ORGANOCATALYTIC METHODOLOGIES TOWARDS ASYMMETRIC HETERO - & CARBOCYCLE SYNTHESIS By Xinliang Ding A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry ÑDoctor of Philosophy 2018 !ABSTRACT ORGANOCATALYTIC METHODOLOGIES TOWARDS ASYMMETRIC HETERO - & CARBOCYCLE SYNTHESIS By Xinliang Ding There are four chapters in this dissertation. In Chapter I, a brief review of organocatalytic Morita -Baylis -Hillman (MBH) reaction is discussed, which covers the mechani sms of N -based and P -based catalytic cycles, the asymmetric format of MBH reaction with different catalyst system s, the application of the MBH reaction and its products, and the deviation of the MBH reaction Ñthe Lewis base catalyzed cyclization reactions. Based on the modified MBH reaction Ñthe formal [4+2] cycloaddition reaction, in Chapter II, we demonstrate a fast assembly towards the synthesis of substituted hexahydro -2H-chromenes in high stereoselectivity, containing up to 5 contiguous stere ocenters via consecutive [4+2]/ [4+2] cycloaddition reactions. Inspired by two observations from the reaction s in Chapter II, methods of a consecutive [4+2] cycloaddition/ Br¿nsted acid catalyzed rearrangement and a consecutive [4+2] cycloaddition/base catalyzed rearrangement toward the synthesis of chiral cyclohex -2-ones and chiral 4 H-pyrans, respectively, have been reported in C hapter III . Gaining the inspiration from both Chapter II and Chapter III, i n Chapter IV, we describe amidi ne mediated the synthesis of pyran derivatives through formal [1,5] -H shift. Furthermore, a rearrangement of some of these pyrans to furnish phenolic derivatives under acidic conditions is also report. Lastly , incorporation of primary amine s in the synthesis of carbocyclic !Ðamino ester from dihydropyran has been investigated as well !"""! Dedicated to Lihui Jia and Joshua J. Ding !"#! ACKNOWLEDGEMENTS First of all, I would like to express my deepest gratitude to my research advisor, Professor Babak Borhan , for his kind and careful guidance, generous support and continuing encouragement. I am grateful to have the op portunity to work on wonderful projects in the group, and learn not only the knowledge of interdisciplinary fields but also the critical scientific thinking of how to solve problems that will definitely benefit for my whole career. Thanks for his mentoring, I feel enjoyable and fulfilling of doing research all the time . Obviously, he made my Ph. D program a precious experience in my whole life. I am greatly thankful to my committee member, Professor Robert E. Maleczka , Professor Xuefei Huang, Professor James H. Geiger, for their constructive suggestions and firm support during my Ph. D. program. I w ould like to thank all the former and current members of the Borhan lab for their invaluable support, intellectual inputs into my research, as well as their friendship in the past few years. Especially, I would like to thank Dr. Chrysoula Vasileiou for her kind help and support, and her effort on proofr eading my dissertation. I immensely appreciate Dr. Kumar Ashtekar, Wei Sheng, Dr. Yi Yi, Dr. Nastara n Salehi M arzijarani and Dr. Hadi Gholami, Dr. Arvind Jaganathan for giving me the opportunities to collaborate with them and to learn from them. The former and current members, Dr. Carmin Burrell, Dr. Camille Watson, Dr. Calvin Grant, Dr. Tetyana Berbasov a, Dr. Ipek Yapici, Dr. Elizabeth M. Santos, Dr. Setare T. Nick, Dr. Bardia Soltanzadeh, Dr. Jun Zhang, Aritra Sarkar, Saeedeh Torabi Kohlbouni, Rahele Esmatpour Salmani, Dan Steigerwald, Debarshi !#!Chakraborty, Soham Maity, Ankush Chakrabarty, Emily Dzurka, Mehdi Moemeni are acknowledged for their support, encouragement and help during my graduate studies. I would like to thank my talented undergraduate students, Neil T. Heberer, Michael S. Behrendt, Christopher Rahn for greatly helping me with my research projects. I would like to extent my sincere gratitude to all my friends, faculty members and staffs for all their help in the chemistry department for their support and encouragement . I specially thank Professor Da niel A. Jones and Professor William D. Wulff for their encouragement and guidance on my job search and projects, respectively . I would like to thank Tayeb Kakeshpour for help me understand the calculation of the mechanistic study. I would like to thank Prof essor Kevin Walker and Professor David B. Collum for their help with my seminar. I would like to thank Dr. Daniel Holmes and Dr. Li Xie for the NMR help, and Dr. Lijun Chen and Dr. Tony Schilmiller for Mass help, and Dr. Richard J. Staples for X-ray crysta llography help. Last but not least, I want to deliver my deepest appreciation to my beloved wife Dr. Lihui Jia, who trusts and encourages me all the time. Her unconditional love and support is driving me to be better through all my life. During my Ph. D pr ogram, she is not only the best friend, but also a good listener and brain trust. She is always inspiring and encouraging me on my research. I appreciate her patience when I got lost and when I am upset. Also, I would like to thank my family, specially my parents, my parents in law and my son Joshua Ding for their endless love and support. !#"!TABLE OF CONTENTS LIST OF TABLES ............................................................................................................ ix LIST OF FIGURES ........................................................................................................... x LIST OF SCHEMES ....................................................................................................... xii KEY TO SYMBOLS AND ABBREVIATIONS ................................................................ xvii Chapter I: A Brief Review of Organocatalytic Morita -Baylis-Hillman (MBH) Reaction .......................................................................................................................... 1 I-1. General introduction of organocatalysis .............................................................. 1 I-2. An introduction of Morita -Baylis -Hillman (MBH) reaction ..................................... 3 I-3. Mechanism .......................................................................................................... 4 I-3.1. Amine -catalyzed MBH reaction .................................................................. 4 I-3.2. Phosphine -catalyzed MBH reaction ........................................................... 7 I-4. Catalytic asymmetric induction of MBH reaction ................................................. 9 I-4.1. Chiral Lewis bases catalyzed MBH reaction .............................................. 9 I-4.2. Chiral Lewis acids catalyzed MBH reaction ............................................. 14 I-4.3. Chiral Br¿nsted acids catalyzed MBH reaction ........................................ 14 I-5. Application of MBH adducts ............................................................................... 17 I-5.1. Transformation of MBH adducts catalyzed by organocatalysts ............... 17 I-5.2. Applications of MBH reaction t oward natural products and drug molecules synthesis ............................................................................................................ 21 I-6. Deviation from MBH reaction -the Lewis base catalyzed cyclization reactions .. 24 REFERENCE S ........................................................................................................ 28 Chapter II: Mechanistically I nspired Route toward Hexahydro -2H-chromenesvia Consecutive [4+2]/[4+2] Cycloaddition Reactions .................................................... 38 II-1. Introduction ....................................................................................................... 38 II-2. Preliminary results from model reactions .......................................................... 41 II-3. Results and discussion ..................................................................................... 43 II-4. Experimental ..................................................................................................... 54 II-4.1. General remarks ...................................................................................... 54 II-4.2. General procedure for formal [4+2] cycloaddition of ethyl -2,3-butadienoate with substituted dienones ............................................................ 55 II-4.3. General procedure for synthesis of aromatic dienones ........................... 69 II-4.4. Synthesis of alkyl substituted dienones II-1n!II-1p ................................. 76 II-4.5. Synthesis of formal [4+2] cycloadditions of unsymmetrically substituted dienones ............................................................................................................ 78 !#"" !II-4.6. Procedures for Diels -Alder reaction of chiral dihydropyrans ( II-3) with dienophiles II-4a!II-4d ....................................................................................... 80 II-4.7. Quantum chemical computational analysis ............................................. 92 APPENDIX ............................................................................................................. 103 REFERENCE S ...................................................................................................... 152 Chapter III: Organocatalytic Asymmetric Synthesis of Cyclohexenone and 4 H-pyran Derivatives: A Divergent Approach ............................................................... 158 III-1. Introduction .................................................................................................... 158 III-2. Preliminary results from model reactions ....................................................... 167 III-3. Results and discussion .................................................................................. 170 III-4. Experimental .................................................................................................. 179 III-4.1. General remarks ................................................................................... 179 III-4.2. General procedure A for Br¿nsted acid -catalyzed cyclohexenones synthesis .......................................................................................................... 180 III-4.3. General procedure B for one -pot synthesis of cyclohexenones III-15I!III-15r ................................................................................................................... 187 III-4.4. General procedure C for base -catalyzed 4 H-pyrans synthesis ............ 192 III-4.5. Synthesis of enone III-13k!III-13l ........................................................ 201 III-4.6. General procedure D for the synthesis of enone III-13m, III-13q ......... 202 III-4.7. General procedure E for the synthesis of enone III-13n, III-13r ........... 203 III-4.8. Synthesis of Diels -Alder reaction adduct III-16ia ................................. 205 APPENDIX ............................................................................................................. 207 REFERENCE S ...................................................................................................... 278 Chapter IV: Amine -mediated Dihydropyran Rearrangements Toward Pyran and Carbocyclic !!Amino Ester Synthesis .................................................................... 286 IV-1. Introduction .................................................................................................... 286 IV-1.1. Amidines, isothioureas and guanidines as nuleophilic catalysts .......... 286 IV-1.2. A brief introduction of pyran and phenol derivatives ............................ 295 IV-2. Amidine -mediated formal [1,5] -H rearrangement towards pyran synthesis from dihydropyran .......................................................................................................... 298 IV-3. Results and discussion .................................................................................. 300 IV-4. Primary amine mediated multi -substituted carbocyclic !Ðamino ester synthesis ............................................................................................................................... 309 IV-5. Experimental ................................................................................................. 314 IV-5.1. General remarks .................................................................................. 314 IV-5.2. General procedure A for DBU -mediated formal [1,5] -H shift toward pyran synthesis .......................................................................................................... 316 IV-5.3. Analytical data for propargyl dihydropyran IV-44s!IV-47s and dihydropyran IV-48s ........................................................................................ 327 IV-5.4. General procedure B for the synthesis of enones IV-44ss!IV-47ss and IV-50ss ............................................................................................................ 331 !#""" !IV-5.5. General procedure C for the synthesis of enones IV-48ss, IV-74ss and IV-75ss ............................................................................................................ 333 IV-5.6. General procedure D for the synthesis of adducts IV-54 and IV-55 .... 336 IV-5.7. General procedure E for the synthesis of carbocyclic !Ðamino ester ......................................................................................................................... 338 APPENDIX ............................................................................................................. 340 REFERENCE S ...................................................................................................... 385 !"$!LIST OF TABLES Table II-1. Substrate scope for the enantioselective synthesis of substituted oxa -trienes ............................................................................................................................. 46 Table II-2. Substrate scope for the formal [4+2] cycloaddtion of allenoate with asymmetric cross -conjugated oxa -trienes ...................................................................... 48 Table III-1. Optimization of reaction condition for acid catalyzed synthesi s of cyclohexanone III-15h .................................................................................................. 167 Table III-2. Optimization of reaction condition for base catalyzed synthesis of 4H-pyran III-16a ........................................................................................................................... 168 Table III-3. Preliminary results of stepwise vs. one-pot synthesis of cyclohexenones and 4H-pyran s ..................................................................................................................... 169 Table III-4. Substrate scope of Br¿nsted acid catalyzed cyclohexenone synthesis .... 171 Table III-5. Substrate scope of DABCO catalyzed 4 H-pyran synthesis ....................... 174 Table III-6. One-pot synthesis of carvone and celery ketone derivatives .................... 176 Table IV-1. Classes of phenolic compounds in plants ................................................. 296 Table IV-2. A series of bases were tested for the rearrangement reactions ................ 299 Table IV-3. Optimization of reaction conditions for the conversion of pyran to salicylate ...................................................................................................................................... 305 !$!LIST OF FIGURES Figure I-1. Other chiral tertiary amine catalysts/ co -catalyst systems involved in MBH/ aza -MBH reactions ......................................................................................................... 12 Figure I-2. Representative examples of other multifunctional catalysts ........................ 13 Figure I-3. Representative transformation s of MBH alcohols ........................................ 18 Figure II-1. a. Two diastereomeric transition states TS -1 and TS-2 calculated at the B2LYP/6 -31G*/SM8 (toluene) level of theory. The bonds h ighlighted in red color depict the unfavorable gauche interaction in TS -2. b. Three possible transition states associated with the [4+2] cycloaddition of II-3a-(S) and II-4a. TS-3(endo) is favored by 2.8 kcal/mol over TS -4(exo) and by 1.8 kcal/mol over TS-5(endo) . The fourth possible TS involving an exo approach of II-4a from the same face as the C4 -Ph substituent cannot be calculated due to severe steric clash between the approach dienophile and the aromatic ring. .................................................................................................................. 44 Figure II-2. a. An equilibrium mixture of putative intermediates in the Morita -Baylis -Hillman reaction of II-1a and II-2. For simplicity, intermediates arising only from the "Ðattack of the enolate are shown. b. ESI -MS spectrum of a reaction mixture ( pre -incubated for 30 min) constituting of a 1:2 ratio of quinuclidine ( C) and allenoate II-2. c. ESI-MS spectrum obtained after 1 h upon addition of II-1a to the mixture of ( C) a nd II-2 ........................................................................................................................................ 51 Figure III-1. Examples of readily available compounds from the chiral pool ............... 158 Figure III-2. 4H-pyrans in natural products and bioactive molecules ........................... 161 Figure III-3. Catalysts used to synthesize both enantiomers of cyclohexenones and 4 H-pyrans ........................................................................................................................... 166 Figure III-4. Proposed cyclization intermediates Int III -15f and Int III -15g .................. 172 Figure III-5. Investigation of the reactivity of enones III-13o to III-13r by 1H NMR analysis ........................................................................................................................ 177 Figure IV-1. Examples of amidine and guanidine containing natural products and drug molecules ..................................................................................................................... 287 Figure IV-2. Structure s and pKas of some representative amidine and guanidine bases ...................................................................................................................................... 288 !$"!Figure IV-3. X-ray crystal structures for IV-45 and IV-38i ............................................ 303 Figure IV-4. Representative example of !Ðamino acid drugs and pharmacologically active !Ðamino acid derivatives ................................................................................... 309 !$""!LIST OF SCHEMES Scheme I -1. Simplified catalytic cycles of four types of organocatalysts ......................... 1 Scheme I -2. General equation of the Morita -Baylis -Hillman (MBH) reaction ................... 3 Scheme I -3. Hill-Issacs proposed mechanism of MBH reaction between acrylonitrile and aldehyde catalyzed by tertiary amines ...................................................................... 5 Scheme I -4. McQuade proposed MBH reaction mechanism: proton -transfer step via a six -membered TS formed with a 2 nd molecule of aldehyde; Aggarwal proposed MBH reaction mechanism: proton -transfer step via a six -membered intermediate formed by autocatalysis ..................................................................................................................... 6 Scheme I -5. Proposed phosphine -catalyzed MBH reaction mechanism ......................... 7 Scheme I -6. Isolated stable phosphonium zwit terions, which are key intermediates of the phosphine -catalyzed MBH reaction ............................................................................ 8 Scheme I -7. Representative examples of substrate -control MBH reactions ................... 8 Scheme I -8. !#ICD initiated asymmetric MBH/ aza #MBH reactions .............................. 10 Scheme I -9. !#ICD-amide served as both Br¿nsted base and Lewis base in aza #MBH reactions ......................................................................................................................... 10 Scheme I-10. !#ICD catalyzed MBH reaction to modify isatin derivatives .................... 11 Scheme I -11. Bifunctional chiral phosphine catalyzed aza -MBH reaction ..................... 12 Scheme I -12. Trifunctional chiral phosphine catalyzed aza -MBH reaction .................... 13 Scheme I -13. Chiral oxazaborolidinium catalyzed three -component MBH reaction ...... 14 Scheme I -14. Chiral thiourea catalyzed aza -MBH reaction ........................................... 15 Scheme I -15. Chiral thiourea catalyzed MBH reaction of cyclohexanone and aldehyde ........................................................................................................................................ 15 Scheme I -16. Three types of chiral Br¿nsted acid catalyzed MBH reactions ................ 16 Scheme I -17. General scheme of the allylic substitution reactions of MBH acetates and carbonates ...................................................................................................................... 19 !$"""!Scheme I -18. Chiral allylic phosphine oxides synthesis through asymmetric allylic substitution of MBH adduct derivatives .......................................................................... 19 Scheme I -19. Chiral phosphine mediated asymmetric intramolecular [3+2] annulation of MBH carbonates ............................................................................................................. 20 Scheme I -20. Phosphine mediated intermole cular [4+1] cycloaddition reaction of MBH carbonates ...................................................................................................................... 20 Scheme I -21. Total synthesis of Phosphonothrixin I-98 ................................................ 21 Scheme I -22. Total synthesis of (±) ÐRicciocarpine A I-99 ............................................. 22 Scheme I -23. Total synthesis of Gradisine alkaloid I-100 .............................................. 22 Scheme I -24. Total synthesis of Salinosporamide I-101 ............................................... 23 Scheme I -25. Total synthesis of himanimide A I-102 .................................................... 23 Scheme I -26. An example of intramolecular Rauhut -Currier reaction ........................... 24 Scheme I -27. General mechanism of organocatalytic cycloaddition reaction ............... 25 Scheme I -28. General mechanism of organocatalytic cycloaddition reaction between $%!Ðunsaturated compounds and allenoate ................................................................... 26 Scheme I -29. The cycloaddition reaction modes affected by different LB catalysts ...... 26 Scheme I -30. NHC-catalyzed [4+2] cycloaddition reaction of allenoate and chalcones ........................................................................................................................................ 27 Scheme II -1. Examples of rece ntly reported chiral Lewis base catalyzed formal [4+2] cycloaddition reaction to assemble dihydropyrans with high stereoselectivity ............... 39 Scheme II -2. Top: Retrosynthetic strategy for the synthesis of hexahydro -2H-chromenes. Bottom: Path A and B represent a simplified mechanistic picture of the canonical vs. the modified Morita -Baylis -Hillman pathway. Possible resonance structures of the amine -allenoate adduct are shown in dashed box with II-2a being the major contributor ............................................................................................................ 40 Scheme II -3. Preliminary results for consecutive [4+2] cycloaddition reactions under optimized conditions using dibenzalacetone ( II-1a) as a model substrate. aIsolated yields. bRatios were determined by HPLC analysis. cReaction was performed using 1 g (4.3 mmol) of II-1a .......................................................................................................... 42 !$"#!Scheme II -4. Diels-Alder reaction of substituted oxa -trienes ( II-3a-c, II-3j) with illustrative dienophile ( II-4a-d). [a] Diels -Alder reaction conditions for each dienophile is as follows: dienophile II-4a: 0.1 M in toluene, reflux, 2 -16 h. Dienophile II-4b: 0.1 M in toluene, reflux, 2 h. Dienophile II-4c: 0.1 M in EtOH/DCM (1:1), 0 ¼C %rt, 12 h. Dienophile II-4d: 0.1 M in toluene, reflux, 12 h. [b] Diastereomeric ratio ( dr) were determined by 1H NMR analysis of the crude reaction mixture. [c] Regioselectivity ( rs) and relative stereochemistry was determined via NMR analysis of the purified product. [d] Isolated yields. [e] Isolated yield for Ôone potÕ consecutive transformations from II-1a as a starting material ...................................................................................................... 49 Scheme III -1. Examples of the Hajos -Parrish -Eder -Sauer -Wiechert reaction ............. 159 Scheme III -2. a. Organocatalytic kinetic resolution via intramolecular aldol reaction; b. An example of a multiple step synthesis of enantiomerically pure cyclohexene ...................................................................................................................................... 160 Scheme III -3. a. Cinchona derived primary amine catalyzed enantioselective intramolecular aldolization; b and c. Proline derivatives cataly zed cascade intermolecular cyclohex -2-enone formation; d. Diamine mediated cascade reaction of cyclohexenone formation ............................................................................................. 162 Scheme III -4. Organocatalytic formal [4+2] cycloaddition for the synthesis of 4 H-pyrans ...................................................................................................................................... 163 Scheme III -5. Organocatalytic [3+3] cycloaddition for the synthesis of 4 H-pyrans ...... 164 Scheme III -6. a: An example of the formation of both dihydropyran and 4 H-pyran under DABCO catalyzed reaction condition; b: Conversion from 4 H-pyran to cyclohexenone; c: One-pot synthesis of cyclohexe none and 4H-pyran from a common intermediate .. 165 Scheme III -7. Acid catalyzed 4 H-pyran formation from dihydropyran ......................... 169 Scheme III -8. Proposed mechanism for the Br¿nsted acid catalyzed cyclohexenone formation ...................................................................................................................... 173 Scheme III -9. Two plausible mechanism of DAB CO catalyzed 4 H-pyran formation. Path a, a Lewis base catalyzed cycle. Path b, a Br¿nsted base catalyzed cycle ................ 175 Scheme IV -1. An example of DBU/ DBN mediated isomerization reaction ................. 288 Scheme IV -2. Formation of unexpected byproduct IV-10 during a DBU involved nucleophilic attack ........................................................................................................ 289 Scheme IV -3. The first direct evidence that DBU/ DBN reacts as nucleophile via reaction with chlorophosphanes IV-11 ......................................................................... 289 !$#!Scheme IV -4. Relative nucleophil icities of selected catalysts. [a] Measurements made in MeCN. M odified scheme from reference 22 ............................................................. 291 Scheme IV -5. General mechanism for amidine and guanidine catalyzed acylation reaction s ....................................................................................................................... 292 Scheme IV -6. Examples of DBU mediated MBH reaction discovered by AggarwalÕs group ............................................................................................................................ 292 Scheme IV -7. DBU catalyzed c ycloaddition reaction of salicy lic aldehydes with allenes to form 2 H-1-chromenes .............................................................................................. 293 Scheme IV -8. Plausible mechanism for DBU catalyzed cycloaddition reaction of salicylic aldehydes with allenes to form 2 H-1-chromenes. Modified scheme from reference 13 ................................................................................................................. 294 Scheme IV -9. (a) A mixture of regio -isomers formation under Diels -Alder reaction of substrate IV-32 and acrylonitrile. (b) DBU catalyzed deconjugation of $%!Ðunsaturated ester IV-34 to form !%"Ðunsaturated ester IV-35. (c) Complete conversion of a mix ture of IV-33 and IV-33Õ to a single isomer IV-33Õ under DBU catalyzed reaction conditions ..................................................................................................................... 297 Scheme IV -10. a). An attempt to synthesize 4 H-pyran IV-36 from dihydropyran IV-32, followed by the Diels -Alder reaction to deliver the adduct IV-33Õ. b). DBU catalyzed formal [1,5] -H rearrangement towards the synthesis of pyran IV-36, which partially rearranged to salicylat e derivative when purified with silica gel ................................... 298 Scheme IV -11. [a] Reaction conditions: substrate (0.2 mmol) was dissolved in toluene (0.1 m L) with DBU (10 equiv.) . [b] Isolated yield (combined yield of pyran and its rearranged phenol side product s) ................................................................................ 301 Scheme IV -12. DBU catalyzed double bond isomerization from 4 H-pyrans to pyrans ...................................................................................................................................... 303 Scheme IV -13. DBU catalyzed oxidation reaction of acetyl dihydropyran IV-51 to pyran IV-52 with air as the oxidant ......................................................................................... 304 Scheme IV -14. Silica catalyzed rearrangement of pyran to salicylate ......................... 306 Scheme IV -15. Diels-Alder reaction of vinyl -pyrans with maleic anhydride to give chromene derivatives ................................................................................................... 307 Scheme IV -16. Plausible mechanism for DBU mediates form [1,5] -H shift and acid catalyzed rearrangement yielding phenol product ........................................................ 308 Scheme IV -17. Attempt to develop one -pot synthesis of pyran IV-37, while an adduct with the MS of [ IV-56+IV-57+DBU+H] + was observed ................................................. 309 !$#"!Scheme IV-18. Two commonly used routes to approach !Ðamino synthesis ............. 310 Scheme IV -19. Representative examples of other methods for !Ðamino acids synthesis. a) Metathesis pathway; b) Amino group conjugation addition pathway; c) Cycloaddition pathway ................................................................................................. 311 Scheme IV -20. Substrate scope of primary amine mediated !Ðamino ester synthesis from dihydropyrans. N.D = not determined .................................................................. 312 Scheme IV -21. a). An assumption of dihydropyridine synthesis from dihydropyran and benzylic amine through an intramolecular ÒN -attackÓ in the process. b). Proposed mechanism for primary amine mediated !Ðamino ester synthesis from dihydropyrans through an intramolecular ÒC -attackÓ in the process .................................................... 314 !$#""!KEY TO SYMBOLS AND ABBREVIATIONS † angstrom Ac acetyl cm-1 wavenumber DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec -7-ene DBN 1,5-diazabicyclo[4.3.0]non -5-ene DCM dichloromethane (DHQ) 2AQN dihydroquinine (anthraquinone -1,4-diyl) diether DHQD-PHN dihydroquinidine -9-phenanthryl ether DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide ee enantioselectivity er enantioselectivity ratio ESI-MS electrospray ionization -mass spectroscopy Et ethyl EtOAc ethyl acetate (Et) 3N triethylamine (Et) 2O diethyl ether equiv equivalent !$#"""!h hour HRMS high-resolution mass spectroscopy IR infrared Me methyl Min minutes M&molar MBH Morita -Baylis -Hillman mM minimolar mg minigram mmol minimole MTBD 7-methyl -1,5,7-triazabicyclo[4.4.0]dec -5-ene m.p. melting point MgSO 4 magnesium sulfate n-Bu n-butyl NHCs N-heterocyclic carbenes NMR nuclear magnetic resonance Na2SO4 sodium sulfate NaOH sodium hydroxide Ph phenyl ppm parts per million QD quinidine QN quinine !$"$!rt room temperature ["] specific rotation # chemical shift TBD triazabicyclodecene THF tetrahydrofuran TLC thin layer chromatography TMG 1,1,3,3-tetramethyguanidine TS transition state > larger than < less than !"!Chapter I : A Brief R eview of Organocatalytic Morita -Baylis-Hillman (MBH) Reaction I-1. General introduction of organocatalysis It was until early this century that organocatalysis was recognized as the third pillar of modern asymmetric catalysis after enzymatic and organometallic catalysis. In recent years, although a new field, organocatalysis has grown dramatically , becoming a thrivi ng area that has been widely applied in asymmetric reactions, as illustrated by the citation statistics from the literature .1 Organocatalysis could be viewed as a catalysis with small organic molecules, where an inorganic element is not pa rt of the active principle. Most but not all o rganocatalysts can be broadly classified into four types , namely Lewis bases, Lewis acids, Br¿nsted bases and Br¿nsted acids (Scheme I-1 ).2 The classification is based on the reaction mechanism (proposed) and the mode of activation of the catalyst Scheme I -1. Simplified catalytic cycles of four types of organocatalysts. SBÑSBBÑPPSAÑSAAÑPPSÑHBH S BBH P PÑHA SH AÑHLewis base catalysis Lewis acid catalysis Br¿nsted acid catalysis Br¿nsted base catalysis SA PH P!