-PrOH 85 -73 III-7 n-PrOH 82 -71 d d d b Isolated yields after column chromatography. ees were determined by GC c d analysis. 1:1 mixture. ent.III-14 was obtained. 20 III.5 Eyring Plot analyses In recent years, the observation of temperature effects in connection with the Eyring theory20 has been used to gain a better understanding of the factors influencing the stereochemical outcome of various reactions. In particular, studies of enantio- and diastereoselective reactions by varying the reaction temperature have shed light on 232 solvent effects and stereoselectivity. 21 Analysis of the logarithmic values of stereoselectivity as a function of reciprocal temperature results in a linear relationship for 22 the equation reported in Figure III-4, known as the modified Eyring equation, ln (k/k') where ln(k/k') = - !!H≠ / RT + !!S≠ / R !!H≠/R !!S≠/R 1/T Figure III-4: Stereoselectivity and thermodynamic parameters: a graphic representation of the Eyring equation ln(k/k') is the natural logarithm of stereoselectivity, and k and k' are the overall rate constants of the reactions leading to the two stereoisomers. According to Eyring theory, when this relationship is plotted, the slope corresponds to the difference in the overall ≠ activation enthalpies (ΔΔH ) and the intercept represents the difference in the overall H N O O (S) Cl NH Cl Cl O III-15 O CHCl3-Hex n-PrOH (DHQD)2PHAL (20 mol%) DCDMH (1.1 equiv) O O (R) Cl NH Cl (R)-III-16 (S)-III-16 Scheme III-6: Test reaction for Eyring plot analyses 233 ≠ activation entropies (ΔΔS ) (Figure III-4). The influence of solvent on stereoselectivity can be considered as a macroscopic effect related to solute–solvent interactions at the molecular level. These interactions differently affect the reaction paths leading to the two stereoisomers by changing the activation parameters and therefore the stereoselectivity. a. b. (S)-Selective reaction: (R)-Selective reaction: TS TS !!G‡ TS !!G‡ !G‡ !G‡ !G‡ TS !G‡ III-15 III-15 (R)-III-16 (S)-III-16 (R)-III-16 (S)-III-16 Figure III-5: Energy diagrams in the chlorocyclization reaction; (a) (S)-Selective reactions. (b) (R)-Selective reactions. The solvent effect can be so significant that it can switch the stereoselectivity from ≠ ≠ enthalpy control (where ΔΔS ≈ 0) to entropy control (where ΔΔH ≈ 0). 23 In our system, with suitable solvents in hand for accessing either enantiomer, our efforts focused on comparing the divergent mechanisms that generate the R or the S enantiomers selectively. To investigate this, the chlorocyclization of carbamate III-15 (synthesized in the same manner shown in Scheme III-1) was selected as a test reaction for further studies. The absolute stereochemistry of (S)-III-16 was verified by X-ray diffraction and was inferred by analogy for other substrates (Scheme III-6). Eyring plot analyses were run for the cyclization of III-15 in the presence of 20 mol% of catalyst. 234 Increased catalyst loading was employed to eliminate the background reaction at 0 ºC. The energy diagram for the chlorocyclization of carbamate III-15 based on the transition state theory is illustrated in Figure III-5. The enantioselectivity in the reaction should ≠ increase, as the absolute value of ΔΔG becomes larger. Table III-5: The effect of temperature on the chlorocyclization reaction of carbamate III-15 H N O O (S) O CHCl3-Hex n-PrOH (DHQD)2PHAL (20 mol%) DCDMH (1.1 equiv) Cl Cl III-15 O Cl NH O Temp NH (R)-III-16 (S)-III-16 Solvent O (R) Cl ee a Temp Config. (%) n-PrOH 0 54 S n-PrOH -10 60 n-PrOH -20 n-PrOH ee a Config. (ºC) (%) CHCl3-Hex 0 65 R S CHCl3-Hex -10 63 R 68 S CHCl3-Hex -20 60 R -25 70 S CHCl3-Hex -25 41 R n-PrOH -30 74 S CHCl3-Hex -30 28 R n-PrOH -40 74 S CHCl3-Hex -40 20 R n-PrOH -55 74 S CHCl3-Hex -55 6 R a (ºC) Solvent Cl ees were determined by GC analysis. In the course of this effort, significant temperature effects on the enantiodivergent chlorocyclization reactions were observed (Table III-5). As the reaction temperature 235 increased the R selectivity in CHCl3-Hexane also increased for the cyclization reaction of carbamate III-15 (+82% ee at 0 ºC as compared to +47% ee at -40 ºC). Conversely, a decrease in reaction temperature resulted in an increase in the S selectivity during the formation of oxazolidinone III-16 in n-PrOH (-74% ee at -40 ºC as compared to -54% ee at 0 ºC). The difference in temperature profiles between the R-selective and S-selective reactions suggest that enthalpy-entropy compensation may contribute to this solvent dependent enantiodivergent system. We hoped to address three important aspects using Eyring plot analyses–first, to explain the different trends in the temperature dependence of enantioselectivity in protic versus aprotic solvents; second, to explain the dependence (or the lack of it) of carbamate structure on the enantioselectivity in the two solvent systems and third, to determine the nature of substrate catalyst interactions on the basis of the differential activation parameters obtained from the Eyring plots. The relative rates for the formation of the S and R products are represented by Equations (1) and (2), respectively, where ΔΔS ≠ represents the differential activation entropy and ΔΔH ≠ represents the differential activation enthalpy. ≠ ≠ ≠ ≠ ln(kS/kR) = - ΔΔH S-R / RT + ΔΔS S-R / R ln(kR/kS) = - ΔΔH R-S / RT + ΔΔS R-S / R (1) (2) The difference in the Gibbs free energy of activation for the formation of the two ≠ diastereomeric transition states can then be correlated to the differential enthalpy (ΔΔH ) 236 ≠ and entropy (ΔΔS ) of activation parameters using Equation 3. A more negative value for ΔΔG≠ will indicate a more spontaneous formation of one diastereomeric transition state ≠ over the other. Attention must be drawn to the fact that the contribution of ΔΔS to the ≠ ≠ value of ΔΔG is temperature dependent unlike the contribution of ΔΔH (See SI). ≠ ≠ ≠ ΔΔG = ΔΔH - TΔΔS (3) In accord with the above Equations, plots of the natural logarithms of the relative rates of formation of (S)-III-16 product, in n-PrOH versus reciprocal temperatures were fitted to straight lines with good correlation coefficients (Figure III-6). These observations confirm that a single mechanism is operative in the catalytic process occurring in n-PrOH over the temperature range of 0 ºC to -30 ºC where maximum stereoselectivity was observed at -30 ºC. (S)-Selective reaction: y = -4.2752 + 1.4957 x ≠ ≠ -ΔΔH S-R / R = +1.4957 ΔΔH S-R = -12.4 kJ mol ≠ ≠ 1 -1 -1 ΔΔS S-R = -35.5 J mol- K ΔΔS S-R / R = -4.2752 237 2 o t=-30 C 1.9 R Ln(k /k ) 1.8 1.7 -1 1.5 ∆∆S= -35.5 Jmol K S 1.6 ∆∆H= -12.4 KJmol -1 -1 1.4 1.3 o 1.2 3.6 t=0 C 3.8 4 -3 -1 4.2 10 T /K -1 4.4 4.6 Figure III-6: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions in n-PrOH On the other hand, Eyring plots of this reaction in CHCl3-Hexane (1:1) showed two Tinv at -20 ºC and -30 ºC. This interruption marks two linear trends, one at a higher T (higher streoselectivity) and one at a lower T with different slopes and intercepts that confirm two different operative mechanisms at different temperatures (Figure III-7). (R)-Selective reaction: y = 3.8324 – 0.62203 x ≠ ≠ -ΔΔH S-R / R = -0.62203 ΔΔH S-R = +5.2 kJ mol ≠ ≠ ΔΔS S-R / R = +3.8324 -1 -1 -1 ΔΔS S-R = +31.8 J mol K 238 (R)-Selective reaction: y = 4.5202 – 0.9585 x ≠ ≠ -ΔΔH S-R / R = -0.9585 ΔΔH S-R = +8.0 kJ mol ≠ ≠ ΔΔS S-R / R = +4.5202 ΔΔS S-R = +37.6 J mol # # -1 1.4 -1 -1 K -1 ∆∆H = +5.2 KJmol 1.6 -1 -1 ∆∆S = +31.8 Jmol K o t=0 C o t=-20 C Ln(k R/kS) 1.2 1 # -1 # -1 0.8 ∆∆H = +8.0 KJmol 0.6 ∆∆S = +37.6 Jmol K -1 o t=-30 C 0.4 0.2 0 3.6 3.8 4 4.2 3 -1 4.4 4.6 -1 10 T / K Figure III-7: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions in CHCl3-Hexane 239 As summarized in Table III-6, the enthalpy-entropy compensation in CHCl3-Hexane is different at -30 ºC (243 K) as opposed to 0 ºC (273 K). At 273 K, the contribution of the ≠ -1 decreased entropy of activation (-TΔΔS R-S = -8.7 kJ mol ) far outweighs the -1 unfavorable decrease in the differential enthalpy of activation (+5.2 kJ mol ) to result in -1 one diastereomeric TS being favored over the other by 3.5 kJ mol . Therefore the stereoselectivity of the R-selective chlorocyclization reaction in CHCl3-Hexane is ≠ governed by the differences in the entropies of activation (ΔΔS R-S) leading to the two possible enantiomeric products. This result is likely manifested by the dependence of Table III-6: Differential enthalpy, entropy and Gibbs free energy for the chlorocyclization reaction ≠ ΔΔH Solvent Temp (K) -1 (kJ mol ) ≠ ΔΔS -1 (J mol ΔΔG -1 K ) ≠ -1 (kJ mol ) CHCl3-Hex 243 +8.0 +37.6 -1.1 CHCl3-Hex 273 +5.2 +31.8 -3.5 n-PrOH 243 -12.4 -35.5 -3.8 n-PrOH 273 -12.4 -35.5 -2.7 enantioselectivity on the steric bulk of the carbamate in CHCl3-Hexane with bulkier carbamates predictably giving lower enantioselectivities. In contrast, in the S-selective ≠ ≠ reaction in n-PrOH, negative values of ΔΔH S-R and ΔΔS S-R control the stereoselectivity. 240 -1 The increase in differential enthalpy activation (-12.4 kJ mol ) is offset by the increased -1 -1 differential entropy of activation (-35.5 J mol K ). The latter has a net lower Table III-7: The effect of temperature on the chlorocyclization reaction of carbamate III-6 H N O O (S) (DHQD)2PHAL (20 mol%) DCDMH (1.1 equiv) ee (ºC) (%) n-PrOH 0 60 S n-PrOH -20 68 n-PrOH -30 n-PrOH -40 Solvent NH O (R) Cl (R)-III-16 (S)-III-16 Temp a O CHCl3-Hex n-PrOH Cl Cl Ph III-17 O Cl NH O Cl Temp ee (ºC) (%) CHCl3-Hex 0 20 R S CHCl3-Hex -20 15 R 74 S CHCl3-Hex -30 10 R 74 S CHCl3-Hex -40 8 R a Config. Solvent a Config. ees were determined by GC analysis. ≠ contribution at lower temperatures (-TΔΔS = +8.6 kJ mol -1 at 243 K as opposed to +9.7 -1 kJ mol at 273 K) leading to one TS being favored over the other by 3.8 kJ mol ≠ -1 at 243 ≠ K (-30 ºC). Hence ΔΔH S-R term is the major influence on lowering the ΔΔG S-R of the favored pathway, indicating that the S-selective reaction is governed by differences in the ≠ enthalpies of activation (ΔΔH S-R). These results seem to suggest that the stabilizing interactions between the substrate and catalyst (presumably by means of π stacking 241 interactions of the olefin substituent and the catalyst) contribute significantly more than the steric repulsion between the substrate and catalyst in n-PrOH. Experimental observations of the negligible effect of the carbamate bulk on the enantioselectivity of this reaction in n-PrOH (See Table III-4) seem to confirm this hypothesis. As shown in Table III-4, modulation of the t-butyl group to benzyl or dimethyl phenyl did not affect the stereoselectivity of the reaction in n-PrOH but the stereoselectivity is diminished in the CHCl3-Hexane solvent system. The benzyl carbamate III-17 was synthesized to compare its Eyring plots of benzyl activation parameters with that of the carbamate III-15. The effect of temperature in the formation of (S)-III-16, in n-PrOH and CHCl3-Hexane was studied (Table III-7). (S)-Selective reaction: y = -2.2574 + 1.0105 x ≠ ≠ -ΔΔH S-R / R = +1.0105 ΔΔH S-R = -8.4 kJ mol ≠ ≠ ΔΔS S-R / R = -2.2574 -1 -1 -1 ΔΔS S-R = -18.8 J mol K The plots of the natural logarithms of the relative rates for the formation of (S)-III-16, in n-PrOH versus reciprocal temperatures were fitted to straight lines with good correlation coefficients (Figure III-8). The results closely mirror those observed for carbamate ≠ ≠ III-15, albeit with lower ΔΔH S-R and ΔΔS S-R. This reaction is also enthalpy driven. 