#!in the catalytic cycle , either by providing or removing electrons or protons from a substrate or a transition state. For example, in a Lewis base ( B:) catalytic cycle, a nucleophilic addition to the substrate ( S) is followed by a reaction , the product ( P) is released and the catalyst is recovered for further turnover. Although the exact mechanisms are not often available, and even more challenging is the fact that some of the organocatalysts are bifunctional, it is still helpful to organize this field with a somewhat logical structure. 2 Among these four, Lewis base catalysts dominate the field with several types of catalysts, such as amines, phosphines and carbenes. However, it is noteworthy that Br¿nsted acid catalysts have grown signif icantly recently and are expected to ultimately del iver extremely active catalysts, which are comparable the efficiency of enzymes, as well as that of the few super active chiral transition metal complexes, such as certain Suzuki reaction catalysts. 3 Organocatalysts have advantage s that are attractive to chemists . More specifically, most of them are stable in air and water, widely available from biological materials, generally inexpensive and easy to prepare, simple to use, both enantioseries are available , and typically they are non-toxic. 1 As a sequence, this field has quickly flooded with research groups, gre atly accelerating the development of thi s area. As a result, it is not surprising that organocatalysts have been used as generic modes of activation and inducti on with many reaction variants, such as Hajos-Parrish -Eder -Sauer -Wiechert reaction, aldol reaction, Michael reaction, Mannich reactio n, Strecker reaction, Morita -Baylis -Hillman reaction , to name a few. For each individual reaction , almost every aspect has been well developed, including substrate scope, innovative catalysts design and !$!synthesis, mechanis tic stud ies, and new applications of the reaction itself and its products . Our journey will begin with one of the famous organocatalytic reactions Ñthe Morita -Baylis-Hillman reaction , as the most important part of my work is based on the modified format of this reaction. I-2. An introduction of Morita -Baylis-Hillman (MBH) reaction The most fundamental reactions of organic chemistry are the C-C bond formation and the functional group transformation s. Among these C -C bond formation reactions , t he Morita -Baylis -Hillman (MBH) tran sformation is an important contributor leading to multifunctional scaffold s. The classical MBH reaction is co mmon ly defined as the C-C bond formation between the !Ðposition of conjugated carbonyl compounds and carbon electrophiles, such as aldehydes and imines , in the presence of a nucleophilic catalyst, part icularly a tertiary amine or a phosphine ( Scheme I -2).4 The origin of this reaction dates back to 1968, when Morita reported this reaction catalyzed by a phosphine .5,6 Four years later, Baylis and Hillman d escribed a similar reaction, however, using an amine as the catalyst .7 After a decade, several groups, including Drewes , Hoffmann , Perlmutter , and Basavaish reinvestigated and explored this reaction as evidenced by their numerous research papers .8-13 During the past few decades, there has been rema rkable progress made by several groups, such as Shi , Aggarwal , Mille r and Zhu,4,14 -17 especially in the Scheme I -2. General equation of the Morita -Baylis -Hillman (MBH) reaction. RRÕXEWG tert. amine or phosphine +EWG XHRRÕR = aryl, alkyl, heteroaryl, etc.; RÕ = H, CO 2RÓ, alkyl, etc.X = O, NCO 2RÓ, NSO 2Ar, etc.EWG = CORÓ, CHO, CN, CO 2RÓ, PO(OEt) 2, SO 2Ph, SO 3Ph, SOPh, etc.!%!area of organocatalytic asymmetric MBH reactions. Meanwhile, mechanistic studies by several grou ps, such as Hoffman , McQuade , Aggarwal , and Coelho have also been investigated .9,15,18 -20 Also, aza -Morita -Baylis -Hillman (aza -MBH) reaction, in which imines, instead of aldehydes, react as the secondary electrophiles, has been widely studied. The reasons for the dramatic growth of MBH /aza -MBH reaction can be attributed to several advantages of this reaction as follows: (i) the starting materials are usually commercially available; (ii) the reaction is easily scaled up to industr ial scale; (iii) it is an atom-economic reaction; (iv) usually the reaction condition is mild; (v) it is often catalyzed by an organocatalysis, as a result, no contamination with heavy -metals; (vi) the scaffolds formed through this reaction contain multi -functionalities that could be easily modified to other synthetically useful products. The MBH reaction has been studied for several decades. In the following paragraphs, the MBH reaction will be reviewed by looking at mechani stic studies, catalysts involved in the reaction , and the applications or transformations of the products of this reaction. I-3. Mechanism I-3.1. Amine-Catalyzed MBH Reaction The elementary steps of the MBH reaction catalyzed by simple amine species have been describe d in detail in the early literature , which generally include three sequential steps: the Michael addition, aldol coupling reaction (involving proton migration) and followed by elimination of the catalyst . This was first proposed by Hoffman 9 and later confin ed by Hill and Isaacs ,21-23 as well as other groups, 24-26 through kinetic studies (Scheme I -3). Take acrylonitrile as an example, the 1 st step of the catalytic cycle starts !&!with the Michael reaction of tertiary amine I-1 to the activated alkene (acrylonitrile I-2), to produce the zwitterionic amine -acrylate I-3, which react s as the secondary nucleophile to attack the aldehyde I-4, generatin g zwitterion I-5, followed by intramolecular proton transfer, leading to the formation of intermediate I-6. Subsequently, elimination of the catalyst I-1 via E2 or E1cb mechanism produce s the product I-7 and recover s the catalyst I-1. The low kinetic isotopic effect (KIE = 1.03 ± 0.1 , in Scheme I -3) indicates the conjugated addition step ! is the MBH rate -determining process (RDS). Later, the isolation of one intermediate which was confirmed by X -ray crystallography and the use of electrospray ioni zation with mass and tandem mass spectrometry to trap all the key intermediates supported the proposed mechanism .8,27 However, when McQuadeÕs 18,19 and AggarwalÕs 15 group s re-investigated this reaction by using carbonyl activated alkenes (such as a ketone) through kinetics and theoretical studies, they observed a significant kinetic isotopic ef fect (KIE = 5.2 ± 0.6 in DMSO , in Scheme I -4), which suggests the relevant proton transfer step III is the rate -determ ining Scheme I -3. Hill -Isaacs proposed mechanism of MBH reaction between acrylonitrile and aldehyde catalyzed by tertiary amines. NR3CNI-2 I-1 step I R3NCNI-3 step II R1HOI-4 R1OCNNR3HkH/kD = 1.03 ± 0.1 I-5 step III R1OHNR3CNstep IV I-6 R1OHCNI-7 !'!step. It is also reported the MBH reaction could be accelerated by protic reagents, such as methanol and phenol , which provides another evidence for their p lausible mechanism .15 As a result, b oth groups proposed a six -membered intermediate form ed during the proton -transfer step. ( Scheme I -4) The difference between these two models is the partner participating in this six -membered ring formation. In McQuadeÕs proposal, the 2 nd molecule of the aldehyde electrophile I-4 is used to form a hemiacetal intermediate I-10a. While in AggarwalÕs proposal, the final product I-12 plays the role of an intermolecular proton transfer agent through intermediate I-10b. As a result, the autocatalytic effect of the product observed in this type r eaction can be explained by !AggarwalÕs model . Apart from kinetic studies, theoretical studies have also suggest ed that Scheme I -4. McQuade proposed MBH reaction mechanism: proton -transfer step via a six -membered TS formed with a 2 nd molecule of aldehyde; Aggarwal proposed MBH reaction mechanism: proton -transfer step via a six -membered intermediate formed by autocatalysis. NR3I-8 1step I I-9 step II R1HOI-4 R1ONR3D(H) I-10 step III step IVa I-10a OXR3NXOXOR1HOI-4 R1ONR3HXOOR1R1OXOOHR1àI-11 R1OHXOI-12 orR1OOOI-13 R1Proton source R1ONR3HI-10b XOHOR2step IVb NR3 + R 2OHR1OHXOI-12 McQuade proposal Aggarwal proposalkH/kD = 5.2 ± 0.6 (in DMSO) !(!these two pat hways are competing mechanisms , with one more favored depending on the specific reaction conditions .28,29 The mechanism will be more complica ted if a co-catalytic system and/or multi -/bifunctional catalyst is used . Furthermore , the mechanistic study of the asymmetric MBH reaction s is even more challenging as several intermediates and transition states are involved in the reaction process .30-33 I-3.2. Phosphine-Catalyzed MBH Reaction Almost identical to the amine -catalyzed MBH reaction, phosphine -catalyzed MBH also proce eds through three steps ; the Michael addition, the aldol reaction and the elimination of the catalyst , with the exception for the formation of a potential phosphorus ylide , such as I-17, after the Michael addition step , delivering olefination product I-21 (Scheme I -5).4 The latter process is n ot observed under mild reaction conditions , requiring elevated temperatures. Scheme I -5. Proposed phosphine -catalyzed MBH reaction mechanism. EWG +PR3R3PEWG R3PEWG I-16 I-17 R1XR1X-R3PO (X=O) XR1EWG R3PR1XHEWG R1EWG I-14 I-15 I-20 I-19 I-18 I-18 I-21 X = O (MBH) X = NTs, NMs etc, (aza-MBH) !)!Recently, the postulated phosphine -catalyzed MBH reaction mechanism was experimentally supported by isolating stabl e phosphonium zwitterion s I-24 and I-26; the intermolecular example by TongÕs group 34 and intramolecular example by Krafft Õs group 35, respectively (Scheme I -6). The X -ray crystal structure of the zwitterion I-24 is shown in Scheme I -6, which is one of the key intermediates of the proposed aza -MBH reaction mechanism .! Scheme I -6. Isolated stable phosphonium zwitterions, which are key intermediates of the phosphine -catalyzed MBH reaction. PPh3++CO2RArHNTs toluene80 ¼C85-90% R = Me, Bn, CH 2CO2Et; Ar = 4-MeOPh, Ph TsN ArCO2RPPh3OBr22PMe3, t-BuOH OMe3PBrI-15 a I-22 I-23 I-24 I-25 I-26 Scheme I -7. Representative examples of substrate -control MBH reactions. a. Chiral electrophiles b. Chiral activated alkenes and alkynes RCHO+OOOOOOODABCO, DMSO rt, 15h, 58-72% OOOOOOOOHR24-44% deI-30 I-31 I-32 Sugar OH+EWG DABCO (1.0 equiv.) sulfolane, rt 12-15 h, 60-85% EWG OHSugar 40 - 95% deI-27 I-28 I-29 NNDABCO!*!I-4. Catalytic Asymmetric Induction of the MBH Reaction The a symmetric version of the MBH reaction was developed several decades ago, including substrate -control (either through electrophiles or activated alkenes) and catalyst -control .4,36 Representative examples are depicted in Scheme I -7 for substrate -control MBH reactions , in which 1,4 -diazabicyclo[2.2.2]octane ( DBACO) was used as the catalyst for both of cases .37,38 Also, a s is described in Scheme I -7, embedding sugar analogues as the auxiliary in substrates, such as I-27 and I-31, is a popular strateg y for substrate -control asymmetric MBH reaction .17,39 -44 However, in recent years, with increasing options for catalyst s and broader substrate scope, more focus has been placed on the organocatalytic a symmetric MBH/aza -MBH reactions, making it as a major objective and central theme . Based on the types of the catalysts used in the reaction, catalyst -control MBH reactions could be divided into three main categories . They are chiral Lewis base catalyzed MBH reaction s,17,42,45 -47 chiral Lewis acid catalyzed MBH reaction s,43,48 and chiral Br¿nsted acid catalyzed MBH rea ctions.44,49,50 Among them, the use of chiral Lewis base s is the most well -developed field, being systematically studied by many research groups globally. 4,36 I-4.1. Chiral Lewis Base Catalyzed MBH Reaction s Either nitrogen -based, or phosphine -based, or the hybridization of both, these Lewis base catalysts have been widely designed and synthesized, for the purpose of applying them to MBH reactions. As a classic example, !-isocupreidine ( !-ICD) is o ne of the most successful chiral tertiary amine catalysts and has been intensively investigated. It was firstly reported by Hetakeyama and co -workers in 1999, studying the asymmetric MBH !"+!reaction of 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) I-33 and aldehydes , delivering MBH adduct with excellent enantioselectivity, as shown in Scheme I -8.31 Subsequently, they were also able to extend this strategy to aza -MBH reaction , by using phosphonate protected imine I-36,51 with moderate to good enantioselectivity . Scheme I -8. !-ICD initiated asymmetric MBH/ aza -MBH reactions. OOCF3CF3!-ICD (10-20 mol%) RCHO-55 ¼C, DMF 1-72 h !-ICD (10 mol%) -55 ¼C, DMF 2-120 h OOCF3CF3ROH31-58% 91-99% ee+OORROI-33 I-34 I-35 0-25% 4-85% eecis :trans = 69:31 to 95:5 R = C 6H5, 4-(O 2N)C 6H4Cinnamyl, Et, i-Pr, i-Bu, c-Hex ArHNP(O)Ph 2I-36 OOCF3CF3ArNH42-97% 54-73% eeI-37 Ph2(O)P Ar = C 6H5, 4-(MeO)C 6H44-(O 2N)C 6H4, Naphth-1-yl NHNOOH!-ICD Scheme I -9. !-ICD -amide served as both Br¿nsted base and Lewis base in aza -MBH reaction. R3OR1NHSO 2R2SO2Ph+I-41 (10 mol%) I-42 (10 mol%) 10 ¼C, DCM4 † MS,1-72 h R3OR2O2SHN R1I-38 I-39 I-40 R1 = alkyl; R 3 = OAr, Me, H R2 = p-methoxyphenyl (PMP), 2-trimethylsilylehtyl 54-99% 87-94% eeNOHNONHOArAr = 9-anthracenyl or Ph I-41 I-42 !""!Later, the !-ICD catalyst has been modified and applied to even a broa der substrate scope for the MBH/aza -MBH reactions by several other groups, delivering excellent yield s, as well as enantioselectivities . For example, ZhuÕs group reported a !-ICD-amide I-41 catalyzed aza -MBH reaction between a readily available !Ðamidosulfones and different types of Michael acceptors (!"#-unsaturated ester, ketone and aldehyde, see Scheme I -9).52 During this cascade process, the catalyst !-ICD-amide I-41 serve s as a trifunctional catalyst , trigger ing the generation of the N-sulfonylimine in situ as a Br¿nsted base , which initiates the aza -MBH reaction as a Lewis base. In addition , the amide residue play s a role as H -bonding donor to assist the high en antioselectivity. It was also discovered that the additive !Ðnaphthol can enhance the enantioselectivity of this reaction through H-bonding. Several groups have applied the !-ICD catalyst in other MBH reaction s when isatin derivatives reacted as activate d ketones. The obtained adducts could be further transformed to 3 -aryl -3-hydroxypyrrolidin -2-ones, as precursors for promising drug candidates for treatment of HIV -1 infection. 53 (see Scheme I -10) Not only cinchona alkaloid derived catalysts, but also other chiral amine catalysts have been used for the MBH/aza -MBH reactions . These include FuÕs planar chiral DMAP I-47,47 isothiourea I-48,47 proline derived diamine I-49,42 a dual catalytic system Scheme I -10. !-ICD catalyzed MBH reaction to modify isatin derivatives. O+OR2NOOR1!-ICD (10 mol%) rt, DCM 40 hNOR1HOOOR2rt, MeOH 12 hBnNH 2NOBnHOCO2MeNHBn I-43 I-44 I-45 I-46 R1 = Bn, allyl, 9-anthracenylmethyl, Me, Tf R2 = 2- or 1-naphthyl, Ph up to 99% yield, 96% ee87% yield, 91% ee!"#!composed of chiral !$guanidininoester I-50 and PPh 3,54 a guanidine I-51/azole I-52 co-catalytic system, 46 an acid Ñbase bifunctional catalyst I-53,45 to name a few (see Figure I-1). Chiral phosphine catalysts have also been developed and applied efficiently in MBH/aza -MBH reactions . Furthermore, multifunctional catalysts have been designed and synthesized, namely, the combination of Lewis basic and Br¿nsted basic/acidic moieties within one chiral backbone. Many of these novel catalysts are efficient in MBH/aza -MBH or its related reactions. 16,55 Figure I-1. Other chiral tertiary amine catalysts/ co -catalyst systems involved in MBH/ aza -MBH reactions . FeNMe2NPh5I-47 Fu (+)-DMAP NSNPhI-48 (-)-Tetramisole NNMe 2I-49 Me2NNNMe 2CO2Mei-PrI-50 Me2NNHNMe 2NHNO2N+OHOHNNHI-51 I-52 I-53 Scheme I-11. Bifunctional chiral phosphine catalyzed aza -MBH reaction . OArNHPG SO2Ph+I-54 (10 mol%) -20 ¼C, 48 h chloroform:H 2O = 20:1 OGPHN ArI-56 I-55 I-57 PG = Boc, Bz, CO 2EtAr = 4-F 3CC6H4, 3-MeC 6H4 3-ClC 6H4, 2-MeOC 6H4 2-ClC 6H4, 2-furyl 51-98% yield 57-93% eeOHPPh2I-54 !"$! Based on 1,1Õ -bi-2,2Õ-naphthol (BINOL) backbone , ShiÕs group first reported chiral bifunctional phosphine I-54 could be used in the asymmetric aza -MBH rea ction of N-tosyl imines with several vinyl ketones (see Scheme I -11).56 Similarly, using the same backbone, LiuÕs group further developed several trifunctional chiral phosphine catalysts, containing a Lewis base, a Br¿nsted base and a Br¿nsted acid moiet y. An example of the latter trifunctional catalyst is compound I-61 described in Scheme I -12.57 In this example, the phosphine moiety reacts as a Lewis base, secondary amine reacts as a Br¿nsted base and the phenol moiety plays the role of the Br¿nsted acid. Also, i n this reaction, cat alytic amount of benzoic acid was used to increase both the reaction rate and enantioselectivit y. It is hypothesized that the favored transition state involv es the PPh2NHOOOEt I-62 PPh2NHNHSCF3CF3I-63 PPh2ONHTs SiPPh2OHI-64 I-65 Figure I-2. Representative examples of other multifunctional catalysts . Scheme I-12. Trifunctional chiral phosphine catalyzed aza -MBH reaction . NTs RO+OR2I-61 (10 mol%) benzoic acid (50 mol%) rt, DCM I-59 I-58 NHTs ROR = m-NO 2, p-Br, p-Cl, o-Cl p-F, p-NO 2, o-NO 2, p-Me o-MeO, m-MeO 86-96% yield 59-92% eeI-60 NHPPh2I-61 OH!"%!formation of hydrogen bonding and chiral ion pair between the catalyst and the benzoic acid after protonation. 58 Sev eral multifunctional chiral phosphine catalysts with different backbones and/or hybridized Br¿nsted acid moi eties are also reported with application s in the MBH/aza -MBH and related reactions. Representative examples are shown in Figure I-2.4 I-4.2. Chiral Lewis Acid Catalyzed MBH Reaction s Not as popular as chiral Lewis base s, there are interesting reports about us ing chiral Lewis acids as effective catalysts for MBH reactions. The chiral cationic oxazaborolidinium catalyst I-69 as an example, RyuÕs group reported a highly enantioselective and Z-controlled three -component coupling reaction s with acetylenic esters, aldehydes and trimethylsilyl iodide (TMSI) (see Scheme I -13).43 Both enantiomers were obtained for this three -component coupling reaction by using an S- or R-oxazaborolidinium salt . Apart from boron reagents, other metal containing Lew is acids (such as Ti, La and Ba) , combined with chiral ligands and/or achiral Lewis bases , also have been utilized for asymmetric MBH reactions . I-4.3. Chiral Br¿nsted Acid Catalyzed MBH Reaction s Typically , the role of a chiral Br¿nsted acid in an asymmetric MBH/aza -MBH reaction is to provide a local chiral environment through H -bonding in the transition state of the Scheme I-13. Chiral oxazaborolidinium catalyzed three -component MBH reaction . RHO+OEt O+TMSI I-69 (20 mol%) -78 ¼C, DCM I-66 I-67 I-68 ROEt IOOH50-99% yield 62-94% eeNBOHHPhPhTfOI-69 !"&!reaction. As a result, several important H -bonding scaffolds , including chiral thioureas, chiral proline derivatives and chiral thiols, have been applied for the asymmetric MBH/aza -MBH reactions. Successful examples are reported !when t hese scaffolds are used either as a moiety of a chiral bifunctional catalyst, or as a component in a co -catalytic system. For example, in 2005, JacobsenÕs and co -workers described a chiral thiourea catalyst I-70 for the highly enantioselective aza -MBH reaction between methyl acrylate and arylimines (Scheme I -14).59 Later, Ito described an efficient chiral biaryl -based bis(thiourea) organocatalyst I-74 for MBH reactions of cyclohexenones and aldehydes (Scheme I -15).60 In both reactions , the thiourea agents function as co -catalysts for the purpose of forming a local chiral environment. Meanwhile , researchers also developed a series of chiral bifunctional organocatalysts by taking advantage of the naturally exist ing ArNO+OMe I-70 (10 mol%) DABCO (1.0 equiv.) 4 ¼C, xylenes 3 † sieves I-72 I-71 ArCO2MeI-73 HNsHNNsNHNHSI-70 NOBnMeNHOt-But-But-Bu25-49% yield 87-99% eeScheme I-14. Chiral thiourea catalyzed aza -MBH reaction . Scheme I-15. Chiral thiourea catalyzed MBH reaction of cyclohexanone and aldehydes . RCHO+OI-74 (20 mol%) DABCO (20 mol%) neat, rt OROHI-75 I-76 I-77 NHHNSNHArHNSArAr = 3,5-CF 3C6H3I-74 48-86% yield 62-96% ee!"'!chiral backbones, such as amino acids . LuÕs group 61 first synthesized an effective L- threonine -derived bifunctional phosphine -thiourea catalyst I-78 for the asymmetric MBH reactions of acrylates with aromatic aldehydes (Scheme I -16 a). Also, they revealed the importance of H -bonding interactions for achieving high enantioselectivity by investigating the influences of several achiral protic additives, such as MeOH, PhOH and PhCOOH. Proline carboxylic or alcoholic derivatives are reported as robust Br¿nsted acid catalysts for MBH /aza -MBH reaction s as well. In contrast to thiourea catalysts, som e proline derivatives could catalyze MBH reaction s individually since they carry a secondary amine as the Lewis base moiety. But proline derived co-catalytic systems are also well Scheme I-16. Three types of chiral Br¿nsted acid catalyzed MBH reactions . R1CHO+OR2OI-78 (10 mol%) THF, rt, 4 † MS OR2OR1OHI-79 I-80 I-81 25-92% yield 70-90% eeNHNHSOTBS PPh2FI-78 a. chiral thiourea as MBH catalyst b. chiral proline derivative as MBH catalyst c. chiral thiol as MBH catalyst +I-82 (40 mol%) DABCO (20 mol%) KF (5 equiv.) CHCl3, 20 ¼COArHNI-83 I-84 E-I-85 46-87% yield E/Z 10:1-19:1 82-99% eeCHOR1ArSO2PhNHRRR1OArHNZ-I-85 R+R1NHCO2HI-82 PhOOI-86 (5 mol%) 5 vol% K 2CO3MeCN, 70 ¼C 0.25 hPhOOH81% yield 43% eeI-88 I-87 OHOHSHSHI-86 !"(!established . Scheme I -16 b provides an example reported by Vesel !Õs group ,49 in which (S)-proline I-82 was identified as the best Br¿nsted acid catalyst , together with DABCO as the Lewis base co -catalyst. In addition, an excess amount of KF was used as an additive to enhance the diastereoselectiv ity of this reaction. Recently , MillerÕs group 50 uncovered that ortho -mercaptobenzoic acid, ortho-mercaptophenols and their analogues as efficient thiol catalysts for both the MBH and the Rauhut-Currier reactions (see example in Scheme I -16 c). I-5. Application of MBH Products Besid e the development of MBH reaction , the transformation of MBH products have also attracted a great deal of attention from organic chemists .62,63 As multi -functionalized scaffolds (including at least three functional groups in close proximity Ñhydroxyl/amino, alkene and electron -withdrawing groups) , these products could be facilely and flexibly converted into other synthons based on different strategies. As a result, many investigators have focused efforts on modifying these functionalities either individually or collectively. In fact, some of these methodologies have been successfully employed in the synthesis of a variety of biologically active molecules and natural products .64 I-5.1. Transformation s of MBH Products Catalyzed by Organocatalysts More recently, both Basavaiah 36 and Shi 4 have reviewed the transformation s of MBH products from different aspects. From a systematic viewpoint , Basavaiah summarize d most of the reactions in pictorial form s, covering the synthetic transformations of MBH alcohols, acetates and bromides, where these MBH products have been employed as substrates in a number of named and unnamed reactions, such as Heck reaction, Friedel -!")!Crafts reaction, isomerization an d hydrogenation. 36,65 Figure 3 illustrates some representative transformations of MBH alcohols. 36 Also, efforts have been made to convert these MBH products into various tri -substituted alkenes with defined stereochemistry. More importantly, the MBH adducts and their derivatives have been used to construct biologically important carbo - and heterocyclic molecules. 64,65 Shi has desc ribed allylic substitution reactions of MBH acetates and carbonates, and annulation of MBH acetates and carbonates with electron -deficient olefins. 4 After a quinidine-catalyzed SN2Õ reaction to produce chiral MBH propargylic ethers reported by Basavaiah ,65 asymmetric transformations of MBH products via substitution of MBH ROHEWG Hydrog- enationROHEWG ROHEWG +Heck reaction Mitsunobu reaction Friedel- Crafts reaction ROEWG ArREWG OC(O)R 1REWG HPhaminohyd- roxylation allyl amination Rearr- angement Isomeri- zation Photo che- mical rearr- angement ROHCO2MeOHNHTs ROHCO2MeNHBn RCNOHROEWG ROOEWG = COMe EWG = CN EWG = CO 2MeEWG = CO 2MeFigure I-3. Representative tra nsformations of MBH alcohols . !"*!acetates/carbonates by different types of nucleophiles have become widely investigated and intensively reported. 66-71 The general equation of the allylic substitution reactions of MBH acetates and carbonates is illustrated in Scheme I -17.4 In 2004, KrischeÕs group 72,73 reported intermo lecular allylic substitution reacti ons of MBH products using phosphine catalysts to form C -C and C -hetero atom bonds . In these reactions, N - and C -nucleophiles, such as 4,5 -dichlorophthalimides and 2 -trimethylsilyloxyfuran (TMSOF) were employ ed to furnish allylic amines and %Ðbutenolides in high regio - and diastereoselectivity and in good yields, respectively. Later, several other groups developed chiral Lewis base catalyzed allylic substitution reactions of MBH products , achieving excellent enantioselectivities with good yields. Overall, 1,1Õ -bi-2-naphthol (BINOL) and cinchona alkaloid derived Lewis bases are commonly used for this transformation. More recently, WangÕs group 74,75 reported quinidine catalyzed allylic substitution reaction of MBH carbonates with phos phine oxides to directly approach Scheme I-17. General scheme of the allylic substitution reactions of MBH acetates and carbonates . R1LGR2OR1LB!!"LGR2OLewis Base (LB) Nu substitution at the !#position R1NuR2O*R1 = alkyl or aryl group R2 = alkyl or alkyloxy group LG = OAc, OBoc Scheme I-18. Chiral allylic phosphine oxides synthesis through asymmetric allylic substitution of MBH adduct derivatives . ArOBoc COOMe quinidine (20 mol%) 0 ¼C, xylenes 60 h, 4 † MS PORRHArPCOOMe ORR63-98% 44-97% eeI-89 I-90 I-91 !#+!optically active allylic phosphine oxides in an easy and efficient way with satisfactory enantioselectivities and yields ( Scheme I -18). MBH acetates and carbonates can undergo annulation reactions with electron -deficient olefins to construct multifunctional carbo - and hetero -cyclic co mpounds. 76-79 During the annulation reaction, in the presence of tertiary phosphines, the in situ generated phosphorus ylides derived from MBH acetates and carbonates , are very reactive 1,3 -dipoles intermediates. Both intermolecular and intramolecular [3+2] cycloaddition reactions have been reported .80,81 An example from TangÕs group 82 is illustrated in Scheme I -19, in which a spirobiindane -based chiral phosphine I-92 was used as the catalyst . Interesting ly, Zhang, 76 Huang78 and HeÕs 83 groups have simultaneously reported [4+1] annulations recently, utilizing MBH acetates Scheme I-19. Chiral phosphine mediated asymmetric intramolecular [3+2] annulation of MBH carbonates . XCOR1COR2OBoc RI-92 (10 mol%) -5 ¼C, toluene XRCOR1HHR2OCXRCOR1HHR2OC+I-93 I-94 I-94Õ 76-98% yield I-94/I-94Õ > 95/5 - 10/90 77-95% eeI-92 POMe Scheme I-20. Phosphine mediated intermolecular [4+1] cycloaddition reaction of MBH ca rbonates . PPh3 (20 mol%) rt, DCM, 24 h NR1R2Ts+CO2R3OBoc NTsR2R1CO2R380-99% yield, dr >20:1 I-95 I-96 I-97 !#"!and carbonates , as shown in Scheme I -20. In this reaction, MBH carbonate was reacted as a C1 synthon. I-5.2. Applications of the MBH Reaction toward Natural Produc ts and Drug Molecules Synthesis One of the major goals in organic synthetic chemistry is the synthesis of complex natural products from common, simple and commercially available starting materials. Toward this objective, organic chemists have devoted a great deal of effort into constructing simpl e scaffolds decorated with densely functional ized groups, which present opportunities not only directed to the target compounds, but also to construct a library of analogues. Morita -Baylis -Hillman (MBH) reaction meets this requirement by providing diversely functional ized scaffolds, such as alkene -hydroxyl -carbonyl and alkene -amino -carbonyl functional groups , which are important synthons of medicinally bioactive compounds and natural pr oducts. As a result, it is not surprising that this reaction has been utilized in the synthesis of a range of molecules , obtained from Scheme I-21. Total synthesis of Phosphonothrixin I-98. MeOHCO2Me1. (EtO) 2P-Cl, Et 3N2. 80 ¼C, 2 hmethyl acrylate (1.0 equiv) DABCO (0.09 mol%) 0 ¼C, dioxane 8 hMeCHO (1.2 equiv) 74% yield 60% yield MeCO2MePO(OEt) 2DIBAL-H Et2O, 0 ¼C79% yield MePO(OEt) 2OH1. TBSCl, imidazole DMF, 94% yield 2. OsO 4, NMO, DCM rt, 80% yield MePO(OEt) 2OTBS OHOHPDC/Celite DCM80% yield MePO(OEt) 2OTBS OOH1. TMSI, DCM 2. aq. HF, MeCN 83% yield MeOHOOHPO(OH) 2I-98 !##!microbial, animal, moss, terrestrial and marin e origins . Also, some of the MBH product s are precursors to several drug molecules or their intermediates. Recently, a number of reviews describing the application s of the MBH reaction towards the synthesis of natural products and drug molecules or their intermediates have been discussed systematically and extensively .36,62 ,64,84 -89 Based on the origins of the natural products, representative examples (in simplified sequences ) of each origin have been selected to demonstrate the applications of the M BH reaction in total synthesis. Phosphonothrixin I-98 in Scheme I -21 is a phosphorous containing herbicidal natural product of microbial origin , isolated from Saccharothrix sp. ST -888 and the synthesis was reported by FieldsÕs group .90 (±) ÐRicciocarpine A I-99 in Scheme I -22, a furanosesquiterpene from moss , isolated from the liverwort Ricciocarpos natans , exhibi ts its good molluscicidal activity against the water snail Biomphalaria glabrata , with synthesis reported from KrischeÕs group .91 Grandisine alkaloid I-100, isolated from the leaves of the Australian rainforest tree Elaeocarpus grandis , are of terrestrial origin, exhibiting affinity for the human &Ðopioid receptor and the synthesis was performed by Tamura and co -workers (Scheme I -23).92 Scheme I-22. Total synthesis of (±) ÐRicciocarpine A I-99. PBu3 (20 mol%) t-BuOH, 135 ¼C 81% yield SEtOOOSEtOOO3 steps OOHHI-99 Scheme I-23. Total synthesis of Gradisine alkaloid I-100. NOOHCAcOEtO TfOH, Me 2S, MeCN -35 ¼C-rt, 2 h 67% yield dr = 96:4 NOOHCHAcO9 steps NOHOOHI-100 !#$!Salinosporamide A I-101 is a bioactive natural product of a marine organism with effective proteasome inhibition property, widely distributed in ocean sediments. CoreyÕs group 93 utilized an intramolecular MBH reaction to achieve the synthesis of this molecule, as shown in Scheme I -24. Basavaiah Õs group 94 developed the synthesis of the biologically active himanimide A I-102, which is a natural product with animal origin , in 11.38% overall yield ( Scheme I -25). As can be see n, the MBH reaction has made tremendous contribution s to the realms of syn thetic chemistry and continues to offer more opportunities for future applications. Scheme I-24. Total synthesis of Salinosporamide I-101. MeO HNOCO2MeHOPTSA, PhMe reflux, 12 h 80% yield MeO ONCO2Me4 steps ONOPMBCO2MeOBn quinuclidine, DME 0 ¼C, 7 d90% yield NOPMBCO2MeOHOBn 9 steps NHOOOClOHHI-101 Scheme I-25. Total synthesis of himanimide A I-102. TBDMSO OCO2Etacrylonitrile, DABCO rt, 4 d 48% yield TBDMSO HOCO2EtCNCH3SO3H, C6H6reflux, 4 h 47% yield HONHOOK2CO3, acetone reflux, 6 h 50% yield BrONHOOI-102 !#%!Hence, there is no doubt that further studies of this reaction will be also important for the synthetic chemistry field. I-6. Deviation s from the MBH reaction Ñthe Lewis base catalyzed cyclization reactions The most relevant to the Morita -Baylis -Hillman (MBH) reaction is the Rauhut -Currier (RC) reaction, also known as vinylogous Morita -Baylis -Hillman reaction. In general, it is a reaction that involves any coupling of one active/latent enolate to a second Michael acceptor, creating a new C -C bond between the !Ðpositi on of one activated alkene and the #Ðposition of a second alkene under the influence of a nucleophilic catalyst. 95 An intramolecular RC type of reaction developed by ChristamnÕs group 96 is a s an example given in Scheme I -26. Mechanistically , the RC reaction is essentially a variant of the MBH reaction. Interestingly, nucleophilic organocatalysts, such as tertiary amines, phosphines and N-heterocyclic carbenes (NHCs) catalyzed cycloaddition reactions are bec oming more popular as these reactions are efficient methods for carbo - and hete rocycl es synthesis. Generally , these organocatalytic cycloaddit ion reactions proceed via a zwitterion -oriented strategy depicted in Scheme I -27, in which the addition of a nucleophilic organocatalyst Scheme I-26. An example of intramolecular Rauhut -Currier reaction . CHOArONHPhOTMS Ph¥ AcOH (20 mol%) DCM, rt OHCArOup to 73% yield up to 96% ee!#&!to the electrophilic substrate generates the zwitterion intermediate . The intermediate then undergoes the addition with the second electrophilic substrate, followed by cyclization and relea se of the catalyst to provide carbo - and heterocyclic products. 97 From a mechanistic view point, it is reasonable to attribute these organocatalytic cycloaddition reactions as deviations of the Morit a-Baylis -Hillman reaction in general . As a zwitterion -oriented synthetic strategy, these reactions are more tunable with subtle change s of the catalysts, substrates or reaction conditions, which provide s a divergent synthetic route to produce a diverse set of carbo - and heterocycles .97 The influence of catalysts on the mode of the cycloaddition reaction provide s a good example to illustrate this conclusion. In organocatalytic reactions of allenoates and activated alkenes, generally, phosphine catalysts will deliver [3+2] cycloaddition reaction products, while amine catalysts will furnish [ 4+2] cycloaddition products or via an intermediate of Rauhut-Currier reaction to provide [ 4+2] cycloaddition products (see Scheme I -28). YuÕs group 98 employed DFT calculations to investigate the different behaviors of these Nucleophilicorganocatalysts (amines, phosphines, NHCs) Electrophilic substrate 1 Zwiiterionic intermediate Intermediate Electrophilic substrate 2 Carbo- and heterocyclic productScheme I-27. General mechanism of organocatalytic cycloaddition reaction . !#'!catalysts. They show that the formation of the [3+2] phosphorus ylide is exergonic, which leads to the kinetically more favored [3+2] cycloadd ition, as compared to the [4+2] Scheme I-28. General mechanism of organocatalytic cycloaddition reaction between !"#Ðunsaturated compounds and allenoate . CO2R+R1OPhosphine-catalyzed !-[3+2] cycloaddition "-[3+2] cycloaddition R1OCCO2RCO2RCOR1+"-[4+2] cycloaddition !-[4+2] cycloaddition Rauhut-Currier !OOOCO2RR1R1CO2RR1CO2RRO2CR1OAnnulation PR3CO2RR1OCR1OCNR3CO2RExergonic stable Endergonic stable Scheme I-29. The cycloaddition reaction modes affected by different LB catalysts . CO2R+LBLB = PR 3, NR3 or NHCs LBOROLBOORorE-adduct Z-adduct Phosphines R1R2X[3+2] XXCO2RR1R2PR3CO2RR2R1++X = CH-EWG (electron-deficient alkene) NTs (imine) O (ketone) Amines [4+2] [2+2] [2+2+2] R2R1OOCO2RR2R1NR3+R1 = Ph or EWG R1R2XX = O or NTs XRO2CR2R1NHCsNR3+PhCF3XOOF3CPhCO2RF3CPh+NHCs!#(!cycloaddition. However, the formation of [3+2] ammonium ylide is endergonic , which enables the [ 4+2] cycloaddition reaction. More interestingly, further DFT calculation from the same group showed NHC -allenoate intermediates are the most exergonic .99 These adducts are even more stable than the expected [2+2] cycloaddition product, instead, the thermodynamically controlled [2+2+2] annulation occur s when NHCs react as the catalyst . A summary of these three types of Lewis bases catalyz ed cycloaddition reaction s is shown in Scheme I -29. However, examples of [4+2] cycloaddition catalyzed by phosphines 100 or NHCs 101 have also been reported. Scheme I -30 shows an example of NHC -mediated [ 4+2] cycloaddition reaction. Also, even though both DMAP and DABCO are N -based catalysts, they deliver ( Z) and ( E) stereoisomers, respectively .102 More investig ations are necessary to further understan d the underpinnings of the Lewis base catalyzed cycloaddition reactions. Scheme I-30. NHC -catalyzed [4+2] cycloaddition reaction of allenoate and chalcones . 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S51;2F SL2<;C!R;/0>1?3!?B!L22;3?/>;!_1>:!8:/20?3;O!GE3>:;F1F!?B![?2EFNaF>1>N>;;6! ?1$%,"3'1B'*%+",-.'45&2-6#%7' !"'#$!P8!,'-4!$$'"6 !!,"+#-!J1N4!Q6!]6I!5N4!Q6!J6I!QN4!L6!.6I!e134!56!K6I!.;3D4!c6!96!51=;CF;!FE3>:;F1F!?B!@E C/3?!#4$ Sa!13N3/a2;!J;_1F!a/F;F!0/>/2EV;1?3F6! G&#%"5&I%1,' !"'%$!>99% yield up to 98% ee ( 3 equiv )R1R2O( 1 equiv )ONONH(DHQD)-9-Phenanthryl ether CO2Bn20 mol % QN-OMe toluene, -30 ¼C, 36 hOR1R2CO2Bnup to 97% yield up to 90% ee ( 2 equiv )R1R2O( 1 equiv )CNNCNOONO10 mol % cat. ether, rt, 48 h OR2O2CR1O( 1.5 equiv )R2O2CR1O( 1 equiv )( R 1 and R2 = aryl or alkyl ) 24 examplesup to >95% yield 97-99.5% ee NHOCF3CF3HNOPPh2OTBDPS TBSO CO2R220 mol % cat. CH3CN, rt, 24 h OPR1CO2R2up to 93% yield up to 96% ee ( 1. 2 equiv )PR1O( 1 equiv )OR3OOR3OR3OOR3ONONH!%&!synthesis of substituted dihydropyrans. 14 As shown in Scheme II -2, when allenoate II-2 was utilized as the primary electrophile, two possible zwitterions could be formed in an equilibrium . These intermediates could follow two paths to yield different products Ñthe Rauhut Currier product and the formal [4+2] cycloadduct. As reported, proton transfer is the rate determining step associated with the Baylis -Hillman reaction (path A, II-2d !!II-CO2EtR3NII-2 NR3OOEt electrostatically favored amine catalyst allenoateR1OR3NCO2EtR1R2OH(!-attack) NR3proton transfer (slow) Baylis-Hillman product CO2EtR3N!R1R2O(" -attack) EtO ONR3OR1R2Path A Path B EtO ONR3OR1R2OR1R2OOEt R3NCO2EtR3NCO2EtR3NR3NCO2EtR1R2OE1cB R1R2ONR3OEtO OOEt Formal [4+2] cycloadduct II-2a II-2b II-2c II-2b II-2c II-3 reactive canonical forms II-2d II-2e II-2f II-2g 154II-1 II-1 "R2OR2CO2EtOR2CO2EtR1EWG R3R1CO2EtR1R2OHII-4 II-3 II-2 II-1 Diels- Alder modified Baylis-Hillman 45Scheme I I-2. Top: Retrosynthetic strategy for the synthesis of hexahydro -2H-chr omenes. Bottom: Path A and B represent a simplified mechanistic picture of the canonical vs. the modified Morita -Baylis -Hillman pathway. Possible resonance structures of the amine -allenoate adduct are shown in dashed box with II-2a being the major contribu tor. !%'!2e).16,17 We planned to circumvent path A by utilizing acyclic enones/dienones II-1 as secondary electrophiles , as well as using aprotic solvent or neat reaction condition s. Under t hese condition s, t he relatively fast intramolecular trapping of the oxyanion II-2f, siphon s the reaction towards formation of the corresponding dihydropyran II-3 in high yields and enantioselectivity, via path B (the modified Morita -Baylis -Hillman route). The sequence of events highlighted in path B is akin to the Mor ita-Baylis -Hillman reaction (thus referred to as the modified MBH) that has been interrupted with an intramolecular cyclization, pri or to the elimination of the amine cataly st, which regenerates the olefin . To generate the required diene II-3 for the 2 nd cycloaddition ÑDiels-Alder reaction, we designed a similar transformation initiated with a symmetric dienone (such as II-1 in Scheme I I-2). Furthermor e, we surmised that the enantio enriched C4 substituent in II-3, would serve as a stereo -chemical driver of the subsequent [4+2] cycloaddition reaction. The conjugated diene motif in II-3 displays a unique integration of two key features: a) the extended cross -conjugation of the pyranyl oxygen atom (O1) results in an electronic bias that may allow regioselective trapping of a n unsymmetrically substituted dienophile; b) the nucleophilic carbon (C5) and the stereo -chemical driver (C4 substituent), both being part of a conformationally rigid cyclic framework, may allow an easy access to the diastereo selective [4+2] cycloaddition reaction. II-2. Preliminary results from model reactions The aforementioned hypotheses w ere readily examined by simply subjecting a model dienone, dibenzalacetone II-1a, to the organocatalytic asymmetric formal [4+2] cycloaddition reaction under already optimized set of conditions (see Scheme II -3). In the !%(!previous report, we demonstrated that catalysts A and B were the optimum for the formal [4+2] cycloaddition, delivering both enantiomers. In the model reaction, catalysts A and B delivered oxa -triene II-3a-(S) and II-3a-(R), respectively. Using catalyst A under neat reaction conditions, oxa -triene II-3a-(S) was obtained in 98% yield and 98% ee. A consequent treatment of this oxa -triene with maleic anhydride II-4a furnished the stereo -pentad II-5aa as a single diastereomer in 78% yield. This offers an alternative approach, compar ed to previous methodologies, 18-26 directed towards controlling ste reoselectivity in cycloaddition reactions of dienes bearing an allylic chiral center. 27-29 Scheme I I-3. Preliminary results for consecutive [4+2] cycloaddition reactions under optimized conditions using dibenzalacetone ( II-1a) as a model substrate. aIsolated yields. bRatios were determined by HPLC analysis. cReaction was performed using 1 g ( 4.3 mmol) of II-1a. ONONH(A) DHQPHN OOOONNOONHN(B) (DHQ) 2AQN OPhCO2EtPhII-5aa toluene (0.1M) 110 ¼C, 2-3 h, 78%CO2Et10 mol% catalyst , rt, 48 h dibenzalacetone II-1a (1.0 equiv) II-2 (2.0 equiv) catalyst product yield a% eeb(A) II-3a -(S)98%c98(B) II-3a -(R)74%87*OPhCO2EtPhOOOHOOO(1.5 equiv) II-4a OPhCO2EtPh98% ee>98:2 drII-3a -(S)II-3a -(R) or ( S)******single isomer by 1H NMR !%"! II-3. Results and discussion . Encouraged by the preliminary results, we planned to explore this consecutive [4+2] cycloaddition further. However, intrigued by the levels of stereoinducti on, we decided to employ quantum chemical computational analysis of the transition states (TS) at the B3LYP/6 -31G*/SM8 (toluene) level of t heory to probe the origins of stereoselectivity , especially in the substrate -controlled Diels -Alder reaction step .30-34 To reduce the computational expense, we used hydroquinidine (QD) instead of catalyst A for our calculation. In agreement with the earlier discoveries ,14 the diastereomeric tr ansition state of the formal [4+2] cycloaddition : TS -1 ( Figure II -1a) that leads to the formation of product II-3a-(S), was favored by 2.7 kcal/mol (corresponding to er = 99:1) over TS -2. The steric congestion (gauche interactions as highlighted by bonds in red color) and the diminished electrostatic stabilization (as determined by the distance of C=O !"ááá!+NR4) in TS -2, make it energetically less favorable than TS -1. The computational an alysis corroborates the experimental results in the initial formal [4+2] cycloaddition (98% ee using the catalyst A, see II-4. experimental for details). Next, we examined the stereoinduction associated with the Diels -Alder reaction of the model reaction between substrate II-3a-(S) with maleic anhydride II-4a. In line with the experimentally observed endo -selectivity, 22,35 TS-3endo was found to be m ore favored than TS -4exo by 2.8 kcal/mol ( Figure II -1b). TS-4exo also suffers from the electrostatic repulsion between the electron density on the proximal carbonyl of II-4a and the "Ðcloud of the C4 phenyl substituent in II-3a-(S) (see II-4. Experimental for details). Furthermore, !%%!the corresponding TS -5endo involved in the approa ch of dienophile II-4a from the sterically HHNHONOOHHORe face attack on dibenzalacetone yields the ( S)-enantiomer of II-3a Si face attack on dibenzalacetone yields the ( R)-enantiomer of II-3a TS-1 TS-2 NOHNOOHHHOHOOààCONR4!-!+= 3.4 † CONR4!-!+= 4.1 † II-3a -(S)II-4a àTS-3 (endo) 2.0 †2.6 †II-5aa TS-4 (exo) 2.0 †2.4 †TS-5 (endo) 2.1 †2.6 †OPhEtO 2CPhOOOa.b.""H(rel) = 0.0 kcal/mol ""H(rel) = 2.8 kcal/mol ""H(rel) = 1.8 kcal/mol ""H(rel) = 0.0 kcal/mol ""H(rel) = 2.7 kcal/mol HFigure II-1. a. Two diastereomeric transition states TS -1 and TS -2 calculated at the B2LYP/6 -31G*/SM8 (toluene) level of theory. The bonds highlighted in red color depict the unfavorable gauche interactions in TS -2. b. Three possible transition states associated with the [4+2] cycloaddition of II-3a-(S) and II-4a. TS -3(endo) is favored by 2.8 kcal/mol over TS -4(exo) and by 1.8 kcal/mol over TS -5(endo) . The fourth possible TS involving an exo approach of II-4a from the same face as the C4 -Ph substituent cannot be calculated due to severe steric clash between the approach dienophile and the aromatic ring. !%)!hindered face of the diene is disfavored by 1.8 kcal/mol over TS -3endo (check dashed box in Figure II -1b). Although the B3LYP/6 -31G* level of the theory underestimate s the energetics of secondary interactions in the Diels -Alder reaction, 36,37 it clearly depicts the correct energetic trend as o bserved experimentally . An exhaustive analysis at the MP2 level of theory can be attempted (requires longer time and higher computational expense) to capture the pr ecise energetics in the Diels -Alder reaction, however, our approach utilizes the B3LYP/6 -31G* analysis to map the reaction pathway and compare s the relative energies of the transition states involved at a relatively low computational expense . Overall, the stereochemical driver of the C4 substituent, obtained from the initial formal [4+2] cycloaddition, perfectly governs the stereospecificity in the concomitant Diels-Alder reaction. To explore the scope of this consecutive [4+2]/[4+2] cycloaddition reaction , we decided to focus on each step separately. For the scope of the 1 st formal [4+2] cycloaddition reaction, a series of substituted dienones ( II-1a Ð II-1p) were screened with allenoate II-2 under the optimized reaction condition (see Table II -1). To access both enantiomers of the corresponding dihydropyrans II-3a Ð II-3p, both catalyst A and B (see Scheme II -2) were employed in this reaction. Similar to previous observations, 14 catalyst A displayed better results than catalyst B with regards to both efficiency and stereoinduction. Regardless of the electro nic properties of the attached substituents on the aryl substrate, electron donating groups (entries II-2 Ð II-6 and II-13), electron withdrawing groups (entries II-7 Ð II-12), and even aliphatic substituents (entries II-14 Ð !%+!II-16) showed excellent enantioinductions by using catalyst A for the reaction. The X-ray crystal structures of derivatives of II-3b-(S) and II-3j-(S) provided unequivocal evidence entry R cat. product time (h) %yielda %eeb 1 Ph A II-3a-S 40 98c 98 B II-3a-R 8 74 87 2 o-OMe -C6H4 A II-3b-S 60 60d 90 B II-3b-R 60 65d 82 3 m-OMe -C6H4 A II-3c-S 12 98 96 B II-3c-R 12 87 88 4 p-OMe -C6H4 A II-3d-S 60 25d 94 B II-3d-R 60 20d 76 5 o-Me-C6H4 A II-3e-S 40 75 88 B II-3e-R 10 68 82 6 p-Me-C6H4 A II-3f-S 60 43d 94 B II-3f-R 60 57d 72 7 o-F-C6H4 A II-3g-S 48 78 92 B II-3g-R 48 71 88 Table II -1. Substrate scope for the enantioselective synthesis of substituted oxa -trienes !!%,! entry R cat. product time (h) %yielda %eeb 8 o-Br-C6H4 A II-3h-S 30 95 88 B II-3h-R 30 95 78 9 p-Br-C6H4 A II-3i-S 40 66 94 B II-3i-R 40 32 72 10 o-Cl-C6H4 A II-3j-S 25 99e 90 B II-3j-R 25 89 84 11 p-Cl-C6H4 A II-3k-S 48 58 91 B II-3k-R 48 36 88 12 2-furyl A II-3l-S 48 27 95 B II-3l-R 48 32 78 13 1-naphthyl A II-3m-S 40 76 92 B II-3m-R 40 69 72 14 n-propyl A II-3n-S 72 28 (52) d,f 90 B II-3n-R 72 24 (50) d,f 67 15 isopropyl A II-3o-S 72 29 (87) d,f 94 B II-3o-R 72 23 (80) d,f 58 16 Me A II-3p-S 36 48 90 B II-3p-R 36 26 72 [a] Isolated yields. [b] Ratios were determined by HPLC analysis using chiral stationary phase columns. [c] Reactions was performed on a 1 g scale of II-1a. [d] Longer reaction times led to degradation of allenoate II-2 and incomplete conversion of dienones was observed. [e] Reaction was performed on a 0.5 g scale of II-1j. [f] Numbers in parentheses refer to yield based on recovered starting material. Table II-1. (contÕd) !!%#!for the absolute stereochemistry of the products obtained using catalyst A (see Scheme II-4, dashed box). These results also further confirmed the quantum chemical computational analysis (see Figure II -1a) that revealed both the absence of gauche interaction ( steric ) and the stronger electrostatic stabilization in TS -1 is responsible for favoring the ( S)-enantiomer. We have also explored the formal [4+2] cycloaddition reaction with unsymmetrically substituted dienones. Table II-2 summarizes the results of all four substrates with both catalysts . Although the resulting products were obtained with modest regio selectivity of entry R1 R2 cat. %yielda II-3 / II-3Õb 1 p-Br-C6H4 p-OMe -C6H4 A 48 2:3 B 19 2:3 2 p-Cl-C6H4 p-OMe -C6H4 A 19 2:3 B nd 2:3 3 Ph Cy A 54 3:5 B 46 3:5 4 Ph t-Bu A 50 1:10 B 31 1:10 Table II -2. Substrate scope for the formal [4+2] cycloaddition of allenoate with asymmetric cross -conjugated oxa -trienes ![a] Isolated yields. [b] Ratios were determined by 1H NMR after purified by column. nd = not determined. !%$!2:3 (entries 1 and 2) to good regio selectivity 1:10 (entry 4) , they were inseparable by ORRCO2EtII-3a-c, II-3j CNCNNCNCOOONOCNDienophilesII-4a II-4b II-4c II-4d ORCO2EtRXYEWG XYEWG R2R2HORRCO2EtHOOOORRCO2EtHCNNCNCNCII-5 ORRCO2EtONHPhOPhPhCO2EtHNCR = Ph: II-5aa , 84%d (78%) e = o-OMe-C 6H4: II-5ba , 32%d = o-Cl-C 6H4: II-5ja , 58%d>98% drbR = Ph: II-5ab , 98%d (92%) e = o-OMe-C 6H4: II-5bb , 87%d = o-Cl-C 6H4: II-5jb , 86%d>98% drbR = Ph: II-5ac , 77%d = o-OMe-C 6H4: II-5bc , 75%d = m-OMe-C 6H4: II-5cc , 76%d = o-Cl-C 6H4: II-5jc , 80%d>98% drb, >98% rs cconditions aII-5ba II-5ja X-ray crystal structures (3.0 equiv) (4S)(4S)OPhPhCO2EtHNCII-6ad, 41%d>98% drb, >98% rsc0.1 equiv DBU 0.5 equiv Py II-5ad 467DCM, reflux 12 hScheme II -4. Diels -Alder reaction of substituted oxa -trienes ( II-3a-c, II-3j) with illustrative dienophiles ( II-4a-d). [a] Diels -Alder reaction conditions for each dienophile is as follows: dienophile II-4a: 0.1 M in toluene, reflux, 2 -16 h. Dienophile II-4b: 0.1 M in toluene, reflux, 2 h. Dienophile II-4c: 0.1 M in EtOH/DCM (1:1), 0 ¼C -rt, 12 h. Dienophile II-4d: 0.1 M in toluene, reflux, 12 h. [b] Diastereomeric ratios ( dr) were determined by 1H NMR analysis of the crude reaction mixture. [c] Regioselectivity ( rs) and relative stereochemistry was determined via NMR analysis of the purified product. [d] Isolated yields. [e] Isolated yield for Ôone potÕ consecutive transformations from II-1a as a starting material. !)&!analytical techniques to evaluate the stereoinduction . As shown in Table II-2, both electronic properties of the substitution on the aryl substrates and the steric congestion of the substitutions play a role in guiding the selectivity. In general , a. the products are formed in favor of the electron -withdrawing substitution side ; b. the formal [4+2] cycloaddition reaction prefers the less bulky substituents . As a proof -of-principle, we next explored the ability of these dihydropyrans to control the facial -, regio - and stereoinduction of the Diels -Alder reaction. A summary of the results of 11 cycloaddition reactions between either II-3a-(S), II-3b-(S), II-3c-(S) or II-3j-(S) and an illustrative set of dienophiles II-4a Ð II-4d is shown in Scheme II -4. Dienophiles II-4a and II-4b displayed exclusive diastereoselective addition, while dienophiles II-4c and II-4d not only displayed this good diastereos electivity, but also exhibited excellent regioselection. Furthermore, these sequential transformations (the formal [4+2] cycloaddition reaction followed by the concomitant Diels -Alder reaction) were also performed efficiently as a Ôone potÕ Domino reaction (see Scheme II -4, products II-5aa and II-5ab). As anticipated, the cross -conjugation of the endocyclic oxygen (O1) not only enhances the HOMO energy of the diene motif in II-3, but also generates an electronic bias that allows regio -specific trapping of t he dienophiles II-4c and II-4d, thus validating the initial hypothesis. One interesting observation is the reaction between II-3a and II-4d, which furnish the formation of an isomeric mixture of products II-5ad and II-6ad in nearly equimolar ratios. Fortuitously, upon treatment with DBU in refluxing DCM, the mixture was cleanly converted to yield the endocyclic product II-6ad in high regio - and diastereoselectivity. Unlike the other Diels -Alder reaction products depicted i n Scheme !)'!II-4, the adduct II-6ad (and for that matter II-5ad) is the result of an exo [4+2] cycloaddition reaction (see II-4. experimental for details of the stereochemical assignment based on NMR studies). Although we see no evidence of the endo product during the course of the reaction, we cannot exclude the possibility of either epimerization at C6 or a reversible Diels-Alder process that ultimately settles for the thermodynamic product. NII-2 quinuclidine CNOEtO II-2 NCO2EtOOEt II-2 II-2 /CII-2 2/CII-2 3/CII-1a NCO2EtPhOPhII-2 polymeric adducts (C)irreversible [4+2] adduct II-1a NCO2EtCO2EtPhOPhII-1a -II-2 /CII-1a -II-2 2/C306090% relative intensity 0100200300400500m/z 112.1123 224.1647[C+H] +[II-2 /C + H] +[II-2 2/C + H] +336.2175[II-2 3/C + H] +448.2698C + II-2 (1:2) a.b.C + II-2 + II-1a (1:2:2) c.306090% relative intensity 0100200300400500m/z 112.1123 [C+H] +[II-2 /C + H] +224.1647[II-3a + H] +347.1627[II-2 3/C + H] +448.2679[II-1a -II-2 /C + H] +458.2654[II-1a -II-2 2/C + H] +570.3079OPhCO2EtPhII-3a Figure II -2. a. An equilibrium mixture of putative intermediates in the Morita -Baylis -Hillman reaction of II-1a and II-2. For simplicity, intermediates arising only from the !Ðattack of the enolate are shown. b. ESI -MS spectrum of a reaction mixture (pre -incubated for 30 min) constituting of a 1:2 ratio of quinuclidine ( C) and allenoate II-2. c. ESI -MS spectrum obtained after 1 h upon addition of II-1a to the mixture of ( C) and II-2. !)(!The mechanistic nuances underpinning the formal [4+2] cycloaddition reaction of allenoate ( the primary electrophile) with dibenz alacetone (the secondary electrophile) are more complex than the simplified picture depicted in Scheme II -2, leading to the following central question. Despite the possibility for the formation of several theoretic al adducts (based on the relative reactivity of the primary and the secondary electrophile), which factor governs the formation of II-3 as the predominant product? To address this question, ESI-MS was utilized to investigate the identity of stable in termediates that arise during the reaction between II-1a and II-2 with the catalyst of quinuclidine C (an achiral surrogate of catalysts A and B) (see Figure II -2). Upon the nucleophilic attack of the Lewis base C on allenoate II-2, the zwitterionic intermediate II-2/C will be generated. Th e resulting enolate can attack another allenoate II-2 to furnish the intermediate II-22/C. Sequential additions of II-2 will yield the trimeric adduct II-23/C and high oligomers that constitute several polymer ic adducts in equilibrium. These key intermediates were directly intercepted by ESI -MS spectrometry analysis of a pre -incubated mixture of C and II-2 (see Figure II -2b). When this mixture was treated with the secondary electrophile II-1a, intermediates 1a-2/C en route to product II-3a and higher order adduct 1a-22/C were observed (see Figure II -2c). The final ESI -MS spectrum displayed the same peaks regardless of the order of addition of II-1a, II-2 and C. MS spectra obtained at longer time points depict the anticipated difference in relative intensities of the intermediates as the reaction progress to yield more product. Furthermore, for simplicity, Figure II -2 depicts adducts that arise only from #Ðattack of the allenoate whereas, the actual mixture may comprise equilibrating intermediates formed via # and $ attack. This study suggests that !)"!the reaction of II-1a, II-2 and C directly furnished a mixture of several adducts in equilibrium. However, the irreversibility associated with the ring closure step (see dashed box, Figure II -2a), adventitiously siphons the equilibrium mixture to the desir ed cycloadduct II-3a. In summary, a two -step process is developed for the efficiency synthesis of hexahydro -2H-chromenes in high stereoselectivity. The asymmetric formal [4+2] cycloaddition reaction provides the dihydropyrans in high stereoselectivity, whi ch will react as a diene in the concomitant Diels -Alder reaction. The ensuing Diels -Alder reaction is also under strict regio - and stereochemcial control. The C4 stereocenter of the dihydropyran, established during the initial [4+2] cycloaddition, is the s tereochemical driver, whereas the cross -conjugation of pyranyl oxygen (O1) aids to generate an electronic bias for the observed regioselectivity in the Diels -Alder rea ction. This methodology provides a complementary approach to control the stereochemistry in Diels -Alder reactions of chiral dienes, 19,23,25,26 unlocking opportunities towards expanding the repertoire of regio - and stereoselective reactions of chiral dienes. !)%!II-4. Experimental. II-4.1. General remarks: All reactions were carried out in flame dried or oven dried glassware under in ert gas atmosphere or in a desiccator. Unless specifi ed, the reagents were purchased from commercial sources. THF and diethyl ether were distilled from sodium b enzophenone ketyl. Methylene chloride, toluene and triethylamine were dried over CaH 2 and freshly distilled prior to use. Ethyl -2,3-butadienoate was synthesized as reported 38 and stored at -20 ¼C. Column chromatography was performed using Silicycle 60 †, 35 -75 #m silica gel. Thin layer chromatography was performed using 0.2 mm thickness silica gel 60 F254 plates and visualized using UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. 1H NMR and 13C NMR, as well as all the 2D NMR spectra, were obtained using a 500 MHz Varian NMR spectrometer and referenced using the residual 1H peak from the deuterated solvent . For HRMS (ESI) analysis, a Waters 2795 (Alliance HT) instrument was used and referenced against Polyethylene Glycol (PEG -400-600). Infrared spectra were reported on a Nicolet IR/42 spectrometer FT -IR (thin film, NaCl cells). Optical rotations were obtained on a Jasco P -2000 polarimeter at 20 ¡C and 589 nm. T he specific rotations were calculated according to the equation [ $]20D = (100 $)/( l $ c), where l is the path length in decimeters and c is the concentration in g/100mL. !))!II-4.2. General procedure for formal [4+2] cycloaddition of ethyl -2,3-butadienoate with substituted dienones: A mixture of ethyl -2,3-butadienoate (2.0 equiv ) and the corresponding dienone (1.0 equiv) with 10 mol% chiral amine cataly sts (A or B) was charged in a 1 dram vial and stirred at room temperature. (Note: The order of addition did not make any difference to the selectivity or the yield. ) Most importantly, the efficiency of stirring this neat reaction is highly crucial for opti mum yields. The progress of the reaction w as monitored by TLC. When the dienone was consumed completely, usually around 8 -72 h, the reaction mixture was diluted with 100-200 µL of DCM or ethyl acetate and directly purified by silica gel column chromatography using ethyl acetate and hexane s as eluents. II-3a-S: Ethyl ( E)-2-((S)-4-phenyl-6-((E)-styryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (956.0 mg, 8.5 mmol) and II-1a (1.0 g, 4.3 mmol) , 1.45 g ( 98% yield) of the pure product was isolated as a white solid , m.p 85 ¡C; 1H NMR (500 MHz, CDCl 3) ! 7.43 -7.47 (2H, m), 7.30 -7.38 (4H, m), 7.22 -7.29 (4H, m ), 6.98 (1H, ORCO2EtRCO2EtRRO(2-5 equiv) (1 equiv) II-1a -pII-2 II-3a -p(R or S)*10 mol % catalyst neat, rt OCO2EtPhPhII-3a- S!)+!d, J = 16.0 Hz), 6.53 (1H, d, J = 16.0 Hz ), 5.71 (1H, s ), 5,36 (1H, d, J = 4.0 Hz), 4.07-4.18 (2H, m), 3.68 -3.75 (2H, m), 3.08 -3.16 (1H, m ), 1.25 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.3, 166.1, 148.6, 143.0, 136.4, 128.7, 128.7, 128.6, 128.0, 127.3, 127.0, 126.7, 121.4, 108.5, 99.4, 59.6, 36.2, 31.0, 14.3 ppm ; IR (film) 3028, 2980, 1708 (s), 1657 (s), 1278, 1118 (s), 691 cm -1. HRMS (ESI) Calculated Mass for C 23H23O3: 347.1647 ([M+H] +), Found 347.1640 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ-H column (5% isopropanol in n-hexanes at 1.0 mL/min), R t = 48.9 min (minor) and 54.3 min (major), II-3a-S (98% ee): [%]20D= -137 (c = 2.00, CDCl 3). II-3b-S: Ethyl ( E)-2-((S)-4-(2-methoxyphenyl) -6-((E)-2-methoxystyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20 .0 mg, 0.18 mmol) and II-1b (26.5 mg, 0.09 mmol) , 21.9 mg ( 60% yield) of the pure product was isolated as a pale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.47 (1H, dd, J = 9.0 Hz, 2.0 Hz) , 7.15-7.30 (4H, m), 6.85-6.98 (4H, m ), 6.60 (1H, d, J = 16.0 Hz ), 5.70 (1H, s ), 5. 31 (1H, d, J = 4.5 Hz), 4.06 -4.16 (3 H, m ), 3.89 (3H, s), 3.86 (3H, s ), 3.51 (1H, dd, J = 16.0 Hz, 6.5 Hz), 3.27 (1H, dd, J = 15.0 Hz, 7.0 Hz), 1.24 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDC l3) ! 167.4, 167.0, 157.1, 156.8 , 149.2, 130.9, 129.0, 127.9, 127.7, 127.0, 125.6, 123.2, 122.3, 120.7, 120.6, 110.9, 110.4, 108.1, 99.1, 59.5, 55.4, 29.7, 29.3, 14.3 ppm; IR (film) 3078, OCO2EtII-3b- SOMe OMe !),!2933, 2838, 1708 (s), 1656 (s), 1598, 1498 (s), 1244 (s), 1118 (s), 752 cm -1. HRMS (ESI) Calculated Mass for C 25H27O5: 407.1858 ([M+H] +), Found 407.1850 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (20% isopropanol in n-hexanes at 1.0 mL/min) , R t = 19.5 min (minor) and 40.2 min (major), II-3b-S (90% ee): [ %]20D= -52 (c = 1.92, CDCl 3). II-3c-S:!Ethyl ( E)-2-((S)-4-(3-methoxyphenyl) -6-((E)-3-methoxystyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1c (26.5 mg, 0.09 mmol) , 35.9 mg ( 98% yield) of the pure product was isolated as a colorless oil; 1H NMR (500 MHz, CDCl 3) ! 7.19 -7.25 (2H, m), 7.01 -7.06 (1 H, m ), 6.90 -6.97 (2 H, m ), 6.75-6.85 (4H, m ), 6.49 (1H, d, J = 15.5 Hz), 5.69 (1H, s ), 5,33 (1H, d, J = 3.5 Hz), 4.07 -4.15 (2 H, m ), 3.82 (3H, s ), 3.78 (3H, s ), 3.63 -3.72 (2H, m), 3.06 -3.14 (1H, m), 1.24 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.3, 166.1, 159.8, 159.8, 148.5, 144.6, 137.9, 129.7, 129.6 , 128.6, 121.7, 119.7, 119.3, 113.7, 113.0, 112.2, 111.9, 108.6, 99.4, 59.6, 55.2, 55.2, 36.2, 30.8, 14.3 ppm; IR (film) 3052, 2937, 2837, 1707 (s), 1656 (s), 1600 (s), 1488 (s), 1272 (s), 1120 (s), 1048 (s) cm -1. HRMS (ESI) Calculated Mass for C 25H27O5: 407.1858 ([M+H] +), Found 407.1855 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column OCO2EtII-3c- SOMe MeO !)#!(25% isopropanol in n-hexanes at 1.0 mL/min) , R t = 43.4 min (minor) and 55.9 min (major), II-3c-S (96% ee): [ %]20D= -118 (c = 3.59, CDCl 3). II-3d-S: Ethyl ( E)-2-((S)-4-(4-methoxyphenyl) -6-((E)-4-methoxystyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1d (26.5 mg, 0.09 mmol) , 9.1 mg ( 25% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.37 -7.40 (2H, m ), 7.14 -7.18 (2H, m), 6.92 (1H, d, J = 16.0 Hz), 6.83 -6.90 (4H, m ), 6.39 (1H, d, J = 16.0 Hz), 5.68 (1H, s ), 5,28 (1H, d, J = 4.5 Hz), 4.08 -4.16 (2H, m ), 3.83 (3H, s ), 3.79 (3H, s ), 3.60 -3.68 (2H, m ), 3.08 -3.15 (1H, m), 1.25 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.4, 166.4, 159.6, 158.4, 148.6, 135.2, 129.2, 128.3, 128.1, 128.0, 119.3, 114.1, 114.0, 107.8, 99.2, 59.6, 55.3, 55.3, 35.3, 31.2, 14.3 ppm; IR (film) 2930, 2837, 1708 (s), 1656 (s), 1663 (s), 1512 (s), 1251 (s), 1176 (s), 1118 (s), 1037 (s) cm -1. HRMS (ESI) Calculated Mass for C 25H27O5: 407.1858 ([M+H] +), Found 407.1847 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (1% isopropanol in n-hexanes at 1.2 mL/min) , R t = 58.0 min (minor) and 68.7 min (major), II-3d-S (94% ee): [%]20D= -113 (c = 0.90, CDCl 3). OCO2EtII-3d- SOMe MeO !)$! II-3e-S: Ethyl ( E)-2-((S)-6-((E)-2-methylstyryl) -4-(o-tolyl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1e (23.6 mg, 0.09 mmol) , 25.3 mg ( 75% yield) of the pure product was isolated as a c olorless oil; 1H NMR (500 MHz, CDCl 3) ! 7.48 -7.54 (1 H, m ), 7.13 -7.24 (8 H, m ), 6.46 (1H, d, J = 16.0 Hz), 5.72 (1H, s ), 5 .32 (1H, d, J = 4.0 Hz), 4.09 -4.16 (2H, m ), 3.91-3.96 (1H, m ), 3.78 (1H, dd, J = 15.0 Hz, 6.5 Hz), 2.98 (1H, dd, J = 15.0 Hz, 8.5 Hz), 2.42 (3H, s ), 2.41 (3H, s ), 1.25 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 167.3,166.3, 149.2, 140.9, 136.2, 135.5, 135.4, 130.6, 130.5, 127.9, 126.8, 126.6, 126.4, 126.2, 126.0, 125.2, 122.5, 108.7, 99.3, 59.6, 32.4, 29.7, 19.8, 19.3, 14.3 ppm; IR (film) 3020, 2927, 1709 (s), 1656 (s), 1461, 1254, 1118 (s), 1049 (s) 802 , 753 cm -1. HRMS (ESI) Calculated Mass for C25H27O3: 375.1960 ([M+H] +), Found 375.1966 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% isopropanol in n-hexanes at 1.0 mL/min) , R t = 16.7 min (minor) and 33.0 min (major), II-3e-S (88% ee): [ %]20D= -78 (c = 0.81, CDCl 3). OCO2EtII-3e- S!+&! II-3f-S: Ethyl ( E)-2-((S)-6-((E)-4-methylstyryl) -4-(p-tolyl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol% catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1f (23.6 mg, 0.09 mmol) , 14.5 mg ( 43% yield) of the pure product was isolated as a c olorless oil; 1H NMR (500 MHz, CDCl 3) ! 7.32 -7.37 (2 H, m ), 7.12 -7.17 (6 H, m ), 6.94 (1H, d, J = 16.5 Hz), 6.47 (1H, d, J = 16.0 Hz), 5.69 (1H, s ), 5,34 (1H, d, J = 3.0 Hz), 4.08-4.16 (2H, m ), 3.64-3.72 (2 H, m ), 3.04-3.13 (1H, m ), 2.35 (3H, s ), 2.33 (3H, s ), 1.25 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.4, 166.4, 148.6, 140.0, 138.0, 136.4, 133.7, 129.4, 129.3, 128.5, 127.2, 126.6, 120.5, 108.3, 99.2, 59.6, 35.8, 31.1, 21.3 , 14.3 ppm; IR (film) 3022, 2923, 2856, 1708 (s), 1656 (s), 1636 (s), 1513, 1276, 1117 (s), 1048, 810 cm-1. HRMS (ESI) Calculated Mass for C 25H27O3: 375.1960 ([M+H] +), Found 375.1951 ([M+H] +). The enantiomeric excess was deter mined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (8% isopropanol in n-hexanes at 0.3 mL/min) , R t = 97.8 min (minor) and 166.4 min (major), II-3e-S (88% ee): [ %]20D= -138 (c = 0.71, CDCl 3). OCO2EtII-3f- SOCO2EtII-3g- SFF!+'!II-3g-S: Ethyl ( E)-2-((S)-4-(2-fluorophenyl) -6-((E)-2-fluorostyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol% catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1g (24.3 mg, 0.09 mmol) , 26.8 mg ( 78% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.45 -7.52 (1 H, m ), 7.19 -7.25 (3 H, m ), 7.02-7.15 (5H, m ), 6.63 (1H, d, J = 16.0 Hz), 5.73 (1H, s ), 5,35 (1H, d, J = 4.0 Hz), 4.05 -4.17 (3 H, m), 3.56 (1H, dd, J = 15.5 Hz, 6.5 Hz), 3.34 (1H, dd, J = 15.5 Hz, 7.5 Hz), 1.25 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.1, 165.5 , 160.6 (d, 1JC,F = 260.75 Hz ), 160.5 (d, 1JC,F = 233.6 Hz ), 149.0, 129.4 (d, 2JC,F = 13.6 Hz ), 129.3 (d, 3JC,F = 8.8 Hz ), 128.5 (d, 3JC,F = 5.8 Hz ), 128.5, 127.7 (d, 3JC,F = 3.9 Hz ), 124.3, 124.2 (d, 3JC,F = 8.8 Hz ), 124.2, 123.7 (d, 3JC,F = 5.9 Hz ), 121.4 (d, 3JC,F = 3.9 Hz ), 115.9 (d, 2JC,F = 22.4 Hz ), 115.4 (d, 2JC,F = 22.4 Hz ), 107.7, 99.9, 59.7, 29.2, 29.1, 14.2 ppm; 19F NMR (470 MHz, CDCl 3) ! -116.8Ñ-117.9 (1F, m.), -118.6Ñ-118.8 (1F, m.) ppm; IR (film) 3066, 2928, 2863, 1708 (s), 1657 (s), 1583, 1488 (s), 1456, 1269.0, 1231, 1124 (s), 1047, 755 cm -1. HRMS (ESI) Calculated Mass for C 23H21F2O3: 383.1459 ([M+H] +), Found 383.1473 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% i sopropanol in n-hexanes at 1.0 mL/min) , R t = 15.8 min (minor) and 19.9 min (major), II-3g-S (92% ee): [ %]20D= -130 (c = 1.14, CDCl 3). OCO2EtII-3h- SBrBr!