242 2 o t=-30 C 1.9 Ln(K S/KR) 1.8 1.7 ∆∆H= -8.4 KJmol 1.6 -1 -1 -1 ∆∆S= -18.8 Jmol K 1.5 o t=0 C 1.4 1.3 3.4 3.6 3.8 4 4.2 4.4 10-3T-1/K-1 Figure III-8: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions of carbamate III-17 in n-PrOH On the other hand, Eyring plots of the reaction of carbamate III-17 in CHCl3-Hexane (1:1) showed a different pattern ascompared to carbamate III-15. Two Tinv at -20 ºC and ≠ ≠ -30 ºC were observed. In comparison to III-15 ΔΔH R-S and ΔΔS R-S for III-17 were lower (Figure III-9). The stereoselectivity for the R-selective chlorocyclization reaction of carbamte III-17 in CHCl3-Hexane is also governed by the differences in the entropy of ≠ activation (ΔΔS R-S). (R)-Selective reaction: y = 1.6841 – 0.55701 x ≠ ≠ -ΔΔH S-R / R = -0.55701 ΔΔH S-R = +4.6 kJ mol ≠ ≠ ΔΔS S-R / R = +1.6841 -1 -1 -1 ΔΔS S-R = +14.0 J mol K 243 0.45 ∆∆H= +4.6 KJmol 0.4 -1 Ln(k R/kS) -1 -1 ∆∆S= +14.0 Jmol K 0.35 0.3 0.25 0.2 0.15 3.4 3.6 3.8 4 4.2 4.4 10-3T-1/ K-1 Figure III-9: Eyring plots of ln[(100 + %ee)/(100 - %ee)] vs. 1/T for chlorocyclization reactions of carbamate III-17 in CHCl3-Hexane One can also imagine that the switch in enantioselectivity by changing the solvent from CHCl3-Hexane to n-PrOH can be due to conformational changes of the catalyst in different solvents. To test this hypothesis the conformation of the catalyst was examined by NMR ROESY studies in deuterated methanol as replacement n-PrOH. The observed ROESY between the ethyl group of the quinuclidine moiety and also Hc with Hd indicates that the catalyst, (DHQD)2PHAL, adapts an open conformation (Figure III-10), 244 which is also supported by the small Ha-Hb coupling constant (suggesting the dihedral angle close to 90 degree). These ROESY studies suggests that (DHQD)2PHAL adopts the same conformation to what Sharpless has reported for the (DHQD)2PHAL in chloroform. 24 These results together suggest that the origin of the solvent-dependent stereodiscrimination is controlled by the enthalpy-entropy compensation and not conformational changes in the catalyst. N MeO Hb N Hc Ha O N N HN O H MeO N Figure III-10: Structure of (DHQD)2PHAL in chloroform and methanol based on the NMR ROESY studies III.6 Additive Optimization Experiments With the discovery that -30 ºC was an optimal temperature in providing chloro-oxazolidinone (S)-III-16 in n-PrOH and 0 ºC was the effective temperature for (R)-III-16 in CHCl3-Hexane, a series of experiments were conducted to optimize the selectivity. Initial efforts focused on evaluating the selectivity of the reaction by addition of different acids. Several acidic additives were screened for reaction in n-PrOH. Addition of 1.0 equivalent of p-TsOH or acetic acid resulted in decreased selectivities 245 (Table III-8, entries 2,3), citric acid had little effect (Table III-8, entry 4). Unlike other acid additives, benzoic acid (1.0 equiv) generated a reproducible increase in selectivity to 91% ee (Table III-8, entry 5). Further increase of benzoic acid to 2.0 and 5.0 equivalents did not offer any additional increases in selectivity. Since benzoic acid and acetic acid have almost the same acidity, the increase in selectivity with benzoic acid cannot be solely due to acidity, and points to interaction between benzoic acid and substrate or catalyst. Other substituted benzoic acids with Table III-8: Acid additives loading screening in n-PrOH O H N O O Cl III-15 O DCDMH (1.1 equiv) (DHQD)2PHAL (20 mol%) n-PrOH, -30 ºC, additive (1.0 equiv) Cl a Cl (S)-III-16 Additive Yield (%) - 89 90 -20 AcOH 87 -20 Citric acid 92 -73 Benzoic acid 94 b -74 p-TsOH a NH -91 ee (%) Isolated yields after column chromatography. b ees were determined by GC analysis. electron donating and electron withdrawing groups were screened. As outlined in Table III-9, electron donating groups (entries 2, 5, 7, 12) and electron withdrawing groups 246 (entries 3, 4, 6) did not improved the selectivity. Having more bulky benzoic acid (entry 8) or with two electron donating groups (entries 10, 11) did not change the selectivity. 3,5-Dinitro benzoic acid provides the desired product with the lowest selectivity (80% ee, Table III-9, entry 9). Overall, addition of 1.0 equivalent of benzoic acid resulted in increasing the selectivity of the chlorocyclization reaction in n-PrOH. The effect of this additive on the reaction in CHCl3-Hexane was then studied (Table III-10). A drop in selectivity was realized when 1.0 or 5.0 equivalents of benzoic acid was added to reaction in Table III-9: Screening of different benzoic acid O H N O O Cl III-15 DCDMH (1.1 equiv) O (DHQD)2PHAL (20 mol%) n-PrOH, -30 ºC, ArCO2H (1.0 equiv) Cl Entry ee (%) 1 Ph 2 a Cl (S)-III-16 Entry Ar ee (%) -91 7 3-hydroxy-Ph 4-amino-Ph -87 8 2,4,6-trimethyl-Ph -88 3-chloro-Ph -88 9 3,5-dinitro-Ph -80 4 4-cyano-Ph -83 10 3,5-dimethoxy-Ph -89 5 4-methoxy-Ph -86 11 3,5-dimethyl-Ph -89 6 4-nitro-Ph -83 12 4-hydroxy-Ph a -86 3 a Ar NH -85 ees were determined by GC analysis. CHCl3-Hexane (Table III-10, entries 2, 3). Triethyl amine was tolerated at 0.1 equivalent loading (60% ee), but a significant drop in selectivity was observed when larger amounts 247 were added. Addition of 1.0 equvalent not only led to low selectivity (26% ee) but also resulted in low coversion of reaction (entries 4-7). Imidazole (0.1 equivalent) were decreased the selectivity to 28% ee (entry 8) and a larger amount (1.0 equivalent) cause a complete loss of selectivity and low conversion (entry 9). Diisopropyl ethylamine resulted in low selectivity (entry 10) and both diisopropyl amine and pyridine cause no conversion of the reaction (entries 11 and 12). Inorganic bases such as sodium carbonate had little effect on the selectivity (entry 13). Addition of Lewis acids such as copper triflate (entry 14) and silver triflate (entry 15) produced a decline from 65% ee to 56% and 44% ee, respectively. Drying agents had little effect on the stereochemical course of the reaction. The addition of anhydrous magnesium sulfate (entry 16) led to the production of (R)-III-16 with lower selectivity. The addition of 20% w/w loading of activated 4 Å molecular sieves returned the chlorooxazolidinone in 61% ee (entry 17). In summary, the best results were obtained with no additive for CHCl3-Hexane solvent system. 248 Table III-10: Screen of additives loading in CHCl3-Hexane O NH O H N O O Cl III-15 DCDMH (1.1 equiv) Cl (DHQD)2PHAL (20 mol%) CHCl3-Hex, 0 ºC, additive Entry Additive Additive Yield (equiv) (%) (R)-III-16 Cl ee (%) a 1 - - 85 +65 2 Benzoic acid 1.0 80 +58 3 Benzoic acid 5.0 87 +52 0.1 92 +60 0.2 78 +46 0.5 70 +38 1.0 20 +26 0.1 79 +28 1.0 18 0 0.1 78 +36 1.0 0 - 1.0 0 - 4 5 6 7 Et3N Et3N Et3N 8 Et3N Imidazole 9 Imidazole 10 11 12 i-Pr2NEt i-Pr2NH Pyridine 13 Na2CO3 0.1 83 +60 14 Cu(OTf)2 AgOTf 0.1 81 +56 0.1 83 +44 MgSO4 Molecular sieves 1.0 79 +56 20% w/w 83 +61 15 16 17 a b Isolated yields. ees were determined by GC analysis. III.7 Catalyst and Additive Loading Screening in n-PrOH 249 b As a final screen, the chlorocyclization reaction in n-PrOH was evaluated using different loading of catalyst and benzoic acid as the optimal additive for this reaction. By going down to 1 mol percent of catalyst the same selectivity was observed, but 0.5 mol Table III-11: Catalyst and additive loading screening in n-PrOH O O O Cl III-15 DCDMH (1.1 equiv) Cl (DHQD)2PHAL (x mol%) n-PrOH, -30 ºC, Cl benzoic acid (y equiv) a (S)-III-16 X Y Yield (%) 20.0 1.0 94 1.0 90 -91 1.0 1.0 88 -92 0.5 1.0 94 -86 0.1 1.0 90 -74 1.0 0.5 98 -92 1.0 0.1 91 b -91 10.0 a NH O H N -90 Isolated yields after column chromatography. ee (%) b ees were determined by GC analysis. percent of catalyst returned (S)-III-16 in slightly lower enantiopurity (Table III-11, entry 4). The loading of the catalyst could be reduced to 0.1 mol percent while still maintaining relatively moderate selectivity (74% ee, Table III-11, entry 5). In short, the catalyst loading study with the improved reaction conditions confirmed the catalyst loading of 1 mol percent to be optimal for maintaining enantioselectivity near 90% ee. 250 We next turned to a study of the benzoic acid loading. So far the best results (Table III-11, entry 6) were obtained by adding 0.5 equivalent of benzoic acid. By addition of 0.1 equivalent of benzoic acid a slight drop in selectivity (90% ee) of the reaction was realized to (Table III-11, entry 7). III.8 Substrate Scope for Enantiodivergent Chlorocyclization Reaction Having discovered optimal conditions for the enantiodivergent chlorocyclization of carbamates, a number of analogues carbamates were prepared and evaluated using the standard conditions. In total, ten carbamates were prepared (Figure III-11). All the H N H N O O H N F H N Cl O III-18 III-22 O O H N F3C O O O O III-15 CF3 H N Ph III-21 Cl O H N Cl O F3C III-4 O III-23 H N O O III-19 H N III-24 O O O O N H O III-20 III-25 Figure III-11: Carbamate substrates 251 O substrate were readily prepared in a similar fashion as shown in Scheme III-7, with the exception of substrate III-22 and III-25, which faced low conversion in the first step of coupling with propargyl alcohol. For those two substrates, an alternative way outlined in Scheme III-8 was used. CuI OH ArBr, Mg, Et2O Ar Ar Br reflux 1. NaN3 2. PPh3 H N Ar Ar OH CBr4, PPh3 CH2Cl2 NH2 (Boc)2O, Et3N CH2Cl2 O O Scheme III-7: Synthesis of carbamate substrates Aside from exploring the substrate scope for this new reaction this exercise was undertaken to confirm some of the hypotheses gleaned from the Eyring plot analyses. For example, it was expected that any significant changes in steric parameters of the substrate will likely affect enantioselectivities in CHCl3-Hexane more significantly than in n-PrOH. As summarized in Table III-12, a series of substrates with aryl substituents on the olefin gave consistently high enantioselectivity (-80 to -92% ee) in n-PrOH. The enantioselectivity in n-PrOH was independent of the electron rich/poor nature of the aryl substituent and also independent of the steric bulk of the substituent. In sharp contrast, in the CHCl3-Hexane solvent system, even small variations in the aryl substituent had 252 O N-K+ O O Br A O N A DMF O O O A NH2NH2•H2O N O A H N EtOH NH2 A PPh3CH3Br NaHMDS, THF -60 ºC to rt (Boc)2O, Et3N CH2Cl2 O O A: , Cl Cl III-22 III-25 Scheme III-8: Synthesis of carbamate III-22 and III-25 profound effect on the enantioselectivity (+82 to -6% ee) of the transformation. A few trends and results merit special mention. Comparison of entries 1-3 indicate that the enantioselectivity progressively decreases as the size of the substituent at the para position of the ring increases indicating that steric (and hence entropic destabilization) factors play a vital role in the CHCl3-Hexane system. Comparison of entries 5 and 6 indicate that the two isosteric but electronically different substituents 4-CF3C6H4 and 4-CH3C6H4 give practically no stereoinduction in CHCl3-Hexane (+2% ee and 0% ee respectively) confirming that electronic (and hence enthalpic stabilization) factors play a negligible role in CHCl3-Hexane. Having two electron withdrawing group in meta positions resulted in no conversion after 24 h (Table III-12, entry 9). 