+(!II-3h-S: Ethyl ( E)-2-((S)-4-(2-bromophenyl)-6-((E)-2-bromostyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1h (35. 3 mg, 0.09 mmol) , 43.1 mg ( 95% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.54 -7.61 (3H, m ), 7.35 (1H, d, J = 16.0 Hz), 7.26 -7.31 (2H, m), 7.21 -7.25 (1H, m), 7.08 -7.15 (2H, m ), 6.48 (1H, d, J = 16.0 Hz), 5.75 (1H, s), 5,37 (1H, d, J = 4.5 Hz), 4.17-4.23 (1H, m ), 4.06 -4.17 (2H, m ), 3.58 (1H, dd, J = 15.5 Hz, 6.5 Hz ), 3.30 (1H, dd, J = 15.0 Hz , 6.5 Hz ), 1.24 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.0, 165.1, 149.1, 141.3, 136.2, 133.2, 133.0, 129.2, 128.5, 128.5, 127.8, 127.6, 127.6, 126.6, 124.4, 124.1, 123.8, 108.0, 100.3, 59.7, 35.5, 29.0, 14.3 ppm; IR (film) 3061, 2979, 2937, 1708 (s), 1658 (s), 1565, 1467, 1438, 1294, 1275, 1164, 1119 (s), 1047, 1024, 752 cm -1. HRMS (ESI) Calculated Mass for C 23H21Br2O3: 502.9857 ([M+H] +), Found 502.9856 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% iso propanol in n-hexanes at 1.0 mL/min) , R t = 20.8 min (minor) and 41.3 min (major), II-3h-S (88% ee): [ %]20D= -71 ( c = 2.57, CDCl3). II-3i-S: Ethyl ( E)-2-((S)-4-(4-bromophenyl)-6-((E)-4-bromostyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-OCO2EtII-3i- SBrBr!+"!1i (35.3 mg, 0.09 mmol) , 30.0 mg ( 66% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.40 -7.49 (4 H, m ), 7.28 -7.33 (2H, m), 7.07 -7.13 (2H, m ), 6.91 (1H, d, J = 16.0 Hz), 6.49 (1H, d, J = 16.5 Hz ), 5.70 (1H, s ), 5 .31 (1H, d, J = 4.5 Hz ), 4.07 -4.17 (2H, m ), 3.63-3.71 (1H, m ), 3.59 (1H, dd, J = 15.0 Hz, 6.0 Hz), 3.19 (1H, dd, J = 15.0 Hz, 8.0 Hz), 1.25 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.1, 16 5.3, 148.7, 141.8, 135.3, 131.8, 131.7, 129.0, 128.2, 127.7, 121.9, 121.8, 120.8, 108.1, 99.9, 59.8, 35.7, 30.6, 14.3 ppm; IR (film) 3024, 2928, 2854, 1706 (s), 1655 (s), 1587, 1489(s), 1288, 1275, 1273, 1118 (s), 1073, 1010, 814 cm -1. HRMS (ESI) Calculate d Mass for C 23H21Br2O3: 502.9857 ([M+H] +), Found 502.98 42 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OD -H column (2% isopropanol in n-hexanes at 1.2 mL/min) , R t = 13.0 min (minor) and 15.7 min (major), II-3i-S (94% ee): [ %]20D= -107 (c = 0.61, CDCl 3). II-3j-S: Ethyl ( E)-2-((S)-4-(2-chlorophenyl)-6-((E)-2-chlorostyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (369.4 mg, 3.3 mmol) and II-1j (500.0 mg, 1.6 mmol) , 0.34 g (quantitative yield) of the pure product was isolated as a pale yellow oil (0.25 gram scale reaction); 1H NMR (500 MHz, CDCl 3) ! 7.55 -7.60 (1 H, m), 7.35 -7.41 (3 H, m ), 7.16 -7.26 (5 H, m ), 6.52 (1H, d, J = 16.0 Hz ), 5.75 (1H, s ), 5 .37 (1H, d, J = 5.0 Hz), 4.19-4.27 (1 H, m ), 4.06 -4.17 (2 H, m ), 3.56 (1H, dd, J = 16.0 Hz, 6.5 OCO2EtII-3j- SClCl!+%!Hz), 3.34 (1H, dd, J = 16.0 Hz, 7.5 Hz), 1.24 (3H, t, J = 6.5 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 167.0, 165.2, 149.2, 139.7, 134.5, 133.7, 133.5, 129.9, 129.7, 128.9, 128.4, 128.2, 127.1 , 126.9, 126.5, 124.9, 123.7, 107.9, 100.2, 59.7, 32.8, 28.9, 14.2 ppm; IR (film) 3065, 2980, 2928, 2854, 1708 (s), 1658 (s), 1471, 1442, 1374, 1348, 1295, 1276, 1118 (s), 1049 (s), 755 cm -1. HRMS (ESI) Calculated Mass for C 23H21Cl2O3: 415.0868 ([M+H] +), F ound 415.0863 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (1% isopropanol in n-hexanes at 0.3 mL/min) , R t = 50.9 min (minor) and 55.1 min (major), II-3j-S (90% ee): [ %]20D= -115 ( c = 3.25, CDCl3). II-3k-S:!Ethyl ( E)-2-((S)-4-(4-chlorophenyl)-6-((E)-4-chlorostyryl) -3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1k (27.3 mg, 0.09 mmol) , 21.7 mg ( 58% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.34 -7.40 (2H, m ), 7.27 -7.33 (4H, m), 7.14 -7.19 (2H, m ), 6.93 (1H, d, J = 15.5 Hz ), 6.48 (1H, d, J = 16.0 Hz), 5.70 (1H, s ), 5 .31 (1H, d, J = 4.5 Hz), 4.06 -4.17 (2H, m ), 3.65-3.73 (1H, m ), 3.59 (1H, dd, J = 15.0 Hz, 6.5 Hz ), 3.18 (1H, dd, J = 15.0 Hz, 8.0 Hz), 1.25 (3H, t, J = 6.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.2, 165.4, 148.7, 141.3, 134.8, 133.7, 132.7, 128.9, 128.8, 128.7, 127.9, 127.7, 121.7, OCO2EtII-3k- SClCl!+)!108.1, 99.9, 59.8, 35.6, 30.7, 14.3 ppm; IR (film) 3051, 2980, 2927, 2854, 1707 (s), 1657 (s), 1491 (s), 1344, 1288, 1274, 1119 (s), 1092, 818 cm -1. HRMS (ESI) Calculated Mass for C 23H21Cl2O3: 415.0868 ([M+H] +), Found 415.0862 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRAL PAK OD -H column (1% isopropanol in n-hexanes at 1.0 mL/min) , R t = 16.8 min (minor) and 24.2 min (major), II-3k-S (91% ee): [ %]20D= -139 (c = 1.33, CDCl 3). II-3l-S: Ethyl ( E)-2-((S)-4-(furan -2-yl)-6-((E)-2-(furan -2-yl) vinyl)-3,4-dihydro-2H-pyran-2-ylidene) acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1l (19.3 mg, 0.09 mmol) , 7.9 mg ( 27% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.32 -7.40 (2 H, m ), 6.74 (1H, d, J = 15.5 Hz ), 6.38 -6.45 (2 H, m ), 6.33 -6.38 (1H, m ), 6.27 -6.30 (1H, m ), 6.07 -6.11 (1H, m), 5.76 (1H, s ), 5 .36 (1H, d, J = 4.5 Hz ), 4.11 -4.21 (2H, m ), 3.75 -3.81 (1H, m ), 3.55 (1H, dd, J = 15.0 Hz, 6.0 Hz), 3.39 (1H, dd, J = 15.5 Hz, 7.5 Hz ), 1.28 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 167.3, 165.5, 155.1, 152.4, 148.4, 142.7, 141.8, 119.5, 116.7, 111.8, 110.2, 109.9, 105.2, 105.1, 99.7, 59.7, 29.9, 27.5, 14.3 ppm; IR (film) 2960, 2927, 2858, 1708 (s), 1657 (s), 1284, 1119 (s), 734 cm -1. HRMS (ESI) Calcu lated Mass for C 19H19O5: 327.1232 ([M+H] +), Found 327.1241 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (15% isopropanol in n-OCO2EtII-3l- SOO!++!hexanes at 1.0 mL/min) , R t = 13.6 min (minor) and 21.9 min (major), II-3l-S (95% ee): [%]20D= -90 (c = 0.73, CDCl 3). II-3m-S: Ethyl ( E)-2-((S)-4-(naphthalen -1-yl)-6-((E)-2-(naphthalen -1-yl)vinyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1m (30.1 mg, 0.09 mmol) , 30.5 mg ( 76% yield) of the pure product was isolated as a p ale yellow oil; 1H NMR (500 MHz, CDCl 3) ! 8.24 (1H, d, J = 8.5 Hz ), 8.15 (1H, d, J = 8.5 Hz ), 7.76 -7.93 (5H, m ), 7.70 (1H, d, J = 7.0 Hz), 7.42 -7.62 (7H, m ), 6.65 (1H, d, J = 15.5 Hz), 5.83 (1H, s ), 5.5 2 (1H, d, J = 4.0 Hz), 4.54 -4.61 (1H, m), 4.06 -4.12 (2H, m ), 3.93 (1H, dd, J = 15.0 Hz, 5.5 Hz ), 3.37 (1H, dd, J = 15.5 Hz, 8.5 Hz ), 1.20 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.2, 166.1, 149.1, 138.2, 134.0, 134.0, 133.7, 131.3, 131.0, 129.1, 128.6, 128.4, 127.6, 126.4, 126.2, 125.9, 125.7, 125.6, 125.5, 125.5 124.3, 124.1, 123.7, 123.5, 122.8, 108.9, 99.8, 59.7, 32.0, 29.9, 14.2 ppm; IR (film) 3058, 2926, 2854, 1706 (s), 1654 (s), 1509, 1284, 1259, 1118 (s), 1049, 798, 777 cm -1. HRMS (E SI) Calculated Mass for C 31H27O5: 447.1960 ([M+H] +), Found 447.1954 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (10% isopropanol in n-hexanes at 1.0 mL/min) , R t = 10.5 min (minor) and 8.8 min (major), II-3m-S (82% ee): [ %]20D= -84 (c = 1.03, CDCl 3). OCO2EtII-3m- S!+,! II-3p-S: Ethyl ( E)-2-((S)-4-methyl -6-((E)-prop-1-en-1-yl)-3,4-dihydro-2H-pyran-2-ylidene)acetate: Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1p (9.9 mg, 0.09 mmol) , 9.6 mg ( 48% yield) of the pure product was isolated as a c olorless oil; 1H NMR (500 MHz, CDCl 3) ! 6.00 -6.08 (1 H, m ), 5.73 -5.79 (1H, m), 5.5 6 (1H, s ), 4.85 -4.89 (1H, m), 4.15 (2H, dd, J = 14.5 Hz, 7.0 Hz ), 3.45 (1H, dd, J = 15.0 Hz, 5.5 Hz), 2.60 (1H, dd, J = 15.5 Hz, 9.0 Hz), 2.38-2.48 (1H, m ), 1 .78 ( 3H, d, J = 6.5 Hz ), 1.28 (3H, t, J = 7.0 Hz), 1.06 ( 3H, d, J = 6.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.7, 176.6, 147.3, 125.6, 124.4, 108.2, 98.4, 59.5, 30.4, 24.6, 20.7, 17.9, 14.3 ppm; IR (film) 3045, 2934, 2929, 2863, 1710(s), 1674, 1648 (s), 1375, 1117 (s), 1052,974 cm -1. HRMS (ESI) Calculated Mass for C 13H19O3: 223.1334 ([M+H] +), Found 223.1342 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRAL PAK AI column (n-hexanes at 1.0 mL/min) , R t = 18.9 min (minor) and 21.5 min (major), II-3p-S (90% ee): [ %]20D= -88 (c = 1.29, CDCl 3). II-3n-S: Ethyl (E) -2-((S)-6-((E)-pent-1-en-1-yl)-4-propyl-3,4-dihydro-2H-pyran-2-ylidene)acetate : Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1n (15.0 OCO2EtII-3p- SOCO2EtII-3n- S!+#!mg, 0.09 mmol) , 7.0 mg (28 % yield) of the pure product was isolated as a c olorless oil; 1H NMR (500 MHz, CDCl 3) ! 6.03 (1H, d t, J = 1 5.5 Hz, 7.0 Hz ), 5. 75 (1H, d, J = 1 5.5 Hz ), 5.57 (1H, s ), 4. 93-4.96 (1H, m ), 4.15 (2H, q, J = 7.0 Hz ), 3. 32 (1H, dd, J = 15.0 Hz, 6.0 Hz), 2. 81 (1H, dd, J = 15. 0 Hz, 8.5 Hz ), 2. 28-2.36 (1H, m ), 2. 04-2.12 (2H, m ), 1.31-1.48 (6H, m ), 1.2 7 (3H, t, J = 7.0 Hz ), 0.87-0.95 (6H, m) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.8, 147.4, 1 30.7, 123.3, 107.1, 98.4, 59.5, 37.4, 34.5, 29.4, 28.4, 22.3, 19.8, 14.3, 14.0, 13.7 ppm; IR (film) 2959, 2930, 2873, 1711 (s), 1648 (s), 1464, 1376, 1286, 1118 (s), 1051, 962, 846 cm -1. HRMS (ESI) Calculated Mass for C 17H27O3: 279.1960 ([M+H] +), Found 279.1969 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AI column (n-hexanes at 0.5 mL/min) , R t = 19.3 min (minor) and 22.4 min (major), II-3n-S (90% ee): [ %]20D= -108 (c = 0.55, CDCl 3). II-3o-S: Ethyl (E)-2-((R) -4-isopropyl-6-((E)-3-methylbut -1-en-1-yl)-3,4-dihydro-2H-pyran-2-ylidene)acetate : Using 10 mol % catalyst A, II-2 (20.0 mg, 0.18 mmol) and II-1o (15.0 mg, 0.09 mmol) , 7.3 mg (29 % yield) of the pure product was isolated as a colorless oil; 1H NMR (500 MHz, CDCl 3) ! 6.01 (1H, d d, J = 1 5.5 Hz, 7.0 Hz ), 5. 74 (1H, dd, J = 1 5.5 Hz , 1.0 Hz ), 5.5 6 (1H, s ), 4. 97-5.00 (1H, m ), 4.15 (2H, q, J = 6.5 Hz ), 3. 22 (1H, dd, J = 15.0 Hz, 6.0 Hz ), 2. 99 (1H, dd, J = 15. 0 Hz, 7.5 Hz ), 2. 32-2.41 (1H, m ), 2. 08-2.15 (1H, m), 1.58-1.65 (1H, m ), 1.2 7 (3H, t, J = 6.5 Hz ), 1.03 (6H, d, J = 7.0 Hz), 0.90-OCO2EtII-3o- S!+$!0.96 (6H, m) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.3, 167.8, 147.9, 137.4, 120.5, 105.8, 98.2, 59.5, 36.2, 32.1, 30.9, 25.9, 22.2, 22.2, 19.9, 19.5, 14.3 ppm; IR (film) 3043, 2961 (s), 2933, 2872, 1710 (s), 1670, 1647 (s), 1465, 1374, 1281, 1174, 1118 (s), 966, 844 cm-1. HRMS (ESI) Calculated Mass for C 17H27O3: 279.1960 ([M+H] +), Found 279.19 73 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AI column (n-hexanes at 0.1 mL/min) , R t = 96.5 min (minor) and 101.3 min (major), II-3o-S (94% ee): [ %]20D= -96 (c = 1.46, CDCl3). II-4.3. General procedure for synthesis of aromatic dienones : To a solution of the corresponding aryl aldehyde (2.0 equiv) and acetone (1.0 equiv) in the mixed solvent of methanol/H 2O ( v/v = 1:1 ), 6M NaOH (6.0 equiv) was added dropwise (ap proximately 2 drops/sec to avoid formation of side products) . The reaction mixture warmed up rapidly forming a cloudy suspension. The mixture was allowed to stir at room temperature for another hour. The reaction was neutralized with the addition of HCl (concentrated), followed by extraction wit h dichlormethane. T he combined organic extracts were washed with brine, dried over sodium sulfate, filtrated through celite, concentrated under rotavapor, and finally subjected to purification by silica gel flash column chromatography or by recrystallizati on. ROH+O(2.0 equiv) (1.0 equiv) 6M NaOH, MeOH/H 2Ort, 1h RROII-1a-m !,&! II-1a: (1E, 4E)-1,5-diphenylpenta -1,4-dien-3-one (Dibenzalacetone) : Using benzaldehyde (573.0 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol) , 322.6 mg (51 % yield) of the pure product was isolated as yellow needle shaped crystals, mp 111 ¡C (lit. 39 112 ¡C). 1H NMR (500 MHz, CDCl 3) ! 7.73 (2H, d, J = 15.6 Hz ), 7.61-7.60 (4H, m ), 7.4 1-7.60 (6H, m ), 7.07 (2H, d, J = 16.2 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.9, 143.3, 134.8, 130.5, 129.0, 128.4, 125.4 ppm. II-1b: (1E, 4E) -1,5-bis(2 -methoxyphenyl)penta -1,4-dien-3-one): Using 2 -anisaldehyde (735.2 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 762.9 mg ( 96% yield) of the pure product was isolated as a y ellow solid, mp 110 ¡C (lit .40 118-120 ¡C). 1H NMR (500 MHz, CDCl 3) ! 8.07 (2H, d, J = 16.0 Hz), 7.63 (2H, dd, J = 7.5 Hz, J = 1.5 Hz ), 7.63 (2H, td, J = 7. 5 Hz, J = 1.5 Hz ), 7.18 (2H, d, J = 16.0 Hz), 6.99 (2H, t, J = 7.0 Hz ), 6.94 (2H, d, J = 8.5 Hz ), 3.92 (6H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 190.0, 158.5, 138.2, 131.5, 128.7, 126.2, 124.0, 120.7, 111.1, 55.5 ppm. OI-1a OII-1b OO!,'! II-1c: (1E,4E)-1,5-bis(3 -methoxyphenyl)penta -1,4-dien-3-one: Using 3 -anisaldehyde (735.2 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 437.1 mg (55 % yield) of the pure product was isolated as a y ellow oil (lit .41 yellow solid 64 -65 ¡C). 1H NMR (500 MHz, CDCl3) ! 7.71 (2H, d, J = 16.0 Hz ), 7. 34 (2H, t, J = 8.0 Hz ), 7. 20-7.24 (2H, m), 7.1 2-7.16 (2H, m), 7.07 (2H, d, J = 15.5 Hz ), 6. 97 (2H, dd, J = 8.0 Hz, 2.5 Hz ), 3.86 (6H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.9, 159.9, 143.3, 136.2, 130.0, 125.7, 121.1, 116.4, 113.2, 55.4 ppm. II-1d: (1E,4E)-1,5-bis(4 -methoxyphenyl)penta -1,4-dien-3-one: Using 4 -anisaldehyde (735.2 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 492.7 mg (62% yield) of the pure product was isolated as a y ellow solid 120 ¡C (lit. 41 128-130 ¡C). 1H NMR (500 MHz, CDCl3) ! 7.70 (2H, d, J = 15.5 Hz), 7.54 -7.60 (4H, m), 6.91 -6.98 (6 H, m ), 3.85 (6H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.8, 161.5, 142.6, 130.1, 127.6, 123.5, 114.4, 55.4 ppm. OII-1c OOII-1d OOO!,(! II-1e: (1E,4E)-1,5-di-o-tolylpenta -1,4-dien-3-one: Using o-tolualdehyde ( 648.8 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 587.9 mg (83% yield) of the pure product was isolated as a yellow solid, mp 70 ¡C (lit. 41 98-100 ¡C). 1H NMR (500 MHz, CDCl 3) ! 8.05 (2H, d, J = 16.0 Hz ), 7.64 -7.68 (2H, m), 7.29 -7.34 (2H, m), 7.22 -7.27 (2H, m), 7.00 (2H , d, J = 15.5 Hz), 2.49 (6H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.9, 140.9, 138.2, 133.8, 130.9, 130.2, 126.7, 126.4, 126.4, 19.9 ppm. II-1f: (1E,4E)-1,5-di-p-tolylpenta -1,4-dien-3-one: Using p-tolualdehyde (648.8 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 517.1 mg ( 73% yield) of the pure product was isolated as a y ellow solid, mp 166 ¡C (lit. 42 177.0-177.5 ¡C). 1H NMR (500 MHz, CDCl 3) ! 7.72 (2H, d, J = 16.0 Hz ), 7.52 (4H, d, J = 8.5 Hz ), 7.22 (4H, d, J = 8.5 Hz ), 7.05 (2H, d, J = 15.5 Hz ) 2.39 (6H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 189.1, 143.2, 141.0, 132.1, 129.7, 128.4, 124.6, 21.5 ppm. OII-1e OII-1f OII-1g FF!,"!II-1g: (1E,4E)-1,5-bis(2 -fluorophenyl)penta -1,4-dien-3-one: Using 2 -fluoraldehyde (670.2 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 357.6 mg (49 % yield) of the pure product was isolated as a dark brown solid, mp 52 ¡C (lit. 43 68-70 ¡C). 1H NMR (500 MHz, CDCl 3) ! 7.87 (2H, d, J = 16.0 Hz ), 7.61-7.67 (2H, m ), 7. 35-7.42 (2H, m ), 7. 10-7.23 (6H, m ), ppm; 13C NMR (125 MHz, CDCl 3) 189.0, 162.6 (d, 1JC,F = 252.4 Hz ), 136.1 (d, 4JC,F = 2.9 Hz ), 131.9 (d, 3JC,F = 8.5 Hz ), 129.3 (d, 4JC,F = 2.8 Hz ), 127.6 (d, 3JC,F = 6.6 Hz ), 124.5 (d, 3JC,F = 3.9 Hz ), 122.8 (d, 2JC,F = 11.4 Hz ), 116.3 (d, 2JC,F = 21.9 Hz). II-1h: (1E,4E)-1,5-bis(2 -bromophenyl)penta -1,4-dien-3-one: Using 2 -bromobenzaldehyde (999. 1 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 328.2 mg (31 % yield) of the pure product was isolated as an orange solid, mp 94 ¡C (lit. 44 97 ¡C). 1H NMR (500 MHz, CDCl 3) ! 8.09 (2H, d, J = 16.0 Hz ), 7.62-7.74 (4H, m ), 7. 34-7.40 (2H, m), 7. 24-7.29 (2H, m ), 7.03 (2H, d, J = 16.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.7, 142.0, 134.8, 133.5, 131.4, 127.8, 127.8, 127.7, 125.9 ppm. II-1i: (1E,4E)-1,5-bis(4 -bromophenyl)penta -1,4-dien-3-one: Using 4 -bromobenzaldehyde (999.1 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 1.03 g II-1h OBrBrOII-1i BrBr!,%!(97% yield) of the pure product was isolated as an orange solid, mp 205 ¡C (lit. 42 212.2-212.9 ¡C). 1H NMR (500 MHz, CDCl 3) ! 7.67 (2H, d, J = 15.5 Hz ), 7.55 (4H, d, J = 8.0 Hz), 7.47 (4H, d, J = 8.0 Hz ), 7.05 (2H, d, J = 16.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.3, 142.2, 133.6, 132.2, 129.7, 125.7, 124.9 ppm. II-1j. (1E,4E)-1,5-bis(2 -chlorophenyl)penta -1,4-dien-3-one: Using 2-chlorobenzaldehyde ( 759.1 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 409.3 mg (50 % yield) of the pure product was isolated as an orange solid, mp 108 ¡C (lit. 42 112.5-113.0 ¡C). 1H NMR (500 MHz, CDCl 3) ! 8.14 (2H, d, J = 16.0 Hz ), 7.70-7.76 (4H, m ), 7.42-7.48 (2H, m ), 7. 30-7.38 (2H, m ), 7.08 (2H, d, J = 16.5 Hz ) ppm; 13C NMR (125 MHz, CDCl3) ! 189.0, 139.4, 135.4, 133.0, 131.3, 130.3, 127.7, 127.5, 127.1 ppm. II-1k: (1E,4E)-1,5-bis(4 -chlorophenyl)penta -1,4-dien-3-one: Using 4 -chlorobenzaldehyde (759.1 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 802.2 mg (98% yield) of the pure product was isolated as a yellow solid, mp 170 ¡C (lit. 42 184-186 ¡C). 1H NMR (500 MHz, CDCl 3) ! 7.73 (2H, d, J = 16.0 Hz ), 7.61 (4H, d, J = 8.5 Hz), 7.45 OII-1j ClClOII-1k ClCl!,)!(4H, d, J = 9.0 Hz ), 7.09 (2 H, d, J = 15.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.3, 142.1, 136.5, 133.2, 129.5, 129.3, 129.2, 125.7 ppm. II-1l: (1E,4E)-1,5-di(furan -2-yl)penta -1,4-dien-3-one: Using 2 -furaldehyde (518. 9 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 341.3 mg (59 % yield) of the pure product was isolated as a black oil (lit. 45 Solid 59 -60 ¡C ). 1H NMR (500 MHz, CDCl 3) ! 7.52 (2H, d, J = 1.0 Hz), 7.48 (2H, d, J = 16.0 Hz ), 6.92 (2H, d, J = 15.5 Hz ), 6.69 (2H, d, J = 3.5 Hz) , 6.50 (2H, dd, J = 3.5 Hz, J = 1.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.1, 151.5, 144.9, 129.2, 123.2, 115.9, 112.6 ppm. II-1m: (1E,4E)-1,5-di(naphthalen -1-yl)penta -1,4-dien-3-one: Using 1-naphthaldehyde (843.4 mg, 5.4 mmol) and acetone (156.8 mg, 2.7 mmol), 243.8 mg (27% yield) of the pure product was isolated as a yellow solid, mp 113 ¡C (lit. 46 134-135 ¡C). 1H NMR (500 MHz, CDCl 3) ! 8.66 (2H, d, J = 16.0 Hz ), 8.29 (2H, d, J = 9.0 Hz), 7.87 -7.98 (6H, m), 7.51-7.65 (6H, m), 7.25 (2H, d, J = 14.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 188.6, 140.4, 133.7, 132.2, 131.7, 130.8, 128.8, 128.1, 127.0, 126.3, 125.5, 125.2, 123.4 ppm. OII-1l OOOII-1m !,+!II-4.4. Synthesis of alkyl substituted dienones II -1n Ð II-1p:42,47 A solution of ketone (1.0 equiv ), ethylene glycol ( 7.1 equiv ) and 4 mol % of p-TsOH in benzene was refluxed for 24 h, with azotropic removal of water (Dean -Stark apparatus). The reaction mixture was then cooled to room temperature and quenched with water and the separated aqueous layer was extracted with ether. The combined organic layers were wash ed with dilute base 10% (wt) NaOH solution, and dried with Na 2SO4. After filtration, the solution was concentrated under the reduced pressure to furnish the 2,2-dipropyl -1,3-dioxolane (quantitative yield) as a pale-yellow oil, which was used for the next s tep without further purification. To the above ketal ( 1.0 equiv ) in Et 2O was added bromine (2.02 equiv ) at room temperature. After the addition was complete, Na 2CO3 (4.4 equiv ) was added in one portion and the resulting mixture was stirred overnight at room tempera ture. After this time, the reaction mixture was filtered through cotton and concentrated to dryness. The obtained dibromo species was dissolved in methanol , and NaOH (8.7 equiv ) was added at room temperature. The mixture was re fluxed for two days. Once the mixture was cooled RROHOOHp-TsOH, reflux RRi. Br 2, Na2CO3, Et 2O, rt ii. NaOH, MeOH, reflux iii. aq. H2SO4, Et 2O, rt RROquantitative OORROO= propyl, II-1n , 21%= isopropyl, II-1o , 13%= Me, II-1p , 50% yield R!,,!down to room temperature again, it was diluted with water and extracted with n -pentane. The organic phase was dried over MgSO 4. After removal of the solvent the desired material was obtained. The crude diene ketal was placed without further purification in a flask, containing Et 2O and sulfuric acid (3% ). The mixture was stirred for 3 h, the organic phase was separated, the water phase was extracted with Et 2O, and the combin ed organic phase was dried over Na 2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 -5% EtOAc in hexane) to furnish the desired product. II-1o: (2E,5E) -hepta -2,5-dien-4-one: Using 4-heptanone (3.0 g, 26.3 mmol), 520.0 mg (50% yield) of the pure product was isolated as a pale-yellow oil. 1H NMR (500 MHz, CDCl3) ! 6.91 (2H, qd, J = 15.5 Hz, 7.0 Hz), 6.34 (2H, dd, J = 15.5 Hz, 1.5 Hz), 1.91 (6H, d, J = 6.5 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 189.3, 142.9, 130.2, 18.4 ppm. II-1n: (4E,7E) -undeca-4,7-dien-6-one: Using undecan -6-one (3.0 g, 17. 6 mmol), 615.2 mg (21% yield) of the pure product was isolated as a pale-yellow liquid . 1H NMR (500 MHz, CDCl 3) ! 6.90 (2H, d t, J = 16.0 Hz , 7.0 Hz), 6.33 (2H, d t, J = 16.0 Hz, 1.5 Hz), 2.22 OII-1o OII-1n !,#!(4H, qd, J = 7.0 Hz, 1.5 Hz ), 1.47-1.55 (4H, m ), 0.95 (6H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 189.7, 147.7, 128.8, 34.7, 21.4, 13.7 ppm. II-1o: (3E,6E) -2,8-dimethylnona -3,6-dien-5-one: Using 2,8-dimethylnonan -5-one ( 3.0 g, 17.6 mmol), 380.7 mg (13% yield) of the pure product was isolated as a pale yellow liquid. 1H NMR (500 MHz, CDCl 3) ! 6.87 (2H, d d, J = 16.0 Hz , 7.0 Hz ), 6.33 (2H, d d, J = 16.0 Hz, 1.5 Hz ), 2.44-2.54 (2H, m), 1.09 (12H, d, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl3) ! 190.3, 153.9, 125.9, 31.3, 21.4 ppm. II-4.5. Synthesis of formal [4+2] cycloadditions of unsymmetrically substituted dineones:48 OII-1o ClO+NOHONO1) Et 3N, 0 ¼C2) DMAP, 0 ¼Cn-BuLi OPOOOR2HOORK2CO3ethanolIntermediate I (64% yield) R2 = Cy, II-1s (70% yield) R2 = t-Bu, II-1t (29% yield) OPOOIntermediate II (64% yield) !,$!The intermediates N-methoxy -N-methylcinnamamide (intermediate I) and (E)-dimethyl 2 -oxo -4-phenylbut -3-enylphosphonate (intermediate II) , as well as compound II-1s were prepared by previously reported procedures. 48 II-1s: 1H NMR (500 MHz, CDCl 3) ! 7.65 (1H, d, J = 16.0 Hz ), 7.54-7.61 (2H, m), 7.37-7.42 (3H, m), 6.99 (1H, d, J = 16.5 Hz), 6.95 (1H, dd, J = 15.5 Hz, 6.5 Hz ), 6.38 (1H, dd, J = 15.5 Hz, 1.0 Hz ) 2.17-2.27 (1H, m), 1.74-1.87 (4H, m), 1.27 -1.37 (2H, m), 1.15 -1.27 (4H, m) ppm; 13C NMR (125 MHz, CDCl3) ! 189.7, 153.2, 142.9, 134.9, 130.3, 128.9, 128.3, 128.2, 126.8, 124.8, 40.9, 31.8, 25.9, 25.7 ppm. II-1t was synthesized in a similar fashion as described below: To a solution of phosphonate (200.0 mg, 0.79 mmol) in ethanol (4.0 mL) was added K 2CO3 (100.0 mg, 0.72 mmol) and allowed to stir for 0.5 h. After cooling the reaction mixture to 0 ¡C, a solution of aldehyde (61.6, 78 #L, 0.72 mmol) in ethanol (1.0 mL) was added dropwise and stirred overnight. The reaction was quenched with 1 M HCl (aq) (15.0 mL), extracted with dichloromethane (3 $15mL), and the organic layer s combined. The extract was drie d with Na 2SO4, filtrated and concentrated under reduced pressure. The crude material was purified by flash silica column chromatography with EtOAc in hexane (1.5% -20%) to furnish II-1t (49.6 mg, 29% yield) as a yellow oil. 1H NMR (500 MHz, CDCl 3) ! 7.66 (1H, d, J = 16.0 Hz ), 7.56-7.62 (2H, m), 7.38-7.42 (3H, m), 7.00 (1H, d, J = 16.0 Hz ), 7.00 (1H, d, J = 16.0 Hz ), 1.14 (9H, s) ppm ; 13C NMR (125 MHz, CDCl 3) ! 189.8, 157.9, 142.9, 130.3, 128.9, 128.3, 124.9, 124.5, 28.8 ppm. !#&!II-4.6. Procedures for Diels -Alder reaction of chiral dihydropyrans (II -3) with dienophiles II-4a Ð II-4d: General procedure for Diels -Alder reaction using dienophiles II -4a and II-4b: A solution of diene (0.05 mmol) and dienophile (0.15 mmol ) in anhydrous toluene (0.5 mL) was refluxed in an oil bath. The reaction was monitored by TLC , which was completed in as early 2 h and up to 3 days. The solvent was removed under nitrogen flow and the residue was directly purified by silica gel column chromatography usi ng ethyl acetate/hexane with different percentage as eluents , typically (1.5% to 20% gradient) . II-5aa: Ethyl ( E)-2-((3a S,4S,9S,9aS,9bR)-1,3-dioxo-4,9-diphenyl-1,3,3a,4,8,9,9a,9b-octahydro -7H-furo[3,4 -f]chromen -7-ylidene) acetate : Using II-3a (17. 3 mg, 0 .05 mmol) and II-4a (14.7 mg, 0.15 mmol) , 18.7 mg (84 % yield) of the pure product was isolated as a c rystalline white solid, mp 184 -188 ¡C. 1H NMR (500 MHz, CDCl 3) ! 7.43-7.44 (4H, m), 7.40-7.42 (2H, m), 7.28-7.34 (2H, m), 7.22 -7.23 (2H, m), 5.73 (1H, dd , J = 3.5 Hz, 3.0 Hz ), 5.54 (1H, d, J = 2.0 Hz), 4.33 (1H, dd , J = 16.0 Hz, 3.0 Hz ), 4.16 (2H, ORRCO2EtII-3 ORCO2EtREWG EWG R2R2HII-5 Toluene, reflux II-4 (3.0 equiv) (S)(S)OCO2EtPhPhHII-5aa OOO!#'!ddd, J = 15.0 Hz, 7.0 Hz, 1.0 Hz ), 3.95 (1H, dddd , J = 15.0 Hz, 13.5 Hz, 12.0 Hz, 3.0 Hz ), 3.77-3.80 (1H, m), 3.46 (1H, t, J = 9.5 Hz ), 3.33 (1H, dd, J = 9.0 Hz, 5.0 Hz ), 2.89 (1H, dddd, J = 10.0 Hz, 7.0 Hz, 5.0 Hz, 3.0 Hz ), 2.58 (1H, dddd, J = 16.0 Hz, 16.0 Hz, 13.5 Hz, 2.0 Hz), 1.26 (3H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 170.7, 168.7, 167.3, 166.9, 151.5, 140.2, 137.5, 133.0, 129.7, 129.2, 12 8.7, 128.5, 128.3, 128.0, 127.9, 127.5, 104.7, 98.0, 69.2, 64.0, 59.8, 47.8, 42.9, 42.8, 41.3, 35.1, 31.5, 14.3 ppm; IR (film) 3062, 2928, 2854, 1779 (s), 1701, 1629 (s), 1337, 1170, 1135 (s), 939, 703 cm-1. HRMS (ESI) Calculated Mass for C 27H25O6: 445.1651 ([M+H] +), Found 445.1653 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column, R t = 24.7 min (minor) and 31.3 min (major), II-5aa (96% ee). [%]20D= +75 (c = 1.00, CH2Cl2). The relative stereochemistry is assigned based on NOESY experiments. II-5ba: Ethyl ( E)-2-((3a S,4S,9S,9aS,9bR)-4,9-bis(2 -methoxyphenyl) -1,3-dioxo-1,3,3a,4,8,9,9a,9b-octahydro -7H-furo[3,4 -f]chromen -7-ylidene) acetate : Using II-3b (20 .3 mg, 0.05 mmol) and II-4a (14.7 mg, 0.15 mmol) , 8.1 mg (32 % yield) of the pure product was isolated as a c rystalline colorless solid, mp 166 ¡C. 1H NMR (500 MHz, CDCl3) ! 7.35 (1H, dd , J = 7.5 Hz, 1.5 Hz ), 7.28-7.33 (2H, m), 7.15 (1H, dd , J = 8.0 Hz, 1.5 Hz), 6.89 -7.01 (4H, m), 5.56-5.65 (1H, m), 5.47 (1H, d , J = 1.5 Hz ), 4.15-4.22 (2H, OCO2EtHII-5ba OOOOO!#(!m), 4.12 (2H, q, J = 7.0 Hz), 4.04 -4.09 (1H, m), 3.79 -3.91 (7H, m), 3.56 (1H, t , J = 9.0 Hz), 3.31 (1H, dd , J = 9.0 Hz, 5.0 Hz ), 3.22-3.28 (1H, m), 1.26 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl3) ! 171. 2, 169.5, 168.1, 167.6, 158. 1, 156.9, 151.5, 129.7, 129.2, 129.0, 128.9, 128.1, 125.7, 121.1, 120.8, 111.3, 110.3, 104.2, 97.2, 61.0, 59.6, 55.7, 55.4, 55.2, 45.5, 44.1 , 35.6, 29.7, 14. 4 ppm; IR (film) 3068, 2927, 2851, 1855, 1780(s), 1703, 1628(s), 1494, 1463, 1245(s), 1135(s), 1027, 930, 755 cm -1. HRMS (ESI) Calculated Mass for C 29H29O8: 505.1862 ([M+H] +), Found 505.1865 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column, R t = 24.5 min (min or) and 71.2 min (major), II-5ba (96% ee): [ %]20D= +33 ( c = 0.52, CDCl3). II-5ja: Ethyl ( E)-2-((3a S,4S,9S,9aS,9bR)-4,9-bis(2 -chlorophenyl)-1,3-dioxo-1,3,3a,4,8,9,9a,9b-octahydro -7H-furo[3,4 -f]chromen -7-ylidene) acetate: Using II-3j (20.8 mg, 0.05 mmol) and II-4a (14.7 mg, 0.15 mmol) , 14.9 mg (58 % yield) of the pure product was isolated as a c rystalline colorless solid, mp 173 ¡C. 1H NMR (500 MHz, CDCl3) ! 7.41 -7.48 (3H, m), 7.27 -7.36 (4 H, m ), 7.22 -7.25 (1H, m), 5.65 -5.68 (1 H, m ), 5.52-5.54 (1H, m ), 4.43 -4.53 (1H, br, m), 4.17 -4.31 (3 H, m ), 4.14 (2H, q, J = 7.0 Hz ), 3.68 -3.78 (2 H, m ), 3.38 -3.46 (1H, br, m), 1.27 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, OCO2EtHII-5ja OOOClCl!#"!CDCl3) ! 168. 6, 167.2, 151.9 , 135.1, 133.6, 130.1, 129.6, 129.2, 129.1, 128.3, 127.6, 127.4, 103.8, 98.2, 59.9, 45.1, 43.6, 37.7, 31.6, 22.7, 14. 3, 14. 2 ppm; I R (film) 3067, 2973, 2932, 2888, 1851, 1781(s), 1702, 1630(s), 1476, 1377, 1339, 1257, 1165, 1141(s), 1038, 953, 756 cm -1. HR MS (ESI) Calculated Mass for C 27H23O6Cl2: 513.0872 ([M+H] +), Found 513.0875 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column, R t = 14.3 min (minor) and 40.1 min (major), II-5ja (91% ee): [ %]20D= +62 ( c = 1.11, CDCl 3). II-5ab: Ethyl 2 -((4S,4aS,7R,E)-5,5,6,6-tetracyano -4,7-diphenyl-3,4,4a,5,6,7-hexahydro-2H-chromen-2-ylidene) acetate : Using II-3a (17.3 mg, 0.05 mmol) and II-4b (19.2 mg, 0.15 mmol) , 23.3 mg (98 % yield) of the pure product was isolated as an o ff white solid, decomposes above 160 ¡C. 1H NMR (500 MHz, CDCl 3) ! 7.46-7.51 (5H, m), 7.37-7.42 (5H, m), 5.75 (1H, dd , J = 3.0 Hz, 2.0 Hz ), 5.67 (1H, br, s), 4.45 (1H, t , J = 3.0 Hz), 4.05-4.09 (2H, m), 3.58 -3.66 (3H, m), 3.54 (1H, ddd , J = 15.0 Hz, 7.0 Hz, 0.5 Hz ), 1.18 (3H, t, J = 5.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 166.3, 164.4, 146.2, 137.7, 132.1, 130.5, 130.5, 129.6, 129.4, 129.0, 127.9, 111.0, 109.9, 109.3, 108.3, 105.6, 101.1, 60.1, 46.3, 44.9, 44.7, 41.5, 40.5, 32.7, 14.2 ppm; IR (film) 3066, 3035, 2984, 2936, 2906, 2255, 1730(s), 1706(s), 1643(s), 1456, 1331, 1249, 1201(s), 1175(s), 1148(s), 1127(s), 1044, 848, 762, 703 cm -1. HRMS (ESI) Calculated Mass for C 29H23N4O3: 475.1770 OCO2EtPhPhHCNNCNCNCII-5ab !#%!([M+H] +), Found 475.1776 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (10% isopropanol in n-hexanes at 1.0 mL/min) , R t = 10.8 min (minor) and 16.4 min (major), II-5ab (96% ee): [ %]20D= +106 ( c = 2.63, CDCl3). II-5bb: Ethyl 2 -((4S,4aS,7S,E)-5,5,6,6-tetracyano -4,7-bis(2 -methoxyphenyl) -3,4,4a,5,6,7-hexahydro-2H-chromen-2-ylidene) acetate : Using II-3b (20.3 mg, 0.05 mmol) and II-4b (19. 2 mg, 0.15 mmol) , 23.3 mg (87 % yield) of the pure product was isolated as a crystalline pale yellow solid, m.p. 64 -66 ¡C. 1H NMR (500 MHz, CDCl 3) ! 7.36-7.46 (3H, m), 7.25 (1H, dd , J = 8.0 Hz, 2.0 Hz ), 6.91-7.04 (4H, m), 5.55-5.60 (2H, m), 5.01 -5.05 (1H, m), 4.34 (1H, dt , J = 11.0 Hz, 2.5 Hz ), 4.13 (2H, q , J = 7.0 Hz ), 3.97 (1H, dd , J = 17.5 Hz, 3.5 Hz ), 3.94 (3H, s), 3.92 (3H, s), 3.58 (1H, ddd , J = 18.0 Hz, 12.5 Hz, 2.5 Hz ), 3.42 (1H, td, J = 12.0 Hz, 4.0 Hz ), 1.26 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.0, 165.0, 158.9, 157.4, 145.9, 131.8, 131.8, 131.5, 131.0, 122.9, 121.5, 121.1, 120.4, 111.9, 111.6, 110.7, 110.2, 110.1, 108.4, 103.3, 99.3, 60.0, 55.3, 55.2, 44.2, 41.9, 39.8, 39.7, 38.9, 30.5, 14.3 ppm;. IR (film) 3072, 2975, 2927, 2845, 2255, 1707(s), 1705(s), 1603, 1589, 1493, 1465, 1341, 1288, 1249(s), 1182( s), 1127(s), 1027, 910, 772, 734 cm -1. HRMS (ESI) Calculated Mass for C 31H27N4O5: 535.1981 ([M+H] +), OCO2EtHNCNCNCII-5bb CNOO!#)!Found 535.1984 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (10% isopropanol in n-hexanes at 1.0 mL/min) , Rt = 8.8 min (minor) and 12.6 min (major), II-5bb (88% ee): [ %]20D= +128 ( c = 0.98, CDCl 3). II-5jb: Ethyl 2 -((4S,4aS,7S,E)-4,7-bis(2 -chlorophenyl)-5,5,6,6-tetracyano -3,4,4a,5,6,7-hexahydro-2H-chromen-2-ylidene) acetate : Using II-3a (20. 8 mg, 0.05 mmol) and II-4a (14.7 mg, 0.15 mmol) , 23.4 mg (86 % yield) of the pure product was isolated as a crystalline light brown solid, m.p. 68 -70 ¡C. 1H NMR (500 MHz, CDCl 3) ! 7.53-7.59 (2H, m), 7.46-7.51 (1H, m), 7.38 -7.46 (2H, m), 7.34 -7.38 (3H, m), 5.65-5.69 (1H, m), 5.63 -5.65 (1H, s), 5.15 -5.19 (1H, m), 4.07 -4.14 (3H, m), 3.98 -4.04 (1H, m), 3.82 (1H, dd , J = 17.0 Hz, 4.5 Hz ), 3.52 (1H, dd , J = 17.0 Hz, 9.5 Hz ), 1.22 (3H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 166.3, 163.4, 145.7, 135.7, 134. 3, 132.0, 131.8, 131.2, 131.0, 130.5, 130.2, 127.9, 127.5, 110.9, 109.3, 109.0, 108.5, 105.0, 100.8, 60.2, 43.0, 31.1, 14.2 ppm. IR (film) 3069, 2983, 2929, 2873, 2257, 1706(s), 1644(s), 1477, 1379, 1336, 1278, 1203, 1180(s), 1151(s), 1129(s), 1041, 759, 7 34 cm -1. HRMS (ESI) Calculated Mass for C 29H21N4O3Cl2: 543.0991 ([M+H] +), Found 543.1000 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -OCO2EtHNCNCNCII-5jb CNClCl!#+!H column (10% isopropanol in n-hexanes at 1.0 mL/min) , R t = 9.1 min (minor) and 16.9 min (major), II-5jb (86% ee): [%]20D= +94 ( c = 0.97, CDCl 3). Specific procedure for synthesizing compound II-6ad: A solution of II-3a (0.05 mmol) and II-4d (0.15 mmol ) in anhydrous toluene (0.5 mL) was refluxed in an oil bath. The reaction was monitored by TLC , which was completed in 24 h. The solvent was removed under nitrogen flow and the residue was directly purified by silica gel column chromatography using ethyl acetat e/hexane (0-1:4) as eluents to provide II-5ad (8.2 mg, 41% yield) as yellow oil. To a solution of II-5ad (43.3 mg, 0.1 mmol) in dichloromethane (1 mL), DBU (1.5 mg, 1.5 #L) and pyridine (4.0 mg, 4.0 #L) were added at room temperature. Then the reaction mixture was heated to reflux for 12 h. The mixture was cooled, concentrated and purified OPhPhCO2EtHNCOPhPhCO2EtHNCII-6ad 10 mol% DBU, 50 mol% pyridine II-5ad DCM, reflux 12 htoluene, reflux 12 hCN(3.0 equiv) OPhPhCO2EtII-3a II-4d !#,!by silica gel chromatography column using ethyl acetate/hexane (0-1:5) as eluents to give II-6ad (43.0 mg) in quantitative yield as a light-yellow oil. II-6ad: Ethyl 2 -((4S,4aR,6S,7R)-6-cyano-4,7-diphenyl-4a,5,6,7-tetrahydro -4H-chromen-2-yl) acetate : 1H NMR (500 MHz, CDCl 3) ! 7.36-7.40 (2H, m), 7.27 -7.34 (6H, m), 7.17 -7.21 (2H, m), 5.36 (1H, dd , J = 5.0 Hz, 2.0 Hz ), 4.87 (1H, d , J = 1.5 Hz ), 4.23 (2H, q , J = 7.0 Hz ), 3.92 (1H, br, s ), 3.20-3.27 ( 3H, m), 2.79 -2.83 (1H, m), 2.69 -2.76 (1H, m), 1.74 (1H, ddd , J = 8.5 Hz, 2.0 Hz ), 1.58 ( 1H, dd d, J = 14.5 Hz, 9.5 Hz, 3.5 Hz), 1.31 (3H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 169.6, 152.1, 146.0, 142.0, 141.2, 128.8, 128.3, 127.9, 127.6, 127.3, 121.1, 104.4, 102.9, 61.1, 44.0, 43.2, 39.4, 35.8, 32.2, 25.5, 14.2 ppm; IR (film) 3029, 2926, 2854, 2241, 1737 (s), 1691 (s), 1631, 1602, 1452, 1339, 1256 (s), 11 69 (s), 1031 (s), 758, 702 cm -1. HRMS (ESI) Calculated Mass for C26H26NO3: 400.1913 ([M+H] +), Found 400.1926 ([M+H] +). The relative stereochemistry is assigned based on NOESY experiments. General procedure for Diels -Alder reaction using dienophiles II -4c: To a solution of nitrosobenzene ( 3.0 equiv ) in EtOH/DCM (0.1 mL/0.1 mL), II-3 (1.0 equiv) was added at 0 ¡C. The solution was gradually warmed up to room temperature. The reactions monitored by TLC required between 4 h to 12 h to complete. The reaction was quenched by H 2O (1 mL) and extracted by DCM (1 mL) twice. The combined organic ORRCO2EtII-3 II-5 NOPhDCM/EtOH = 1:1 II-4 (3.0 equiv.) 