253 Table III-12: Substrate scope for enantiodivergent chlorocyclization reaction Ar/R Ar/R O + DCDMH (1.1 equiv) O n-PrOH (0.025M) O O H N NH Cl O CHCl3-Hex (0.025M) (DHQD)2PHAL (1 mol%) (DHQD)2PHAL (20 mol%) 0 oC Benzoic acid (0.5 equiv) Cl oC -30 A B Yield (%) Entry Ar/R (A) a ee (%) (A) O Ar/R Yield (%) b (B) NH a ee (%) (B) b 1 87 -80 83 +82 2 4-F-C6H4 92 -87 90 +75 3 4-Cl-C6H4 98 -92 97 +65 4 4-Ph-C6H4 86 -86 83 +50 5 4-Me-C6H4 90 -82 86 0 6 4-CF3-C6H4 78 -80 80 +2 7 3,4-Cl-C6H3 80 -88 81 +22 8 2,4,6-Me-C6H2 -83 40 (50) 9 3,5-ditrifluoromethylPh - - - - 10 a C6H5 PhCH2 87 -51 80 +65 c 58 (70) d d -6 b Isolated yields after column chromatography. ees were determined by GC and HPLC analyses. c In the presence of 2.0 equiv DCDMH. d Conversion of the reaction. Finally, a benzyl substituent gave better enantioselectivity in the CHCl3-Hexane solvent system (+65% ee) as opposed to the n-PrOH solvent system (-51% ee; Table III-12, entry 254 10) indicating that interactions between catalyst and substrate may be crucial in n-PrOH while reducing steric interactions between substrate and catalyst is of greater importance in the CHCl3-Hexane system. In n-PrOH, the fact that the enantioselectivity observed in this cyclization is independent of the carbamate structure, taken together with the necessity of the aromatic ring, raises the possibility that stabilizing interactions between substrate and catalyst may play a key role in asymmetric induction. An Eyring analysis of the enantioselectivity for the cyclization of carbamate III-15 was linear over a 30 ºC range (Figure III-6). Evaluation of the differential activation parameters derived from these plots revealed that the enantioselectivity was enthalpically controlled. This enthalpy driven behavior suggests the potential for a strong interaction between the carbamate and the catalyst in the dominant transition state for the transformation. On the other hand, the entropically controlled behavior of this reaction in CHCl3-Hexane suggests a much weaker intermolecular interaction between the carbamate and catalyst. Further, the results from the substrate scope study in CHCl3-Hexane indicate a strong steric interaction between the substrate and catalyst, leading to the erosion of selectivity as the steric demand of the substrate aryl ring increased. These observations further added credence to the entropy driven nature of this reaction in CHCl3-Hexane. Nonetheless, we are still pursuing a more refined understanding of the factors that lead to this relatively rare solvent dependant divergence in enantio-selectivity with the same chiral catalyst. 255 We were delighted to see if the same reaction conditions could be extended to trans-disubstituted and 1,1-disubstituted carbonate olefin substrates. trans-Disubstituted carbamate III-26 shows no conversion in the presence and absence of catalyst. The DCDMH H N Ph O no reaction CHCl3-Hex, rt, 24 h O III-26 (DHQD)2PHAL (10 mol%) DCDMH Ph O O O III-27 (DHQD)2PHAL (10 mol%) no reaction CHCl3-Hex, rt, 24 h DCDMH Ph O III-28 O O (DHQD)2PHAL (10 mol%) no reaction CHCl3-Hex, rt, 24 h Scheme III-9: The test reaction of carbamate III-26 and carbonate III-27 and III-28 reason can be the geometry of trans carbamate, which cannot adopt the necessary trajectory for cyclization. There is also no reaction for trans and 1,1-disubstituted carbonate. This results show that the presence of nitrogen in substrate is important for cyclization (Scheme III-9). In conclusion, we have developed the first solvent dependent enantiodivergent chlorocyclization of carbamates catalyzed by (DHQD)2PHAL. This methodology enables selective access to both enantiomers of oxazolidinones using a single chiral organocatalyst. Kinetic analyses uncovered that the origin of solvent-dependent 256 stereodiscrimination is controlled by the enthalpy-entropy compensation. The stereoselectivities of S-selective cyclization in alcoholic solvents are governed by the ≠ differences in the enthalpies of activation (ΔΔH S-R), whereas the stereodiscrimination process for the R-selective reaction is governed by differences in the entropies of ≠ activation (ΔΔS R-S). Additional efforts to understand the mechanism of this rare enantioswitching process are underway. 257 III.9 Experimental Section Commercially available starting materials were obtained from Aldrich or Fluka and were used without further purification. Unless otherwise mentioned, solvents were purified as follows: tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/benzophenone; methylene chloride (CH2Cl2) and toluene (PhCH3) was dried over calcium hydride (CaH2) and freshly distilled prior to use; DMF, DMSO, Et3N, and HMPA were distilled from CaH2 and stored over 4 Å molecular sieves. 4 Å molecular sieves were dried at 160 ºC under vacuum prior to use. All of the spectral data for known compounds either match those reported by Aldrich or by comparison to the literature report. 1 H NMR spectra were measured at 300, 500 or 600 MHz on a Varian Gemini-300, a Varian VXR-500 or Varian Inova-600 instrument respectively. Chemical shifts are reported relative to residual solvent (δ 7.24 ppm for CDCl3). 13 C NMR spectra were measured at 75 MHz on a Varian Gemini-300, at 125 MHz on a Varian VXR-500 or 150 MHz on a Varian Inova-600 instrument. Chemical shifts are reported relative to the central line of CDCl3 (δ 77.0 ppm). High resolution mass spectra were measured at the Michigan State University, Mass Spectrometry Laboratory. Optical rotations were measured on a Perkin-Elmer polarimeter (model 341) using a 1 mL capacity quartz cell with a 10 cm path length in chloroform. Analytical thin layer chromatography (TLC) was performed using pre-coated silica 258 gel 60 F254 plates. Compounds were visualized with UV light, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH. Column chromatographic purifications were performed using Silicycle 40-60 Å, 30-75 µm silica gel. All compounds purified by chromatography were sufficiently pure for use in further experiments. GC analysis was performed using HP (6890 series) GC system equipped with an Altech SE-54, 30 m × 320 µm × 0.25 µm column. Enantiomeric excess for all products was judged by GC and HPLC analysis using DAICEL CHIRALPAK OD-H column. General procedure for the synthesis of allylic alcohol: To a solution of magnesium (0.24 g, 10 mmol) in Et2O (10 mL) aryl bromide (10 mmol) was added at 0 ºC. The reaction mixture was heated to reflux for 2 h. CuI (0.11 g, 0.6 mmol) was then added at room temperature. The reaction mixture was allowed to stir at rt for 0.5 h. Propargyl alcohol (0.23 g, 4 mmol) in Et2 O (4 mL) was added dropwise at rt. The reaction was then heated to reflux for 24 h. After cooling to rt, NH4Cl (aq.) was added dropwise carefully. The organic phase was separated and the aqueous phase extracted with Et2O (3 x 50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo. Crude products were purified by silica gel column chromatography using EtOAc-Hexane (30%) as the eluent. OH 259 87% yield, colorless liquid 1 H NMR (500 MHz, CDCl3) δ 7.28-7.35 (m, 5H), 5.45 (d, J = 1.2 Hz, 1H), 5.33 (d, J = 1.2 Hz, 1H), 4.53 (d, J = 4.5 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 147.1, 138.4, 128.4, 127.8, 125.9, 112.3, 64.6. OH F 88% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.37-7.42 (m, 2H), 6.98-7.04 (m, 2H), 5.39 (d, J = 1.2 Hz, 1H), 5.31 (d, J = 1.2 Hz, 1H), 4.48 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 163.3, 146.2, 134.5, 127.8, 127.7, 112.7, 65.1. OH Cl 80% yield, colorless liquid 1 H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.5, 2H), 7.30 (d, J = 8.5, 2H), 5.44 (d, J = 1.2, 1H), 5.34 (d, J = 1.2, 1H), 4.48 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 146.1, 136.9, 133.7, 128.6, 127.4, 113.3, 64.9. OH Ph 83% yield, white solid, MP: 116 ºC 260 1 H NMR (300 MHz, CDCl3) δ 7.30-7.60 (m, 9H), 5.52 (d, J = 1.2 Hz, 1H), 5.37 (d, J = 1.2 Hz, 1H), 4.57 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 147.2, 141.2, 141.1, 137.8, 129.3, 127.7, 127.5, 127.4, 126.9, 113.2, 65.5. OH 88% yield, white solid, MP: 50 ºC 1 H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.41 (d, J = 1.2 Hz, 1H), 5.28 (d, J = 1.2 Hz, 1H), 4.51 (s, 2H), 2.33 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 147.8, 137.6, 134.4, 129.2, 126.0, 114.8, 65.2, 21.2. OH F3C 78% yield, white solid 1 H NMR (300 MHz, CDCl3) δ 7.42-7.68 (m, 4H), 5.51 (d, J = 1.2 Hz, 1H), 5.43 (d, J = 1.2 Hz, 1H), 4.54 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 146.1, 142.1, 129.9, 126.4, 125.4, 123.8, 114.8, 64.8. OH 78% yield, colorless liquid 1 H NMR (600 MHz, CDCl3) δ 6.86 (s, 2H), 5.54 (d, J = 1.2 Hz, 1H), 4.96 (d, J = 1.2 Hz, 1H), 4.18 (d, J = 6.0 Hz, 2H), 2.26 (s, 3H), 2.20 (s, 6H); 261 13 C NMR (150 MHz, CDCl3) δ 144.9, 136.6, 135.7, 128.7, 128.1, 113.7, 61.9, 20.8, 19.7. General procedure for the synthesis of allylic bromide: To a solution of allyl alcohol (0.81 mmol) in DCM (1.5 mL), PPh3 (0.25 g, 0.97 mmol) was added at 0 ºC, and the mixture was stirred for 10 min. CBr4 (0.046 g, 0.89 mmol) was added portionwise, and the mixture was stirred for 3 h at 0 ºC. The solvent was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using pentane to yield allyl bromide. Br 92% yield, colorless liquid 1 H NMR (500 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 5.54 (d, J = 1.2 Hz, 1H), 5.47 (d, J = 1.2 Hz, 1H), 4.37 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 144.2, 137.6, 128.5, 128.3, 126.1, 117.2, 34.2. Br F 95% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.42-7.42 (m, 2H), 7.01-7.07 (m, 2H), 5.47 (d, J = 1.2 Hz, 1H), 5.45 (d, J = 1.2 Hz, 1H), 4.33 (s, 2H); 13 132.7, 129.5, 116.3, 113.6, 34.1. 262 C NMR (125 MHz, CDCl3) δ 163.4, 146.6, Br Cl 90% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.25-7.36 (m, 4H), 5.45 (d, J = 1.2 Hz, 1H), 5.55 (d, J = 1.2 Hz, 1H), 4.33 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 141.1, 138.2, 136.0, 131.4, 130.2, 119.0, 34.2. Br Ph 1 H NMR (300 MHz, CDCl3) δ 7.31-7.61 (m, 9H), 5.60 (d, J = 1.2 Hz, 1H), 5.50 (d, J = 1.2 Hz, 1H), 4.40 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 147.5, 141.3, 141.1, 138.4, 129.3, 127.9, 127.7, 127.5, 126.8, 113.2, 35.0. Br 98% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.50 (d, J = 1.2 Hz, 1H), 5.42 (d, J = 1.2 Hz, 1H), 4.35 (s, 2H), 2.34 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 148.0, 137.7, 134.6, 129.0, 126.5, 116.1, 35.2, 21.3. Br F3C 263 94% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.42-7.71 (m, 4H), 5.58 (d, J = 1.2 Hz, 1H), 5.56 (d, J = 1.2 Hz, 1H), 4.35 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 145.2, 142.9, 130.0, 126.9, 125.6, 124.0, 115.4, 32.4. Br 90% yield, colorless liquid 1 H NMR (600 MHz, CDCl3) δ 6.87 (s, 1H), 6.80 (s, 1H), 5.72 (d, J = 1.2 Hz, 1H), 5.09 (d, J = 1.2 Hz, 1H), 4.12 (s, 2H), 2.26 (s, 3H), 2.37 (s, 6H); 13 C NMR (150 MHz, CDCl3) δ 142.7, 136.5, 135.0, 128.8, 128.1, 113.9, 32.9, 20.9, 19.8. General procedure for the synthesis of allylic amine: Allyl bromide (4.20 mmol) dissolved in THF-H2O (4:1) (20 mL) was treated with NaN3 (0.33 g, 5.04 mmol) at rt. After TLC analysis revealed the complete consumption of starting material, PPh3 (1.65 g, 6.30 mmol) was added to the reaction vessel. After 8 h at ambient temperature, the reaction was concentrated to remove most of the THF. The resulting suspension was diluted with HCl (aq.) and extracted with ether (3 x 50). The aqueous layer was then basified by adding solid KOH and extracted with ether (3 x 50). The combined organics were dried (Na2SO4) and concentrated to give the crude amine, which was usually pure enough to use in the next step. 264 NH2 96% yield, yellow liquid 1 H NMR (500 MHz, CDCl3) δ 7.27-7.40 (m, 5H), 5.33 (d, J = 1.2 Hz, 1H), 5.20 (d, J = 1.2 Hz, 1H), 3.70 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 149.4, 139.5, 132.3, 131.5, 128.3, 111.0, 45.8. NH2 F 75%, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.37-7.42 (m, 2H), 6.97-7.03 (m, 2H), 5.27 (d, J = 1.2 Hz, 1H), 5.19 (d, J = 1.2 Hz, 1H), 3.65 (s, 2H); 13 C NMR (150 MHz, CDCl3): δ 162.9, 147.5, 132.6, 132.2, 131.6, 128.2, 127.4, 114.9, 45.3. NH2 Cl 71% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.27-7.35 (m, 4H), 5.32 (d, J = 1.2 Hz, 1H), 5.23 (d, J = 1.2 Hz, 1H), 3.66 (d, J = 5.5 Hz, 2H), 1.40 (br s, 2H); 13 142.1, 138.3, 136.7, 131.6, 130.4, 120.5, 45.2. NH2 Ph 95% yield, colorless liquid 265 C NMR (150 MHz, CDCl3) δ 1 H NMR (300 MHz, CDCl3) δ 7.29-7.69 (m, 9H), 5.70 (br s, 2H), 5.39 (d, J = 1.2 Hz, 1H), 5.24 (d, J = 1.2 Hz, 1H), 3.74 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 147.7, 141.0, 139.7, 138.4, 129.1, 128.3, 127.9, 127.1, 126.8, 113.5, 45.0. NH2 77% yield, colorless liquid 1 H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.29 (d, J = 1.2 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 3.68 (s, 2H), 2.33 (s, 3H); 13 C NMR (150 MHz, CDCl3): δ 145.2, 136.8, 132.4, 131.7, 128.8, 111.2, 43.3, 20.8. NH2 F3C 90% yield, yellow liquid 1 H NMR (300 MHz, CDCl3) δ 7.24-7.69 (m, 4H), 5.39 (d, J = 1.2 Hz, 1H), 5.32 (d, J = 1.2 Hz, 1H), 3.71 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 147.3, 140.2, 131.6, 128.5, 128.0, 123.8, 112.7, 45.0. NH2 87% yield, yellow liquid 1 H NMR (300 MHz, CDCl3) δ 6.84 (s, 2H), 5.43 (d, J = 1.2 Hz, 1H), 4.89 (d, J = 1.2 Hz, 1H), 3.36 (s, 2H), 2.23 (s, 3H), 2.18 (s, 6H); 13 266 C NMR (150 MHz, CDCl3) δ 143.1, 137.2, 135.3, 128.9, 128.1, 114.2, 44.9, 20.8, 19.8. A mixture of 2-bromo-1-(3,4-dichlorophenyl) ethanone (4.0 g, 15.4 mmol), potassium phthalimide (3.0 g, 16.2 mmol) and dry DMF (17 mL) was heated overnight at 55 °C under nitrogen, after which the solvent was removed under reduced pressure. The solid residue was triturated with CHCl3 (20 mL), filtered, and washed with CHCl3 (3 x 20 mL). The combined organic extracts were successively washed with aqueous NaOH (0.2 M, 20 mL) and H2O (40 mL), and then dried (MgSO4). The solvent was removed at reduced pressure to afford a crude solid, which was purified by flash chromatography on silica gel using EtOAc-hexane (10%) to give the product (67% yield, 3.4 g). 1 H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.0, 3.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.75 (dd, J = 5.0, 3.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.05 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 189.2, 167.7, 138.8, 134.2, 133.9, 133.8, 132.1, 131.1, 130.1, 127.1, 123.6, 44.0. To a stirred suspension of (bromomethyl) triphenylphosphonium bromide (4.5 g, 10.2 mmol) in THF (60 mL) under nitrogen at -60 ºC was added sodium bis(hexamethylsilyl)amide (6 mL, 2.0 M in THF). The resulting red solution was stirred at -60 ºC for 40 min, and then a solution of starting material (3.1 g, 9.2 mmol) in THF (10 mL) was added. The reaction was allowed to warm slowly to rt and stirred overnight before being quenched with H2O and extracted with Et2O. The extract was dried over MgSO4, filtered and concentrated to dryness. Flash chromatography using hexane afforded the product (77% yield, 2.3 g). 267 1 H NMR (300 MHz, CDCl3) δ 7.83 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 5.44 (t, J = 0.9 Hz, 1H), 5.26 (t, J = 1.5 Hz, 1H), 4.63 (t, J = 1.2 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 167.8, 140.6, 138.5, 134.2, 132.6, 132.1, 131.9, 130.3, 128.5, 125.7, 123.5, 16.1, 41.0. The starting material (0.24 g, 0.74 mmol) was suspended in EtOH (2 mL) and hydrazine hydrate (0.07 mL, 64% solution, 1.48 mmol) was added. The mixture was heated to reflux for 1.5 h. The reaction was then cooled to rt and H2O (5 mL) was added. The solution was concentrated in vacuo. To the residue was added aqueous solution of HCl (10%, 5 mL) and the mixture was stirred at 90 ºC for 15 h. After cooling to 0 ºC the white precipitate was filtered off. The filtrate was basified with NaOH pellets and extracted with CH2Cl2 (three times). The organic layer was washed with brine, dried over Na2SO4, filtered and the solvents were removed under reduced pressure to afford the desired amine (80% yield, 0.12 g). 1 H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 5.35 (d, J = 1.2 Hz, 1H), 5.28 (d, J = 1.2 Hz, 1H), 3.66 (s, 2H), 1.25 (br s, 2H); 13 C NMR (125 MHz, CDCl3) δ 147.6, 139.9, 132.6, 131.6, 130.3, 128.1, 125.4, 113.0, 45.9. The starting material (0.20 g, 0.74 mmol) was then suspended in EtOH (2 mL) and hydrazine hydrate (0.07 mL, 64% solution, 1.48 mmol) was added. The mixture was 268 heated to reflux for 1.5 h, was cooled to rt and H2O (5 mL) was added. The solution was concentrated in vacuo. To the residue was added aqueous solution of HCl (10%, 5 mL) and the mixture was stirred at 90 ºC for 15 h. After cooling to 0 ºC the white precipitate was filtered off. The filtrate was basified with NaOH pellets and extracted with CH2 Cl2 (three times). The organic layer was washed with brine, dried over Na2SO4, filtered and the solvents were removed under reduced pressure to afford the free amine (84% yield, 0.9 g). 1 H NMR (300 MHz, CDCl3) δ 7.13-7.25 (m, 5H), 4.94 (d, J = 1.2 Hz, 1H), 4.88 (d, J = 1.2 Hz, 1H), 3.70 (s, 2H), 3.36 (s, 2H); 13 C NMR (150 MHz, CDCl3) δ 142.3, 138.2, 132.3, 131.9, 128.3, 114.8, 45.3, 41.0. A solution of di-tert-butyl dicarbonate (0.71 g, 3.14 mmol) in dry DCM (1 mL) was added under nitrogen at 0 ºC to a solution of allylamine (0.5 g, 2.85 mmol) and triethylamine (0.87 mL, 6.27 mmol) in dry DCM (2 mL). The reaction mixture was stirred at rt for 24 h. The solvent was removed in vacuo, and the residue was dissolved with DCM (6 mL) and water (4 mL). The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic extracts were washed with water (5 mL), dried (MgSO4), filtered, and concentrated. The resulting mixture was purified by flash chromatography on silica gel using EtOAc-hexane (10%) to give the carbamate. H N O O 89% yield, yellow liquid 269 1 H NMR (300 MHz, CDCl3) δ 7.25-7.41 (m, 5H), 5.40 (d, J = 1.2 Hz, 1H), 5.21 (d, J = 1.2 Hz, 1H), 4.62 (br s, 1H), 4.17 (d, J = 5.5 Hz, 2H), 1.42 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 144.7, 138.5, 128.1, 127.5, 125.8, 112.6, 78.9, 43.9, 28.1. H N O O F 87% yield, yellow liquid 1 H NMR (300 MHz, CDCl3) δ 7.33-7.38 (m, 2H), 6.95-7.02 (m, 2H), 5.32 (d, J = 1.2 Hz, 1H), 5.18 (d, J = 1.2 Hz, 1H), 4.11 (s, 2H), 1.40 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 163.6, 155.6, 145.8, 128.0, 127.7, 115.7, 112.6, 78.7, 43.9, 28.0. H N O O Cl 92% yield, white liquid 1 H NMR (300 MHz, CDCl3) δ 7.27-7.32 (m, 4H), 5.39 (d, J = 1.2 Hz, 1H), 5.22 (d, J = 1.2 Hz, 1H), 4.59 (br s, 1H), 4.15 (d, J = 5.5 Hz, 2H), 1.41 (s, 9H); 13 C NMR (125 MHz, CDCl3) δ 155.0, 145.9, 137.2, 133.8, 128.8, 127.4, 112.8, 79.2, 44.0, 28.2. H N O O Ph 90% yield, white liquid 1 H NMR (300 MHz, CDCl3) δ 7.32-7.59 (m, 9H), 5.47 (d, J = 1.2 Hz, 1H), 5.24 (d, J = 1.2 Hz, 1H), 4.62 (br s, 1H), 4.20 (d, J = 5.5 Hz, 2H), 1.43 (s, 9H); 270 13 C NMR (150 MHz, CDCl3) δ 154.8, 147.3, 141.5, 141.1, 138.0, 129.4, 127.8, 127.7, 127.3, 126.9, 113.0, 78.8, 44.1, 28.1. H N O O 80% yield, white liquid 1 H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.36 (d, J = 1.2 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 4.13 (d, J = 5.5 Hz, 2H), 2.33 (s, 3H), 1.42 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.4, 147.9, 137.6, 134.2, 129.0, 126.2, 114.5, 78.9, 44.1, 28.2, 21.2. H N O O F3C 86% yield, yellow liquid 1 H NMR (300 MHz, CDCl3) δ 7.43-7.65 (m, 4H), 5.45 (d, J = 1.2 Hz, 1H), 5.30 (d, J = 1.2 Hz, 1H), 4.17 (d, J = 5.5 Hz, 2H), 1.42 (s, 9H); 13 C NMR (125 MHz, CDCl3) δ 155.5, 146.1, 142.3, 129.8, 126.6, 125.5, 123.7, 114.6, 79.0, 43.8, 28.1. H N Cl O O Cl 87% yield, white solid; MP: 77 ºC 1 H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 5.40 (d, J = 1.2 Hz, 1H), 5.25 (d, J = 1.2 Hz, 1H), 4.60 (br s, 1H), 4.09 (d, J = 5.5 271 Hz, 2H), 1.41 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 142.9, 138.5, 132.3, 131.5, 130.1, 127.9, 125.3, 114.4, 79.4, 43.8, 28.1. H N O O 91% yield, yellow liquid 1 H NMR (300 MHz, CDCl3) δ 6.84 (s, 2H), 5.38 (d, J = 1.2 Hz, 1H), 4.89 (d, J = 1.2 Hz, 1H), 3.79 (s, 2H), 2.25 (s, 3H), 2.19 (s, 6H), 1.43 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 144.8, 136.4, 135.7, 128.8, 128.3, 113.8, 79.2, 43.9, 28.1, 20.7, 19.7. O N H O 87% yield, white liquid 1 H NMR (300 MHz, CDCl3) δ 7.15-7.29 (m, 5H), 4.97 (d, J = 1.2 Hz, 1H), 4.83 (d, J = 1.2 Hz, 1H), 3.64 (d, J = 5.5 Hz, 2H), 3.34 (s, 2H), 1.42 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.6, 142.4, 138.5, 132.4, 131.8, 128.3, 114.5, 79.4, 44.8, 41.0, 28.1. General procedure for the catalytic asymmetric chlorocyclization of carbamates in n-PrOH (A): DCDMH (10 mg, 0.041 mmol, 1.1 equiv) was suspended in n-PrOH (1.4 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to -30 ºC in an immersion cooler. (DHQD)2PHAL (0.3 mg, 1 mol%) was then introduced along with benzoic acid (3 mg, 0.018 mmol, 0.5 equiv). After stirring vigorously for 10 min, the substrate (0.037 mmol, 1.0 equiv) was added in a single 272 portion. The vial was capped and the stirring was continued at -30 ºC until the reaction was complete (TLC). The reaction was quenched by the addition of 2% aq. NaOH (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexane (20-50%) as the eluent. General procedure for the catalytic asymmetric chlorocyclization of carbamates in CHCl3-Hex (B): DCDMH (10 mg, 0.041 mmol, 1.1 equiv) was suspended in CHCl3-Hex (1:1 mixture, 1.4 mL) in a screw capped vial equipped with a stir bar. The resulting suspension was cooled to 0 ºC in an immersion cooler. (DHQD)2PHAL (6 mg, 20 mol%) was then introduced. After stirring vigorously for 10 min, the substrate (0.037 mmol, 1.0 equiv) was added in a single portion. The vial was capped and the stirring was continued at 0 ºC until the reaction was complete (TLC). The reaction was quenched by the addition of 2% aq. NaOH (3 mL) and diluted with DCM (3 mL). The organics were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organics were dried over Na2SO4 and concentrated in the presence of a small quantity of silica gel. Pure products were isolated by column chromatography on silica gel using EtOAc-Hexane (20-50%) as the eluent. 