0 ¼C ! r.t., 4-12 h ORRCO2EtONPhH!##!layers were dried with anhydrous Na 2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate -hexane s as eluents. II-5ac: Ethyl ( E)-2-((3R,8R,8aR)-1,3,8-triphenyl -3,7,8,8a-tetrahydro -1H,6H-pyrano[3,2 -c][1,2]oxazin -6-ylidene) acetate : Using II-3a (20.0 mg, 0 .058 mmol) and II-4c (18.6 mg, 0. 174 mmol) , 20.3 mg (77 % yield) of the pure product was isolated as a yellow oil. 1H NMR (500 MHz, CDCl 3) ! 7.40 -7.50 (5H, m), 7.06 -7.16 (7H, m), 6.85 -6.89 (1H, m), 6.77 -6.81 (2H, m), 5.71 -5.74 (1H, m), 5.66 -5.68 (1H, m ), 5.47-5.50 (1H, m ), 4.39 (1H, ddd, J = 8.0 Hz, 2.0 Hz, 2.0 Hz), 4.07-4.15 (2H, m ), 3.98 (1H, dd, J = 16.0 Hz, 3.5 Hz), 3.53 (1H, ddd, J = 9.0 Hz, 9.0 Hz, 3.5 Hz), 3.13 (1H, ddd, J = 16.0 Hz, 8.5 Hz, 8.0 Hz), 1.21 (3H, t, J = 6 .5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.8, 167.0, 148.7, 146.8, 142.8, 138.2, 128.9, 128.7, 128.6, 128.4, 128.3, 127.2, 126.6, 122.8, 117.7, 108.0, 99.5, 75.3, 62.3, 59.7, 41.2, 31.8, 14.3 ppm ; IR (film) 3062, 3031, 2979, 2925, 2854, 1708(s), 1641(s), 1493, 1454, 1304, 1153(s), 1132(s), 1040, 758, 697 cm -1. HRMS (ESI) Calculated Mass for C 29H28NO4: 454. 2018 ([M+H] +), Found 454.2030 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (2% isopropanol in n-hexanes at 0.8 mL/min) , R t = 13.2 min (major) and 15.0 min (minor), II-5ac (96% ee): [ %]20D= -64 (c = 1.06, CDCl 3). ONOCO2EtPhPhHII-5ac Ph!#$! II-5bc: Ethyl ( E)-2-((3R,8R,8aR)-3,8-bis(2 -methoxyphenyl) -1-phenyl-3,7,8,8a-tetrahydro -1H,6H-pyrano[3,2 -c][1,2]oxazin -6-ylidene) acetate : Using II-3b (23. 6 mg, 0.058 mmol) and II-4c (18.6 mg, 0.174 mmol) , 22.3 mg (75 % yield) of the pure product was isolated as a light brown solid, amorphous. 1H NMR (500 MHz, CDCl 3) ! 7.56 (1H, dd, J = 8.0 Hz, 2.0 Hz ), 7.35 (1H, ddd, J = 7.5 Hz, 7.5 Hz, 1.5 Hz), 7.00 -7.10 (5H, m ), 7.92-7.95 (1H, m ), 6.83-6.86 (2H, m ), 6.76 -6.81 (1H, m), 6.68 -6.74 (2H, m ), 5.95-5.98 (1H, m), 5.63 -5.65 (1H, s ), 5.56 -5.58 (1H, m ), 4.80 (1H, ddd, J = 9.0 Hz, 2.0 Hz, 2.0 Hz ), 4.05-4.11 (2H, m), 3.86 -3.90 (1H, m), 3.85 (3H, s), 3.74 -3.80 (1H, m), 3.67 (3H, s ), 3.14 (1H, ddd, J = 16.5 Hz, 9.0 Hz, 1.5 Hz), 1.21 (3H, t, J = 7.5 Hz ) ppm. 13C NMR (125 MHz, CDCl3) ! 170.1, 167.3, 157.2, 157.1, 156.8, 148.9, 147.4, 130.1, 129.9, 129.7, 128.7, 128.4, 128.3, 127.9, 126.6, 121.6, 120.6, 120.4, 116.5, 110.6, 110.4, 107.4, 97.8, 69. 2, 61.0, 59.5, 59.1, 55.4, 54.7, 31.3, 14.3 ppm; IR (film) 3 058, 2988, 2930, 2906, 2839, 1735, 1707(s), 1637(s), 1599(s), 1494(s), 1463, 1248(s), 1153(s), 1120(s), 1030, 753, 693 cm -1. HRMS (ESI) Calculated Mass for C 31H32NO6: 514.2230 ([M+H] +), Found 514.2236 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (10% isopropanol in n-hexanes at 0.6 mL/min) , R t = 9.4 min (major) and 12.9 min (minor), II-5bc (84% ee): [ %]20D= -51 (c = 1.69, CDCl 3). ONOCO2EtHII-5bc OOPh!$&! II-5cc: Ethyl ( E)-2-((3R,8R,8aR)-3,8-bis(3 -methoxyphenyl) -1-phenyl-3,7,8,8a-tetrahydro -1H,6H-pyrano[3,2 -c][1,2]oxazin -6-ylidene) acetate : Using II-3c (23.6 mg, 0.058 mmol) and II-4c (18.6 mg, 0.174 mmol) , 22.6 mg (76 % yield) of the pure product was isolated as a yellow oil. 1H NMR (500 MHz, CDCl 3) ! 7.35 (1H, t , J = 8.0 Hz ), 7.00-7.11 (5H, m), 6.94 (1H, dd, J = 3.0 Hz, 1 .0 Hz ), 6.88 (1H, t , J = 7.5 Hz ), 6.80-6.84 (2H, m), 6.64-6.69 (2H, m), 6.57 -6.60 (1H, m), 6.70 -6.72 (1H, m), 5.65 -5.68 (1H, m), 5.44 -5.46 (1H, m), 4.37 (1H, dt, J = 8.5 Hz, 2.0 Hz ), 4.08-4.15 (2H, m), 4.00 (1H, dd, J = 16.0 Hz, 3.5 Hz ), 3.85 (3H, s), 3.66 (3H, s), 3.51 (1H, dd d, J = 9.0 Hz, 9.0 Hz, 3.0 Hz ), 3.06 (1H, ddd, J = 15.5 Hz, 8.5 Hz, 1.0 Hz ),1.22 (3H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.9, 166.9, 1 59.7, 159.4, 148.5, 146.9, 144.5, 139.7, 129.7, 129.4, 128.7, 122.8, 120.5, 119.5, 114.0, 114.0, 112.6, 112.5, 108.0, 99.4, 75.3, 62.5, 59.7, 55.3, 55.0, 41.2, 31.6, 14.3 ppm; IR (film) 3060, 2927, 2836, 1707 (s), 1641 (s), 1600 (s), 1491 (s), 1464, 1263 ( s), 1139 (s), 1130 (s), 1045 (s), 689 cm -1. HRMS (ESI) Calculated Mass for C31H32NO6: 514.2230 ([M+H] +), Found 514.2236 ([M+H] +). ONOCO2EtHII-5cc PhOO!$'! II-5jc: Ethyl ( E)-2-((3R,8R,8aR)-3,8-bis(2 -chlorophenyl)-1-phenyl-3,7,8,8a-tetrahydro -1H,6H-pyrano[3,2 -c][1,2]oxazin -6-ylidene) acetate: Using II-3j (24. 1 mg, 0.058 mmol) and II-4c (18.6 mg, 0.174 mmol) , 24.2 mg (80 % yield) of the pure product was isolated as a yellow oil. 1H NMR (500 MHz, CDCl 3) ! 7.68 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.43 (1H, dd, J = 7.0 Hz, 1.5 Hz), 7.30 -7.38 (2H, m), 7.22 -7.25 (1H, m), 7.11 -7.18 (2H, m ), 7.03 -7.08 (3H, m ), 6.87 (1H, t, J = 7.5 Hz ), 6.80 -6.84 (2 H, m ), 5.91-5.93 (1H, m), 5.73-5.75 (1H, m), 5.60 -5.62 (1H, m), 4.60 -4.66 (1H, m), 4.00 -4.12 (3H, m ), 3.72 (1H, dd, J = 16 .0 Hz, 4.0 Hz), 3.15 (1H, ddd, J = 16.5 Hz, 8.5 Hz, 1.5 Hz), 1.17 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.9, 166.8, 160.1, 148.9, 146.4, 139.4, 136.0, 133.7, 129.8, 129.7, 129.6, 129.6, 128.6, 127.9, 127.0, 123.5, 118.7, 107.8, 99.6, 72.8, 59.7, 31.5, 29.7, 22.7, 14.2 ppm. IR (film) 3064, 2981, 2931, 2905, 2871, 1737, 1708(s), 1642(s), 1493, 1478, 1243, 1196(s), 1157(s), 1039, 754 cm -1. HRMS (ESI) Calculated Mass for C 29H26NO4Cl2: 522.1239 ([M+H] +), Found 522.1252 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (2% isopropanol in n-hexanes at 0.8 mL/min) , R t = 14.8 min (minor) and 17.3 min (major), II-5jc (83% ee): [ %]20D= -25 (c = 0.32, CDCl 3). ONOCO2EtHII-5jc ClClPh!$(!II-4.7 Quantum chemical computational analysis: General Considerations: Full optimizations for all conformations of the model systems were performed in simulated toluene at the B3LYP/6 -31G*/SM8 level using the Spartan -14 software running on Macintosh and Linux platform. To verify convergence and consistency of the optimizations, a number of examples were re -optimized from multiple starting points; energetic variations of 0.02 kcal/mol or less were found among these calculated structures. To confirm that each structure was a true minimum, vibra tional analyses were performed . Since analytical second derivatives are not available in SM8 solvated wavefunctions, these analyses relied on finite difference calculations. Similar to total energy calculations , their consistency was checked in multiple ru ns, and showed negligible variation. For comparison, the relative enthalpies ( &H¡rel ) calculated by including zero -point and thermal corrections to 298.15 K are given in kcal/mol. It is these latter values that appear in the manuscript. Importantly, differ ences between relative E and relative H¡ values are generally small enough that either set of data could be used to arrive at the conclusions. All Transition State (TS) structures were validated as first -order stationary points (i.e. a single imaginary fre quency) by vibrational analysis. Single -point solvation energies in simulated toluene were calculated at the B3LYP/6 -31G*/SM8 level of theory. All values are in kcal/mol , eV or hartrees . !$"!A. Cartesian Coordinates for Transition State -1 (TS -1): Atom X Y Z 1 C C7 -0.0739432 -3.8932465 1.2778687 2 C C1 -1.1534715 -3.6455902 0.2130982 3 H H3 -0.8390065 -4.0483414 -0.7524698 4 H H5 -2.0785155 -4.1586585 0.4986699 5 C C2 -1.4525411 -2.1298323 0.0849976 6 H H7 -2.3406172 -1.8619704 0.6563140 7 C C3 -0.4913839 -3.1443495 2.5529348 8 H H2 -1.5279600 -3.3807464 2.8187947 9 C C4 -0.3462612 -1.6320497 2.3118344 10 H H9 -1.1698308 -1.0806059 2.7490995 11 H H10 0.6068365 -1.2467411 2.6787461 12 C C5 1.2718369 -3.3010522 0.8121051 13 H H13 1.9297445 -3.2412008 1.6904701 14 C C6 1.0278899 -1.8598001 0.3045865 15 H H14 0.9800600 -1.8287455 -0.7819368 16 N N2 -0.3222020 -1.3312929 0.8024095 17 H H18 0.1403438 -3.4307591 3.4010952 18 H H19 0.0147179 -4.9659502 1.4763947 19 C C8 2.0341569 -4.1026985 -0.2586010 20 H H1 2.8990292 -3.4979320 -0.5615713 21 H H4 1.4111659 -4.2158104 -1.1558113 22 C C9 2.5271278 -5.4735796 0.2155143 23 H H8 3.1274012 -5.9588252 -0.5620165 24 H H11 1.6990054 -6.1502708 0.4572040 25 H H12 3.1554624 -5.3816153 1.1097223 TS-1 H¡ = -2191.40190 hartree &H¡rel = 0.00 kcal/mol HHNHONOOHHOTS-1 OàCONR4!-!+= 3.4 †!$%! 26 C C10 -1.6823950 -1.6853987 -1.3715557 27 H H16 -1.6458579 -0.5931087 -1.4214667 28 C C11 -3.0764821 -2.1682363 -1.8710116 29 H H17 -3.0023789 -2.2631101 -2.9611594 30 H H21 -3.2666308 -3.1790631 -1.4949899 31 O O1 -0.6529741 -2.2438686 -2.1974355 32 H H20 -5.0472360 -2.5349139 -0.0036559 33 C C13 -5.1452665 -1.6003347 -0.5490087 34 C C14 -4.2327415 -1.2596737 -1.5229441 35 N N1 -6.4258420 0.4259503 -0.8329588 36 C C16 -4.4273252 -0.0125292 -2.2061199 37 C C17 -6.2220412 -0.7318983 -0.2416610 38 C C18 -5.5445278 0.7944258 -1.8095252 39 C C19 -3.5872231 0.4547205 -3.2426193 40 H H24 -6.9375388 -1.0187576 0.5282409 41 H H25 -6.6062027 2.6282794 -2.1414601 42 C C20 -3.8183021 1.6728145 -3.8602497 43 H H27 -2.7409571 -0.1280633 -3.5892348 44 C C21 -4.9172649 2.4748970 -3.4604555 45 C C22 -5.7555390 2.0344302 -2.4605710 46 H H29 -5.1066345 3.4297979 -3.9369273 47 O O2 -2.9405075 2.0213025 -4.8441743 48 C C15 0.5717084 0.8945919 0.0359336 49 C C23 -0.5180681 0.1608913 0.5910907 50 C C24 -1.6755436 0.8023580 1.0101232 51 H H32 -1.6863673 1.8579896 0.7643023 52 C C28 -2.8576976 0.3904042 1.7352280 53 H H28 0.2711035 1.8407531 -0.4033492 54 O O3 -3.6913952 1.4550977 1.8925201 55 C C26 -4.8877046 1.2349616 2.6634395 56 H H30 -5.3251984 0.2735583 2.3845641 57 H H34 -4.6132683 1.1803814 3.7246486 58 C C27 -5.8330111 2.3895437 2.3852061 59 H H33 -6.1420473 2.3866052 1.3353997 60 O O4 -3.1517620 -0.7249154 2.1858131 61 H H36 -6.7293560 2.2930075 3.0085831 62 H H15 1.8226276 -1.2003243 0.6615926 63 H H35 -5.3569840 3.3490906 2.6125758 64 H H37 -0.6659843 -1.7762532 -3.0466097 65 C C12 -3.1218149 3.2592969 -5.5170217 66 H H6 -3.0461315 4.1098510 -4.8274852 67 H H22 -4.0870634 3.2992573 -6.0381629 68 H H23 -2.3152167 3.3187963 -6.2497564 69 C C25 3.9645687 0.7049255 0.6979760 70 O O5 3.6581415 -0.4880667 0.9873651 71 C C29 5.3172707 1.0144425 0.1662698 72 C C30 6.2377050 0.0507800 -0.0303995 73 H H26 5.5310957 2.0583566 -0.0576557 74 H H38 5.9228431 -0.9625234 0.2167759 75 C C31 3.0795622 1.8047042 0.8539981 76 C C32 1.7964817 1.6181395 1.4349137 77 H H39 3.3806004 2.7848881 0.4956708 78 C C33 7.6030002 0.1979545 -0.5371628 79 C C34 10.2502614 0.3657448 -1.5159795 80 C C35 8.1958512 1.4445404 -0.8220811 !$)! 81 C C36 8.3775141 -0.9577426 -0.7535877 82 C C37 9.6821450 -0.8780513 -1.2370466 83 C C38 9.4984033 1.5259311 -1.3038112 84 H H41 7.6311988 2.3576468 -0.6570322 85 H H42 7.9399429 -1.9296863 -0.5367550 86 H H43 10.2557266 -1.7881956 -1.3944128 87 H H44 9.9333749 2.5002036 -1.5131383 88 H H45 11.2680509 0.4334250 -1.8911376 89 C C39 1.0395008 2.7851525 1.9686733 90 C C40 -0.3963129 4.9745918 3.0263536 91 C C41 0.3782439 2.6906600 3.2028502 92 C C42 0.9569021 4.0026119 1.2699084 93 C C43 0.2500175 5.0834255 1.7912098 94 C C44 -0.3280973 3.7732784 3.7303025 95 H H46 0.4335837 1.7609152 3.7637021 96 H H47 1.4502102 4.0995276 0.3058988 97 H H48 0.2019154 6.0150284 1.2326829 98 H H49 -0.8262277 3.6742379 4.6914814 99 H H50 -0.9480487 5.8183612 3.4322070 100 H H31 1.2987233 0.3658025 -0.5631743 101 H H40 1.7578489 0.7480506 2.0879904 B. Cartesian Coordinates for Transition State -2 (TS -2): Atom X Y Z 1 C C7 0.4057419 -4.0002737 1.2168415 2 C C1 -0.4092211 -3.9157327 -0.0826647 3 H H3 0.0515952 -4.5170973 -0.8706842 4 H H5 -1.4158237 -4.3151287 0.0860535 TS-2 &H¡ = -2191.39758 hartree &&H¡rel = 2.71 kcal/mol TS-2 NOHNOOHHHOHOàCONR4!-!+= 4.1 †!$+! 5 C C2 -0.5372507 -2.4438512 -0.5445837 6 H H7 -1.4721537 -2.0014531 -0.1960490 7 C C3 -0.1699925 -2.9724546 2.1996894 8 H H2 -1.2541245 -3.1048220 2.2966900 9 C C4 0.1592526 -1.5547908 1.7015179 10 H H9 -0.6959877 -0.9015331 1.8061093 11 H H10 1.0315718 -1.1061230 2.1821079 12 C C5 1.8739729 -3.6122144 0.9492475 13 H H13 2.3430766 -3.4247720 1.9246338 14 C C6 1.8907891 -2.2855568 0.1478401 15 H H14 2.1048476 -2.4746234 -0.9008302 16 N N2 0.5317337 -1.5894253 0.1996414 17 H H18 0.2638140 -3.1029793 3.1975119 18 H H19 0.3411708 -5.0112251 1.6318426 19 C C8 2.7249756 -4.6740190 0.2276745 20 H H1 3.6930440 -4.2184597 -0.0237637 21 H H4 2.2591442 -4.9330046 -0.7322111 22 C C9 2.9769640 -5.9419563 1.0504081 23 H H8 3.6354003 -6.6310171 0.5101979 24 H H11 2.0489270 -6.4818750 1.2705627 25 H H12 3.4577597 -5.7038269 2.0071059 26 C C10 -0.4988560 -2.2853299 -2.0698433 27 H H16 -0.4142652 -1.2207677 -2.3072862 28 C C11 -1.7947306 -2.8384557 -2.7248389 29 H H17 -1.6049390 -2.8915776 -3.8050088 30 H H21 -1.9510464 -3.8701755 -2.3925129 31 O O1 0.6414586 -2.9886460 -2.5775235 32 H H20 -3.8898478 -3.3992585 -1.0672630 33 C C13 -3.9945944 -2.4416800 -1.5712722 34 C C14 -3.0332266 -2.0131824 -2.4598875 35 N N1 -5.3422734 -0.4599308 -1.8421756 36 C C16 -3.2445705 -0.7492467 -3.1047122 37 C C17 -5.1228405 -1.6329592 -1.2889631 38 C C18 -4.4240947 -0.0137689 -2.7500905 39 C C19 -2.3656266 -0.2000180 -4.0662117 40 H H24 -5.8643728 -1.9797531 -0.5702778 41 H H25 -5.5586535 1.7749235 -3.0854802 42 C C20 -2.6224421 1.0271878 -4.6544628 43 H H27 -1.4689405 -0.7246701 -4.3761501 44 C C21 -3.7851287 1.7571274 -4.2991590 45 C C22 -4.6587098 1.2384926 -3.3692358 46 H H29 -3.9947123 2.7172055 -4.7564436 47 O O2 -1.7056253 1.4558787 -5.5691567 48 C C15 1.7126881 0.1779852 -1.1784993 49 C C23 0.5892952 -0.1931058 -0.3890807 50 C C24 -0.3870112 0.7564787 -0.1293520 51 H H32 -0.1561041 1.7281657 -0.5505215 52 C C28 -1.7334844 0.6870803 0.4022335 53 H H28 1.4790903 0.9388079 -1.9150594 54 O O3 -2.3011636 1.9239671 0.3955396 55 C C26 -3.6655609 1.9951254 0.8546222 56 H H30 -4.2834140 1.3177237 0.2566735 57 H H34 -3.7109788 1.6546784 1.8950279 58 C C27 -4.1124543 3.4392887 0.7149271 59 H H33 -4.0630861 3.7614884 -0.3303963 !$,! 60 O O4 -2.3654199 -0.3010736 0.7896736 61 H H36 -5.1471168 3.5436870 1.0599268 62 H H15 2.5977981 -1.5740991 0.5744628 63 H H35 -3.4800869 4.1052712 1.3112186 64 H H37 0.7790263 -2.7077330 -3.4950557 65 C C12 -1.8999280 2.7164799 -6.1936903 66 H H6 -1.9114156 3.5338460 -5.4610073 67 H H22 -2.8290552 2.7402562 -6.7779944 68 H H23 -1.0498346 2.8483703 -6.8652828 69 C C25 2.2766133 1.3486482 2.1240631 70 O O5 2.5891766 0.1300419 2.2773458 71 C C29 1.6842660 2.1160935 3.2468140 72 C C30 1.5212465 1.5746164 4.4696522 73 H H26 1.3923342 3.1437432 3.0387644 74 H H38 1.8568737 0.5444194 4.5831460 75 C C31 2.4772726 2.0369434 0.8969223 76 C C32 3.0798527 1.3472455 -0.1755851 77 H H39 2.1657598 3.0729560 0.8055755 78 C C33 0.9527486 2.2027307 5.6634607 79 C C34 -0.1367489 3.3156271 8.0223909 80 C C35 0.4538772 3.5207561 5.6831309 81 C C36 0.8884751 1.4619769 6.8588378 82 C C37 0.3520301 2.0084712 8.0231861 83 C C38 -0.0816312 4.0677685 6.8445248 84 H H41 0.4847381 4.1198018 4.7776802 85 H H42 1.2681034 0.4426007 6.8648579 86 H H43 0.3157959 1.4128066 8.9319484 87 H H44 -0.4599346 5.0870793 6.8330563 88 H H45 -0.5563601 3.7456304 8.9280320 89 C C39 3.6888789 2.0646344 -1.3277908 90 C C40 4.8862212 3.3504428 -3.5398676 91 C C41 4.8291309 1.5306237 -1.9494701 92 C C42 3.1570803 3.2583300 -1.8464957 93 C C43 3.7488503 3.8935879 -2.9367535 94 C C44 5.4251174 2.1646781 -3.0393604 95 H H46 5.2578106 0.6092095 -1.5611011 96 H H47 2.2699386 3.6927628 -1.3926224 97 H H48 3.3202819 4.8174391 -3.3178522 98 H H49 6.3121964 1.7325694 -3.4961514 99 H H50 5.3464843 3.8472226 -4.3900222 100 H H31 2.3735585 -0.5837343 -1.5706167 101 H H40 3.6569891 0.4864086 0.1550001 !$#!C. Cartesian Coordinates for Transition State -3 (TS -3): Atom X Y Z 1 C C1 0.8609413 -0.6213862 -1.4622941 2 C C3 -0.1214979 0.3349001 0.6197591 3 C C4 -0.3358583 -2.0058724 0.2473504 4 O O1 -0.1401574 -0.9480645 1.1117391 5 C C6 -0.2128968 -1.7117673 -1.2201091 6 C C25 0.4810300 0.5996585 -0.6323544 7 H H11 -1.1845350 -1.3679335 -1.6039467 8 H H2 1.8068919 -1.0107097 -1.0676956 9 H H12 0.0177369 -2.6379998 -1.7472858 10 C C5 -0.6333198 -3.1790976 0.8388777 11 H H4 -0.7033349 -3.2111872 1.9202898 12 C C7 -0.9480849 -4.4147057 0.1104858 13 O O2 -0.9152825 -4.5939012 -1.0968605 14 O O3 -1.3339495 -5.3765223 0.9855187 15 C C8 -1.7689675 -6.6235958 0.4018068 16 H H6 -0.9282780 -7.0814931 -0.1307006 17 H H7 -2.5509107 -6.4146552 -0.3359579 18 C C9 -2.2736922 -7.5011268 1.5323946 19 H H8 -1.4772285 -7.7062169 2.2550018 20 H H9 -2.6325761 -8.4560909 1.1319269 21 H H10 -3.1015162 -7.0160364 2.0605908 22 C C10 1.0568327 -0.3118607 -2.9353945 23 C C11 1.4422109 0.2188359 -5.6726712 24 C C12 0.0329422 0.2579918 -3.7065100 25 C C13 2.2764658 -0.6077009 -3.5581101 26 C C14 2.4693060 -0.3456696 -4.9160718 27 C C15 0.2225235 0.5212362 -5.0629469 28 H H1 -0.9259333 0.4906058 -3.2476529 29 H H13 3.0801222 -1.0464673 -2.9712006 30 H H14 3.4227451 -0.5835682 -5.3801299 31 H H15 -0.5836431 0.9600871 -5.6450251 TS-3 &H¡ = -1494.13590 hartree &&H¡rel = 0.00 kcal/mol àTS-3 (endo) 2.0 †2.6 †!$$! 32 H H16 1.5890323 0.4221644 -6.7299712 33 C C16 -0.5295210 1.3182271 1.5237564 34 H H17 -0.7660406 0.9906283 2.5324941 35 C C24 -0.5633517 2.6659889 1.2037551 36 C C18 -0.9302586 3.7222625 2.1422133 37 C C19 -1.8086151 5.7246784 3.9054352 38 C C20 -0.6429962 3.6391487 3.5184458 39 C C21 -1.6348059 4.8453016 1.6640764 40 C C22 -2.0837037 5.8295505 2.5389700 41 C C23 -1.0773974 4.6354271 4.3885374 42 H H5 -0.0513109 2.8113265 3.8964504 43 H H19 -1.8550035 4.9229848 0.6014666 44 H H20 -2.6505143 6.6757202 2.1584094 45 H H21 -0.8390705 4.5651591 5.4461535 46 H H22 -2.1549526 6.4948428 4.5895281 47 H H23 -0.6031739 2.9451972 0.1553829 48 H H25 0.0566285 1.4331372 -1.1859028 49 O O4 2.8464826 1.3140396 1.9569881 50 C C2 2.3751606 2.6610736 1.8436844 51 C C17 1.9216492 2.8418467 0.4776435 52 C C26 2.1468622 1.6524358 -0.2396700 53 C C27 2.8757383 0.7437521 0.7091525 54 H H26 1.7077216 3.8229125 0.0777766 55 H H27 2.4472006 1.6342442 -1.2833918 56 O O5 3.3993931 -0.3207610 0.4919843 57 O O6 2.4267609 3.3990249 2.7938080 D. Cartesian Coordinates for Transition State -4 (TS -4): Atom X Y Z 1 C C1 1.3529596 -0.8480866 -0.6481265 2 C C3 -0.6149020 0.3851006 0.3294388 3 C C4 -0.5092905 -1.9853883 0.6386729 TS-4 &H¡ = -1494.13138 hartree &&H¡rel = 2.84 kcal/mol àTS-4 (exo) 2.4 †2.1 †!'&&! 4 O O1 -0.9314114 -0.7445835 1.0530671 5 C C6 0.3414423 -2.0239968 -0.5918822 6 C C29 0.6031812 0.4617746 -0.3835385 7 H H11 -0.3190341 -1.9610197 -1.4687688 8 H H2 2.0875289 -1.0015283 0.1521533 9 H H12 0.8441130 -2.9895164 -0.6492338 10 C C5 -0.9580850 -3.0187990 1.3800552 11 H H4 -1.6051881 -2.8051352 2.2234882 12 C C7 -0.6895625 -4.4326152 1.0898376 13 O O2 0.0188370 -4.8904528 0.2074056 14 O O3 -1.3787017 -5.2158617 1.9576026 15 C C8 -1.2603182 -6.6394878 1.7501498 16 H H6 -0.2048214 -6.9229348 1.8152408 17 H H7 -1.6020921 -6.8778677 0.7371436 18 C C9 -2.1034559 -7.3251691 2.8092053 19 H H8 -1.7488143 -7.0754865 3.8145043 20 H H9 -2.0471515 -8.4119987 2.6830346 21 H H10 -3.1528927 -7.0229818 2.7294786 22 C C10 2.0964289 -0.8816115 -1.9777059 23 C C11 3.4499487 -1.0696478 -4.4362634 24 C C12 1.4201005 -0.6656794 -3.1866635 25 C C13 3.4599346 -1.1928796 -2.0206757 26 C C14 4.1328625 -1.2847779 -3.2389442 27 C C15 2.0897353 -0.7577325 -4.4071045 28 H H1 0.3577990 -0.4297768 -3.1806294 29 H H13 4.0025436 -1.3416402 -1.0921101 30 H H14 5.1940016 -1.5186214 -3.2499475 31 H H15 1.5475959 -0.5895429 -5.3340107 32 H H16 3.9739869 -1.1424784 -5.3854304 33 C C16 -1.4374917 1.4752955 0.6035458 34 H H17 -2.2236404 1.3121392 1.3358137 35 C C28 -1.1833966 2.7591099 0.1325998 36 C C18 -1.9308131 3.9446049 0.5564207 37 C C19 -3.3747255 6.2405716 1.3000909 38 C C20 -2.5862310 4.0111384 1.8022614 39 C C21 -1.9917170 5.0638127 -0.2938387 40 C C22 -2.7163738 6.1962092 0.0699950 41 C C23 -3.3005718 5.1466543 2.1684880 42 H H5 -2.5166270 3.1763164 2.4942848 43 H H19 -1.4679021 5.0376955 -1.2448427 44 H H20 -2.7621049 7.0464876 -0.6042265 45 H H21 -3.7945950 5.1844204 3.1357829 46 H H22 -3.9345556 7.1261664 1.5878684 47 O O4 2.6401692 3.2994098 -0.5567025 48 C C24 2.8436114 2.0271833 -0.0557758 49 C C25 1.6938132 1.6886289 0.8471346 50 C C26 1.0469011 2.9159888 1.0954363 51 C C27 1.6178570 3.9249831 0.2053396 52 H H24 1.8709370 0.9400227 1.6115766 53 H H25 0.5137011 3.2043304 1.9878685 54 O O5 1.3561103 5.0875225 0.0380212 55 O O6 3.8092344 1.3687130 -0.3348211 56 H H28 -0.6292714 2.8741055 -0.7932937 57 H H30 0.6104043 1.1689129 -1.2084704 !'&'!E. Cartesian Coordinates for Transition State -5 (TS -5): Atom X Y Z 1 C C1 1.2099891 -0.3471042 -1.2800966 2 C C3 0.2734533 0.4472441 0.9054393 3 C C4 0.7973839 -1.8951960 0.6561338 4 O O1 0.3694607 -0.8230627 1.4099870 5 C C6 0.7550584 -1.7495885 -0.8344474 6 C C25 0.4811677 0.7262971 -0.4665002 7 H H11 -0.2819923 -1.9167358 -1.1448726 8 H H2 2.2673951 -0.2408241 -0.9892722 9 H H12 1.3667268 -2.5317808 -1.2835679 10 C C7 1.5912905 -4.2576008 0.8089053 11 O O2 1.7957316 -4.5165365 -0.3666533 12 O O3 1.7729394 -5.1592587 1.8086631 13 C C8 2.2069066 -6.4801433 1.4150166 14 H H6 2.6820114 -6.8835522 2.3130711 15 H H7 2.9525666 -6.3873576 0.6210412 16 C C9 1.0358452 -7.3445767 0.9697317 17 H H8 0.2689351 -7.3923471 1.7500195 18 H H9 1.3828268 -8.3639438 0.7644093 19 H H10 0.5878308 -6.9429787 0.0568042 20 C C10 1.1668548 -0.1284825 -2.7885856 21 C C11 1.1538459 0.3529657 -5.5649571 22 C C12 2.1809780 0.6267717 -3.3946327 23 C C13 0.1443219 -0.6436374 -3.5997932 24 C C14 0.1402725 -0.4040312 -4.9754608 25 C C15 2.1761479 0.8702510 -4.7683740 26 H H1 2.9901157 1.0224863 -2.7835894 27 H H13 -0.6638268 -1.2188678 -3.1593251 28 H H14 -0.6603367 -0.8133706 -5.5859152 29 H H15 2.9751546 1.4560282 -5.2156076 30 H H16 1.1486091 0.5351967 -6.6361722 31 C C16 -0.2082550 1.3871035 1.8226156 TS-5 &H¡ = -1494.13309 hartree &&H¡rel = 1.8 kcal/mol à2.0 †TS-5 (endo) 2.6 †!'&(! 32 H H17 -0.5406519 1.0037565 2.7829210 33 C C24 -0.3691868 2.7274526 1.5073844 34 C C18 -0.9826042 3.7284035 2.3719023 35 C C19 -2.0919751 5.7220064 4.0142521 36 C C20 -1.9059339 3.3948018 3.3817145 37 C C21 -0.6474764 5.0845689 2.1892436 38 C C22 -1.1898776 6.0712053 3.0057048 39 C C23 -2.4490860 4.3837527 4.1959135 40 H H5 -2.2183532 2.3638275 3.5108206 41 H H19 0.0552628 5.3564683 1.4043900 42 H H20 -0.9130820 7.1110553 2.8560713 43 H H21 -3.1654391 4.1116971 4.9657839 44 H H22 -2.5228204 6.4911146 4.6494097 45 H H23 0.2078272 3.1322538 0.6826189 46 H H25 0.8346269 1.7325675 -0.6736259 47 O O4 -3.1060526 0.5688202 0.2196682 48 C C2 -2.2679826 0.1088159 -0.7577732 49 C C17 -1.3474266 1.2275106 -1.1658063 50 C C26 -1.8725443 2.3774922 -0.5408898 51 C C27 -2.9873292 1.9972776 0.3008425 52 H H26 -0.9941825 1.2255563 -2.1916098 53 H H27 -1.7021314 3.4084872 -0.8167359 54 O O5 -3.7616493 2.6239252 0.9762221 55 O O6 -2.3232885 -1.0258272 -1.1684288 56 C C5 1.1397717 -2.9816431 1.3779094 57 H H4 1.0621748 -2.9287144 2.4580821 !'&"! APPENDIX !'&%! OCO2EtPhPhII-3a- SOCO2EtPhPhII-3a- S!'&)! OCO2EtII-3b- SOMe OMe OCO2EtII-3b- SOMe OMe !'&+! OCO2EtII-3c- SOMe MeO OCO2EtII-3c- SOMe MeO !'&,! OCO2EtII-3d- SOMe MeO OCO2EtII-3d- SOMe MeO !'&#! OCO2EtII-3e- SOCO2EtII-3e- S!'&$! OCO2EtII-3f- SOCO2EtII-3f- S!''&! OCO2EtII-3g- SFFOCO2EtII-3g- SFF!'''! OCO2EtII-3h- SBrBrOCO2EtII-3h- SBrBr!''(! OCO2EtII-3i- SBrBrOCO2EtII-3i- SBrBr!''"! OCO2EtII-3j- SClClOCO2EtII-3j- SClCl!''%! OCO2EtII-3k- SClClOCO2EtII-3k- SClCl!'')! OCO2EtII-3l- SOOOCO2EtII-3l- SOO!''+! OCO2EtII-3m- SOCO2EtII-3m- S!'',! OCO2EtII-3p- SOCO2EtII-3p- S!''#! OCO2EtII-3n- SOCO2EtII-3n- S!''$! OCO2EtII-3o- SOCO2EtII-3o- S!'(&! OCO2EtHNCNCNCII-5ab NCOCO2EtHNCNCNCII-5ab NC!'('! OCO2EtHNCNCNCII-5bb NCOOOCO2EtHNCNCNCII-5bb NCOO!"##! OCO2EtHNCNCNCII-5jb NCClCl!"#$!OCO2EtHNCNCNCII-5jb NCClCl!"#$! OCO2EtPhPhHII-5aa OOOOCO2EtPhPhHII-5aa OOO!"#$!OCO2EtHII-5ba OOOOO!"#%!OCO2EtHII-5ba OOOOO!"#&! OCO2EtHII-5ja OOOClCl!"#'!OCO2EtHII-5ja OOOClCl!"#$! ONOCO2EtPhPhHII-5ac PhONOCO2EtPhPhHII-5ac Ph!"#$! ONOCO2EtHII-5bc PhOO!"#"! ONOCO2EtHII-5bc PhOO!"#%! ONOCO2EtHII-5cc PhOO!"##! ONOCO2EtHII-5cc PhOO!"#&!ONOCO2EtHII-5jc ClClPh!"#'!ONOCO2EtHII-5jc ClClPh!"#$! OCO2EtPhPhHII-6ad NCOCO2EtPhPhHII-6ad NC!"#%!!!!!!"#"$"%"&"'"(")"*"+","OPhHhNCHgHdHiHjHeOOobserved nOes HckHaHbfII-6ad "-."/0123"4'"5#$ "!"#&!Crystal Structure: !!!!!OCO2EtHII-5ja OOOClCl!"#'!!"#$%& '!"#$%&'()*%+",')-(&".))$/(*%'01"2345 67"%*/"89:(;%+0*'"<1)'$)=(&">(1=+%&0-0*'"?%$%-0'0$1"2@ A345B7"C)$" (()'*" D"!"#"(1"/0C(*0/"%1"4EB")C"'F0"'$%&0")C"'F0")$'F)G)*%+(10/" !$%D""+,-. 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!6748 "!"""#"9:&;< "C#!($'#!>#("!(&$>!#(!C(!*''(!($$%!(>#&!##!C>!#%"#!##)%!('')!#*!C%!(('"!()"$!$%*)!##!C&!>(%"!(")"!>(((!#*!C") !>('>!>"&$!%)*&!('!C"" !%">&!>'&(!%($%!$>!C"* !&%>&!$("$!$%>>!$)!C"# !&$'"!$)%>!>$)#!>)!C">j !&%#&!>"#"!(%"'!%*!C">= !%'')!$))>!(($'!%*!C">0 !%&*%!>)>#!()&>!%*!C"$ !""')!#((>!>#"(!#%!C"%j !"*$#!"%&>!>#>)!#'!C"%= !*%*'!"&%*!>#%)!#'!C"' !"*(*!**(%!%">*!#$!C*"j !X''%!X&*!$&##!>>!C*"= !X*)*$!$'%!$%'&!>>!C**j !X")%)!X*#!&)*"!"*>!C**= !X*#&#!X*%%!%%"(!"*>!C**0 !X*""'!%#(!%'%%!"*>!C*> !*#>)!*)(&!*')"!>)!C*$ !%""!*&'%!*>)(!>&!C*% !X#&)!#&>)!#**%!$"!C*& !"#$!#&&>!(#%%!(%!C*'j !(#'$!")"$!#''%!$(!C*'= !(*(>!"%">!##%'!$(!C*'0 !#*">!'$(!#>"%!$(!C*Kj !%#%!%)#(!(">#!"&'!!">"!C*K= !""*&!%(#*!#(#*!"&'!C"Kj !>'%#!%&%>!#("(!&$!C"K= !%*"$!%(#(!#$'$!&$! Experimental Single crystals of C 31H32Cl4O8 [BB715a] were used as received . A suitable crystal was selected and mounted using a small amount of paratone oil on a nylon loop on a 'Bruker APEX -II CCD' diffractomete r. The crystal was kept at 1 73(2) K during data collection. Using Olex2 [1], the structure was solved with the olex2.solve [2] structure solution program using Charge Flipping and refined with the XL [3] refinement pac kage using Least Squares minimiz ation. "?!e<.<;,6O?!j84,! 01234?!j%"a!>' X%>?!#?!KH/.51:8ba!f?u?!N*))&O?!j84,!01234?!j$(a!""* X"**?!Crystal stru cture determination of [BB715a] Crystal Data for C 31H32Cl4O8 (M =674.36 g/mol): orthorhombic, space group P2 12121 (no. 19), a = 10.9256(4) †, b = 14.7077(4) †, c = 19.6645(8) †, V = 3159.90(19) †3, Z = 4, T = 173.0 K, µ(CuK !) = 3.823 mm -1, Dcalc = 1.418 g/cm 3, 15359 reflections measured (7.506¡ " 2# " 143.998¡), 5984 unique ( Rint = 0.0820, R sigma = 0.0958) which were used in all calculations. The final R1 was 0.0631 (I > 2 $(I)) and wR2 was 0.1646 (all data). Refinement model description Number of restraints - 0, number of constraints - unknown. Details: 1. Fixed Uiso At 1.2 times of: All C(H) groups, All C(H,H) groups At 1.5 times of: All C(H,H,H) groups 2.a Ternary CH refined with riding coordinates: C3(H3), C4(H4), C5(H5), C8(H8 ), C16(H16) 2.b Secondary CH2 refined with riding coordinates: C17(H17A,H17B), C21(H21A,H21B), C2S(H2SA,H2SB), C1S(H1SA,H1SB) 2.c Aromatic/amide H refined with riding coordinates: C7(H7), C10(H10), C11(H11), C12(H12), C13(H13), C19(H19), C25(H25), C26(H2 6), C27(H27), C28(H28) 2.d Idealised Me refined as rotating group: C15(H15A,H15B,H15C), C22(H22A,H22B,H22C), C29(H29A,H29B,H29C) This report has been created with Olex2, compiled on 2015.01.26 svn.r3150 for OlexSys. Please let us know if there are any errors or if you would like to have additional features. !">*! REFERENCE S !">#!REFERENCE S N"O!u:bH,.8H/6b">&? !!N#O!L,l.a&a&, XH/_,H251 a&a&, XH/_,H251< X*!C X8H1<;/6/ X(a&X5:<.3!:6! 4H/:1!=:<.#''#-&)$()?-,1)?#&$1()9)?$&2+@#-6) -G=JH!7Oa!>)&? !!N>O!e/!=/66/l:../a!L?!i?v!0<66<1a![?!+H/!H251(!N")O!z,6Ga!{?v!E,6Ga!+?v!+<6Ga!{?!A6,64:<3/./84:l/!j;:6/ X0,4,.2Y/5!c(r*d !j667.,4:<63!<9! j../6<,4/3!,65!D_< X5:/6/3o!j6!j32;;/41:8!K264H/3:3!<9!e:H251#$"? !!N""O!x,6Ga!C? X=?v!UH,(? !!N"#O!UH,6Ga!K?v!i7#''#-&) -G==H!7M!N*"Oa! >%#*?!!N">O!L/:a!0? XJ?v!n:,6Ga!x?v!z/:a!x?v!KH:a!u?!A6,64:<3/./84:l/!K264H/3:3!<9!C:GH.2!E7684:<6,.:Y/5! LH<3BH<6,4/ XK7-34:474/5!L21,63!<1!e:H251Oa!""#*&? !!N"$O!C7,6Ga!f?!+?v!i,6b,7a!+?v!x7a!0?!C?!j!0<;B74,4:<6,.!K4752o![/,84:l:42!e:99/1/68/!-/4F//6! LH<3BH:6/ X!,65!j;:6/ X0,4,.2Y/5!028.<,55:4:<63!<9!j../6<,4/3!,65!A6<6/3?! *+,-(.%)+/) 0-1.($2)34#5$&'-6) -G=LH!NP!N(Oa!"%))? !!N"%O!Al,63a!0?!j?v!u:../1a!K?!n?!j;:6/ X8,4,.2Y/5!8<7B.:6G!<9!,../6:8!/34/13!4H!78H!N("Oa!"*#'(? !!N"&O!jG? !!">>!N*"O!f,../2a!f?v!L,4Y/.a!u?!0H:1,.!5:/6/3!91<;!/6,64:<;/1:8,..2!B71/!/6<6/3?!C:GH.2! 34/1/<3/./84:l/!:641,;<./87.,1!e:/.3 Xj.5/1!1/,84:<6!:6l<.l:6G!/4H/6/37. 9<6,4/3?! *+,-(.%)+/) '4#)34#5$2.%)B+2$#'6 DE#-F$()G-.(&.2'$+(&)7) =KK5a!**'%? !!N**O!f./:4/1a![?v!L,k7/44/a!i?!j?!K@fuj XL@!@w+A[j0+@Dw!jK!j!0Dw+[Dii@wf!Ej0+D[!@w!+CA! K+A[ADKAiA0+@T@+x!DE!jee@+@Dw X[Aj0+@DwK?! A22+,('&)+/)34#5$2.%)=#&#.-24) =KM>H!7C!N'Oa!#*&? !!N*#O!C,;,5,a!+?v!K,4#''#-&) =KMKH!ML!N($Oa!$()>? !!N*(O!w:8<.,<7a!J?!0?v!K625/1a!K?!j?v!u<64,G6<6a!+? v!T,33:.:bO!K:/G/.a!0?v!+H<164<6a!A?![?!0DwED[uj+@Dwji!uDeAi!ED[!jKxuuA+[@0!e@AiK XjieA[! [Aj0+@DwK!z@+C!0C@[ji!e@AwAK?! G#'-.4#;-+()>#''#-&) =KMMH!8P!N("Oa!>**>? !!N*$O!+1:B,4H2a![?v!0,11<..a!L?!n?v!+H<164<6a!A?![?!jKxuuA+[@0!e@AiK XjieA[![Aj0+@DwK!z@+C! 0C@[ji!e@AwAK! X!0Dw+[Di!DE!Ej0@ji!KAiA0+@T@+x!+C[DmfC!Cxe[DfAw X=Dwe@wf?! *+,-(.%)+/)'4#)A5#-$2.()34#5$2.%)B+2$#'6) =KKGH!778!N"&Oa!$%(#?!!N*%O!f:7.:,6H!HO!N"&Oa!('%'? !!N*&O!n:6a!U ?!0?v!x,6Ga![?!n?v!e7a!x?v!+:F,1:a!=?v!f,6G7.2a![?v!0H:a!x?![?!A6,64:<3/./84:l/! @641,;<./87.,1!E<1;,.!*r(!j667.,4:<6!<9!j812.,4/3!,65!,.BH,a-/4, Xm63,471,4/5!@;:6/3! 0,4,.2Y/5!-2!j;:6#''#-&) -G=-H!7H!Oa!%"%? !!N#)O!C/H1/a! z?!n?v!e:48H9:/.5a![?v!L%? !!N#"O!C,1:H,1,6a!L?!0?v!LH!8O!N#Oa!*"#? !!N#*O!=/8b/a!j?!e?!e/63:42 97684:<6,.!4H/1;<8H/;:3412?!@@@?!+H/!1<./!<9!/_,84!/_8H,6G/?! G4#) *+,-(.%)+/)34#5$2.%)E46&$2&) =KK>H!POa!>$(&? !!">$!N##O!=/8b/a!j?!e?!j!wAz!u@{@wf!DE!Cj[+[AA XED0J!jwe!iD0ji!eAwK@+x XEmw0+@Dwji! +CAD[@AK?! *+,-(.%)+/)34#5$2.%)E46&$2&) =KK>H!PO!N*Oa!"#%*? !!N#(O![,GH,l,8H,1:a!J?!L/13B/84:l/!<6!~e/63:42!97684:<6,.!4H/1;<8H/;:3412?!@@@?!+H/!1<./!<9! /_,84!/_8H,6G/~! X!=/8b/!je!N"''#O!n!0H/;!LH23!'&o>$(& X>*?! G4#+-#'$2.%)34#5$&'-6) A22+,('&) -GGGH!7LM!N#X(Oa!#$"?!!N#>O!0<1/2a!A?!n?!0,4,.24:8!/6,64:<3/./84:l/!e:/.3 Xj.5/1!1 /,84:<63o!u/4H<53a!;/8H,6:34:8! 9765,;/64,.3a!B,4HF,23a!,65!,BB.:8,4:<63?! A(1#I.(;'#)34#5$# DJ('#-(.'$+(.%)K;$'$+() -GG-H!<7!N")Oa!"$>)? !!N#$O!i/F,13a!A?!f?! 3+5Q,'.'$+(.%)34#5$&'-6R)J('-+;,2'$+()'+)'4#)G4#+-6).(;)AQQ%$2.'$+(&)+/) :+%#2,%.-).(;)S,.(',5):#24.($2 &T)B#2+(;)K;$'$+( a!*)""? !!N#%O!z:3/a!J?!A?v!zH//./1a![?!j?!e<6<1 X,88/B4<1 X,33:34/5!e:/.3 Xj.5/1!1/,84:<6!<9!,64H1,8/6/! ,65!4/41,82,6%? !!N()O!i:,6Ga!f?!j?v!KH,H!7P!N*>Oa! &#(*?!!N(#O!j5,;3a!=?!J?v!E/134.a!A?!u?v!e,l:3a!u?!0?v!C/1<.5a!u?v!J714b,2,a!K?v!0,;,.:/1a![?!E?v! C<..:6G3H/,5a!u?!f?v!J,71a!f?v!K,73l:../a!A?!j?v![:8b./3a!E?![?/4!,.?!K264H/3:3!,65!-:<.#''#-&) -GGMH!7O!N(Oa!">*>? !!">%!N(>O!e/<6GHa!C?!j?!L?v!z26-/1Ga!C?!KL@[jwAK!?(?!iDwf![jwfA!KC@Aie@wf!AEEA0+K!=x! =AwUAwA!+CDLLCAwA!jwe!Em[jw![@wfK!@w!L[D+Dw!ujfwA+@0![AKDwjw0A!KLA0+[j! DE!e@j[xiKL@[DJA+DwAK?! G#'-.4#;- +()=K5IH!87!N#Oa!>">? !!N($O!K/-/34,a![?v!L:YY74:a!u?!f?v!u:66,,15a!j?!n?v!E/1:6G,a!=?!i?!0#''#-&) -GGLH!C!N*)Oa!#$)'? !!N(&O!K:.l,673a!j?!0?v!f1<<;-1:5G/a!=?!n?v!j651/F3a!=?!@?v!J<8:99 one-pot 74 97 R1 = PhCH=CH III-15h stepwise 98 94 R2 = Ph one-pot 85 95 III-16h stepwise 69 97 one-pot 61 94 Table III -3. Preliminary results of stepwise vs. one-pot synthesis of cyclohexenones and 4 H-pyra ns [a] Isolated yields. [b] Ratios were determined by chiral HPLC analysis. Scheme III -7. Acid catalyzed 4H-pyran formation from dihydropyran . OPhCO2BnTsOH (50 mol%) toluene, reflux, 12 h OPhCO2BnNCNCBrBr82% ee60% yield 82% ee!"+'!Table III -2). When DABCO was use d as the catalyst, higher temperature (110 ¼C) was necessary for the success of this reaction (entry 1 -2, Table III -2). Increas ing of the catalyst did not improve the yield further (entry 3, Table III -2). Both DBU and Et 3N gave similar results as DABCO for this transformation (entry 4 -5, Table III -2). However, D BU was too basic , potentially epi merizing the chiral center of the substrate, as discu ssed in Chapter IV. Pyridine was not an effective base for this reaction either (entry 6, Table III -2). Interestingly, TongÕs group reported that TsOH could catalyzed this rearrangem ent with a similar substrate, as shown in Scheme III -7.60 ! ! !To compare the efficiency of stepwise vs one -pot synthesis of both cyclohexenone and 4 H-pyran, we commenced our investigation with subjecting dihydropyran s III-14a and III-14h to either catalytic HCl or DABCO reaction condition (see Table III -3 for details). Gratifyingly, we isolated product s III-15a and III-16a in 75% overall yield, without compromising enantioselectivity, with 98% ee and >99% ee, respectively. More importantly, similar results, 86% yield with 97% ee of III-15a and 74% yield with 97% ee of III-16a, were achieved in a one-pot format. Not surprisingly, product III-16a was also successfully converted into cyclohexenone III-15a under the same acidic condition. Similarly, the same outcome for stepwise vs. one-pot was observed with substrate III-14h (see Table III-3). III-3. Results and discussion. Encou raged by our preliminary results , we analyzed the scope of our methodology with a series substrates. The 1 st step, the formal [4+2] cycloaddition reaction, has already !"