273 O O Cl Cl 1 NH O NH O H NMR (500 MHz, CDCl3) δ 7.37-7.41 (m, 5H), 5.29 (br s, 1H), 4.11 (d, J = 9.0 Hz, 1H), 3.74-3.86 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 155.6, 144.7, 128.1, 127.6, 125.8, 112.6, 44.0, 28.1; HRMS: Calcd. for C10H10ClNO2 211.0400, Found: 211.0402. Resolution of enantiomers: GAMMA DEX 225; 60 ºC for 2 min, 60 ºC to 140 ºC ramp (2 ºC/min), 140 ºC for 10 min, 140 ºC to 220 ºC (1 ºC/min), 220 ºC for 40 min; RT1 = 20 124.4 min (S-enantiomer), RT2 = 125.1 min (R-enantiomer); [α]D = +12.5, -12.8 (c = 0.66, CHCl3) O O O NH O Cl Cl F F 1 NH H NMR (300 MHz, CDCl3) δ 7.35-7.39 (m, 2H), 7.06-7.12 (m, 2H), 5.08 (br s, 1H), 4.09 (d, J = 9 Hz, 1H), 3.70-3.85 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H); 1 13 C NMR (150 MHz, 3 CDCl3) δ 163.5 (d, JC,F = 247 Ηz), 155.6, 145.6, 128.0 (d, JC,F = 8.6 Ηz), 115.9 (d, 2 JC,F = 21.2 Ηz), 112.6, 43.9, 28.2; HRMS: Calcd. for C10H9ClFNO2 229.0306, Found: 229.0310. 274 Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp (5 ºC/min), 220 ºC for 40 min; RT1 = 37.6 min (S-enantiomer), RT2 = 38.6 min 20 (R-enantiomer); [α]D = +4.8, -4.1 (c = 0.58, CHCl3) O O NH O NH O Cl Cl Cl Cl 1 H NMR (300 MHz, CDCl3) δ 7.31-7.41 (m, 4H), 5.30 (br s, 1H), 4.08 (d, J = 9 Hz, 1H), 3.70-3.84 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 155.5, 145.7, 134.0, 128.9, 127.5, 112.8, 43.8, 28.2; HRMS: Calcd. for C10H9Cl2NO2 245.0010, Found: 245.0019. Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp (5 ºC/min), 220 ºC for 60 min; RT1 = 53.9 min (S-enantiomer), RT2 = 56.3 min 20 (R-enantiomer); [α]D = -6.0, +4.5 (c = 0.33, CHCl3) ORTEP drawing of the (S)-product (at 50% thermal ellipsoids): O O O O NH NH Cl Cl Ph Ph 275 1 H NMR (300 MHz, CDCl3) δ 7.24-7.64 (m, 9H), 5.11 (br s, 1H), 4.10 (d, J = 9 Hz, 1H), 3.77-3.91 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 155.3, 147.5, 141.3, 141.1, 138.1, 130.1, 127.8, 127.2, 126.7, 112.8, 44.0, 28.1; HRMS: Calcd. for C16H14ClNO2 287.0713, Found: 287.0708. Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp (5 ºC/min), 220 ºC for 200 min; RT1 = 192.2 min (S-enantiomer), RT2 = 199.1 min 20 (R-enantiomer); [α]D = -8.0, +4.5 (c = 0.5, CHCl3) O O O O NH Cl Cl Me Me 1 NH H NMR (300 MHz, CDCl3) δ 7.25-7.28 (d, J = 8.0, 2H), 7.18-7.21 (d, J = 8.0, 2H), 5.34 (br s, 1H), 4.08 (d, J = 9 Hz, 1H), 3.71-3.84 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H), 2.34 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 147.8, 137.9, 129.3, 126.3, 113.8, 44.1, 28.2, 21.2; HRMS : Calcd. for C11H12ClNO2 225.0557, Found: 225.0550. Resolution of enantiomers: CHIRALCEL OD-H, 5% IPA-Hexane, 0.5 mL/min, 208 nm, 20 RT1 = 81.5 min (S-enantiomer), RT2 = 93.9 min (R-enantiomer); [α]D 0.33, CHCl3) 276 = -25.0 (c = O O O NH O NH Cl Cl CF3 F3C 1 H NMR (300 MHz, CDCl3) δ 7.51-7.65 (m, 4H), 5.38 (s, 1H), 4.14 (d, J = 9 Hz, 1H), 3.74-3.88 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H), 2.34 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 155.5, 146.3, 142.5, 129.8, 126.7, 123.7, 114.4, 43.9, 28.1; HRMS: Calcd. for C11H9ClF3NO2 279.0274, Found: 279.0286. Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp (5 ºC/min), 220 ºC for 40 min; RT1 = 35.9 min (S-enantiomer), RT2 = 37.3 min 20 (R-enantiomer); [α]D = +16.0, -0.5 (c = 0.083, CHCl3) O O O O Cl 1 Cl Cl Cl Cl NH Cl NH H NMR (300 MHz, CDCl3) δ 8.00 (s, 1Η), 7.47-7.51 (m, 2H), 5.75 (br s, 1H), 4.07 (d, J = 9 Hz, 1H), 3.70-3.84 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H), 2.34 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 155.6, 144.7, 128.5, 128.1, 127.6, 125.8, 124.5, 112.6, 44.0, 28.1; HRMS: Calcd. for C10H8Cl3NO2 278.9621, Found: 278.9620. Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp 277 (5 ºC/min), 220 ºC for 100 min; RT1 = 87.2 min (S-enantiomer), RT2 = 96.8 min 20 (R-enantiomer); [α]D = -8.3, +2.1 (c = 0.58, CHCl3) O O O Me NH O NH Me Cl Me Cl Me Me 1 Me H NMR (300 MHz, CDCl3) δ 6.84 (s, 2H), 5.12 (br s, 1H), 4.19 (d, J = 9 Hz, 1H), 3.82-3.90 (ddd, J = 12.0, 9.0, 12.0 Hz, 3H), 2.39 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 145.0, 136.3, 135.9, 128.7, 113.8, 43.9, 28.1, 20.8, 19.7; HRMS: Calcd. for C13H16ClNO2 253.0869, Found: 253.0874. Resolution of enantiomers: GAMMA DEX 225; 90 ºC for 2 min, 90 ºC to 220 ºC ramp (5 ºC/min), 220 ºC for 60 min; RT1 = 53.3 min (S-enantiomer), RT2 = 55.5 min 20 (R-enantiomer); [α]D = -52.0, -4.0 (c = 0.083, CHCl3) O O O O NH Cl Cl 1 NH H NMR (600 MHz, CDCl3) δ 7.25-7.31 (m, 5H), 4.93 (br s, 1H), 3.62 (d, J = 8.5 Hz, 1H), 3.58 (d, J = 11.5 Hz, 1H), 3.49 (d, J = 11.5 Hz, 1H), 3.40 (d, J = 8.5 Hz, 1H), 3.10 (d, J = 6.5 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 155.5, 142.6, 138.5, 132.5, 128.3, 114.3, 44.3, 41.1, 28.1; HRMS: Calcd. for C11H12ClNO2 225.0557, Found: 225.0551. 278 Resolution of enantiomers: GAMMA DEX 225; 60 ºC for 2 min, 60 ºC to 140 ºC ramp (2 ºC/min), 140 ºC for 10 min, 140 ºC to 220 ºC (1 ºC/min), 220 ºC for 40 min; RT1 = 20 127.8 min (S-enantiomer), RT2 = 128.0 min (R-enantiomer); [α]D 0.66, CHCl3) 279 = -14.8, +19.0 (c = III.10 References 280 REFERENCES 1. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis, Springer, Berlin, New York, 1999. 2. Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37, 2922. 3. Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. 4. Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org. Chem. 2007, 72, 1276. 5. Cainelli, G.; Giacomini, D.; Galletti, P.; Quintavalla, A. Eur. J. Org. Chem. 2002, 3153. 6. Sohtome, Y.; Shin, B.; Horitsugi, N.; Takagi, R.; Noguchi, K.; Nagasawa, K. Angew. Chem. Int. Ed. 2010, 49, 7299. 7. Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 5030. 8. Kim,Y. H. Acc. Chem. Res. 2001, 34, 955. 9. Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 5, 719. 10. Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Chem. Soc. Rev. 2003, 32, 115. 11. Hayashi, M.; Tanaka, T. Synthesis 2008, 3361. 12. Batók, M. Chem. Rev. 2010, 110, 1663. 13. Sohtome, Y.; Tanaka, S.; Takada, K.; Yamaguchi, T.; Nagasawa, K. Angew. Chem. Int. Ed. 2010, 49, 9254. 14. Messerer, M.; Wennemers, H. Synlett 2011, 499. 15. Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934. 16. Cainelli, G.; Giacomini, D.; Galletti, P. Chem. Commun. 1999, 567. 281 17. Cainelli, G.; Galletti, P.; Giacomini, D. Chem. Soc. Rev., 2009, 38, 990. 18. Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298. 19. Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R.; Borhan, B. Angew. Chem. Int. Ed. 2011, 50, 2593. 20. Eyring, H. J. Chem. Phys. 1935, 3, 107. 21. Cainelli, G.; Giacomini, D.; Galletti, P. Chem. Commun., 1999, 567–572. 22. Glasstone, S.; Laidler, K. J.; Eyring, H. The Theory of Rate Processes, McGraw-Hill, New York, 1941, ch. 4, p. 153. 23. Cainelli, G.; Galletti, P.; Giacomini, D.; Orioli, P. Tetrahedron Lett., 2001, 42, 7383–7385. 24. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 1278. 282 CHAPTER IV Sulfur Ylide-Mediated Chemistry IV.1. Introduction The first literature example of a sulfur ylide-mediated epoxidation reaction was 1 reported by Johnson in 1958. Reaction of the stable and isolable 9-dimethylsulfonium fluorenylide IV-1 (Figure IV-1) with 4-nitrobenzaldehyde did not afford an alkene, which had been expected on the basis of related reactions of phosphorus ylides. Instead, an epoxide was isolated. Several years later, Corey and Chaykovsky developed alternative ylides (dimethylsulfonium ylide IV-2 and dimethylsulfoxonium ylide IV-3, Figure S O S IV-2 IV-3 S IV-1 Figure IV-1: First literature example of sulfur ylides 2 IV-1), which have since found widespread use in synthesis. 3 The reaction of a sulfonium ylide with an aldehyde initially forms betaine intermediates that undergoes subsequent ring closure to furnish an epoxide with regeneration of the sulfide. To render the process catalytic, the sulfide must be converted back into the ylide under suitably mild conditions. This is particularly important when chiral sulfides are employed. Two 283 general methods exist for converting a sulfide into a sulfur ylide: alkylation with a suitable electrophile followed by deprotonation of the resulting sulfonium salt or reaction with a diazo compound in the presence of a metal catalyst. The addition of dimethylsulfonium methylide IV-2 to carbonyl compounds is irreversible and generates epoxides from aldehydes and ketones, even if the substrates are α,β−unsaturated carbonyls. 4, 5 In contrast, the stabilized dimethylsulfoxonium methylide IV-3 can be generated and used at rt or even higher temperatures. As a consequence of the increased stability, the ylide is much less reactive than dimethylsulfonium methylide IV-2. It will also react with carbonyls to form epoxides, but reacts with α,β−unsaturated carbonyls systems to form cyclopropanes as a result of the reversibility of its addition to carbonyls. 4, 5 In addition to their nucleophilic properties, both ylides can also function as reasonably strong bases, the less stabilized ylide IV-2 functioning as a stronger base than the stabilized IV-3. X O S X IV-3 X + R1 X = O, NTS R R R1 R R1 Scheme IV-1: The ylide-mediated ring expansion of epoxides and aziridines There are various other uses for sulfur ylides, for example, 2,3-sigmatropic rearrangement reactions and other rearrangements such as the Stevens reaction. Other reported ylide chemistry is the ring expansion of epoxides and aziridines to the 284 6, 7 corresponding oxetanes and azetidines, respectively (Scheme IV-1). It is necessary to use the more stable dimethylsulfoxonium methylide IV-3 as the carbon transfer reagent, as elevated temperatures are usually necessary to effect these transformations. The use of dimethylsulfonium methylide IV-2 yields the corresponding allylic alcohols and amines from epoxides and aziridines, respectively. 8, 9 The scope of the ring expansion reactions using IV-3 is limited to cis substituted and terminal epoxides/aziridines. Due to the steric hindrance encountered in opening trans or highly substituted heterocycles with dimethylsulfoxonium methylide IV-3. Exceptions are epoxides/aziridines that contain highly electron-withdrawing groups, such as electron-deficient aromatic rings. In these selected cases, IV-3 can be induced to open more hindered epoxides and aziridines. IV.1.1. The Ylide-Mediated Homologative Ring Expansion of 2,3-Epoxy-1-ols Three factors are of great importance in accomplishing the transformation of the 2,3-epoxy-1-ol to the 2,3-disubstituted THF ring (Scheme IV-2). The first issue is to 3 O 2 R 1 R 3O 4 2 1 HO OH R O OAc O R O HO R O Nu HO HO Scheme IV-2: Transformation of 2,3-epoxy-1-ols to 2,3,5-trisubstituted tetrahydrofurans 285 O R OH IV-4 R R O Pyne rearrangement-O O base IV-5 R O O- 5-exo-tet -DMSO R O S O IV-6 O S IV-3 OIV-8 IV-7 Scheme IV-3: An ylide-mediated homologative ring expansion relay of epoxy alcohol IV-4 to IV-8 HO determine the best reagent to transfer a carbon atom to the 2,3-epoxy-1-ol. A second issue is concerned with where the new carbon-carbon bond must be formed (between the C1 of the 2,3-epoxy-1-ol and C4 of the appropriate nucleophile). Finally, a method for cyclization to the final THF must be found, as a new bond between the oxygen of the THF and C4 must be formed. A potential solution to all three of these issues is illustrated in Scheme IV-3. The control of regiochemistry of nucleophilic attack on the 2,3-epoxy-1-ol was the first issue to be addressed (Scheme IV-3). There are two electrophilic positions at C2 and C3 of the 2,3-epoxy-1-ol, but nucleophilic attack at either of those carbons would not lead to the desired tetrahydrofuran. Rather, attack of the nucleophile at C1 of the epoxy alcohol is necessary. The Payne rearrangement reaction has been shown to be a very useful method for revealing the latent electrophilicity of the C1 carbon. 10 The importance of a Payne rearrangement into the reaction shown in Scheme IV-3 should allow for selective ylide attack at C1 of the epoxy alcohol IV-6, which would lead to the 286 intermediate IV-7 (Scheme IV-3). The next question was to determine what nucleophile could be used to attack the less hindered 1,2-epoxy-3-ol generated via the Payne rearrangement reaction. It was envisioned that the best way to accomplish both the ring opening of the epoxy alcohol and subsequent closure to the heterocycle might be to use a compound that contains within itself both a good nucleophile and a good leaving group, or in other words SN2, an ylide. The nucleophilic carbon portion of the ylide could attack the 2,3-epoxy-1-ol, at the same time installing a good leaving group in the molecule. An intramolecular displacement of the leaving group by an alkoxide present in IV-7 could yield either an oxetane or the desired THF via a 5-exo-tet ring closure. Ylides are present in a number of synthetically important transformations, most notably the Wittig reaction to form alkenes from carbonyl compounds and phosphonium ylides. 11 However, phosphonium ylides have not been shown to be particularly reactive toward epoxides. Sulfur ylides, on the other hand, especially dimethylsolfonium and dimethylsulfoxinium methylide, have been shown to react readily with epoxides to formed allylic alcohols or oxetanes, respectively.8 Thus, it might be feasible to use the anionic carbon portion of a sulfur ylide to transfer a carbon to the epoxy alcohol substrates, utilizing dimethylsulfide or DMSO as a good leaving group for cyclization to the 2,3-substituted tetrahydrofuran (Scheme IV-3). Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily accessed via Sharpless asymmetric epoxidation, are a useful method for the preparation of many types 287 of enantiomerically enriched compounds. 12-14 We were interested in transferring the chirality of an epoxy alcohol to a tetrahydrofuran (THF) via a ring expansion reaction. It was envisioned that this could be accomplished by attacking the epoxide with a carbon-based nucleophile containing within itself a good leaving group. A common reaction illustrating the use of such a nucleophile is the Wittig olefination. 10, 15 Preliminary screening of phosphonium, ammonium, arsenium, and sulfur-based ylides prompted the use of dimethylsulfoxonium methylide, an ylide useful HO O S D-(-)-DET Ti(OiPr)4 OBn tBuOOH 88% yiled, 92% ee IV-9 OBn OH O IV-10 I NaH/DMSO 85 ºC, 36h 96% yield, 92% ee HO BnO O IV-11 D-(-)-DET Ti(OiPr)4 HO OBn IV-12 tBuOOH 88% yiled, 97% ee O OBn O S I NaH/DMSO 85 ºC, 36h OH IV-13 78% yield, 97% ee HO BnO O IV-14 Scheme IV-4: Synthesis of 2,3-disubstituted THF rings for the preparation of oxetanes from epoxides. easy preparation of this ylide 16b 8, 11, 16a The heat stability, reactivity, and allows convenient access to 2,3-disubstituted THF rings 288 in a highly distereoselective and enantioselective fashion. The overall strategy is depicted in Scheme IV-4. Asymmetric epoxidation of allylic alcohols such as IV-9 and IV-12 yields epoxides IV-10 and IV-13, respectively. The reaction of IV-10 and IV-13 with the ylide generated from trimethylsulfoxonium iodide affords the 2,3-disubstituted THF rings IV-11 and IV-14 in good yields with complete control of stereochemistry. 4, 5 Thus, a cis epoxide yields the corresponding cis-disubstituted THF ring while the trans epoxide gives the trans-disubstituted THF ring. This new method for the synthesis of 2,3-disubstituted THF rings was develop in our group. 17 The stereochemistry that is set by the asymmetric epoxidation is translated fully to the final product. Since it is relatively simple to obtain 2,3-epoxy-alcohols in high enantiomeric excess via the Sharpless asymmetric epoxidation, this can be a powerful methodology in gaining entry into the synthesis of THF rings with stereodefined substituents (Scheme IV-5). HO O S O IV-15 R HO I n-BuLi, THF -78 ºC to rt R O IV-16 Scheme IV-5: Synthesis of 2,3-disubstituted THF rings IV-16 289 IV.2 The Use of Alternate Ylides for Extension of THF Rings Formation Alternate ylides can be used to initiate the epoxide opening reaction. Ylides that transfer alkyl groups other than methylenes can provide an additional source for the O R1 LG OH R IV-17 R HO O 5R 1 IV-18 Scheme IV-6: Synthesis of 2,3,5-trisubstituted THF rings IV-18 synthesis of THF rings. 18-27 These ylides will enable access to C5-substituted ring systems (Scheme IV-6). To address the shortcoming associated with using substituted ylides (lack of stereochemical control at C5), bis-functionalized ylides was studies. For example, reaction of the ylide generated from IV-20 with IV-19 should yield IV-22. The product IV-22 is an acetal, which upon treatment with a Lewis acid will lead to the formation of an oxonium species. Intermolecular trapping of the oxonium, along the lines demonstrated elegantly by Woerpel and coworkers should lead to the synthesis of 2,3,5-trisubstituted THF rings such as IV-23 with absolute control of stereochemistry 28, 29 (Scheme IV-7). A number of these ylides undergo epoxide formation with ketones/aldehydes provides strong evidence that under the appropriate reaction conditions we should be able to direct the reactions as desired towards the synthesis of multiply substituted THF rings. 30-34 290 1. O S O IV-20 O BnO OH 2. Protection BnO PO IV-19 O BnO Nuc O BnO PO PO IV-22 OMe Lewis acid IV-21 Nuc IV-23 Scheme IV-7: Proposed synthesis of 2,3,5-trisubstituted THF rings IV.2.1 Method Development for Ylide-Mediated Ring Expansion Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily accessed via Sharpless asymmetric epoxidation, are a useful method for the preparation of many types 15, 35-39 of enantiomerically enriched compounds. As previously mentioned in the introduction, we were interested in transferring the chirality of an epoxy alcohol to a tetrahydrofuran (THF) via a ring expansion reaction with the substitution of different nucleophiles at C5 (shown in Scheme IV-7). It was envisioned that this could be accomplished by attacking the epoxide at C1 (via a Payne rearrangement reaction) with a carbon-based nucleophile containing within itself a good leaving group. Preliminary screening of phosphonium, ammonium, arsenium, and sulfur-based ylides prompted the use of dimethylsulfoxonium methylide, an ylide useful for the preparation of oxetanes from epoxides. 11, 40, 41 It was hope that the utilization of the ylides should provide 291 access to 2,3,5-trisubstituted THF rings with stereochemical control. To begin the study, the racemic epoxide was generated by treatment of the cis-allylic alcohol with mCPBA. The synthesis of desired bis-functionalized sulfonium and sulfoxonium ylides (Figure IV-2) was considered. First, the synthesis of sulfonium ylide O S S X Y IV-24 X Y IV-25 Figure IV-2: Desired bis-functionalized ylides IV-25 with methoxy group as a leaving group was attempted. Sulfide IV-26 was treated with methanol in the presence of pyridine, however, no desired product was obtained after 24 h (Scheme IV-8). Use of sodium hydride (2.0 equiv) as base and addition of Cl S IV-26 Cl S Pyridine, MeOH 0 no reaction ºC-rt NaH (2.0 equiv) NaI, MeOH no reaction dimethoxyethane, rt IV-26 Cl S IV-26 NaH (2.0 equiv) NaI, BnOH dimethoxyethane, rt 85% yield BnO S IV-27 Scheme IV-8: Attempt for synthesis of bis-functionalized ylides 292 sodium iodide still did not lead to product. Replacement of methanol with benzyl alcohol under the same reaction condition provided the desired sulfide IV-27 was prepared in 85% yield (Scheme IV-8). Cl S IV-26 BnO MeOTf, rt 90% yield MeOTf, rt S 40% yield Cl S OTf IV-28 BnO S OTf IV-29 IV-27 Scheme IV-9: Synthesis of bis-functionalized ylides IV-39 and IV-40 Treatment of sulfide IV-27 with methyl iodide to generate the desired bis-functionalized sulfonium ylide, was not successful and led to degradation. Reversing Cl S H2O2 (3.0 equiv) OTf no reaction acetone, rt IV-28 BnO S H2O2 (3.0 equiv) OTf IV-29 Cl acetone, rt no reaction NaIO4 (7.5 equiv) RuCl3•H2O (0.4 equiv) S OTf IV-28 degraded MeCN, CCl4, H2O, rt NaIO4 (7.5 equiv) BnO S RuCl3•H2O (0.4 equiv) OTf MeCN, CCl4, H2O, rt degraded IV-29 Scheme IV-10: Attempts for oxidation of sulfonium IV-39 and IV-40 293 the order of alkylation was considered. Methylation of IV-26 in the presence of methyl iodide failed, however, the use of methyl triflate yielded sulfonium IV-28 in 90% yield (Scheme IV-9). Methylation of sulfide IV-27 under the same reaction condition also provided the desired sulfonium IV-29 in 40% yield (Scheme IV-9). The synthesis of the sulfoxonium by the oxidation of sulfonium IV-28 and IV-29 was pursued using two different approaches. Oxidation with hydrogen peroxide failed gives the desired product. Use of sodium periodate and catalytic amount of the ruthenium chloride also failed, leading to the degradation of the starting material (Scheme IV-10). BnO OH O IV-30 + Cl NaH (10.0 equiv) S OTf DMSO, 80-85 ºC 72% yield (IV-28, 10.0 equiv) O O BnO Cl IV-31 Scheme IV-11: Reaction of epoxy alcohol IV-41 with sulfonium IV-39 With the failure of the sulfonium oxidation, the reaction of the epoxy alcohol IV-30 with the sulfonium IV-28 and IV-29 was examined. The reaction of epoxy alcohol with sulfonium IV-29 in the presence of sodium hydride and DMSO failed, returning starting material. The same reaction condition was also applied with sulfonium IV-28 (Scheme IV-11). Interestingly, the reaction of epoxy alcohol IV-30 with 10.0 equiv of sulfonium IV-28 proceeded well to generate the unexpected chloro-1,3-dioxane IV-31 in 72% yield as the sole diastereomer, with no formation of the desired 2,3,5-trisubstituted THF rings. 