+"!been studied in detail. We focus ed our study on the 2 nd step, which is the acid or base catalyzed rearrangement reaction . Table III -4. Substrate scope of Br¿nsted acid catalyzed cyclohexenone synthesis OR2R1CO2EtOR2R1CH3CN, 80 !, 4 hIII-14 III-15 a,b,cOEtO 2CPhPhOEtO 2CPhPhOEtO 2CPhBrOEtO 2CPhCNOEtO 2CPhBrOPhOMe III-15b 89%, 93% ee (96% ee)III-15ae d>99%, 90% ee (88% ee)III-15a 81%, 98% ee (97% ee)III-15d 74%, 94% ee (97% ee)III-15c 62%, 94% ee (96% ee)III-15be d70%, 92% ee (91% ee)OEtO 2COMe ClOEtO 2COMe OMe O2NFClOOOMe III-15gÕ e85%, 94% ee (97% ee)III-15f >99%, 94% ee (97% ee)III-15e 74%, 94% ee (95% ee)OEtO 2CPhPhIII-15h 85%, 94% ee (98% ee)OEtO 2CIII-15i >99%, 88% ee (87% ee)ClIII-15g (not observed) ClEtO 2CEtO 2COEtO 2CHCl (50 mol%) [a] Isolated yields. [b] Ratios were determined by chiral HPLC analysis. [c] Data in the parenthesis are the ee value of III -14 from formal [4+2] cycloaddition reaction. [d] The enantiomer of III -14 was used as the substrate. [e] 2.0 equiv. HCl was used at refluxed condition in a sealed tube . !"+(!As shown in Table III -4, regardless of the electronic properties of the substituents attached, most of the substituted aryl and alkenyl dihydropyrans delivered the cyclohexenones with good to excellent yields (up to quantitative yield) and excellent retention of enantioselectivi ty (up to 98% ee) ( III-15a Ð III-15f, III-15h Ð III-15i). As expected, both enantiomers III-14ae and III-14be furn ish ed cyclohexenones III-15ae and III-15be, correspondingly . Interestingly , substrate III-14g with o-Cl phenyl substituent did not cyclize to provide the desired cyclohexenone III-15g, presumably on account of steric congestion (see Int III -15g in Figure III -4 for explanation). However, it was found that once the reaction was performed under a more forcing condition (2.0 equiv. HCl , at refluxed condition in a sealed tube ), decarboxylated product III-15gÕ was formed as the major product . In contrast, ortho substituted , but with the ability to form intramolecular H-bonding, such as III-14f, can deliver the desired cyclohexenone product . We speculated that the formation of H -bonding between the methoxy group with proximal carbonyl group of Int III -15f (see Figure III -4), not only locked the rotation of the methoxy phenyl substitution, but also increased the electrophilicity of this car bonyl. The combination of both effects contributes to the success of this transformation (for substrate III-14f, quantitative yield and 94% ee was achieved). Of note, the X-ray crystal structures of Figure III -4. Proposed cyclization intermediates Int III -15f and Int III -15g . OOOOOOOOHCl!steric hindrance Int III-15g HFOOHH-bonding "Int III-15f !"+)!compounds III-15b and III-15d (see III-4 Experimental section) provided unequivocal evidence for the absolute stereochemistry of the products. With these observations, we speculate the mechani sm of this transformation as follows, dihydropyrans undergo hydrolytic cleavage to 1,5 -diketone, followed by intramolecular aldol reaction , and dehydration, sequentially , to furnish the desired cyclohexenones (see Scheme III -8). Parallel to th ese experiment s, a number of substrates were screened for the synthesis of 4 H-pyrans, the results of which are indicated in Table III -5. Gratify ingly, regardless of the nature of the substituents on the aromatic ring , namely the electronic properties and the substitution patterns , all the aryl, alkenyl and hetero -aryl were compatible with our methodology ( III-16aÐIII-16j), furnish ing the 4 H-pyrans with moderate to excellent yields (up to 92%) and excellent retention of enantioselectivity (up to >99% ee). Enantiomers III-16ae and III-16be were obtained when III-14ae and III-14be were used as the starting materials . Noteworthy , for substrate III-14d, milder conditions (60 ¡C) must be applied instead of refluxing to minimize the ep imerization of the benzylic center, as the electron withdrawing group makes the benzylic H more acidic. Due to the dual Scheme III -8. Proposed mechanism for the Br ¿nsted acid catalyzed cyclohexenone formation. OR1R2OEt O*H+OR1R2OEt O*H2OR2*-H+-H+-H2OOEtO OR1R2*OR1R2OEt O*OHH+R1OHOEt OH+H+OOEtO OR1R2*OH!"+*!functions of DABCO, namely the basicity and nucleophilicity, t wo plausible mechanism s are presented in Scheme III -9. In path a , DABCO reacts as a Lewis base, which leads to a Michael addition reaction to form enolate Int a . After intramolecular deprotonation, enol Int b is formed with the DABCO catalyst being ejected . Eventually, Int b undergoes Table III -5. Substrate scope of DABCO catalyzed 4 H-pyran synthesis OR2R1CO2EtDABCO (50 mol%) toluene, reflux, 12 h OR2R1CO2EtOPhPhCO2EtOPhCO2EtBrOPhCO2EtBrOPhPhCO2EtIII-14 III-16 a,b,cIII-16 b63%, 91% ee (96% ee)III-16 aed90%, 82% ee (88% ee)III-16 a81%, >99% ee (97% ee)III-16 bed43%, 87% ee (91% ee)OPhCO2EtOPhCO2EtCNOMe OCO2EtOMe O2NOCO2EtFIII-16 e28%, 96% ee (95% ee)III-16 c70%, 94% ee (96% ee)III-16 de92%, 92% ee (97% ee)III-16 f70%, 95% ee (97% ee)OMe OPhCO2EtOCO2EtPhClOMe OCO2EtBrOIII-16 j63%, 91% ee (96% ee)III-16 h90%, 94% ee (98% ee)III-16 g66%, 96% ee (97% ee)OCO2EtIII-16 i80%, 91% ee (87% ee)ClCl[a] Isolated yields. [b] Ratios were determined by chiral HPLC analysis. [c] Data in the parentheses are the ee values of III-14 from the formal [4+2] cycloaddition reaction. [d] The enantiomer of III-14 was used as the substrate for this transformation. [e] The reaction temperature was 60 ¡C. !"+#!tautomerization to deliver the 4 H-pyran product. 51 Alternatively, DABCO can react as a Br¿nsted base , deprotonate ing the #ÐH of the substrate to form a conjugated enolate intermediate Int c , which is protonated at its !ÐC sequentially to deliver the 4H-pryan product III-16. The application of the 4 H-pran was demonstrated by compound III-16i, which was subjected to the Diels -Alder reaction to provide the adduct III-16ia as a single isomer with out compromising enantioinduction (89% ee of III-16ia vs 91% ee of the starting material III-16i) (see the III-4. Experimental for more details). To demonstrat e the application of our methodology of cyclohexenone synthesis methodology , one -pot format s to synthesize the derivatives of carvone and celery ketone were investigated (see Table III -6 for details). Notably, for substrates III-13kÑIII-13h, H2SO4 instead of HCl was used for carvone derivati ves synthesis, since the isopropenyl group is sensitive towards HCl . In fact, HCl addition of the isopropenyl group was Scheme III -9. Two plausible mechanisms of DABCO catalyzed 4 H-pyran formation. Path a , a Lewis base catalyzed cycle. Path b , a Br¿nsted base catalyzed cycle. OArArOOArArOOEt OArNN***ArNNNNHOHOEt OEt Int a Int b OArArHOOEt OArArOOEt OArCO2EtNN***ArNNNNHOArCO2Et*ArPath a: Path b: Int c NNH!"+&!observed in the reaction . Not surprisingly, some of the carvone or celery ke tone derivatives gave lower yields (substrate III-14k gave no pro duct) , due to the low reactivity of enones III-13 in the formal [4+2] cycloaddition reaction. To compare the reactivity of the series of enones, 1H NMR analysis was performed . As shown in Figure III -5, the more downfield in chemical shift of the "ÐH in enones III-13o to III-13r indicate s the more electrophilic nature (more reactive ) of the "ÐC towards the formal [4+2] cycloaddition reaction. Therefore, a trend in increasing conversion from III-15o to III-15r (12.0% to 100.0%) corroborate s with the NMR study . However, it is noteworthy that excellent enantioselectivities (80% to 95% ee) were obtained for all derivatives. It should be Table III -6. One -pot synthesis of carvone and celery ketone derivatives [a] Isolated yields over two steps. [b] Ratios were determined by chiral HPLC or GC analysis. [c] HCl was used at the 2 nd step. [d] H 2SO4 was used at the 2 nd step. [e] Data in the parentheses were the 1H NMR yields of the formal [4+2] cycloaddition reaction, which was determined by crude 1H NMR with MTBE as the internal standard. ND = not determined. OEtO 2CR1R2CO2EtR1R2O(2.0 equiv) (1 equiv) DHQDPHN (10 mol%) neat, rt, 48 h III-12 III-13 III-15 a,bHCl (50 mol%) or H 2SO4 (50 mol%) CH3CN, 80 ¡C, 4 hOEtO 2COEtO 2COEtO 2CPhOEtO 2COEtO 2CPhIII-15l d19%, 86% eeIII-15m d17%, 89% eeIII-15o c,e12% (12.0%), 95% eeIII-15p c,e21% (21.5%), ND III-15q c,e59% (88.0%), 90% eeOEtO 2CIII-15k reaction fails at 1 st step OEtO 2CEtO 2COEtO 2CEtO 2CIII-15n d36%, NDIII-15r c,e64% (100.0%), 80% ee!"++!mentioned that several attempts to increase the yields of substrates with low reactivity were infructuous . The attempts included using "-ICD as the catalyst, elongating the reaction time, adding more allenoate or setting up the reaction in mmol scale ( it was demonstrated that the formal [4+2] cycloaddition reaction is more efficient when performed in larger scale , as described in Chapter II . In summary, we have elaborated a one -pot protocol to for the divergently synthesis of either chiral cyclohexenone or 4 H-pyran derivatives with excellent enantioselectivity and good yield by sequential modified Morita -Baylis -Hillman reaction/ Br¿nsted acids catalyzed rearrangement reaction or modified Morita -Baylis -Hillman rea ction/ base Figure III -5. Investigation of the reactivity of enones III -13o to III -13r by 1H NMR analysis. OHaOOPhOHaOHaOHa!"+$!catalyzed rearrangement reaction, re spectively. Also, the practicality of this methodology was validated in the synthesis of several chiral carvone and celery ketone synthesis. !"+%!III-4. Experimental. III-4.1. General remarks: Unless specifi ed, all reagents were purchased from commercial sources and used without purification . THF and diethyl ether were distilled from sodium benzophenone ketyl. Methylene chloride, toluene and triethylamine were dried over CaH 2 and freshly distilled prior to use. Ethy l-2,3-butadienoate was synthesized as reported 67 and stored at -20 ¼C. Enones were synthesized as reported 59,66 unless otherwise specified. Column chromatography was performed using Silicycle 60 †, 35 -75 !m silica gel. Thin layer chromatography was performed using 0.2 mm thickness silica gel 60 F254 plates and visualized using UV light, iodine, potassium permanganate stain, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. 1H NMR and 13C NMR, as well as all the 2D NMR spectra, were obtained using a 500 MHz Varian NMR spectrometer and referenced u sing the residual 1H peak from the deuterated solvent . For HRMS (ESI) analysis, a Waters Xevo G2 -XS QTOF mass spectrometer (Agilent) instrument was used and referenced against Polyethylene Glycol (PEG-400-600). Optical rotations were obtained on a Jasco P -2000 polarimeter at 20 ¡C and 589 nm. The specific rotations were calculated according to the equation [ !]20D = (100 !)/( l " c), where l is the path length in decimeters and c is the concentration in g/100mL. !"$'!III-4.2. General procedure A for Br¿nsted acid-catalyzed cyclohexenones synthesis: All the dihydropyran derivatives III-14 were synthesized by reported procedure .59,66 To a solution of the corresponding compound III-14 (1.0 equiv) in CH 3CN, concentrated HCl solution or dilute H 2SO4 solution (2 N) (50 mol % equiv) was added. The solution was heated up to 80 ¡C and kept at this temperature for 4 hours. The mixture was concentrated under N 2 flow (or basified by saturated NaHCO 3 solution, extracted by DCM and concentrated under reduced pressure if H 2SO4 was used as the catalyst). The residue was purified by silica gel column chromatography using ethyl acetate in hexane (1.5% to 20%) as the eluent. III-15a-R: Ethyl ( R)-5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate : Compound III-14a (32.0 mg, 0.1 mmol) was subject to general procedure A to provide 25.9 mg (81% yield) of the pure product as a colorless oil ; 1H NMR (500 MHz, CDCl 3) # 7.39-7.34 ( 7H, m), 7.31 -7.25 ( 3H, m), 4.10 (2H, q, J = 7.0 Hz), 3.58-3.50 (1H, m), 3.01-2.97 (2H, m ), 2.86 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.78 (1H, dd, J = 16.0 Hz, 14.0 Hz), 1.03 OR2R1CO2EtOEtO 2CR2R1III-14a-i III-15a-i CH3CN, 80 !, 4 hHCl or H 2SO4 (50 mol%) **OEtO 2CPhPhIII-15a !"$"!(3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 194.9, 166.5, 158. 7, 142. 4, 138. 6, 133.0, 129. 7, 128.9, 128.6 , 128. 1, 127.3, 126.6 , 61. 3, 43.7 , 40. 2, 39. 3, 13.8 ppm. HRMS (ESI) Calculated Mass for C 21H21O3: 321.1491 ([M+H] +), Found 321.1503 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% isopropanol in n-hexanes at 1.0 mL/min), Rt = 36.0 min (minor) and 52.2 min (major), III-15a-R (98% ee): [ $]20D = -47 (c = 1.90, CDCl 3). III-15b-R: Ethyl ( R)-4-bromo-5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate : Compound III-14b (39.9 mg, 0.1 mmol) was subject to general procedure A to provide 35.5 mg (89% yield) of the pure product as a colorless crystalline solid, mp 112-114 ¡C; 1H NMR (500 MHz, CDCl 3) # 7.51 -7.46 (2H, m), 7.41 -7.34 (5H, m), 7.18 -7.13 (2H, m), 4.10 (2H, dd, J = 7.0 Hz , 7.0 Hz ), 3.55-3.46 (1H, m), 3.00-2.90 (2H, m ), 2.8 3 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.7 4 (1H, dd, J = 16.0 Hz, 14.0 Hz), 1.02 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 194.4, 166.4, 15 8.3, 141.3, 138.4, 133.1, 132.0, 129.7, 128.6, 128.4, 126.6, 121.0, 61.3, 43.5, 39.6, 39.0, 13.7 ppm. HRMS (ESI) Calculated Mass for C 21H20O3Br: 399.0596 ([M+H] +), Found 399.0590 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -OPhIII-15 bBrEtO 2C!"$(!H column (20% isoprop anol in n-hexanes at 1.0 mL/min), R t = 19.9 min (minor) and 57.8 min (major), III-15b-R (93% ee): [ $]20D = -24 (c = 3.08, CDCl 3). III-15c-R:!Ethyl ( R)-4-methoxy -5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate : Compound III-14c (35.0 mg, 0.1 mmol) was subject to general procedure A to provide 21.7 mg ( 62% yield) of the pure product as a colorless oil; 1H NMR (500 MHz, CDCl 3) # 7.40 -7.35 (5H, m), 7.22 -7.17 (2H, m), 6.92 -6.87 (2H, m), 4.10 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.81 (3H, s), 3.53 -3.44 (1H, m), 2.98 -2.92 (2H, m), 2.83 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.74 (1H, dd, J = 16.0 Hz, 14.0 Hz), 1.02 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 195.1 166.6, 158.8, 158.7, 138.6, 134.6, 133.0, 129.6, 128.6, 127.6, 126.6, 114.2, 61.2, 55.3, 44.1, 39.6, 39.4, 13.8 ppm. HRMS (ESI) Calculated Mass for C 22H23O4: 351.1596 ([M+H] +), Found 351.1599 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (20% isopr opanol in n-hexanes at 1.0 mL/min), R t = 30.7 min (major) and 50.2 min (minor), III-15c-R (94% ee): [ $]20D = -28 (c = 1.12, CDCl 3). ! OEtO 2CPhIII-15 cOMe OEtO 2CPhIII-15 dCN!"$)!III-15d-R:!Ethyl ( R)-4-cyano-5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate : Compound III-14d (34.5 mg, 0.1 mmol) was subject to general procedure A to provide 25.5 mg ( 74% yield) of the pure product as a colorless crystalline solid, mp 120-121 ¡C; 1H NMR (500 MHz, CDCl 3) # 7.70 -7.65 (2H, m), 7.44 -7.34 (7H, m), 4.10 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.67 -3.56 (1H, m), 3.02 -2.93 (2H, m), 2.86 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.77 (1H, dd, J = 16.0 Hz, 14.0 Hz), 1.03 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 193.7, 166.2, 157.9, 1 47.5, 138.2, 133.2, 132.8 , 129.9, 128.7, 127.6, 126.6, 118.5, 111.3, 61.4, 43.1, 40.1, 38.5, 13.7 ppm. HRMS (ESI) Calculated Mass for C22H20NO3: 346.1443 ([M+H] +), Found 346.1444 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (20% isopropanol in n-hexanes at 1.0 mL/min), R t = 56.9 min (minor) and 68.1 min (major), III-15d-R (94% ee): [ $]20D = -27 (c = 3.08, CDCl 3). III-15e-R:!Ethyl ( R)-4-methoxy -4''-nitro -5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate: Compound III-14e (39. 5 mg, 0.1 mmol) was subject to general procedure A to provide 29.2 mg (74% yield) of the pure product as a colorless oil; 1H NMR (500 MHz, CDCl 3) # 8.27 -8.22 (2H, m), 7.58 -7.52 (2H, m), 7.22 -7.17 (2H, m), 6.94-6.87 (2H, m), 4.11 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.81 ( 3H, s), 3.56 -3.47 (1H, m), 2.97 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.92 -2.83 (2H, m), 2.77 (1H, dd, J = 16.0 Hz, 14.0 Hz), 1.07 OEtO 2CIII-15 eO2NOMe !"$*!(3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 194.4, 165.7, 158.8, 155.5, 148.1, 144.9, 134.3, 133.9, 127.8, 127.6, 123.8, 114.3, 61.7, 55.3, 43.9, 39.4, 39.3, 13.9 ppm . HRMS (ESI) Calculated Mass for C 22H22NO6: 396.1447 ([M+H] +), Found 396.1449 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (20 % isopropanol in n-hexanes at 1.0 mL/min), R t = 48.4 min (minor) and 75.6 min (major), III-15e-R (94% ee): [ $]20D = -6 (c = 0.94, CDCl 3). III-15f-R:!Ethyl ( R)-4-fluoro -2''-methoxy -5'-oxo-1',2',5',6'-tetrahydro -[1,1':3',1'' -terphenyl] -4'-carboxylate : Compound III-14f (36.8 mg, 0.1 mmol) was subject to general procedure A to provide 36.7 mg (quantitative yiled) of the pure product as a colorless oil; 1H NMR (500 MHz, CDCl 3) # 7.35 -7.30 (1H, m), 7.26 -7.21 (2H, m), 7.16 -7.12 (1H, m), 7.06-7.01 (2H, m), 6.96 -6.89 (2H, m), 4.11 (2H, ddd, J = 7.0 Hz, 7.0 Hz, 2.0 Hz), 3.83 (3H, s), 3.57-3.47 (1H, m), 3.00 -2.88 (2H, m), 2.83 (1H, dd, J = 16.0 Hz, 4.0 Hz), 2.77 (1H, dd, J = 16.0 Hz, 14.0 Hz), 0.93 (3H, t, J = 7.0 Hz) ppm ; 13C NMR (125 MHz, CDCl3) # 194.6 , 165.8, 161.7 (d, 1JC,F = 243.9 Hz), 159.3, 155.8, 138.5 (d, 4JC,F = 3.1 Hz ), 133.7, 130.6, 128.2 (d, 3JC,F = 7.4 Hz ), 128.0, 127.7, 120.5, 115.6 (d, 2JC,F = 21.3 Hz), 111.0, 60.9, 55.7, 44.4, 39.5, 38.8, 13.7 ppm. HRMS (ESI) Calculated Mass for C22H22O4F: 369.1502 ([M+H] +), Found 369.1503 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (10% OEtO 2CIII-15 fFOMe !"$#!isopropanol in n-hexanes at 1.0 mL/min), R t = 24.9 min (minor) and 29.3 min (major), III-15f-R (94% ee): [ $]20D = -41 (c = 1.16, CDCl 3). III-15gÕ-S: ( S)-1-(2-chlorophenyl)-3-(4-methoxyphenyl)hexane -1,5-dione: Compound III-14g (38.5 mg, 0.1 mmol) was subject to a modified general procedure A to provide 28.1 mg (85% yield) of the pure product as a colorless oil; 1H NMR (500 MHz, CDCl 3) # 7.38-7.32 (2H, m), 7.27 -7.22 (2H, m), 7.14 -7.10 (2H, m), 6.83 -6.76 (2H, m), 3.81-3.74 (1H, m), 3.77 ( 3H, s), 3.32 (1H, dd, J = 16.0 Hz, 7.0 Hz), 3.23 (1H, dd, J = 16.0 Hz, 7.0 Hz), 2.85 (1H, dd, J = 16.0 Hz, 7.0 Hz), 2.79 (1H, dd, J = 16.0 Hz, 7.0 Hz), 2.06 ( 3H, s) ppm; 13C NMR (125 MHz, CDCl 3) # 207.3, 201.9, 158.3, 139.3, 135.1, 131.6, 130.7, 130.4, 128.9, 128.4, 126.8, 114.0, 55.2, 49.8, 49.1, 36.2, 30.4 ppm . HRMS (ESI) Calculated Mass for C 19H20O3Cl: 331.1101 ([M+H] +), Found 331.1091 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (15% isopropanol in n-hexanes at 1.0 mL/min), R t = 46.7 min (minor) and 62.3 min (major), III-15gÕ-S (94% ee): [ $]20D = -12 (c = 1.66, CDCl 3). ClOOOMe III-15 gÕOEtO 2CPhIII-15 hPh!"$&!III-15h-R:!Ethyl ( R,E) -3-oxo-5-styryl -1,2,3,6-tetrahydro -[1,1' -biphenyl]-4-carboxylate: Compound III-14h (34.6 mg, 0.1 mmol) was subject to general procedure A to provide 29.4 mg ( 85% yield ) of the pure product as a colorless crystalline solid, mp 124-128 ¡C; 1H NMR (500 MHz, CDCl 3) # 7.47 -7.28 (10H, m), 7.11 (1H, d, J = 16.0 Hz), 7.04 (1H, d, J = 16.0 Hz), 4.43 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.48 -3.35 (1H, m), 3.12 (1H, ddd, J = 17.0 Hz, 5.0 Hz, 2.0 Hz), 2.82 (1H, ddd, J = 16.0 Hz, 5.0 Hz, 2.0 Hz), 2.80 -2.68 (2H, m), 1.41 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 195.2, 166.8, 152.1, 142.8, 138.3, 135.5, 132.4, 129.8, 129.0, 128.3, 127.6, 127.3, 126.8, 124.9, 61.7, 44 .0, 39.8, 33.3, 14.4 ppm. HRMS (ESI) Calculated Mass for C 23H23O3: 347.1647 ([M+H] +), Found 347.1655 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (20% isopropanol in n-hexanes at 1.0 mL/min), Rt = 31.2 min (minor) and 43.6 min (major), III-15h-R (94% ee): [ $]20D = -64 ( c = 1.45, CDCl3). III-15i-R:!Ethyl ( R,E) -2'-chloro-5-(2-chlorostyryl) -3-oxo-1,2,3,6-tetrahydro -[1,1' -biphenyl]-4-carboxylate : Compound III-14i (41.5 mg, 0.1 mmol) was subject to general procedure A to provide 41.3 mg (quantitative yield ) of the pure product as a pale yellow crystalline solid , mp 168 -169 ¡C; 1H NMR (500 MHz, CDCl 3) # 7.61 -7.56 (1H, m), 7.51 (1H, d, J = 16.0 Hz), 7.46 -7.42 (1H, m), 7.41 -7.37 (1H, m), 7.36 -7.31 ( 2H, m), 7.30 -7.23 OEtO 2CIII-15 iClCl!"$+!(3H, m), 7.01 (1H, d, J = 16.0 Hz), 4.42 (2H, q, J = 7.0 Hz ), 4.01 -3.90 (1H, m), 3.19 (1H, ddd, J = 18.0 Hz, 6.0 Hz, 2.0 Hz), 2.86 -2.67 (3H, m), 1.40 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 194.9, 166.6, 151.8, 139.6, 134.5, 134.1, 133.7, 133.0, 130.5, 130.2, 130.1, 128.5, 127.5, 127.4, 127.2, 127.2, 67.8, 42.7, 35.9 31.4, 14.3 ppm. HRMS (ESI) Calculated Mass for C 23H21O3Cl2: 415.0868 ([M+H] +), Found 415.0868 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD-H column (3% isopropanol in n-hexanes at 0.8 mL/min), R t = 33.1 min (minor) and 35.7 min (major), III-15i-R (91% ee): [ $]20D = -112 (c = 0.66, CDCl 3). III-4.3. General procedure B for one-pot synthesis of cyclohexenones III-15lÑIII-15r: To a mixture of the corresponding enone III-13 (1.0 equiv) and catalyst (10 mol% ) in a vial with stirring bar, allenoate III-12 (2-4 equiv) was added. The reaction was kept at room temperature for 48 h. The mixture was diluted by CH 3CN, and transferred to a sealed tube by a pipette. To the solution, HCl or H 2SO4 (50 mol%) was added , followed by heating to 80 ¼C. After 4 h , the reaction solution was worked up (when HCl was used as the catalyst, the reaction solution was worked up by removing the solvent under N 2 flow; when H 2SO4 was used as the catalyst, the reaction was worked up by adding saturated NaHCO 3, and extracted with EtOAc and concentrated under rota vap), and the compound was purified following general procedure A. OEtO 2CR1R2CO2EtR1R2O(2.0 equiv) (1 equiv) DHQDPHN (10 mol%) neat, rt, 48 h III-12 III-13 III-15 HCl (50 mol%) or H 2SO4 (50 mol%) CH3CN, 80 ¡C, 4 h!"$$! III-15l-R:!Ethyl ( R,E) -2-(3-methylbuta -1,3-dien-1-yl)-6-oxo-4-(prop -1-en-2-yl)cyclohex -1-ene-1-carboxylate : Compound III-12l (32.4 mg, 0. 2 mmol) was subject to general procedure B to provide 10.4 mg ( 19% yield ) of the pure product as a colorless oil ; 1H NMR (500 MHz, CDCl 3) # 6.86 (1H, d, J = 16.0 Hz), 6.42 (1H, d, J = 16.0 Hz), 5.28 -5.32 (2H, m), 4 .87-4.90 (1H, m), 4.83 -4.85 (1H, m), 4.37 (2H, ddd, J = 7.0 Hz, 7.0 Hz, 1.5 Hz), 2.84 (1H, ddd, J = 17.5 Hz, 4.5 Hz, 1.5 Hz), 2.72 -2.79 (1H, m), 2.64 (1H, ddd , J = 16.0 Hz, 3.5 Hz, 1.5 Hz), 2.37 -2.48 (2H, m), 1.87 -1.91 (3H, m), 1.79 -1.82 (3H, m), 1.36 (3H, t, J = 7.0 Hz) ppm ; 13C NMR (125 MHz, CDCl3) # 195.6, 166.8, 152.5, 146.0, 141.5, 140.7, 132.3, 125.5, 123.0, 111.3, 61.5, 42.3, 40.8, 30.3, 20.4, 18.1, 14.3 ppm. HRMS (ESI) Calculated Mass for C 17H23O3: 275.1647 ([M+H] +), Found 275.1642 ([M+H] +). T he enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (3% isopropanol in n -hexanes at 0.6 mL/min), R t = 16.7 min ( major ) and 18.0 min ( minor ), III-15l-R (86% ee): [ $]20D= -28 (c = 0.18, CH 2Cl2). III-15m-R:!Ethyl ( R)-3-oxo-5-(prop -1-en-2-yl)-3,4,5,6-tetrahydro -[1,1' -biphenyl]-2-carboxylate : Compound III-12m (34.4 mg, 0.2 mmol) was subject to general procedure OEtO 2CIII-15 lOEtO 2CIII-15 mPh!"$%!B to provide 9.6 mg ( 17% yield ) of the pure product as a colorless oil ; 1H NMR (500 MHz, CDCl3) # 7.34 -7.43 (5H, m), 4.81 -4.92 (2H, m), 4.07 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.68 -2.95 (4H, m), 2.49 (1H, dd, J = 16.0 Hz, 13.5 Hz), 1.80 (3H, s), 1.00 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 195.3, 166.5, 159.0, 145.7, 138.8, 132.9, 129.6, 128.6, 126.6, 111.3, 61.2, 42.0, 41.2, 36.6, 20.5, 13.7 ppm. HRMS (ESI) Calculated Mass for C 18H21O3: 285.1491 ([M+H] +), Found 285.1490 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H col umn (5% isopropanol in n -hexanes at 1.0 mL/min), R t = 13.3 min (minor) and 15.5 min (major), III-15m-R (89% ee): [ $]20D= -21 (c = 0.58, CH 2Cl2). III-15n-R:!Diethyl ( R)-3-oxo-5-(prop -1-en-2-yl)cyclohex -1-ene-1,2-dicarboxylate : Compound III-12n (33.6 mg, 0.2 mmol) was subject to general procedure B to provide 40.0 mg ( 72% yield ) of the pure product as a pale yellow oil ; 1H NMR (500 MHz, CDCl 3) # 4.91 -4.80 (2H, m), 4.32 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4.28 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.88 (1H, ddd, J = 18.5 Hz, 4.0 Hz, 1.5 Hz), 2.80 -2.72 (1H, m), 2.68 (1H, ddd, J = 16.5 Hz, 4.0 Hz, 2.0 Hz), 2.51 (1H, dd, J = 18.5 Hz, 10.5 Hz), 2.43 (1H, ddd, J = 16.0 Hz, 13.5 Hz), 1.80 -1.77 (3H, m), 1.34 (3H, t, J = 7.0 Hz), 1.32 (3 H, t, J = 7.0 Hz) ppm . HRMS (ESI) Calculated Mass for C 15H21O5: 281.13 95 ([M+H] +), Found 281.1389 ([M+H] +). [$]20D= -2 (c = 1.38, CDCl 3). OEtO 2CIII-15 nEtO 2C!"%'! III-15o-R:!Ethyl ( R)-2-methyl -6-oxo-4-propylcyclohex-1-ene-1-carboxylate: Compound III-12o (22.4 mg, 0.2 mmol) was subject to general procedure B to provide 7.6 mg ( 17% yield ) of the pure product as a colorless oil; 1H NMR (500 MHz, CDCl 3) # 4.30 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.49-2.58 (1H, m), 2.35 -2.44 (1H, m), 2.04 -2.17 (3H, m), 1.99 (3H, s), 1.32 -1.38 (4H, m), 1.32 (3H, t, J = 7.0 Hz), 0.88 -0.94 (3H, m) ppm; 13C NMR (125 MHz, CDCl 3) # 195.4, 166.9, 159.5, 133.0, 61. 2, 43.3, 38.3, 37.8, 33.7, 22.1, 19.5, 14.2, 14.0 ppm. HRMS (ESI) Calculated Mass for C 13H20O3Na: 247.1310 ([M+Na] +), Found 247.1309 ([M+Na] +). The enantiomeric excess was determined by GC analysis, using GAMMA DEX 225 chiral stationary phase (T1 = 120 ¡C; rate = 0.1 ¡C/min; T 2 = 140 ¡C, hold 10 min, rate = 10 ¡C/min; T 3 = 200 ¡C), R t = 89.7 min (minor) and 89.9 min (major), III-15o-R (95% ee): [ $]20D= -29 (c = 0.52, CDCl 3). III-15p-R:!Ethyl ( R,E) -6-oxo-2-(pent -1-en-1-yl)-4-propylcyclohex-1-ene-1-carboxylate : Compound III-12p (33.2 mg, 0.2 mmol) was subject to general procedure B to provide 27.8 mg (50% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) # 6.25 -6.40 (2H, m), 4.34 (2H, dd, J = 7.5 Hz, 7.5 Hz), 2.56 -2.77 (2H, m), OEtO 2CIII-15 oOEtO 2CIII-15 p!"%"!2.16-2.24 (2H, m), 2.08 -2.15 (3H, m), 1.47 (2H, td, J = 7.0 Hz, 7.0 Hz), 1.35 -1.42 (4H, m), 1.34 (3H, t, J = 7.0 Hz), 0.93 (3H, t, J = 7.0 Hz), 0.90 -0.94 (3H, m) ppm; 13C NMR (125 MHz, CDCl 3) # 196.3, 167.1, 152.9, 142.2, 131.3, 127.8, 61.4, 43.7, 38.0, 35.6, 33.5, 31.7, 21.9, 19.6, 14.2, 14.0, 13.7 ppm. HRMS (ESI) Calculated Mass for C 17H27O3: 279.1960 ([M+H] +), Found 279.1960 ([M+H] +). [$]20D= -34 (c = 0.5, CDCl3). III-15q-R:!Ethyl ( R)-3-oxo-5-propyl-3,4,5,6-tetrahydro -[1,1' -biphenyl]-2-carboxylate: Compound III-12q (34. 8 mg, 0.2 mmol) was subject to general procedure B to provide 33.7 mg (59% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) # 7.32 -7.42 (5H, m), 4.06 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.74 -2.81 (1H, m), 2.64 -2.70 (1H, m), 2.46 -2.54 (1H, m), 2.19 -2.33 (2H, m), 1.35 -1.47 (4H, m), 0.99 (3H, t, J = 7.0 Hz), 0.93 (3H, t, J = 7.0 Hz) ppm ; 13C NMR (125 MHz, CDCl 3) # 195.7, 166.6, 159.1, 139.0, 133.1, 129.4, 128.5, 126.5, 61.1, 43.4, 38.0, 37.8, 34.1, 19.5, 14.0, 13.7 ppm . HRMS (ESI) Calculated Mass for C 18H23O3: 287.1647 ([M+H] +), Found 287.1645 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column ( 1% isopropanol in n -hexane at 1.0 mL/min), Rt = 25.0 min (minor) and 29.6 min (major), III-15q-R (90 % ee): [ $]20D= -56 (c = 4.09, CDCl3). OEtO 2CIII-15 qPh!"%(! III-15r-R:!Diethyl ( R)-3-oxo-5-propylcyclohex-1-ene-1,2-dicarboxylate: Compound III-12r (34. 0 mg, 0.2 mmol) was subject to general procedure B to provide 36.1 mg (64% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) # 4.31 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4.26 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.79-2.86 (1H, m), 2.59-2.66 (1H, m), 2.09-2.29 (3H, m), 1.35-1.44 (4H, m), 1.32 (3H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz), 0.89-0.93 (3H, m) ppm; 13C NMR (125 MHz, CDCl 3) # 196.2, 165.5, 165.4, 145.0, 137.4, 62.2, 61.7, 43.7, 37.6, 33.5, 31.8, 19.4, 14.0, 13.9, 13.9 ppm. HRMS (ESI) Calculated Mass for C 15H22O5Na: 305.1365 ([M+Na] +), Found 305.1373 ([M+Na] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD -H column (2% isopropanol in n -hexane at 0.3 mL/min), Rt = 74.8 min (major) and 81.3 min (minor), III-15r-R (80% ee): [ $]20D= -35 (c = 1.08, CDCl 3). III-4.4. General procedure C for base-catalyzed 4 H-pyrans synthesis: ! All the dihydropyran derivatives III-14 were synthesized by reported procedure .59,66 To a solution of the corresponding compound III-14 (1.0 equiv) in toluene , DABCO (50 mol% equiv) was added. T he solution was heated to 110 ¡C and kept at this OEtO 2CIII-15 rEtO 2COR2R1CO2EtDABCO (50 mol%) toluene, reflux, 12 h OR2R1CO2EtIII-14a-j III-16a-j **!"%)!temperature for 12 hours. The mixture was concentrated under N 2 flow. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (0-10%) as the eluent. III-16a-S: Ethyl ( S)-2-(4,6 -diphenyl-4H-pyran-2-yl)acetate: Compound III-14a (32.0 mg, 0.1 mmol) was subject to general procedure C to provide 25.9 mg (81% yield) of the pure product as a light orange oil ; 1H NMR (500 MHz, CDCl 3) # 7.59 -7.55 (2H, m), 7.38 -7.27 (7H, m), 7.26 -7.22 (1H, m), 5.44-5.39 ( 1H, m ), 4.92 -4.87 (1H, m), 4.26 -4.23 (1H, m), 4.22 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.27 (1H, d, J = 16.0 Hz), 3.23 (1H, d , J = 16.0 Hz ), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.7, 147.9, 146.4, 144.4, 134.0, 128.6, 128.3, 128.2, 127.9, 126.7, 124.5 103.2, 100.3, 61.1, 39.6, 38.3, 14.2 ppm. HRMS (ESI) Calculated Mass for C 21H21O3: 321.1491 ([M+H] +), Found 321.1483 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (2% isopropanol in n-hexanes at 1.0 mL/min), R t = 21.2 min (major), III-16a-S (>99% ee): [ $]20D = +41 ( c = 0.770, CDCl 3). OIII-16a PhPhCO2Et!"%*! III-16b-S: Ethyl (S)-2-(4-(4-bromophenyl)-6-phenyl-4H-pyran-2-yl)acetate : Compound III-14b (39.9 mg, 0.1 mmol) was subject to general procedure C to provide 25.2 mg (63% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 7.58-7.54 (2H, m), 7.48 -7.44 (2H, m), 7.36 -7.28 (3H, m), 7.22 -7.18 (2H, m), 5.38 -5.34 (1H, m), 4.89 -4.83 (1H, m), 4.22 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4.22 -4.18 (1H, m), 3.26 (1H, d, J = 16.0 Hz), 3.22 (1H, d, J = 16.0 Hz), 1.30 (3H, t, J = 7.0 Hz) ppm ; 13C NMR (125 MHz, CDCl 3) # 169.5, 148.3, 145.4, 144.8, 133.9, 131.7, 129.7, 128.5, 128.3, 124.5, 120.5, 102.7, 99.8, 61.1, 39.6, 37.9, 14.2 ppm. The enantiomeric excess was de termined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% isopropanol in n-hexanes at 1.0 mL/min), R t = 18.0 min (major) and R t = 55.6 min (minor), III-16b-S (91% ee): [ $]20D = +49 ( c = 1.20, CDCl 3). III-16c-S: Ethyl (S)-2-(4-(4-methoxyphenyl) -6-phenyl-4H-pyran-2-yl)acetate : Compound III-14c (35.0 mg, 0.1 mmol) was subject to general procedure C to provide 24.5 mg (70% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 7.59 -7.54 (2H, m), 7.36 -7.28 (3H, m), 7.26 -7.22 (2H, m), 6.90 -6.86 (2H, m), 5.42 -5.36 (1H, m), 4.90 -4.84 (1H, m), 4.21 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4.19 -4.16 (1H, m), 3.80 (3H, OIII-16b PhCO2EtBrOIII-16c PhCO2EtOMe !"%#!s), 3.26 (1H, d, J = 16.0 Hz), 3.22 (1H, d, J = 16.0 Hz), 1.30 (3H, t, J = 7 .0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.8, 158.4, 147.7, 144.2, 138.8, 134.1, 128.9, 128.3, 128.2, 124.4, 114.0, 103.5, 100.6, 61.1, 55.3, 39.6, 37.5, 14.2 ppm . HRMS (ESI) Calculated Mass for C 22H23O4: 351.1596 ([M+H] +), Found 351.1584 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (20% isopropanol in n-hexanes at 1.0 mL/min), R t = 30.7 min (major) and R t = 50.2 min (minor), III-16c-S (94% ee): [ $]20D = +38 ( c = 0.31, CDCl 3). III-16d-S: Ethyl (S) -2-(4-(4-cyanophenyl)-6-phenyl-4H-pyran-2-yl)acetate: Compound III-14d (34.5 mg, 0.1 mmol) was subject to general procedure C to provide 31.7 mg (92% yield) of the pure product as a light orange oil ; 1H NMR (500 MHz, CDCl 3) # 7.65 -7.62 (2H, m), 7.57 -7.53 (2H, m), 7.46 -7.43 (2H, m), 7.41 -7.32 (3H, m), 5.38 -5.33 (1H, m), 4.89 -4.84 (1H, m), 4.34 -4.28 (1H, m), 4.22 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.28 (1H, d, J = 16.0 Hz), 3.24 (1H, d, J = 16.0 Hz), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.4, 151.5, 148.7, 145.3, 133.5, 132.5, 128.7, 128.5, 128.3, 124.5, 118.9, 110.5, 102.0, 98.9, 61.2, 39.5, 38.5, 14.2 ppm . HRMS (ESI) Calculated Mass for C 22H20NO3: 346.1443 ([M+H] +), Found 346.1435 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OD-H column (8% isopropanol in n-OIII-16d PhCO2EtCN!"%&!hexanes at 1.0 mL/min), R t = 14.0 min (major) and R t = 26.0 min (minor), III-16d-S (92% ee): [ $]20D = +49 ( c = 1.19, CDCl 3). III-16e-S: Ethyl (S) -2-(4-(4-methoxyphenyl) -6-(4-nitrophenyl) -4H-pyran-2-yl)acetate: Compound III-14e (39.5 mg, 0.1 mmol) was subject to general procedure C to provide 11.1 mg (28% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 8.21 -8.16 (2H, m), 7.73 -7.68 (2H, m), 7.26 -7.22 (2H, m), 6.91 -6.88 (2H, m), 5.62 -5.57 (1H, m), 4.94 -4.88 (1H, m), 4.23 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4.23 -4.19 (1H, m), 3.80 (3H, s), 3.29 (1H, d, J = 16.0 Hz), 3.25 (1H, d, J = 16.0 Hz), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.5, 158.6, 147.4, 145.9, 144.2, 140.0, 137.8, 128.9 , 125.0, 123.6, 114.1, 104.7, 103.5, 61.2, 55.3, 39.4, 37.5, 14.2 ppm. HRMS (ESI) Calculated Mass for C 22H22NO6: 396.1447 ([M+H] +), Found 396.1423 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OD -H column (3% isopropanol in n-hexanes at 0.3 mL/min), R t = 145.9 min (minor) and R t = 152.7 min (major), III-16e-S (96% ee): [ $]20D = +33 ( c = 0.27, CDCl 3). OIII-16 eCO2EtOMe O2N!"%+! III-16f-S: Ethyl (S) -2-(4-(4-fluorophenyl) -6-(2-methoxyphenyl) -4H-pyran-2-yl)acetate : Compound III-14f (36.8 mg, 0.1 mmol) was subject to general procedure C to provide 25.8 mg (70% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl3) # 7.56 (1H, dd, J = 8.0 Hz, 2.0 Hz ), 7.33 -7.29 (2H, m ), 7.29 -7.25 (1H, m), 7.05 -6.99 (2H, m), 6.96 (1H, td, J = 7.5 Hz, 1.0 Hz ), 6.92-6.89 (1H, m), 5.66 -5.56 (1H, m), 4.87-4.77 (1H, m), 4.27-4.24 (1H, m ), 4.20 (2H, dd, J = 7.0 Hz, 7.0 Hz ), 3.82 (3H, s), 3.21 (1H, d, J = 16.0 Hz), 3.17 ( 1H, d, J = 16.0 Hz), 1.28 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.7, 161.5 (d, 1JC,F = 242.5 Hz), 156.9, 145.0, 144.5, 142.6 (d, 3JC,F = 2.5 Hz), 129.4, 129.3, 128.3, 123.1, 120.4 , 115.2 (d, 2JC,F = 21.3 Hz), 111.3, 104.8, 103.0, 61.0, 55.5, 39.7, 37.8, 14.2 ppm . HRMS (ESI) Calculated Mass for C 22H22O4F: 369.1502 ([M+H] +), Found 369.1490 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK O D-H column ( 1% isopropanol in n-hexanes at 0.7 mL/min), R t = 25.3 min ( minor ) and R t = 33.1 min ( major ), III-16f-S (95% ee): [ $]20D = +87 (c = 0.71, CDCl 3). OIII-16f CO2EtFOMe !"