294 Loadings, ranging from 2.0 to 5.0 equivalents of sulfonium IV-28 were investigated for this reaction. Five equivalent of sulfonium IV-28 were tolerated relatively well and Table IV-1: Sulfonium and base loadings study BnO OH O IV-30 + Cl S O NaH OTf DMSO, 80-85 ºC Cl IV-31 IV-28 Entry Equiv of IV-39 Equiv of NaH 1 10.0 10.0 5.0 10.0 70 3 2.0 10.0 50c 4 10.0 5.0 65 5 10.0 4.0 a, b 72 2 a O BnO 40d Yield (%) Isolated yields after column chromatography. c b 100% d conversion. 60% conversion. 50% conversion. produced the product in 70% yield. Lower amounts (2.0 equiv) caused an incomplete conversion of the reaction (Table IV-1, entries 2, 3). Decreasing the amounts of sodium hydride produced a shallow decline from 72% yield with 10.0 equivalents to 65% yield with 5.0 equivalents (Table IV-1, entry 4). A significant drop in conversion (50%) was realized when 4.0 equiv of base were added (Table IV-1, entry 5). Various cis-epoxy alcohols were prepared from the corresponding allylic alcohol using mCPBA. Replacement of the OBn group from with pentyl (IV-32), the reaction proceeded to generate the desired chloro-1,3-dioxane as the only product in moderate yield (40%), with 35% of starting material was isolated as well (Scheme IV-12). 295 Substrate IV-34, with the oxygen one carbon further away from the epoxide generated the desired product IV-35 in 51% yield. In this reaction 28% of starting material was also OH O IV-32 BnO O IV-34 Cl + S IV-28 OH O IV-36 S IV-28 OH PMBO + Cl Cl + S IV-28 O NaH OTf DMSO, 80-85 ºC 40% yield O Cl IV-33 O NaH O BnO OTf DMSO, 80-85 ºC 51% yield Cl IV-35 O NaH O PMBO OTf DMSO, 80-85 ºC 71% yield Cl IV-37 Scheme IV-12: Substrate scope isolated (Scheme IV-12). These results show that the presence of oxygen in C4 is necessary for full conversion. Other substrate examined was IV-36 with PMB as a BnO Hb Hc O O 9 Cl IV-31 Hb Hc O O BnO 9 Cl IV-38 Hb H c O O 9 BnO Cl IV-39 Figure IV-3: Other possible products protecting group, this substrate led to full conversion and produced IV-37 in 71% yield (Scheme IV-12). 296 The 1D and 2D-NMR of the product is consistent with the three structures illustrated in Figure IV-3. C9 (55.1 ppm), bearing the chloride is the most up-field carbon in the 13C-NMR spectrum (all other sp3 carbon resonances are expected down-field since they are oxygen substitute). The DEPT spectrum clearly shows C9 as a methine, therefore, eliminating IV-38 as a possibility. To distinguish between IV-31 and IV-39, the coupling Cl O O O O ! ! chemical shift = 4.93, 5.07 chemical shift = 5.11, 5.42 coupling constant = 0 coupling constant = 6.1 OH OH O O O O ! ! chemical shift = 4.88, 5.06 chemical shift = 4.78, 4.91 coupling constant = 0 coupling constant = 6.2 HO Br Ph Ph O O O O ! ! chemical shift = 4.87, 5.12 chemical shift = 4.91, 5.26 coupling constant = 0 coupling constant = 6.5 Figure IV-4: Some literature examples for 1,3- dioxolane and 1,3-dioxane of Hb and Hc was investigated. The coupling constant for Hb and Hc is 6.0 Hz (chemical shifts are 4.75 and 5.13 Hz). According to examples found in the literature, the coupling constant of similar 1,3-dioxolane hydrogens in 5 membered ring systems is 0-2 Hz and for 6 membered ring systems is 6.0 Hz (Figure IV-4 illustrates a number of these examples). 42 The observed coupling constant of 6.0 Hz for Hb and Hc suggests structure 297 IV-31 as the product. A possible explanation for this unexpected transformation is shown in Scheme IV-13. The epoxy alcohol IV-30 would generate IV-40 via a Payne rearrangement reaction. BnO OH O IV-30 base BnO O Payne rearrangement O O BnO O IV-40 Cl S IV-28 O O BnO S BnO Cl IV-31 O O O Cl O BnO IV-41 S IV-42 Cl Scheme IV-13: Proposed mechanism Reaction of sulfonium salt IV-28 with ethoxide IV-40 will generate IV-41. Attack of Cl - at C2 of the epoxy alcohol is necessary to generate IV-42 (sulfonium inter or intra molecular can coordinate to the epoxide and activate it like a Lewis acid). closing of IV-42 would lead to the formation of the product IV-31. 298 43 Finally, ring IV.3 Experimental Section Commercially available starting materials were obtained from Aldrich or Fluka and were used without further purification. Unless otherwise mentioned, solvents were purified as follows: tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium/benzophenone; methylene chloride (CH2Cl2) and toluene (PhCH3) was dried over calcium hydride (CaH2) and freshly distilled prior to use; DMF, DMSO, Et3N, and HMPA were distilled from CaH2 and stored over 4 Å molecular sieves. 4 Å molecular sieves were dried at 160 ºC under vacuum prior to use. All of the spectral data for known compounds either match those reported by Aldrich or by comparison to the literature report. 1 H NMR spectra were measured at 300, 500 or 600 MHz on a Varian Gemini-300, a Varian VXR-500 or Varian Inova-600 instrument respectively. Chemical shifts are reported relative to residual solvent (δ 7.24 ppm for CDCl3). 13 C NMR spectra were measured at 75 MHz on a Varian Gemini-300, at 125 MHz on a Varian VXR-500 or 150 MHz on a Varian Inova-600 instrument. Chemical shifts are reported relative to the central line of CDCl3 (δ 77.0 ppm). High resolution mass spectra were measured at the Michigan State University, Mass Spectrometry Laboratory. Optical rotations were measured on a Perkin-Elmer polarimeter (model 341) using a 1 mL capacity quartz cell with a 10 cm path length in chloroform. Analytical thin layer chromatography (TLC) was performed using pre-coated silica 299 gel 60 F254 plates. Compounds were visualized with UV light, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH. Column chromatographic purifications were performed using Silicycle 40-60 Å, 30-75 µm silica gel. All compounds purified by chromatography were sufficiently pure for use in further experiments. A solution of sulfide (104 mmol) in dry CH2Cl2 (100 mL) was cooled to -78 ºC, methyl triflate (12.0 mL, 106 mmol) was added, and the mixture was kept at rt for 3 h. The volatile compounds were evaporated and the solid residue was crystallized (EtOAc) to give the product. 44 (Chloromethyl)dimethylsulfonium trifluoromethanesulfonate MP: 50 – 51 °C 1 H NMR (500 MHz, CDCl3) δ 5.39 (s, 2H), 2.89 (s, 6H). ((Benzyloxy)methyl)dimethylsulfonium trifluoromethanesulfonate MP: 48 – 49 °C 1 H NMR (500 MHz, CDCl3) δ 7.27-7.31 (m, 5H), 5.50 (s, 2H), 4.62 (s, 2H), 2.90 (s, 6H). (Z)-4-(Benzyloxy)but-2-en-1-ol 17 A solution of cis-2-buten-1,4-diol (8.8 g, 100 mmol, 1.0 equiv) in THF (250 mL) was added dropwise to a suspension of NaH (4.4 g of a 60% dispersion in mineral oil, 110 mmol, 1.1 equiv, washed 2 x with dry pentane) in a 4:1 mixture of dry THF/DMSO (500 mL). The mixture was stirred at rt for 30 min, then a solution of benzyl bromide (18.9 g, 300 110 mmol, 1.1 equiv) in THF (250 mL) was added dropwise, followed immediately by tetrabutylammonium iodide (18.5 g, 50 mmol, 0.5 equiv) in one portion. The mixture was heated to 60 ºC overnight. After cooling, an equal volume of water was added and the mixture extracted with portions of diethyl ether (3 x 200 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was column chromatographed using 3:1 hexanes/ethyl acetate to give the title compound as a clear to pale yellow oil (15.4 g, 87% yield). 1 H NMR (300 MHz, CDCl3) δ 7.35 (m, 5H), 5.8 (m, 2H), 4.5 (s, 2H), 4.15 (m, 2H), 4.1 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 137.6, 132.3, 128.2, 127.6, 127.56, 127.5, 72.1, 65.4, 58.1. (Z)-4-((4-Methoxybenzyl)oxy)but-2-en-1-ol 45 A solution of cis-2-buten-1,4-diol (8.8 g, 100 mmol) in THF (250 mL) was added dropwise to a suspension of NaH (4.4 g of a 60% dispersion in mineral oil, 110 mmol, washed 2 x with dry pentane) in a 4:1 mixture of dry THF/DMSO (500 mL). The mixture was stirred at rt for 30 min, then a solution of p-methoxybenzyl bromide (22.0 g, 110 mmol) in THF (250 mL) was added dropwise, followed immediately by tetrabutylammonium iodide (18.5 g, 50 mmol) in one portion. The mixture was heated to 60 ºC overnight. After cooling, an equal volume of water was added and the mixture extracted with portions of diethyl ether (3 x 200 mL).. The combined organics were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed 301 under reduced pressure. The residue was column chromatographed using 3:1 hexanes/ethyl acetate to give the title compound as a clear to pale yellow oil (18.5 g, 89% yield). 1 H NMR (300 MHz, CDCl3) δ 7.22-7.27 (m, 2H), 6.84-6.88 (m, 2H), 5.70-5.85 (m, 2H), 4.44 (s, 2H), 4.16 (m, 2H), 4.06 (d, J = 5.4 Hz, 2H), 3.79 (s, 3H), 1.82 (br s, 1H); 13 C NMR (75 MHz, CDCl3) δ 159.1, 132.3,129.7, 129.2, 127.6, 113.6, 71.8, 65.0, 58.0, 54.9. Oct-2-yn-1-ol 17 A solution of 2-octynaldehyde (2.0 g, 16.1 mmol) was placed in dry THF (100 mL) and cooled to -20 ºC. DIBAL (11.8 mL of 1.5 M solution in toluene, 17.7 mmol) was added dropwise and the reaction was stirred for 3 h. A saturated solution of Rochelle’s salt was carefully added, followed by 0.2 mL glycerol/mmol of DIBAL-H and the biphasic system was stirred at rt for 6 h. The reaction was extracted 3 x with portions of ethyl acetate, the combined organics were washed with brine, and dried over anhydrous sodium sulfate. The crude product was purified via column chromatography (hexanes/ethyl acetate) to give the alcohol in 78% yield (1.6 g). 1 H NMR (300 MHz, CDCl3) δ 4.2 (d, 2H, J = 6.8 Hz), 2.2 (t, 2H, J = 7.1 Hz), 1.9 (br s, 1H), 1.5 (t, 2H, J = 7.1 Hz), 1.2-1.4 (m, 4H), 0.9 (t, 3H, J = 7.1 Hz); 13 C NMR (75 MHz, CDCl3) δ 86.1, 78.3, 51.0, 30.9, 28.2, 22.0, 18.5, 13.8. General procedure for alkyne reduction: The alcohol (7.9 mmol) was placed in ethyl acetate (20 mL) and 5 drops of chloroform. Lindlar’s catalyst (500 mg) was added and the flask was evacuated and filled with a hydrogen atmosphere using a balloon. The 302 suspension was stirred at rt for 5 h, the catalyst was removed via filtration through a pad of celite and the filtrate evaporated under reduced pressure. The crude product was obtained and was not further purified, but subjected to next step. (Z)-Oct-2-en-1-ol 1 46 H NMR (300 MHz, CDCl3) δ 5.50–5.73 (m, 2H), 4.20 (d, J = 5.6 Hz, 2H), 2.07 (td, J = 6.9, 6.8Hz, 2H), 1.51 (br s, 1H), 1.21–1.41 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 133.3, 128.2, 58.5, 31.4, 29.2, 27.4, 22.5, 14.0. (Z)-5-(Benzyloxy)pent-2-en-1-ol 1 17 H NMR (300 MHz, CDCl3) δ 7.3 (m, 5H), 5.8 (m, 1H), 5.6 (m, 1H), 4.5 (s, 2H), 4.1 (m, 2H), 3.5 (t, 2H), 3.1 (br s, 1H), 2.4 (dd, 2H); 13 C NMR (75 MHz, CDCl3) δ 137.7, 130.7, 128.6, 128.2, 127.5, 127.46, 72.8, 68.9, 57.4, 27.7. 47 ((2-Iodoethoxy)methyl)benzene The monobenzylated ethylene glycol (5.0 g, 32.9 mmol) was placed in benzene and iodine (16.5 g, 66.0 mmol), triphenylphosphine (17.5 g, 72.5 mmol) and imidazole (5.5 g, 82.5 mmol) were added and the mixture was stirred vigorously for 4 h. The benzene was evaporated at rt and diethyl ether was added to the residue. The resulting slurry was filtered, the filtrate evaporated and the residue chromatographed (9:1 hexanes/ethyl acetate) to give the iodide in 81% yield (7.0 g). 1 H NMR (300 MHz, CDCl3) δ 7.30–7.36 (m, 5H), 4.58 (s, 2H), 3.73 (t, J = 6.7 Hz, 2H), 3.28 (t, J = 6.7 Hz, 2H); 13 C NMR (75 MHz, CDCl3) δ 138.0, 128.7, 128.1, 128.0, 73.1, 71.0. 303 17 3.2 ((5-(Benzyloxy)pent-2-yn-1-yl)oxy)(tert-butyl)diphenylsilane Dry tetrahydrofuran was combined with BPS-protected propargyl alcohol (11.2 g, 38.2 mmol) and cooled to -78 ºC. A solution of n-BuLi (21.5 mL, 1.6 M solution in hexanes, 34.4 mmol) was added dropwise over 20 min. The reaction was allowed to stir for 1 h, then HMPA that had been distilled over calcium hydride was added and the reaction was stirred an additional 30 min. The iodide (5.0 g, 19.1 mmol) dissolved in THF (20 mL) was added dropwise over 15 min and the reaction was stirred at -78 ºC for 1 h, warmed to 0 ºC for 1 h, then warmed to rt overnight. An equal volume of water was added and the mixture was extracted 3x with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give the product in 68% yield (5.5 g) after column chromatography (9:1 hexanes/ethyl acetate). 1 H NMR (300 MHz, CDCl3) δ 7.8 (m, 4H), 7.4 (m, 11H), 4.6 (s, 2H), 4.4 (m, 2H), 3.5 (m, 2H), 2.5 (m, 2H), 1.1 (s, 9H); 13 C NMR δ (75 MHz, CDCl3) 135.6, 133.2, 129.8, 129.7, 129.4, 128.4, 127.6, 82.2, 79.5, 73.0, 72.9, 68.3, 52.9, 26.7, 20.2. 5-(Benzyloxy)pent-2-yn-1-ol 17 The protected propargyl alcohol (5.0 g, 11.7 mmol) was placed in tetrahydrofuran and a solution of tetrabutylammonium fluoride (35.1 mL, 1.0 M solution in tetrahydrofuran, 35.1 mmol) was added. The solution was stirred overnight and an equal volume of water added. The mixture was extracted 3 x with ethyl acetate, the combined organics were washed with brine, dried over sodium sulfate and the solvent was removed under reduced 304 pressure. The residue was purified by column chromatography (3:1 hexanes/ethyl acetate) to give the alcohol in 90% yield (2.0 g). 1 H NMR (300 MHz, CDCl3) δ 7.3 (m, 5H), 4.6 (s, 2H), 4.2 (m, 2H), 3.6 (t, 2H), 2.55 (m, 2H), 2.0 (br s, 1H); 13 C NMR (75 MHz, CDCl3) δ 137.9, 128.4, 127.7, 83.0, 79.5, 72.9, 68.2, 51.2, 20.1. General procedure for epoxidation: The allylic alcohol (7.9 mmol, 1.0 eq) was placed in dichloromethane (70 mL) and mCPBA (1.9 g, 8.3 mmol, 1.05 eq, as a 77 weight % reagent) was added. The reaction was stirred at rt for 3 h and quenched with water and sodium carbonate. The organic layer was separated and the aqueous layer was extracted 3 x with portions of dichloromethane. The combined organics were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified via column chromatography (hexanes/ethyl acetate) to give the product. 3-((Benzyloxy)methyl)oxiran-2-yl)methanol 1 17 H NMR (300 MHz, CDCl3) 7.36-7.40 (m, 5H), 4.59 (dd, J = 11.7, 11.7 Hz, 2H), 3.70-3.80 (m, 4H), 3.27-3.33 (m, 2H), 2.06 (br s, 1H); 13 C NMR (75 MHz, CDCl3) 137.3, 128.4, 127.9, 127.8, 73.3, 67.9, 60.5, 55.7, 54.7. (3-Pentyloxiran-2-yl)methanol 1 48 H NMR (300 MHz, CDCl3) δ 3.88-3.96 (m, 1H), 3.59-3.68 (m, 1H), 2.90-2.99 (m, 2H), 1.79 (br s, 1H), 1.24-1.71 (m, 8H), 0.84-0.95 (m, 3H); 58.5, 56.1, 31.7, 31.6, 25.7, 22.7, 14.1. 305 13 C NMR (75 MHz, CDCl3) δ 61.7, (3-(2-(Benzyloxy)ethyl)oxiran-2-yl)methanol 1 17 H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 4.50 (s, 2H), 3.80 (m, 1H), 3.50-3.70 (m, 3H), 3.20 (m, 2H), 3.05 (m, 1H), 2.05 (m, 1H), 1.80 (m, 1H); 13 C NMR (75 MHz, CDCl3) δ 137.0, 128.5, 128.1, 127.9, 73.5, 66.6, 59.9, 55.3, 54.8, 28.0. (3-(((4-Methoxybenzyl)oxy)methyl)oxiran-2-yl)methanol 1 17 H NMR (300 MHz, CDCl3) δ 7.25 (m, 2H), 6.90 (m, 2H), 4.45-4.55 (m, 2H), 3.80 (s, 3H), 3.60-3.80 (m, 5H), 3.25 (m, 1H), 3.20 (m, 1H); 13 C NMR (75 MHz, CDCl3) δ 159.5, 129.5, 129.4, 113.9, 73.11, 67.7, 60.7, 55.6, 55.3, 54.7. Sodium hydride (4.0 g as a 60% dispersion in mineral oil, 100 mmol, 10.0 equiv, washed twice with pentane dried over sodium metal) was placed in a flame-dried flask and dry dimethylsulfoxide (100 mL) was added via syringe. Sulfonium (27.5 g, 100 mmol, 10.0 equiv) was added in small portions over 20-30 min. After addition of the Sulfonium IV-28 was complete, the reaction was stirred for an additional 30 min until the bubbling of the milk-white suspension ceased. The epoxy alcohol (10 mmol, 1.0 equiv) dissolved in a small amount of DMSO was added dropwise and the reaction was covered with aluminum foil and heated to 80-85 ºC for 36 h. The dark brown mixture was cooled and diluted with 2 x volume of water and saturated ammonium chloride (1 mL). The reaction was extracted several times with ethyl acetate, the combined organics were washed with brine and dried over anhydrous sodium sulfate. After removal of solvent under reduced pressure, the residue was column chromatographed using a hexane/ethyl acetate gradient to give product. 306 4-((Benzyloxy)methyl)-5-chloro-1,3-dioxane 1 H NMR (500 MHz, CDCl3) 7.25-7.36 (m, 5H), 5.12-5.13 (d, J = 6.0 Hz, 1H), 4.74-4.75 (d, J = 6.0 Hz, 1H), 4.51-4.59 (q, J = 11.5, 7.5 Hz, 2H), 4.17-4.21 (dd, J = 11.5, 1.5 Hz, 1H), 4.00-4.06 (m, 3H), 3.564-3.67 (m, 1H), 3.58-3.61 (m, 1H); 13 C NMR (75 MHz, CDCl3) 137.7, 128.5, 128.9, 127.9, 94.0, 76.8, 73.8, 71.9, 70.2, 55.1; HRMS: Calcd. for C12H15ClO3: 242.0709, Found: 242.0710. 5-Chloro-4-pentyl-1,3-dioxane 1 H NMR (500 MHz, CDCl3) 5.15 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 4.22-4.25 (dd, J = 11.5, 1.5 Hz, 1H), 4.00-4.07 (m, 3H), 1.25-1.69 (m, 8H), 0.85-0.93 (m, 3H). 5-Chloro-4-(((4-methoxybenzyl)oxy)methyl)-1,3-dioxane 1 H NMR (500 MHz, CDCl3) 7.27 (m, 2H), 6.92 (m, 2H), 5.13 (d, J = 6.0 Hz, 1H), 4.78 (d, J = 6.0 Hz, 1H), 4.56-4.64 (dd, J = 11.5, 11.5 Hz, 2H), 4.20-4.26 (dd, J = 11.5, 1.5 Hz, 1H), 4.05-4.09 (m, 3H), 3.82 (s, 3H), 3.65-3.72 (dd, J = 6.0, 6.0 Hz, 1H), 3.63-3.66 (dd, J = 6.0, 6.0 Hz, 1H). 307 IV.4 References 308 REFERENCES 1. Johnson, A. W.; LaCount, R. B. Chem. Ind. (London) 1958, 1440-1441. 2. Corey, E. J.; Chaykovsky, M. J. J. Am. Chem. Soc. 1965, 87, 1353-1364. 3. Gololobov, Y. G.; Nesmeyanov, A. N.; Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 2609-2651. 4. Johnson, A. W. Ylide Chemistry, Academic Press: New York, 1996. 5. Trost, B. M.; Melvin, L. S. Sulfor Ylides, Emerging Synthetic Intermediates, Academic Press: New York, 1975. 6. Okuma, K.; Tanaka, Y.; Shinji, K.; Ohta, H. J. Org. Chem. 1983, 48, 5133–5134. 7. Nadir, U. K.; Koul, V. K. Chem. Commun. 1981, 9, 417–418. 8. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452. 9. Hodgson, D. M.; Fleming, M. J.; Xu, Z.; Lin, C.; Stanway, S. Chem. Commun. 2006, 3226–3228. 10. Payne, G. J. Org. Chem. 1962, 27, 3819–3822. 11. Vedejs, E.; Peterson, M. J. Topics in Stereochemistry, Vol 21, 1994; Vol. 21, pp 1-157. 12. Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry; W. H. Freeman: New York, NY, 2005. 13. Lands, W. E. Biochemistry of Arachidonic Acid Metabolism; Nijhoff; Kluwer Academic Publishers: Boston, MA. 1985. 14. Smith, H. S. Support. Oncol. 2006, 4, 277–287. 15. Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH, Inc.: New York, 1993, pp 101-158. 16. (a) Alcaraz, L.; Cridland, A.; Kinchin, E. Org. Lett. 2001, 3, 4051–4053. (b) Ingold, 309 C. K.; Jessop, J. A. J. Chem. Soc. 1930, 713. 17. Schomaker, J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc. 2004, 126, 13600–13601. 18. Matsuyama, H.; Nakamura, T.; Iyoda, M. J. Org. Chem. 2000, 65, 4796–4803. 19. Romo, D.; Meyers, A. I. J. Org. Chem. 1992, 57, 6265–6270. 20. Gushurst, A. J.; Jorgensen, W. L. J. Org. Chem. 1988, 53, 3397–3408. 21. Bogdanowicz, M. J.; Trost, B. M. Org. Synth. 1974, 54, 27-32. 22. Trost, B. M.; Arndt, H. C. J. Am. Chem. Soc. 1973, 95, 5288–5298. 23. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5311–5321. 24. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5321–5334. 25. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5298–5307. 26. Still, W. C.; Novack, V. J. J. Am. Chem. Soc. 1981, 103, 1283–1285. 27. Naito, T.; Nagase, S.; Yamataka, H. J. Am. Chem. Soc. 1994, 116, 10080–10088. 28. Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208–12209. 29. Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168–169. 30. Baggiolini, E. G.; Hennessy, B. M.; Lacobelli, J. A.; Uskokovic, M. R. Tetrahedron Lett. 1987, 28, 2095–2098. 31. Kaczmarczyk, G.; Jonczyk, A. Synlett 1997, 921-922. 32. Nadir, U. K.; Arora, A. J. Chem. Soc., Perkin Trans 1 1995, 2605–2609. 33. Sato, K.; Sekiguchi, T.; Akai, S. Tetrahedron Lett. 2001, 42, 3625–3628. 34. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1972, 94, 4777–4779. 310 35. Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5, 1789–1791. 36. Poch, M.; Alcon, M.; Moyano, A.; Pericas, M. A. Tetrahedron Lett. 1993, 34, 7781–7784. 37. Choudary, B. M.; Rani, S. S.; Kantam, M. L. Synth. Commun. 1990, 20, 2313–2317. 38. Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986, 51, 5413–5415. 39. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557–1560. 40. Nadir, U. K.; Koul, V. K. Chem. Commun. 1981, 9, 417–418. 41. Fitton, A. O.; Hill, J.; Jane, D. E.; Millar, R. Synthesis 1987, 1140–1142. 42. (a) Crabb, T. A.; Cookson, R. C. Tetrahedron Lett. 1964, 679-686. (b) McCombie, S. W.; Metz, W. A. Tetrahedron Lett. 1987, 383-386. (c) Clausen, R. P.; Bols, M. J. Org. Chem. 2000, 65, 2797–2801. (d) Deutsch, J.; Martin, A.; Lieske, H. Journal of Catalysis 2007, 245, 425-435. 43. Shailaja, M.; Manjula, A.; Rao, B. V. Syn. Commun. 2010, 3629–3639. 44. Kaczmarczyk, G.; Jonczyk, A. Syn. Lett. 1997, 921–922. 45. Sreedhar, E.; Venkanna, A.; Chandramouli, N.;Babu, K. S.; Rao, J. M. Eur. J. Org. Chem. 2011, 1078–1083. 46. Alonso, F.; Osantey, I.; Yus, M. Tetrahedron 2007, 63, 93-102. 47. Borbas, K. E.; Chandrashaker, V.; Muthiah,C.; Kee, H. L.; Holten, D,; Lindsey, J. S. J. Org. Chem. 2008, 73, 3145–3158. 48. Egami, H.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886–5895. 311