%$! III-16g-S:!Ethyl (S)-2-(6-(2-chlorophenyl)-4-(4-methoxyphenyl) -4H-pyran-2-yl)acetate : Compound III-14g (38. 5 mg, 0.1 mmol) was subject to general procedure C to provide 25.4 mg ( 66% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 7.45-7.41 (1H, m), 7.40 -7.36 (1H, m), 7.32 -7.28 (2H, m), 7.27 -7.22 (2H, m), 6.92 -6.87 (2H, m), 5.18 -5.13 (1H, m), 4.89 -4.81 (1H, m), 4.24-4.19 (1H, m), 4.19 (2H, dd, J = 7.0 Hz, 7.0 Hz ), 3.80 (3H, s), 3.19 (1H, d, J = 16.0 Hz), 3.15 (1H, d, J = 16.0 Hz), 1.28 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.7, 158.4, 146.8, 144.3, 138.7, 134.2, 132.8, 130.5, 130.0, 129.6, 128.9, 126.5, 114.0, 105.6, 103.6, 61.0, 55.3, 39.5, 37.6 14.2 ppm . HRMS (ESI) Calculated Mass for C 22H22O4Cl: 385.1207 ([M+H] +), Found 385.1183 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (5% isopropanol in n -hexanes at 1.0 mL/min), Rt = 32.8 min (minor) and R t = 75.4 min (major), III-16g-S (96% ee): [ $]20D = +48 (c = 0.97, CDCl3). III-16h-S: Ethyl (S,E) -2-(4-phenyl-6-styryl -4H-pyran-2-yl)acetate : Compound III-14h OIII-16g CO2EtOMe ClOIII-16h PhCO2EtPh!"%%!(34. 6 mg, 0.1 mmol) was subject to general procedure C to provide 24.2 mg (70% yield) of the pure product as a light orange oil; 1H N MR (500 MHz, CDCl 3) # 7.42-7.39 (2H, m), 7.37-7.28 (6H, m), 7.26 -7.21 (2H, m), 6.89 (1H, d, J = 15.5 Hz), 6.43 (1H, d, J = 15.5 Hz), 5.05-4.97 (1H, m), 4.88 -4.83 (1H, m ), 4.23 (2H, dd, J = 7.0 Hz, 7.0 Hz), 4. 21-4.16 (1H, m), 3.26 (1H, d, J = 16.0 Hz), 3.22 (1H, d, J = 16.0 Hz), 1.31 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.7,147.2, 146.1, 144.2, 136.7, 128.6, 128.6, 128.2, 127.9, 127.7, 126.7, 126.6, 122.0, 105.9, 103.0, 61.1, 39.6, 38.5, 14.2 ppm. HRMS (ESI) Calculated Mass for C 23H23O3: 347.1647 ([M+H] +), Found 347.1625 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OJ -H column (8% isopropanol in n -hexanes at 1.0 mL/min ), R t = 21.4 min (major) and R t = 27.1 min (minor), III-16h-S (97% ee): [ $]20D = -19 (c = 2.49, CDCl 3). III-16i-S: Ethyl (S,E) -2-(4-(2-chlorophenyl)-6-(2-chlorostyryl) -4H-pyran-2-yl)acetate : Compound III-14i (41.5 mg, 0.1 mmol) was subject to general procedure C to provide 33.2 mg ( 80% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 7.53 (1H, d d, J = 8.0 Hz, 2.0 Hz), 7.46 (1H, d d, J = 8.0 Hz, 2.0 Hz), 7.36 (2H, d dd, J = 8.0 Hz, 4.5 Hz, 1.0 Hz), 7.29 (1H, td, J = 8.0 Hz, 1.0 Hz), 7.28 (1H, d, J = 15.5 Hz), 7. 24-7.15 (3H, m), 6.43 (1H, d, J = 15.5 Hz ), 5.13 -5.07 (1H, m), 4.92 -4.86 (1H, m), 4.75 -4.67 (1H, m), 4.24 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.30 (1H, d, J = 16.0 Hz), 3.26 (1H, d, J = 16.0 OIII-16i CO2EtClCl!(''!Hz), 1.31 (3H, t, J = 7.0 Hz) ppm; 13C NMR (12 5 MHz, CDCl 3) # 169.6, 147.9, 145.3, 142.4, 134.8, 133.5, 132.3, 130.5, 129.8, 129.3, 128.7, 127.9, 127.4, 126.8, 126.5, 124.4, 124.4, 105.2, 101.3, 61.1, 39.6, 34.7 , 14.2 ppm . HRMS (ESI) Calculated Mass for C23H21O3Cl2: 415.0868 ([M+H] +), Found 415.0865 ( [M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK OD -H column (1% isopropanol in n -hexanes at 0.8 mL/min), R t = 23.0 min (minor) and R t = 26.5 min (major), III-16i-S (88% ee): [ $]20D = -77 (c = 1.55, CDCl 3). III-16j-S: Ethyl (S,E) -2-(6-(2-bromostyryl) -4-(furan -2-yl)-4H-pyran-2-yl)acetate : Compound III-14j (41.5 mg, 0.1 mmol) was subject to general procedure C to provide 26.1 mg ( 63% yield) of the pure product as a light orange oil; 1H NMR (500 MHz, CDCl 3) # 7.58 (1H, d d, J = 8.0 Hz, 1.0 Hz), 7.41 (1H, d d, J = 8.0 Hz, 1.5 Hz), 7.36-7.34 (1H, m), 7.29 (1H, td, J = 8.0 Hz, 1.5 Hz), 7.19 (1H, td, J = 8.0 Hz, 2.0 Hz), 6.36-6.32 (1H, m), 6.20-6.15 (1H, m), 5.20-5.16 (1H, m), 5.00 -4.95 (1H, m), 4. 41-4.37 (1H, m), 4.18 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3. 20 (1H, d, J = 16.0 Hz), 3. 16 (1H, d, J = 16.0 Hz), 1. 27 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.5, 158.2, 149.2, 145.4, 141.4, 136.0, 133.2, 130.8, 130.1, 127.1, 122.3, 110.4, 105.2, 102.0, 100.3, 61.1, 39.4, 31.8, 14.2 ppm . HRMS (ESI) Calculated Mass for C 15H18O7Br: 389.0236 ([M+H] +), Found 389.0251 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL OIII-16j CO2EtBrO!('"!CHIRALPAK OJ -H column (3% isopropanol in n -hexanes at 0.6 mL/min ), R t = 30.2 min (minor) and R t = 65.6 min (major), III-16j-S (90% ee): [ $]20D = +23 (c = 0.28, CDCl 3). III-4.5. Synthesis of enone III-13k-III-13l:68 To a solution of methacrolein (1.0 g, 1.2 mL, 14.2 mmol) in acetone (6 mL), NaOH (11.4 mg, 0.28 mmol) was added. The reaction mixture was refluxed for 2 h and was then cooled to room temperature. After neutralization with 1 N HCl , the solution was concentrated under vaccum and partitioned with Et 2O (10 mL) and water (10 mL). After separation, the aqueous phase was extracted by Et 2O ( 2"10 mL ). The combined organic phase was dried over anhydrous Na 2SO4, concentrated, and purified by silica gel column chromatography to provide III-13k (500.0 mg, 32% yield) as a light yellow liquid and III-13l (38.6 mg, 3% yield) a s a light yellow liquid. III-13k: 1H NMR (500 MHz, CDCl 3) # 7.19 (1H, d, J = 16.0 Hz ), 6.13 (1H, d, J = 16.0 Hz ), 5.43-5.39 (2H, m), 2.31 (3H, s), 1.90 (3H, d, J = 1.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) # 199.0, 145.9, 140.9, 127.8, 125.1, 27.3, 18.1 ppm. III-13l: 1H NMR (500 MHz, CDCl 3) # 7.35 (2H, dd, J = 16.0 Hz, 1.0 Hz), 6.43 (2H, dd, J = 16.0 Hz, 0.5 Hz), 7.46-7.37 (4H, m), 1.94 (6H, dd, J = 1.0 Hz, 0.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 189.8, 145.5, 141.0, 125.9, 125.4, 18.2 ppm. OH+ONaOH (2 mol%) 60 ¡C, 2 h(5.7 equiv) (1 equiv) OO+III-13k III-13l !('(!III-4.6. General procedure D for the s ynthesis of enone III -13m, III-13q:69 A soluti on of diisopropylamine (1.01 equiv.) in THF at -78 ¡C was treated with n-BuLi (1.0 equiv.) for 30 min. Enone (1.0 equiv.) was added and a fter 30 min, aldehyde (2.0 equiv.) (for methacrolein, 1.5 equiv was used). was added at the same temperature. After another 60 min, the reaction was quenched by addition of HOAc -H2O (1:1 v/v) at -78 ¡C. The flask was warmed to room temperature, followed by separation of the two phases. The aqueous phase was extracted by Et 2O. The combined organic phase was washed by saturated NaHCO 3 and brine, and dried by anhydrous Na 2SO4. The crude aldol product was used for the next step without further purification. The aldol production was dissolved in pyridine (12.4 equiv.) at 0 ¡C and methanesulfonyl chloride (1.22 equiv.) was added. The solution was kept at room temperature overnight and H 2O was added. The mixture was extracted by Et 2O and the combined phase was washed by saturated CuSO 4 and brine. The organic layer was dried over anhyd rous Na 2SO4, then concentrated and re dissolved in Et 2O, and Et 3N (0.8 equiv.) was added and the mixture was stirred at room temperature for 18 h. Water was added to the reaction , followed by extraction with Et 2O. The combined organic layers were washed by cold 1% HCl, saturated NaHCO 3, and then water. The organic phase was dried over MgSO 4, then filtrated and concentrated to give a crude oil that was purified by silica gel column chromatography to deliver the enones. PhO1) LDA (1.0 equiv.) THF, -78 ¡C 2) RCHO (2.0 equiv.) PhOROH1) MsCl (1.2 equiv.) pyridine 2) Et 3N (0.8 equiv.) PhOR!(')! III-13m: Methacrolein (0.87 g, 12.5 mmol) was subject to general procedure D to provide 503.2 mg ( 35% overall yield ) of the pure product as a pale yellow oil; 1H NMR (500 MHz, CDCl3) # 8.01-7.92 (2H, m), 7.61 -7.54 (1H, m), 7.53 -7.44 (3H, m), 6.93 (1H, d , J = 15.5 Hz), 5.47 (2H, dd, J = 15.5 Hz, 1.0 Hz), 2.00 (3H, J = 1.5 Hz) ppm; 13C NMR (125 MHz, CDCl3) # 191.1, 147.2, 141.0, 138.2, 132.7, 128.6, 128.4, 125.8, 122.6, 18.2 ppm. III-13q: Butyraldehyde (1. 80 g, 25 .0 mmol) was subject to general procedure D to provide 1.76 g ( 81% overall yield ) of the pure product as a pale yellow oil; 1H NMR (500 MHz, CDCl3) # 7.96-7.90 ( 2H, m), 7.59-7.53 ( 1H, m), 7.51 -7.44 ( 2H, m), 7.01 (1H, d t, J = 15.0 Hz, 7.0 Hz ), 6.92-6.85 (1H, m), 2.31 (2H, d dd, J = 7.0 Hz, 7.0 Hz, 1.5 Hz ), 1.57 (2H, sextet , J = 7.0 Hz ), 0.98 (3H, t, J = 7.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) # 191.0, 149.9, 138.0, 132.6, 128.5, 128.5, 126.0, 34.9, 21.5, 13.8 ppm. III-4.7. General procedure E for the s ynthesis of enone III-13n, III-13r:70 PhOIII-13 m PhOIII-13 q OCO2Et1) PPh 3 (1.0 equiv.) CCl4, 0 ¡C, 3 h then rt, 36 h 2) Na 2CO3, H2O, 0 ¡C, 1hOCO2EtBrPh3P!('*! A solution of ethyl bromopyruvate (1.0 equiv.) in dry carbon tetrachloride was added dropwise over 0.5 h to a stirred and cooled (0 ¡C) solution of triphenyl phosphine (1.0 equiv.) in dry carbon tetrachloride. The reaction was warmed to room temperature and stirred for an additional 24 h. The supernatant was decanted from the yellow hygroscopic crystals, which were then washed with anhydrous ether by trituration and decantation. The resulting dried sticky solid was dissolved in methanol and the solution was cooled to 0 ¡C. The pH was adjusted to 10 by gradual addition of iced aqueous sodium carbonate (1 N). The solution was diluted with ice water and stirred for 1 h at 0 ¡C, after which the precipitate was collected and washed with cold water. It was then rec rystallized from hot ethanol and water. The resulting ylide crystals separated out as light brown yellow crystals (53% yield). A solution of aldehyde (6.0 equiv.) and yilde (1.0 equiv.) in dried dichloromethane in sealed tube under Ar protection a t room temperature was stirred for 24 h. The mixture was concentrated and separated by silica gel column chromatography to provide III-13n!and!III-13r. III-13n: Methacrolein (752.8 mg, 2.0 mmol) was subject to general procedure E to provide 63.4 mg ( 19% yield ) of the product as a pale-yellow oil, and it was a mixture with another isomer, however, it would affect the cyclohexanone III-15n formation . OCO2Et1) RCHO (6.0 equiv.) DCM, rt, Ar EtO 2CORPh3PEtO 2COIII-13 n !('#! III-13r: Butyraldehyde ( 752.8g, 2.0 mmol) was subject to general procedure E to provide 162.2 mg ( 48% yield ) of the pure product as a pale yellow oil; 1H NMR (500 MHz, CDCl 3) # 7.19 (1H, d t, J = 16.0 Hz, 7.0 Hz), 6.65 (1H, d t, J = 16.0 Hz, 2.0 Hz), 4.35 (2H, d d, J = 7.0 Hz, 7.0 Hz), 2.29 (2H, qd, J = 7.0 Hz, 1.5 Hz), 1.54 (2H, sextet , J = 7.5 Hz), 1.38 (3H, td, J = 7.5 Hz, 0.5 Hz), 0.96 (3H, t, J = 7.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 183.4, 162.4, 155.0, 125.2, 62.3, 35.1, 21.1, 14.1, 13.7 ppm. III-4.8. Synthesis of Diels -Alder reaction adduct III-16ia: To a solution of nitrosobenzene (3.0 equiv.) in EtOH/DCM ( v/v = 1:1 ), 5i (1.0 equiv.) was added at 0 ¡C. The solution was gradually warmed up to room temperature. The reaction was monitored by TLC , and when com pleted, was quenched with H2O and extracted with DCM twice. The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in hexane s (1.5% -20%) as eluents to provide III-16ia (50% isolated yield) as a light oil . EtO 2COIII-13 r OCO2EtIII-16i 91% eeClClDCM/MeOH = 1:1 0 ! " r.t., 12 h NO(3.0 equiv.) OCO2EtClClONPhHIII-16ia 50% isolated yield, 89% ee!('&!III-16ia: 1H NMR (500 MHz, CDCl 3) # 7.72 (1H, dd, J = 7.5 Hz, 1.5 Hz), 7.43 -7.27 (4H, m), 7.19 -7.10 (2H, m), 7.09 -7.00 (3H, m), 6.87 -6.79 (2H, m), 6.79 -6.73 (1H, m), 6.00 (1H, s), 5.55 (1H, s), 4.76 (1H, s), 4.88 -4.37 (2H, m), 4.27 -4.18 (2H, m), 3.24 (1H, d, J = 16.0 Hz), 3.20 (1H, d, J = 16.0 Hz), 1.31 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) # 169.5, 148.7, 146.8, 135.8, 133.4, 130.5, 129.7, 129.6, 129.3, 128.7, 128.6, 128. 0, 127.9, 127.4, 127.1, 126.9, 126.8, 126.5, 121.3 , 105.8, 104.5, 71.9, 61.2, 39.6, 39.1, 34.7, 14.2 ppm. HRMS (ESI ) Calculated Mass for C 29H26NO4Cl2: 522.1239 ([M+H] +), Found 522.1235 ([M+H] +). The enantiomeric excess was determined by HPLC analysis, using DAICEL CHIRALPAK AD-H column ( 2% isopropanol in n -hexanes at 1.0 mL/min), R t = 10.0 min (minor) and R t = 11.3 min (major), III-16ia (89% ee): [ $]20D = + 43 (c = 1.62, CDCl3). !('+! APPENDIX !"#$!!OEtO 2CPhPhIII-15a !"#%!!OEtO 2CPhPhIII-15a !"&#! OEtO 2CPhBrIII-15b !"&&! OEtO 2CPhBrIII-15b !"&"! OPhOMe III-15c EtO 2C!"&'! OPhOMe III-15c EtO 2C!"&(! OEtO 2CPhCNIII-15d !"&)! OEtO 2CPhCNIII-15d !"&*! OEtO 2COMe O2NIII-15e !"&+! OEtO 2COMe O2NIII-15e !"&$! OMe FIII-15f OEtO 2C!"&%! OMe FIII-15f OEtO 2C!""#!!!ClOOOMe III-15gÕ !""&! ClOOOMe III-15gÕ !"""! OEtO 2CPhPhIII-15h !""'! OEtO 2CPhPhIII-15h !""(! OEtO 2CIII-15i ClCl!"")! OEtO 2CIII-15i ClCl!""*! OEtO 2CIII-15l !""+! OEtO 2CIII-15l !""$! OEtO 2CPhIII-15m !""%! OEtO 2CPhIII-15m !"'#! OEtO 2CEtO 2CIII-15n !"'&! OEtO 2CEtO 2CIII-15n !"'"! OEtO 2CIII-15o !"''! OEtO 2CIII-15o !"'(! OEtO 2CIII-15p !"')! OEtO 2CPhIII-15q !"'*! OEtO 2CEtO 2CIII-15r !"'+! OEtO 2CEtO 2CIII-15r !"'$! OPhPhCO2EtIII-16a !"'%! OPhPhCO2EtIII-16a !"(#! OPhCO2EtBrIII-16b !"(&! OPhCO2EtBrIII-16b !"("! OPhCO2EtOMe III-16c !"('! OPhCO2EtOMe III-16c !"((! OPhCO2EtCNIII-16d !"()! OPhCO2EtCNIII-16d !"(*! OCO2EtOMe O2NIII-16e !"(+! OCO2EtOMe O2NIII-16e !"($! OCO2EtFIII-16f OMe !"(%! OCO2EtFIII-16f OMe !")#! OCO2EtClOMe III-16g !")&! OCO2EtClOMe III-16g !")"! OPhCO2EtPhIII-16h !")'! OPhCO2EtPhIII-16h !")(! OCO2EtIII-16i ClCl!"))! OCO2EtIII-16i ClCl!")*! OCO2EtBrOIII-16j !")+! OCO2EtBrOIII-16j !")$! OCO2EtBrOIII-16j !")%! OCO2EtClClONPhHIII-16ia !"*#! OCO2EtClClONPhHIII-16ia !"#$!Crystal Structure: !!! 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S*,*"-'>'2*.( !"+%#!3?!,#-4!$&*'6 !!,##-!?NWUM^214!56!`6L!`VJI4!E6!@6L!B/Z24!96L!=WMJI4!H6L!:W/Q2 ZV4!D6L!82WJ4!>6L!8MM04!.6L!_/1W2J4! _6!KMRW2JVNUVR2QQP!;JNYV1M0!8/TUM!U/]210!DMX2WP01/ F"DFRW1/ZMJMN![V2!>/JNMRTUV[M!&d"! >PRQ/200VUV/JN6! !"#$%&'(A*,,*".( '(!$#!NQ!,$#-4!%*(#6 !!!")'!,#(-!@2JI4!86!H6!D64!D6!a6!j F?QQMJVR!MNUM1N!b1/Z!j FYW/NYW/12JPQV0MJM!MNUM1N!2J0!2RV0!RWQ/1V0MN\! MUWPQ!"4% FYMJU20VMJ/2UM6! !"#[(B>%,8[( !"+)#!?34!"+"6 !!,#)-!c/T4!A6L!:212P2Q0M4!`6L!H2JI4!g6!86L!CM[20/4!>6L!:/M^M4!?6!:/Q0 F>2U2QP3M0! >PRQ/VN/ZM1V32UV/J!/b!>PRQ/Y1/YPQ !?Q^PJPQ!?RMU2UMN\!?!GM1N2UVQM!?YY1/2RW!U/!' F4!# F4!2J0!( FKMZOM1M0!>21O/RPRQMN6! F%#*G$%/,*(78*9&* H1%,*"%$,&-%$2(:/&,&-%( '((+#!I;!,'"-4!$+$$+6 !!,#*-!<21M4!`6!?6L!DMJ0M1N/J4!K6!?6L!=2JJM14!K6!?6L!DM2UWR/R^4!>6!D6!?>A>@;>!=B989<=9@9>B;D9K;=B8A!< 7!BD9!K;>D?9@!?``;B;( !""(#!MM!,$-4!$%"6 !!,(+-!?QQ2VN4!>6L!@VMOP FKTQQM14!76L!8/01VITM34!a6L!>/JNU2JUVMTX4!B6!KMU2Q F71MM!KVRW2MQ F?00VUV/J F;JVU V2UM0!BW1MM F>/ZY/JMJU!8M2RUV/J!b/1!UWM!8MIV/NMQMRUV[M!=PJUWMNVN!/b!DVIWQP! 7TJRUV/J2QV3M0!.P1V0VJMN\!=R/YM4!KMRW2JVNUVR!;J[MNUVI2UV/JN!2J0!?YYQVR2UV/JN6! :0"-+*$%( 5-0"%$2(-6(!"#$%&'(78*9&.,">( '(!*4!&$%$6 ! !"#$!Chapter IV : Amine-mediate d Dihydropyran Rearrangements Toward Pyran and Carbocyclic !ÐAmino Ester Synthesis IV-1. Introduction Optimization of base catalyzed double bond migration from exo - to endo-dihydropyran was described in Chapter II I. During these studies, we observed the formation of pyran , instead of 4 H-pyran , when vinyl dihydropyran (III-14h) was used as the substrate and DBU was used as the catalyst . Further, this pyran derivative partially rearrange d under sil ica gel colum n conditions to phenolic side product s. These observation s, which will be discussed in detail in section IV-2, attract ed our attention to further investigate and explore these transformations, because both pyran and phenolic compounds are important building blocks . Since amidine s are critical bases for the success of this transformation, the chapter will begin with an introduction of amidine family of bases. IV-1.1. Amidines, isothioureas and guanidines as nucleophilic catalysts In the past decade, there has been a dramatic increase in the advancement of organocatalysis. Generally , organocatalysts can be classified into Lewis base s, Lewis acid s, Br¿nsted base s and Br¿nsted acid s.1 Among these, Lewis base catalysts as nucleophilic organocatalysts are the most popular in this field . One of the reasons is that these catalysts are read ily available and easily re-designable. At lea st, three families, including tertiary amines, phosphines and N-heterocyclic carbenes (NHCs) , are common options for a variety of reactions . The principle of this categorization in organocatalysis is based on the pro posed mechanism and the activation mode of the catalyst in the catalytic !"#%!cycle. As a result, it is possible that a catalyst plays an ambiguous role or dual/ multiple roles in a reaction process. Another reason attributed to the puzzl e of this categoriz ation is the dual functions of these catalysts , namely its basicity and nucleophilicity. Amidines and guanidines are such co mpounds , often thought of as strong non-nucleophilic organic bases. However, recently, a number of examples show that these small molecules react as efficient nucleophilic catalysts as well .2 The evidence for the nucleophilic nature of these catalysts is t heir increasing applications on a wide range of reactions, such as acyl transfer s,3,4 aldols,5,6 the Morit a-Baylis -Hillman (MBH) reaction ,7,8 conj ugate addition s,9 and carbonylation s,10 to name a few. Along with the acyl transfer reaction (such as esterification 11,12 and kinetic resolution 13,14 ), which is the most commo n application of these catalysts , the rest of the nucleophilic based reactions are also becoming areas of interest. Amidines and guanidines based molecules are found throughout natur al products and drug s (see Figure IV -1),2 having been widely used in organic chemistry. With their ability of delocalizing the charge over two/three nitrogen atoms after protonation, they are Figure IV-1. Examples of amidine and guanidine contain ing natural products and drug molecules. H2NNHNHCO2HNH2HNONH2NHNHHNL-Arginine Noformycin OHNNH2ONHNH2Pentamidine anti-microbial NNHSHNHNNCNCimetidine histamine receptor antagonist 5!"##!traditionally recognized as strong neutral organic bases. The structures and pK as of several of the most commonly used amidines and guanidines are shown in Figure IV -2.15,16 Among them, the bicyclic ami dines 1,8-diazabicyclo[5.4.0]undec -7-ene (DBU) IV-1 and 1,5 -diazabicyclo[4.3.0]non -5-ene (DBN) IV-2 are r epresentative examples of organocatalysts for base -mediated organic trans formations, such as elimination and isomerization , under milder conditions as compar ed to other types of nitrogen base s.17 For example, DBU has been employed to convert !"#Ðunsaturated nitriles into the corresponding $"!Ðunsaturated isomers , which are thermodynamically more favored .18 (see Schem e IV-1) However, in some of these reactions, unexpe cted side -products were obtained . For instance, in 1981, McCoy reported an unusual tetracyclic dihydropyridin -4-one compound IV-10 was isolated and characterized from the dehydrohalogenation reaction of Figure IV-2. Structures and pK as of some representative amidine and guanidine bases. NNHNNHMe2NNMe 2NH2NNHNHNNHNMeDBU pKa = 23.9 (MeCN) DBN pKa = 23.4 (MeCN) TMG pKa = 23.3 (MeCN) TBD pKa = 26.0 (MeCN) MTBD pKa = 25.4 (MeCN) IV-1 IV-2 IV-3 IV-4 IV-5 Scheme IV-1. An ex ample of DBU/ DBN mediated isomerization reaction. CNOCOMe cat DBU or DBN CNOCOMe !"#&!cyclopropane diester IV-6 when excess DBU was used , as described in Scheme IV -2. It was proposed that incorporation of DBU fragment into the final product IV-10 occurred through nucleophilic attack of intermediate IV-7.19 Later on, in 1993 BertrandÕs group provided direct evidence that DBU and DBN can react as strong nucleophiles through crystallographic studies .20 First t hey isolated and characterized cationic phosphane IV-13, which is the product from DBU/ DBN reacting with chloro -phosphane IV-11, followed by the chloride counter -ion exchange with hexafluorophosphate (see Scheme IV-3). From the X -ray crystal structure ( Scheme IV -3, DBN as an example), it was also NNn+R2NPClNR2n = 1 or 3 HNNnPR2NNR2ClHNNnPR2NNR2PF6KPF6R = i-PrIV-11 IV-12 IV-13 Scheme IV-3. The first direct evidence that DBU/ DBN reacts as nucleophile via reaction with chloro -phosphanes IV-11. ClCO2MeMeO 2CMeO 2CCO2MeNNMeO 2COOMe NNMeO 2COOMe NNOMeO 2CDBU (3 equiv) EtOAc DBU DBU ± H+-MeOH IV-6 IV-7 IV-8 IV-9 IV-10 Scheme IV-2. Formation of unexpected byproduct IV-10 during a DBU involved nucleophilic attack. !"&'!sugges ted that the positive charge is delocalized over both N atoms as both amidine C -N bonds are of similar length. Not only qualitatively (from the observation of experiments), but also quantitatively (from calculation based on the results of expe riments), researchers have demonstrated that DBU and DBN can act as nucleophiles . More recently, to compare the nucleophilicity of DBU and DBN , as well as isothiourea derivatives, with well-known nucleophilic catalysts , Mayr and co -workers have performed a number of kinetic experiments. 21,22 They investigated the equilibrium between a variety of nucleophilic catalysts and a range of benzhydrylium tetrafluoroborate anions by p hotometrical methods. Consequently , the results of these kinetic experiments were analyzed by using Equation IV -1, where k is the second order rate constant, s is the nucleophile -specific slope parameter, N is the nucleophilicity parameter, and E is the electrophilicity parameter. This analysis enabled to directly compare the nucleophilicity parameter ( N) of a number of Lewis basic catalysts, as presented in Sch eme IV -4.22 Interestingly, DBN has a superior nucleophili city over 4-(dimethylamino)pyridine (DMAP), which is co nsidered to be one of the most powerful nucleophilic catalysts. Overall , DBN is more nucleophilic than most of the catalysts studied in Scheme IV , with the exception of 1,4-diazabicylco[2.2.2]octane (DABCO). Besides, this study also revealed that DBU, as well as so me isothiourea derivatives, exhibit comparable nucleophilicity to DMAP. Zipse Õs group also perfo rmed a study , by calculating the methyl cation affinities of over 40 common organocatalysts, which log k = s(E + N) Equation IV-1. Nucleophilicity parameter ( N) used to compare the nucleophilic nature of Lewis basic catalysts. !"&(!coincidently showed DBU and DBN have greater methy l cation affinities than many DMAP and cinchona alkaloid derivatives. 23 From both studies, it was revealed that bicyclic amidines are considerably more basi c than many other Lewis bases. However, t he relatively high basicity of these amines has limited their potential application as Scheme IV-4. Relative nucleophilicities of selected catalysts. [a] Measurements made in MeCN. Modified scheme from reference 22. 10191817161514131211NNNN(DABCO) a(DBU) aNNSPhNNSPhNNSNNPPh3(HBTM) (NMI) aNNSNNSNSNNNNNMe 2NN(DBN) a(DMAP) (DHPB) Nuc+CH2Cl2BF4ArArBF4ArArHNucIV-14 a!"&"!nucleophilic catalysts, because they may lead to the deactivation by competing protonation reaction. Amidine , guanidine and isothiourea derivatives have become popular catalysts as a result of their highly nucleophilic nature. In this field, A number of these catalysts have been successfully applied as acyl transfer agents for several types of acyl donors , including acyl chloride s, acid anhydride s and ester s. A general ized mechanism for these base catalyzed acyl transfer process es is given in Scheme IV -5. Briefly, the catalyst IV-15 activates the acyl donor IV-16 by nucleophilic attack to generate intermediate IV-17, followed by the addition of a nucleophile , the formation of the acylated product IV-18 and regeneration of the catalyst. 2 A less common, but attractive applicat ion i s that some of these bases can be used as catalysts for the Morita -Baylis -Hillman (MBH) reaction. It was first discovered by Aggarwal and co -workers in 1999 that DBU was an efficient catalyst for the MBH reaction, with a faster reaction rate as compared to DABCO initiat ed NNRXONNORXNucH HXRNucO+IV-15 IV-16 IV-17 IV-18 Scheme IV-5. General mechanism for amidine and guanidine catalyzed acylation reactions. RXO+EDBU (1 equiv) rtROHEE = CO 2Me, CN, COR 217-95% yield Scheme IV -6. Examples of DBU mediated MBH reactio n discovered by AggarwalÕs group. !"&)!reactions (see Scheme IV -6).7 Since then , more examples have been reported by different groups, both experimentally and computationally .7,8,24 -26 One of them is from ShiÕs group, in which they found that 10 mol% DBU can be used to catalyze the reaction between salicylic aldehydes and activated allenes to form 2 H-1-chromenes ( Scheme IV -7).8 The authors proposed three pathways to explain the formation of bo th the product and side -product as described in Scheme IV -8. Both pathway A and B show DBU acts as a Lewis base. In pathway A, DBU is believed to activate the allenoate IV-19 to produc e #Ðenolate, which deprotonates the salicylic aldehyde IV-22 to form intermediate IV-23 and IV-24. After a Michael addition between these two intermediates, a zwitterionic intermediate IV-26 is formed. By an intramolecular aldol cyclization, proton transfer and DBU elimination, the final product IV-28 is achieved . In pathway B, the resonance structure IV-21 undergoes an intermolecular MBH reaction, followed by cyclization and DBU elimination to give the final product. However, in pathway C, DBU is bel ieved to react as a Br¿nsted base to deprotonate the salicylic aldehyde , which then attacks the allene, followed by #Ðcycliza tion to produce the side -product IV-31. Nonetheless , a possible $Ðcycliza tion pathway D or intramolecular MBH reaction (see dash box in Scheme IV -8) was not considered , which can also furnish the major product IV-28. From this view point, the role tha t DBU in the process is still unclear. Scheme IV -7. DBU catalyzed cycloaddition reaction of salicylic aldehydes with allenes to form 2 H-1-chromenes. HOOHR1R2R3O+DBU (10 mol%) DMSO, rt or 80 ¼C OR1OHR3OR2R1 = H, Me, OMe, Cl, Br, etc. R2 = Me, Bn R3 = Me, OMe yields: 53-99% !"&*! Scheme IV -8. Plausible mechanisms for DBU catalyzed cycloaddition reaction of salicylic aldehydes with allenes to form 2 H-1-chromenes . Modified scheme from reference 8. CO2EtDBU EtO 2CNR3EtO 2CNR3CHOOHCHOOpath A path B MBH reaction CHOOHNR3EtO OMichael additionOONR3OEt OAldol cyclization OONR3CO2EtH+ transfer and DBU elimination OHOCO2EtOHOCO2EtNR3Cyclization DBU CHOOHCHOODBU DBUH CO2EtOOCO2EtOOCO2Etpath C Cyclization DBUH DBU OHOCO2Etpath D aldol reaction OHOCO2Et!path A and path B DBU as a nucleophilic trigger path C and D DBU as a baseIV-19 IV-20 IV-19 IV-21 IV-22 IV-23 IV-22 IV-22 IV-23 IV-24 IV-25 IV-26 IV-27 IV-28 IV-29 IV-30 IV-28 IV-31 !"&+!IV-1.2. A brief introduction of pyran and phenol derivatives As described in Chapter III , many pyrans and fused pyrans derivatives, such as benzopyran derivatives, are biologically active compounds with antimicrobial, antitumor, antifungal, anticoagulant, antianaphylactic, diuretic and spasmolytic activities .27-30 They are also important motifs that exist in many of natural products, e.g. coumarins, sugars, flavonoids and so on .31-33 Besides, some benzopyran derivatives possess photochemical activities and a number of 2 -amino -4H-pyrans are utilized as photoactive materials, biodegradable agrochemicals and pigments. 34-36 As a matter of fact, many methodologies have been developed for the synthesis of py ran and fused pyran derivatives. For example, the Knoevenagel -hetero -Diels-Alder (DKHDA) cascade reaction is a trusted protocol for the synthesis of pyran scaffolds by reaction of barbituric acid with aromatic aldehydes followed by condensation with ethyl vinyl ether or resorcinol with $"!Ðunsaturated aldehydes. 37,38 Recently, one -pot three components reactions of arylaldehydes, active methylene compounds and electron rich agents are becomi ng one of the most efficient and simplest methods to approach pyran derivatives. 39-41 Although not well reported , our observation that indicates conversion of the pyran s to phenolic compounds , should be further explo red, since it coul d lead to a novel approach for o btaining hard to access phenols. Phenol and its derivatives, most commonly known as phenolic compounds, ubiquitous in plants, are secondary metabolites and essential part of the human diet. Beside contributing to the color and sensory characteristics of fruits and vegetables, they also play a critical role in growth an d reproduction, providing protection against pathogens !"&$!and predators. 42 The antioxidant activity of food phenolic compounds is of nutritional interest as they are associated to the human health through the prevention of several diseases. 43 In additio n, phenolic compounds exhibit a wide range of pharmacological and physiological properties, such as anti -cancer, antioxidant, anti -microbial, anti -allergenic, anti-artherogenic, anti -inflammatory, anti -thrombotic, cardioprotective and vasodilatory effects. 44-49 Structurally, these comp ounds compris e one or more aromatic ring s, bearing one or more hydroxyl substituents, ranging from a simple phenolic molecule (e.g. gallic Table IV -1 Classes of phenolic compounds in plants Class Structure Simple phenolics, benzoquinones C6 Hydroxybenzoic acids C6ÑC1 Acetohophenones, phenylacetic acids C6ÑC2 Hydroxycinnamic acids, phenypropanoids (coumarins, isocoumarins, chromones, chromenes) C6ÑC3 Napthoquinones C6ÑC4 Xanthones C6ÑC1ÑC6 Stilbenes, anthraquinones C6ÑC2ÑC6 Flavonoids, isoflavonoids C6ÑC3ÑC6 Lignans, neolignans (C6ÑC3)2 Biflavonoids (C6ÑC3ÑC6)2 Lignins (C6ÑC3)n Condensed tannins (proanthocyanidins or flavolans) (C6ÑC3ÑC6)n!!!"&%!acid ) to a complex high -molecular weight polymer (e.g. tannins) .42,50 The diversity in structure leads to a wide range of phenolic compounds with over 8,000 variants in nature, however, they are generally categorized as phenolic acids, flavonoids, tannins, stilben es, curcuminoids, coumarins, lignans, quinones and so on, as shown in Table IV -1.50,51 Among these, phenolic acids, flavonoids and tannins are regarded as the main dietary phenolic compounds. 52 Scheme IV -9. (a) A mixture of regio -isomers formation under Diels -Alder reaction of substrate IV-32 and acrylonitrile. (b) DBU catalyzed deconjugation of $"!Ðunsaturated ester IV-34 to form !"#Ðunsaturated ester IV-35. (c) Complete conversion of a mixture of IV-33 and IV-33Õ to a single isomer IV-33Õ under DBU catalyzed reaction condition s. OPhPhCO2Et+120 ¼C, neatOPhPhCO2EtNCHOPhPhCO2EtNCHCNovernight overall 41% yieldOBocHN CO2MeDBU (10 equiv.), benzene reflux, 6 h, quan. OBocHN CO2MeIV-32 a)b)c)IV-33 IV-33Õ IV-34 IV-35 OPhPhCO2EtHNCOPhPhCO2EtHNCIV-33Õ >98% dr, >98% rs0.1 equiv DBU 0.5 equiv pyridine IV-33 DCM, reflux 12 h!"&#!IV-2. Amidine-mediated formal [1,5] -H rearrangement towards pyran synthesis from dihydropyran !In our effort to develop a concise assembly towards hexahydro -2H-chromenes via consecutive [4+2]/[4+2] cycloadditions in Chapter II , it was found that substrate IV-32 react s with acrylonitrile to furnish a mixture of IV-33 and IV-33Õ, as shown in Scheme IV -9a.53 According to the litera ture, DBU is able to initiate de-conjugation of $"!Ðunsaturated ester IV-34 to !"#Ðunsaturated ester IV-35 (Scheme IV-9b).54 Based on this, a mixture of compounds IV-33 and IV-33Õ was subjected to the DBU dictated isomerization reaction condition , which led a single isomer IV-33Õ (Scheme IV -9c). Therefore, it is possible that dihydropyran IV-32 might be converted to 4 H-pyran IV-36, which could potentially react Scheme IV -10. a). An attempt to synthesize 4 H-pyran IV-36 from dihydropyran IV-32, followed by the Diels -Alder reaction to deliver the adduct IV-33Õ . b). DBU catalyzed formal [1,5] -H rearrangement towards the synthesis of pyran IV-36, which partially rearranged to salicylate derivative when purified with silica gel . OPhPhCO2EtDBU (cat), DCM pyridine (cat.) reflux, 3 days DBU (10 equiv) toluene, reflux, 8 h OHCO2 Et (10% isolated yield- minor product once purified by silica gel column)(81% isolated yield )or+OPhPhCO2Et(not observed) OPhPhCO2EtIV-32 IV-37 IV-37i IV-36 a)OPhPhCO2EtHNCIV-33Õ OPhPhCO2Et0.1 equiv DBU 0.5 equiv pyridine DCM,reflux,12 h IV-32 OPhPhCO2EtIV-36 b)toluenereflux CNPhPh!"&&!as a dienophile with acrylonitrile to deliver adduct IV-33Õ as a single isomer (Scheme 10a). Entry base X solvent ¼C/T h/t pKaa,f %/conv. (IV -37/36)b,c,d 1 DBU 0.1 DCM 60 12 11.955 80/trace 2 DBU 0.1 toluene 110 5 11.9 94/trace 3 DBU 1.0 toluene 110 3 11.9 95/trace 4 DBU 10.0 toluene 110 1.5 11.9 >98 /n.o. 5 DBU 10.0 toluene rt 4 11.9 >98 /n.o. 6 DBN 10.0 toluene 110 2 12.7e >98 /n.o. 7 pyridine 10.0 toluene 110 12 5.2156 No reaction 8 Et3N 10.0 toluene 110 12 10.75 n.o./55 9 quinuclidine 10.0 toluene 110 12 11.0 n.o./28 10 DMAP 10.0 toluene 110 12 9.2 n.o./40 11 TMG 10.0 toluene 110 12 13.657 30/60 12 DABCO 10.0 toluene 110 12 8.82 n.o./90 13 Ph3P 10.0 toluene 110 12 20.958 n.o./23 Table IV -2. A series of bases were tested for the rearrangement reaction. Reaction conditions: substrate (0.03 mmol) was dissolved in 0.5 mL solvent. [a] pK a of conjugated acid in water. The aqueous pK a values are from EvanÕs pK a table , otherwise specified. [b] conversion estimated from 1H NMR analysis of the crude reaction mixture. [c] n.o. = not observed. [d] except for product, starting material was observed with trace impurities from 1H NMR of the crude mixture. [e] pK a from San -Apro Ltd. [f] Calculated pK a value of Ph 3P from reference 58. !)''!However , when a reaction was set up under the same reaction condition , surprisingly, compound pyran IV-37 was isolated , instead of the de -conjugated compound IV-36, in 91% yield , as shown in Scheme IV -10b. Moreover , it was also discovered that pyran IV-37 could partially (~ 10%) decompose to salicylate IV-38 when purified by silica gel column . These results are different from those observed in DABCO catalyzed reaction s, in which 4H-pyran derivatives were formed through a formal [1,3] -H rearrangement . Sequentially, these 4H-pyrans could be converted into cyclohexe nones under acidic condition s. The differ ent results could be on account of their differen t basicity . As a result, a series of bases with different basicity and nucleophilicity were test ed. IV-3. Results and discussion To investigate the underpinnings of the basicity and nucleopilicity in the formal [1,5]-H rearrangement reaction , a series of N-based catalysts , as well as Ph 3P, were tested by using racemic IV-32 as a model substrate . As shown in Table IV-2, both DBU and DBN can efficiently catalyze the formal [1,5] -H rearrangement reaction (entry 1 -6), even under room temperature (entry 5), or with 10 mol% of catalyst loading (entry 1 and 2) in different solvents. As noticed, t hese two have the highest pK a aside from tetramethylguanidine (TMG ). However, TMG promoted a sluggish process, giving only 30% of IV-37 with 60% of IV-36 (entry 11, Table IV -2). It suggests that this transformation is presumably the outcome of a combination effect of both basicity and nucleopilicity of the bases. No IV-37 formation was observed for the rest of the bases (entry 7 -10 and 1 2-13, Table IV -2), which have relatively low pK a values, even though Et 3N and quinuclidine have close r pKa value s to DBU (entry 8 -9, Table IV -2). Not surprisingly, no reaction was detected for !)'(!pyridine as it has the lowest pK a value (entry 7, Table IV -2). Even Ph3P with the highest Scheme IV -11. [a] Reaction conditions: substrate (0.2 mmol) was dissolved in toluene (0.1 mL) with DBU (10 equiv.). [b] Isolated yield (combined yield of pyran and it s rearranged phenol side products). OR1R2CO2Ettoluene, rt, 4-12 h OR1R2CO2EtDBU (10.0 equiv) OPhPhCO2EtIV-37 ( >98 %) OCO2EtIV-38 ( 58 %) OCO2EtIV-41 ( 50 %) BrBrOPhCO2EtIV-44 ( 78 %) OCO2EtIV-42 ( 88 %) ClClOPhCO2EtIV-45 ( 97 %) OPhCO2EtIV-46 ( 70 %) OPhPhCO2EtIV-47 ( 90 %) (i-Pr)3SiOCO2EtIV-39 ( 55 %) BrBrOCO2EtBrBrIV-40 ( 55 %) OCO2EtIV-43 ( 80 %) OOOPhPhCO2EtIV-48 ( 71 %) OCO2EtOCO2EtOMe OMe OMe OMe OCO2EtOCO2EtPhIV-49 ( 90 %) Ph(not observed) (not observed) IV-50 ( 50 %) !)'"!pKa value, it was unable to deliver the pyran product, but instead provided 4H-pyran with only 23% conversion (entry 13, Table IV -2). Based on the observation, optimized conditions for our formal [1,5] -H rearrangement were to use DBU (10.0 equiv) in toluene at room temperature (entry 5, Table IV-2). In order to probe the substrate scope for this reaction, a range of dihydropyrans have been prepared and subjected to the optimized reaction conditions ( Scheme IV -11). As can be seen from the results in general , both vinyl and propargyl dihydropyrans were compatible with the reaction. The substrate scope also revealed that the nature of the fragment R 1 did not have a substantial influence on the reaction outcome . In other words, R1 could be aryl regardless of its substitution patterns and/or electronic properties (pro duct IV-37ÑIV-42 and IV-45ÑIV-47, Scheme IV -11), heteroaryl and silyl (product IV-43ÑIV-44, Scheme IV -11) (and presumably alkyl, although none was studied in this case) . In contrast, the electronic nature (relatively electron -rich substitution) of aryl and alkyl as R 2 moieties deteriorate d the formal [1,5] -H rearrangement, but generate 4 H-pyrans through [1,3] -H rearrangement (product IV-49ÑIV-50, Scheme IV -11). Nonetheless, the H of C4 in the dihydropyran should be acidic enough for these ami dines to deprotonate. However, either electron -rich aryl (-OMe, IV-49) or alkyl (IV-50) as R 2, would more or less decrease the acidity of this H. Fortunately, when R 2 was electron -deficient aryl (product IV-38ÑIV-40, IV-42, Scheme IV -11), slightly electron rich aryl (product IV-41 and IV-46, Scheme IV -11), heteroaryl (product IV-43, Scheme IV -11), or just phenyl (product IV-37, IV-44ÑIV-45 and IV-47ÑIV-48, Scheme IV -11), moderate to excelle nt yields were obtained ( 50 - >98%, Scheme IV -11). It was found that some of !)')!these pyrans (see IV-5 Experimental for details) would rearrange to give the corresponding salicylate derivatives when purified by silica gel column (see IV-37i in Figure IV -3. X-ray crystal structures for IV-45 and IV-38i . OPhCO2EtOHCO2EtBrBrIV-45 IV-38i Scheme IV -12. DBU catalyzed double bond isomerization from 4 H-pyrans to pyrans. OR1R2CO2Ettoluene, rt, 4 h OR1R2CO2EtDBU (10.0 equiv) OPhPhCO2EtIV-37 ( 90 %) OCO2EtIV-38 ( 52 %) OCO2EtIV-41 ( 49 %) BrBrOCO2EtIV-37 ( 89 %) ClCl!)'*!Scheme IV-10b as an example) . To simplify the yield calculation, a combination yield of isolate pyr ans and their silylates was reported as the silylates w ere from the pyran rearrangement in the column. Interestingly, even a tri -substituted vinyl di hydropyran could afford the pyran product IV-48 through our methodology (Scheme IV -11). Of note, the configuration s of the product IV-38i and IV-45 were unambiguously assigned by the X -ray crystal structure, as shown in Figure IV-3. To demonstrate the 4 H-pyran was formed as a potential intermediate, a number of 4H-pyrans were subjected to the same reaction condition . As expected, all of the tested substrates were able to furnish the pyran products with similar yields (see Scheme IV -12). Surprisingly , when an acetyl dihydropyran IV-51 was used as substrate for this transformation, it was oxidized to the pyran IV-52 with isomerization of the $"!Ðunsaturated ester moiety from E to Z, as presented in Scheme IV-13. However, no double Scheme IV -13. DBU catalyzed oxidation reaction of acetyl dihydropyran IV-51 to pyran IV-52 with air as the oxidant. OOPhCO2EtDBU (10.0 equiv) toluene, r.t. 4 h (quantitative yield) (not observed) OOPhairOHOPhCO2EtCO2EtIV-51 IV-52 !)'+!bond reduction was observed in this reaction ; presumably the air reacted as the oxidant . The structure of IV-52 was assigned by X-ray crystal lography . Condition Observation (1.5 N) LiOH (10.0 equiv) N.R (4.0 N) LiOH, then HCl (10.0 equiv) conc. HCl (10.0 equiv) trace conc. TFA (10.0 equiv) trace silica, (1.0 N) HCl (10.0 equiv) 15% yield The propensity for pyrans to rearrange to salicylates on silica gel piqued our interest to develop a method, in which salicylate derivatives could be obtained in high yield. However, either acid or base employed to accelerate this transformation failed in giving a decent outcome, as shown in Table IV-3. Interestingly, as can be seen from Scheme IV-14, when pyran IV-38 was treated with silica (20 g/mmol) in EtOAc with water (v:v = 1:1) at room temperature, IV-38i was obtained in quantitative yield. Unfortunate ly, the OHCO2H10% yieldPhPhReaction conditions: 0.1 mmol substrate was used in 1 mL CH 3CN at room temperature. Table IV-3. Optimization of reaction condition s for the conversion of pyran to salicylate !)'$!efficiency of this method was substrate dependent and limited (substrate IV-41 and IV-37, Scheme IV-14). Apparently, m ore opt imization is required to generalize this transformation. Further manipulation was also performed to demonstrate the application of the vinyl pyrans, the products of formal [1,5] -H rearrangement, by Diels -Alder reaction to give chromene derivatives as shown in Scheme IV -15. The adducts were successfully obtained, although with low isolated yi elds. Unfortunately, acrylonitrile and ethyl vinyl ether did not provide conclusive results. Scheme IV -14. Silica catalyzed rearrangement of pyran to salicylate. OHCO2 Et OCO2EtIV-38 IV-38i BrBrEtOAc/H 2O = 100:1 rt, 12 h, c = 0.1M 20 g silica/mmol BrBr(Quantitative yield) OHCO2 Et OCO2EtIV-41 IV-41i EtOAc/H 2O = 100:1 rt, 12 h, c = 0.1M 20 g silica/mmol (~ 10% coversion) OHCO2 Et OCO2EtIV-37 IV-37i EtOAc/H 2O = 100:1 rt, 12 h, c = 0.1M 20 g silica/mmol (~15% conversion) !)'%!Based on base and substrate scope screening, as well as the rearranged salicylates formation, a proposed mechanism is presented in Scheme IV -16. DBU react s as a Br¿nsted base, depro tonating the #ÐH of substrate IV-32 to furnish enolate intermediate, followed by $Ðprotonation to give 4 H-pyran IV-36. As a strong base, DBU will further deprotonate the C4 H to provide a pyran intermediate, which can tautomerize to pyran IV-37 with the assistan ce from DBU. Pyran ring of IV-37 can be hydrolyzed under acidic con dition to a diketone ester , which will cyclize to afford cyclohex a-2,4-dien-1-one intermediate, and eventually tautomerize to salicylate IV-37i as the product. However, we cannot exclude the possibility that DBU reacts as a nucleophile, initiating the reaction in the same way as DABCO , as described in Chapter III . As reported, DBU can be used as a nucleophilic catalyst. Therefore, we tried to develop a one-pot synthesis of pyran IV-37 direc tly from allenoate IV-56 and dibenzylideneacetone IV-57. Interestingly, an adduct with MS of [ IV-56+IV-57+DBU+H] + Scheme IV -15. Diels -Alder reaction of vinyl -pyrans with maleic anhydride to give chromene derivatives. OPhCO2Et(i-Pr)3SiOOOIV-44 IV-53 Toluene, reflux 6 hOPhCO2Et(i-Pr)3SiIV-54 OOO(14% isolated yield) single isomerOCO2EtPhOOOIV-46 IV-53 Toluene, reflux 6 hOCO2EtPhIV-55 OOO(25% isolated yield) single isomer!)'#!was dete cted, as depicted in Scheme IV -17. H owever, an attempt to isolate the adduct was unsuccessful. OPhPhIV-32 NNHOOEt NNHOPhPhOOEt NNHNNOPhCO2EtIV-36 PhHNNNNHOPhCO2EtPhHNNNNHOPhPhCO2EtIV-37 H+OPhPhCO2EtHHOHPhPhCO2EtOH2OHH+PhPhCO2EtOHOPhPhCO2EtOHOH+HPhCO2EtPhOHOH+H2OPhCO2EtPhOOHCO2 Et IV-37i PhPhScheme IV -16. Plausible mechanism for DBU mediates formal [1,5] -H shift and acid catalyzed rearrangement yielding phenol product. !)'&!IV-4. Primary amine mediated multi -substituted carbocyclic !Ðamino ester synthesis Comparing to their $Ðanalogues, although of less importance, conformationally constrained carbocyclic !Ðamino acids have also attracted great attention from both NH2CO2HNMe 2PhCO2EtIV-58 (BAY Y9379 )IV-59 (Tilidin )ONHOONHOHOHNH2H2NOCOIV-61 (MK-6892 )ONNNHOONHCO2HIV-60 (pitucamycin) Figure IV-4. Representative examples of !Ðamino acid drugs and pharmacologically active !Ðamino acid derivatives. Scheme IV -17. Attempt to develop one -pot synthesis of pyran IV-37, while an adduct with the MS of [ IV-56+IV-57+DBU+H] + was observed. PhPhOCO2EtDBU (1.0 equiv) Toluene (0.2 mM), 12 h, rt (1.0 equiv) (2.0 equiv) OPhPhCO2Et(not observed) an adduct with the MS of [ IV-56 +IV-57 +DBU+H] +IV-56 IV-57 !)('!synthetic and medicinal chemists in the past decades due to their critical biological effects. 59-63 Examples of these compounds are found in nature or antibiotics (IV-58 and IV-59, Figure IV-4). Also, they are considered as key precursors for pharmacologically interesting !Ðlactams and other bioactive compounds (IV-60 and IV-61, Figure IV-4).60,64 Besides, these compounds are important building blocks for biologically active small molecules and peptide synthesis with potential pharmacological applications. In peptide synthesis, incorporat ion of novel conformationally restricted !Ðamino acids as subunits , especially into foldamers, is attractive from the aspect of design and synthesis of peptide -based drug molecules with high biological potential. 65,66 Conseque ntly, a great deal of progress has been made in the past 10 years, leading to a large number of original papers Scheme IV-18. Two commonly used routes to approach !Ðamino acids synthesis. OOONH4OHCO2HCONH2CO2RCO2HCO2HNH21. ROH2. OH-3. H+Curtius degradation 1. SOCl 22. NaN33. HClHoffmann degradation NaOH, Br 2DowexIV-62 IV-63 IV-64 IV-65 nCSI nNSO 2ClOn = 1,2 IV-66 H2OHCl, rt nNHOna)b)CO2HNH2HClIV-67 IV-69 IV-68 !)((!and reviews published in this field. 60,64,67 -71 Among these reports, a considerable number of them are about carbocyclic and heterocyclic !Ðamino acid derivative synthesis, both in racemic forms and enantiomerically pure forms. In addition, further manipulation of these !Ðamino acids to heterocycles, peptides, as well as other bioactive derivatives ha s also been reported. 68 There are two general modes commonly used to access to !Ðaminocyclohexanecarboxylic acid. 60,64 One is based on the transformation of hexahydrophthalic by amindation and Hof fman degradation of the resulting amide to the corresponding !Ðaminocyclohexanecarboxylic acid , or an alternative route, in which Curtius degradation is used (see Scheme IV -18a for details) . An alternative route consists Scheme IV-19. Representative examples of other methods for !Ðamino acids synthesis. a) Metathesis pathway; b) Amino group conjugation addition pathway; c) Cycloaddition pathway. a)p-Tol SNOp-Tol SNHOONOMe nn = 1,2 LDA, -78 ¼C, THF NOOMe nGrubbs II NHnNOOMe SOp-Tol nb)CO2t-BuCHOnTHF, -78 ¼C, 2 h then -20 ¼C, 2h PhNLiPhCO2t-BuNPhPhHO1. Pd(OH) 2/C, MeOH H2 (5 atm) 2. TFA, DCM rt then Dowex nCO2HNH2HOc)HNOOEt OMe O+dioxane 110 ¼C CO2MeNHOEtO CO2MeNHOEtO TMSI, CCl 462%TMSI, CCl 457%CO2HNH2CO2HNH2!)("!of the ring -opening transformation of bicyclic !Ðlactams derived from cycloalkenes by the cycloaddition of chlorosulfonylisocyanate (CSI) , as shown in Scheme IV -18b.64 However , other methodologies that utilize other transformations , such as metathesis, amino group conjugate addition, cycloaddition, desymmetrization of meso -anhydrides, have also been developed to overcome certain limitations of the two general approaches (representative examples shown in Scheme IV -1972-74). Furthermore , routes of modification of !Ðketo esters or natural sources are also investigated for the synthesis of !Ðamino acids. 64 During our investigation in cyclohexenone synthesis described in Chapter III, we highlighted that the reaction produces a 1,5 -dicarbonyl intermediate from dihydropyran under acidic ring opening reaction condition. Actually, this intermediate is common for Scheme IV-20. Substrate scope of primary amine mediated !Ðamino ester synthesis from dihydropyrans. N.D = not determined. OR1R2CO2EtR2R3H2NNHR3pyridine (cat.) toluene reflux, overnight CO2EtIV-72 aa-bb IV-70 a-b R1(1.1 equiv) IV-71 a-b NR1R2CO2EtIV-73 R3not observed PhNHPhCO2EtPhPhNHp-MeOC 6H4CO2EtPhPhNHPhCO2EtPhNHp-MeOC 6H4CO2EtIV-72 aa IV-72 ba IV-72 ab IV-72 bb PhPhN.D65%81%53 %!)()!several routes toward pyridine synthesis, such as the Krıhnke 75 and the Hantzsch 76 dihydropyridine (pyridine) synthesis. This piqued our interest to develop a synthesis for dihydropyridine (pyridine) derivatives from our ready available dihydropyrans . We postulated that the benzylic amine attack s the dihydropyran to open the ring, followed by two tautomerizations to furnish the enamine intermediate. An intramolecular ring closing ÒN-attack Ó and an E1cb elimination would provide the dihydropyr idine IV-73 as the product (see Scheme IV -21, pathway A) . However, it turns out that an unexpected carbocyclic !Ðamino ester IV-72 aa was formed. For the initial study of this transformation, two of the benzylic amines, together with two dihydropyran substrates, have been employed to test the substrate scope . Gratifyingly, good results were obtained for the tested substrates (up to 81 % isolated yield , need to be optimized ) (see Scheme IV -20). The structures of IV-72ab was assigned by 2D NMR techniques. A proposed mechanism is depicted in Scheme IV -21b. It is believed that the benzylic amine initiates a ring opening reaction of the dihydropyran to furnish an enolate intermediate, which then undergoes a n intramolecular ring clos ing reaction by ÒC -attackÓ instead of ÒN -attackÓ, followed by dehydration and tautomerization to deliver the !Ðamino ester as the product . We speculate that $ÐC of the !Ðinmino ester intermediate is more nucleophilic as compared to the secondary amine under this reaction condition. Further exploration and mechan istic stud ies of this transformation are needed. In summary, continuous development of the applications of our dihydropyran, an amidine -mediated formal [1,5] -H rearrangement toward pyran synthesis in moderate to !)(*!high yield has been discovered, and some of these pyrans can undergo further rearrangement to salicylate derivatives under acidic condition. Also, we disclosure a primary amine initiated !Ðamino ester synthesis from our dihydropyrans in good yield. OPhOEt OPhPhNH2OPhOEt OHPhNH± H+-H2OPhNPhOOEt HOPhPhCO2EtPhNHPhIV-70 a IV-71 a Ph± H+± H+PhCO2EtPhHONPhIV-72 aa HHOOHH-H2OPhPhONPhOHOEt HOHHPhPhOCO2EtNPhH± H+-H2ONPhOEt OPhPhHO± H+NPhOEt OPhPhHOHNPhOEt OPhPhpath AÑÒN attackÓ path BÑÒC attackÓ IV-73 Scheme IV-21. a). An assumption of dihydropyridine synthesis from dihydropyran and benzylic amine through an intramolecul ar ÒN -attackÓ in the process. b). Proposed mechanism for primary amine mediated !Ðamino ester synthesis from dihydropyrans through an intramolecular ÒC-attackÓ in the process . !)(+!IV-5. Experimental. IV-5.1. General remarks: Molecular sieves (4 †) were dried at 160 ¼C under 0.25 mtorr vacuum prior to use. Unless specified, solvents were purified as follows. Toluene and DCM were dried over CaH2. THF and Et 2O were dried over sodium ( dryness was monitored by colorization of benzophenone ketyl radical); they were freshly distilled prior to use. All the dihydropyrans were prepared as reported. 53,77 Ethyl -2,3-butadienoate was synthesized according reported literature and stored at -20 ¼C.78 1D and 2D NMR spectra were obtained from a 500 MHz Varian NMR spectrometers and referenced using the residual 1H peak from the deuterated solvent. Mel ting point was detected by MelTem 019 . Waters 2795 (Alliance HT) instrument was used for HRMS (ESI) analysis with polyethylene glycol (PEG -400-600) as a reference. Column chromatography was performed using Silicycle 60 †, 35 -75 %m silica gel. Pre-coated 0 .25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, iodine, potassium permanganate stain or phosphomolybdic acid in EtOH stain. !)($!IV-5.2. General procedure A for DBU -mediated formal [1,5] -H shift toward pyran synthesis : To a solution of the corresponding compound ( 1.0 equiv) in toluene , DBU ( 10.0 equiv) was added. Then the solution was stirred at room temperature for 4 -12 hours. The mixture was concentrated under N 2 flow. The re sidue was purified by silica gel column chromatography using ethyl acetate in hexanes (1.5-10%) as the eluent. IV-37: Ethyl (E) -2-(6-phenethyl -4-phenyl-2H-pyran-2-ylidene)acetate : Compound IV-37s (69.3 mg, 0.2 mmol ) was subject to general procedure A to provide 63.0 mg (90% yield) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) ! 8.04 -7.95 (1H, m), 7.57 -7.54 (2H, m), 7.41 -7.38 (3H, m), 7.33 -7.29 (2H, m), 7.25 -7.19 ( 3H, m), 5.95 -5.89 (1H, m), 5.25 (1H, s), 4.18 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.96 (2H, t, J = 7.0 Hz), 2.71 (2H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.1, 166.2, 160.1, 14 3.2, 140.1, 136.4, 129.5, 128.8, 128.5, 128.3, 12 6.3, 1 26.2, 112.5, 102.4, 88.5, 59.0, 35.5, 33.2, 14.6 ppm. HRMS (ESI) Calculated Mass for C 23H23O3: 347.1647 ([M+H] +), Found 347.1659 ([M+H] +). OR1R2CO2Ettoluene, rt, 4-12 h OR1R2CO2EtDBU (10.0 equiv) OPhPhCO2EtIV-37 !)(%! IV-37i: Ethyl 3 -hydroxy-5-phenethyl -[1,1' -biphenyl]-4-carboxylate: 6.9 mg (10% yield) of the pure product was isolated as a colorless oil; 1H NMR (500 MHz, CDCl 3) ! 11.43 (1H, s), 7.58 -7.51 (2H, m), 7.48 -7.35 (3H, m), 7.33 -7.27 (2H, m), 7.25 -7.17 (3H, m), 7.11 (1H, d, J = 2.0 Hz), 6.89 (1H, d, J = 2.0 Hz), 4.50 (2H, dd , J = 7.0 Hz, 7.0 Hz), 3.32 (2H, t, J = 8.0 Hz), 2.94 (2H, t, J = 8.0 Hz), 1.44 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 171.4, 163.1, 146.7, 145.1, 141.7, 139.5, 128.8, 128.4, 128.4, 128.3, 127.1, 126.0, 121.8, 114.2, 110.7, 61.8, 38.4, 38.3, 1 4.3 ppm. HRMS (ESI) Calculated Mass for C 23H23O3: 347.1647 ([M+H] +), Found 347.1653 ([M+H] +). IV-38: Ethyl (E) -2-(6-(2-bromophenethyl) -4-(2-bromophenyl)-2H-pyran-2-ylidene)acetate: Compound IV-38s (50.4 mg, 0. 1 mmol ) was subject to general procedure A to provide 29.2 mg (58% yield) of the pure product as a light yellow crysta l; 1H NMR (500 MHz, CDCl 3) ! 7.72 -7.65 (1H, m), 7.59 -7.51 (2H, m), 7.33 -7.29 (1H, m), 7.28-7.24 (1H, m), 7.24 -7.17 (3H, m), 7.10-7.04 (1H, m), 5.78-5.65 (1H, m), 5.27 (1H, s ), 4.14 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.07 (2H, t, J = 7.0 Hz), 2.70 (2H, t, J = 7.0 Hz), 1.27 OHCO2EtPhPhIV-37i OCO2EtBrBrIV-38 !)(#!(3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.8, 165.6, 158.3, 144.5, 139.3, 139.0, 133.3, 132.9, 130. 6, 130.0, 130.0, 128.1, 127.6, 127.6, 124.3, 121.3, 116.1, 105.3, 89.3, 59.0, 33.6, 33.5, 14.5 ppm. HRMS (ESI) Calculated Mass for C 23H21O3Br2: 502.9857 ([M+H] +), Found 502.9879 ([M+H] +). IV-38i: Ethyl 2' -bromo-3-(2-bromophenethyl) -5-hydroxy-[1,1' -biphenyl]-4-carboxylate: 3.0 mg (3% yield) of the pure product was isolated as a light yellow crystal; mp: 86 -88 ¼C. 1H NMR (500 MHz, CDCl 3) ! 11.37 (1H, s), 7.67-7.62 (1H, m ), 7.56 -7.52 (1H, m), 7.36-7.31 (1H, m), 7.23 -7.18 (3H, m), 7.11 -7.04 (2H, m), 6.93 (1H, d, J = 2.0 Hz), 6.72 (1H, d, J = 2.0 Hz ), 4.50 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.34 (2H, t, J = 7.0 Hz), 3.08 (2H, t, J = 7.0 Hz), 1.44 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 171 .2, 162.3, 146.7, 143.7, 141.1, 140.7, 133.2, 132.8, 130.7, 130.3, 129.2, 127.7, 127.3, 124.6, 124.3, 124.2, 121.9, 116.9, 111.3, 61.9, 38.0, 36.1, 14.2 ppm . HRMS (ESI) Calculated Mass for C 23H21O3Br2: 502.9857 ([M+H] +), Found 502.9860 ([M+H] +). OHCO2EtBrBrIV-38i OCO2EtBrBrIV-39 !)(&!IV-39: Ethyl (E) -2-(6-(3-bromophenethyl) -4-(3-bromophenyl)-2H-pyran-2-ylidene)acetate : Compound IV-39s (50.4 mg, 0. 1 mmol) was subject to general procedure A to provide 27.7 mg (5 5% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl3) ! 7.98 -7.92 (1H, m), 7.66 -7.64 (1H, m), 7.54 -7.45 (2H, m), 7.38 -7.34 (2H, m), 7.29 -7.25 (1H, m), 7.20 -7.14 (1H, m), 7.13 -7.09 (1H, m), 5.86 -5.80 (1H, m), 5.25 (1H, s), 4.17 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.92 (2H, t, J = 7.0 Hz), 2.69 (2H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.9, 165.5, 159.8, 142.3, 141.5, 138.6, 12.5, 131.4, 130.3, 130.1, 129.6, 129.1, 127.1, 124.8, 123.1, 122.6, 113.3, 102.2, 89.6, 59.2, 35.2, 32.8, 14.6 ppm . HRMS (ESI) Calculated Mass for C 23H21O3Br2: 502.9857 ([M+H] +), Found 502.9860 ([M+H] +). IV-39i: Ethyl 3' -bromo-3-(3-bromophenethyl) -5-hydroxy-[1,1' -biphenyl]-4-carboxylate: 2.0 mg (2% yield) of the pure product was isolated as a light yellow oil; 1H NMR (500 MHz, CDCl 3) ! 11.40 (1H,s), 7.66 -7.61 (1H, m), 7.54 -7.43 (2H, m), 7.38 -7.33 (2H, m), 7.32 -7.29 (1H, m), 7.20 -7.14 (1H, m), 7.09 -7.05 (2H, m), 6.81 -6.71 (1H, m), 4.50 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.30 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz), 1.44 (3H, t, J = 7 .0 Hz) ppm . OHCO2EtBrBrIV-39i !)"'! IV-40: Ethyl (E) -2-(6-(4-bromophenethyl) -4-(4-bromophenyl)-2H-pyran-2-ylidene)acetate: Compound IV-40s (50.4 mg, 0. 1 mmol) was subject to general procedure A to provide 27.7 mg (55% yield) of the not pure product as a yellow oil . IV-41: Ethyl (E) -2-(6-(4-methylphenethyl) -4-(p-tolyl) -2H-pyran-2-ylidene)acetate : Compound IV-41s (37.4 mg, 0. 1 mmol) was subject to general procedure A to provide 18.7 mg (5 0% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.98 (1H, d, J = 1.5 Hz), 7.50 -7.44 (2H, m), 7.22 -7.19 (2H, m), 7.12 -7.07 (4H, m), 5.97 -5.90 (1H, m), 5.22 (1H, s), 4.17 (2H, dd , J = 7.0 Hz, 7.0 Hz), 2.92 (2H, t, J = 7.0 Hz), 2.68 (2H, t, J = 7.0 Hz), 2.38 (3H, s), 2.32 (3H, s ), 1.30 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 168.2, 166.4, 160.2, 143.1, 139.9, 137.1, 135.8 , 133.4 , 129.5, 129.2, 128.2, 126.1, 111.7, 102.3 , 88.0, 58.9, 35.6, 32.8, 21.3, 21.0, 14.6 ppm. HRMS (ESI) Calculated Mass for C 25H27O3: 375.1960 ([M+H] +), Found 375.1967 ([M+H] +). OCO2EtBrBrIV-40 OCO2EtIV-41 !)"(! IV-41i: Ethyl 3 -hydroxy-4'-methyl -5-(4-methylphenethyl) -[1,1' -biphenyl]-4-carboxylate : 3.7 mg ( 5% yield) of the pure product was isolated as a light yellow oil; 1H NMR (500 MHz, CDCl 3) ! 11.40 (1H, s), 7. 46-7.42 (2H, m ), 7.26 -7.22 (2H, m), 7.12 -7.08 (5H, m ), 6.87 (1H, d, J = 1.5 Hz), 4.49 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.29 (2H, t, J = 7.0 Hz), 2.89 ( 2H, t, J = 7.0 Hz), 2.40 (3H, s), 2.34 (3H, s), 1.44 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 171.4, 163.1,146.6, 145.2, 138.7, 138.3, 136.6, 135.4, 129.5, 129.0, 128.2, 127.0, 121.6, 113.8, 110.4, 61. 8, 38.6, 37.9, 29.7, 21.2, 14.3 ppm. HRMS (ESI) Calculated Mass for C 25H27O3: 375.1960 ([M+H] +), Found 375.1973 ([M+H] +). IV-42: Ethyl (E) -2-(6-(2-chlorophenethyl) -4-(2-chlorophenyl)-2H-pyran-2-ylidene)acetate : Compound IV-42s (41.5 mg, 0. 1 mmol) was subject to general procedure A to provide 32.0 mg ( 77% yield ) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.73 (1H, d, J = 1.5 Hz), 7.41 -7.34 (2H, m ), 7.32 -7.26 (3H, m ), 7.22 -7.14 (3H, m ), 5.76 -5.71 (1H, m), 5.27 (1H, s), 4.15 (2H, dd , J = 7.0 Hz, 7.0 Hz), 3.07 (2H, OHCO2EtIV-41i OCO2EtClClIV-42 !)""!t, J = 7.0 Hz), 2.71 (2H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 167.8, 165.6, 158.4, 143.1, 137.6, 137.0, 133.8, 132.0, 130.6, 130.0, 130.0, 129.9, 129.5, 127.9, 127.0, 126.9, 116.2, 105.1 , 89.3, 59.0, 33.4, 31.1, 14.5 ppm. HRMS (ESI) Calculated Mass for C 23H21O3Cl2: 415.0868 ([M+H] +), Found 415.0874 ([M+H] +). IV-42i: Ethyl 2' -chloro-3-(2-chlorophenethyl) -5-hydroxy-[1,1' -biphenyl]-4-carboxylate : 9.1 mg (11% yield) of the pure product was isolated as a light yellow oil ; 1H NMR (500 MHz, CDCl 3) ! 11.35 (1H, s), 7.48 -7.42 (1H, m), 7.38 -7.32 (1H, m), 7.32 -7.27 (2H, m), 7.24 -7.20 (1H, m ), 7.18 -7.12 (2H, m), 7.12 -7.06 (1H, m ), 6.96 (1H, d, J = 1.5 Hz), 6.72 (1H, d, J = 1.5 Hz), 4.50 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.33 (2H, t, J = 7.0 Hz), 3.06 (2H, t, J = 7.0 Hz), 1.43 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 171.2, 162.4, 145.1, 1 43.9, 139.1, 139.0 , 130.8, 130.4, 130.0, 129.5, 129.1, 127.5, 126.8, 126.7, 124.2, 117.0 , 111.2, 61.9, 36.0, 35.6, 14.2 ppm. HRMS (ESI) Calculated Mass for C21H21O3Cl2: 415.0868 ([M+H] +), Found 415.0878 ([M+H] +). OHCO2EtClClIV-42i OCO2EtOOIV-43 !)")!IV-43: Ethyl (E) -2-(4-(furan -2-yl)-6-(2-(furan -2-yl)ethyl) -2H-pyran-2-ylidene)acetate : Compound IV-43s (32.6 mg, 0. 1 mmol) was subject to general procedure A to provide 26.1 mg ( 80% yield ) of the pure product as a yellow oil ; 1H NMR (500 MHz, CDCl 3) ! 8.03-7.92 (1H, m), 7.54 -7.42 (1H, m), 7.35 -7.29 (1H, m), 6.78 -6.70 (1H, m), 6.53 -6.44 (1H, m), 6.32 -6.25 (1H, m), 6.08 -6.02 (1H, m), 5.93 -5.86 (1H, m), 5.18 (1H, s), 4.16 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.96 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.0, 165.7, 159.5, 153.7, 150.4, 144.4, 141.3, 132.1, 112.2, 110.3, 110.2, 108.7, 105.7, 99.4, 88.8, 59.0, 32.2, 25.5, 14.6 ppm. HRMS (ESI) Calculated Mass for C 19H19O5: 327.1232 ([M+H] +), Found 3 27.1245 ([M+H] +). IV-44: Ethyl (E) -2-(4-phenyl-6-((E)-2-(triisopropylsilyl)vinyl) -2H-pyran-2-ylidene)acetate : Compound IV-44s (33.2 mg, 0. 1 mmol) was subject to general procedure A to provide mg ( 78% yield ) of the pure product as a yellow oil ; 1H NMR (500 MHz, CDCl 3) ! 8.07 (1H, d, J = 1.5 Hz), 7.66 -7.59 (2H, m), 7.44 -7.39 (3H, m), 6.64 (1H, d, J = 19.0 Hz), 6.45 (1H, d, J = 19.0 Hz), 6.12 (1H, d, J = 1.5 Hz ), 5.35 (1H, s), 4.17 (2H, dd, J = 7.0 Hz, 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.19 -1.14 (3H, m), 1.08 (18H, d, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.1, 165.2, 154.4, 143.3, 136.4, 136.3, 130.9, 129.6, 128.9, 126.2, 114.3, 105.1, 89.4, 59.0, 29.7, 18.7, 18.6, 18.6, 14.6, 10.9 ppm. O(i-Pr)3SiPhCO2EtIV-44 !)"*!HRMS (ESI) Calculated Mass for C 26H37O3Si: 425.2512 ([M+H] +), Found 425.2515 ([M+H] +). IV-45: Ethyl (E) -2-(6-((E)-4-methylstyryl) -4-phenyl-2H-pyran-2-ylidene)acetate: Compound IV-45s (35.8 mg, 0. 1 mmol) was subject to general procedure A to provide 34.7 mg (97% yield) of the pure product was as a dark purple needle crystal; mp: 120 -122 ¼C. 1H NMR (500 MHz, CDCl 3) ! 8.06 (1H, d, J = 2.0 Hz), 7.65 -7.60 (2H, m), 7.45 -7.39 (5H, m), 7.24 (1H, d, J = 17.0 Hz), 7.21 -7.18 (2H, m), 6.58 (1H, d, J = 17.0 Hz), 6.21 -6.16 (1H, m), 5.37 (1H, s), 4.18 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.37 (3H, s), 1.31 (3H, t, J = 7.0 Hz) ppm; 13C N MR (125 MHz, CDCl 3) ! 168.1, 165.2, 155.3, 143.2, 139.2, 1 36.4, 132.9, 132.7, 129.6, 128.9, 127.1, 126.1, 118.7, 113.7 , 105.2, 89.3, 59.1, 29.7, 14.6 ppm. HRMS (ESI) Calculated Mass for C 24H23O3: 359.1647 ([M+H] +), Found 359.1660 ([M+H] +). OPhCO2EtIV-45 OPhCO2EtIV-46 !)"+!IV-46: Ethyl (E)-2-(6-((E)-styryl) -4-(p-tolyl) -2H-pyran-2-ylidene)acetate: Compound IV-46s (35.8 mg, 0. 1 mmol) was subject to general procedure A to provide 25.1 mg (70% yield) of the pure product was as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 8.07 (1H, d, J = 2.0 Hz), 7.55 -7.48 (4H, m), 7.40 -7.36 (2H, m), 7.34 -7.30 (1H, m), 7.27 (1H, d, J = 17.0 Hz), 7.25 -7.22 (2H, m), 6.62 (1H, d, J = 16.0 Hz), 6. 20 (1H, d, J = 2.0 Hz), 5.36 (1H, s), 4.19 (2H, dd, J = 7.0 Hz, 7.0 Hz), 2.40 (3H, s), 1.31 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl3) ! 168.1, 165.3, 155.0, 143.0, 140.0, 135.7, 13 2.6, 129.6, 128.9, 128.8, 127.2, 126.1, 125.7, 119.8, 113.3 , 105.6, 89.1, 59.1, 29.7, 14.6 ppm. HRMS (ESI) Calculated Mass for C 24H23O3: 359.1647 ([M+H] +), Found 359.1659 ([M+H] +). IV-47: Ethyl (E) -2-(4-phenyl-6-((E)-styryl) -2H-pyran-2-ylidene)acetate : Compound IV-47s (34.4 mg, 0. 1 mmol) was subject to general procedure A to provide 31.0 mg ( 90% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 8.08 (1H, d, J = 2.0 Hz), 7.65 -7.61 (2H, m), 7.52 -7.49 (2H, m), 7.45 -7.42 (3H, m), 7.40 -7.37 (2H, m), 7.34 -7.31 (1H, m), 7.27 (1H, d, J = 16.0 Hz), 6.62 (1H, d, J = 16.0 Hz), 6.20 (1H, d, J = 2.0 Hz), 5.39 (1H, s), 4.18 (2H, dd , J = 7.0 Hz, 7.0 Hz), 1. 31 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.0, 165.1, 155.1, 143.1, 136.3, 135.7, 132.7, 129.7, 129.0, 129.0, 128.9, 128.9, 128.7, 127.5, 127.2, 126.2, 125.8, 119.7, 114.0, 105.6, 89.5, 59.1, 53.4, 29.7, 14.6 ppm. OPhPhCO2EtIV-47 !)"$! IV-48: Ethyl (E) -2-(4-phenyl-6-(1-phenylpropan-2-yl)-2H-pyran-2-ylidene)acetate : Compound IV-48s (36.0 mg, 0. 1 mmol) was subject to general procedure A to provide 25.6 mg (71% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.97 (1H, d, J = 2.0 Hz), 7.55 -7.50 (2H, m), 7.41 -7.36 (4H, m), 7.29 -7.27 (1H, m), 7.22 -7.17 (1H, m), 7.15 -7.11 (2H, m), 5.83 (1H, d, J = 2.0 Hz), 5.26 (1H, s), 4.1 7 (2H, dd, J = 7.0 Hz, 7.0 Hz), 3.03 -2.97 (1H, m), 2.81 -2.70 (2H, m), 1.30 (3H, t, J = 7.0 Hz), 1.21 (3H, d, J = 1.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 168.1, 166.2, 163.9, 143.3, 139.2, 136.6, 129.5, 129.0, 128.8, 128.4, 126.3, 126.2, 112.5, 101.4, 88.3, 59.0, 41.0, 40.3, 17.7, 14.6 ppm. HRMS (ESI) Calculated Mass for C 24H25O3: 361.1804 ([M+H] +), Found 361.1821 ([M+H] +). IV-50: Ethyl 2 -(4-methyl -6-(phenylethynyl) -4H-pyran-2-yl)acetate : Compound IV-50s (28.2 mg, 0. 1 mmol) was subject to general procedure A to provide 14.1 mg (50% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.50-7.44 (2H, m), 7.37 -7.29 (3H, m), 5.26 -5.22 (1H, m), 4.69 -4.63 (1H, m), 4.19 (2H, dd, J = 6.5 Hz, 6.5 Hz), 3.10 OPhPhCO2EtIV-48 OCO2EtPhIV-50 !)"%!(2H, d, J = 16.0 Hz ), 3.07-3.00 (1H, m), 1.28 (3H, t, J = 7.5 Hz), 1.14 (3H, d, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 169.6, 144.3, 133.9, 131.7, 128.7, 128.3, 122.1, 113.5, 104.5, 88.4, 83.3, 77.3, 61.0, 39.3, 26.9, 24.4, 14.2 ppm. IV-5.3. Analytical data for propargyl dihydropyran IV-44s to IV -47s and dihydropyran IV-48s: IV-47s: Ethyl ( E)-2-(4-phenyl-6-(phenylethynyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate : Compound IV-47ss (23.4 mg, 0. 1 mmol) was subject to general procedure of dihydropyran synthesis to provide 27.2 mg (79% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.55 -7.48 (2H, m), 7.39 -7.29 (5H, m), 7.28 -7.24 (3H, m ), 5.78 -5.72 (1H, m), 5.66 -5.61 (1H, m), 4.15 -4.07 (2H, m), 3.73 -3.64 (2H, m), 3.17-3.08 (1H, m), 1.24 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.0, 165.5, 142.1, 135.0, 131.8, 129.1, 128.7, 128.4, 127.3, 127.1, 121.6, 114.4, 99.9, 89.3, 82.6, 59.8, 36.2, 30.3, 14.3 ppm. OPhPhCO2EtIV-47s OPh(i-Pr)3SiCO2EtIV-44s !)"#!IV-44s: Ethyl ( E)-2-(4-phenyl-6-((triisopropylsilyl)ethynyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate : Compound IV-44ss (31.3 mg, 0. 1 mmol) was subject to general procedure of dihydropyran synthesis to provide 32.2 mg (76% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.35 -7.30 (2H, m), 7.26 -7.19 (3H, m), 5.70-5.64 (1H, m), 5.64 -5.55 (1H, m), 4.13 -4.06 (2H, m), 3.71 -3.59 (2H, m), 3.07 (1H, qd, J = 8.0 Hz, 1.5 Hz), 1.24 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.1, 165.5, 142.2, 134.9, 128.7, 128.7, 127.3, 127.1, 114.6, 99.8, 99.6, 92.1, 59.7, 36.1, 30.1, 18.6, 14.3, 11.2 ppm. IV-46s: Ethyl ( E)-2-(6-(phenylethynyl) -4-(p-tolyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate : Compound IV-46ss (24.6 mg, 0. 1 mmol) was subject to general procedure of dihydropyran synthesis to provide 22.2 mg ( 62% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.56 -7.49 (2H, m), 7.38 -7.32 (3H, m), 7.16-7.12 (4H, m), 5.83 -5.68 (1H, m), 5.63 (1H, s ), 4.16 -4.07 (2H, m), 3.70 -3.62 (2H, m), 3.17 -3.04 (1H, m), 2.34 ( 3H, s), 1.25 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.1, 165.6, 139.1, 136.6, 134.9, 131.7, 131.7, 129.4, 129.1, 129.0, 128.4, 128.3, 127.9, 127.1, 121.7, 114.7, 99.8, 89.2, 82.6, 59.7, 35.8, 30.3, 29.7, 21.0, 14.3 ppm. OPhCO2EtIV-46s !)"&! IV-45s: Ethyl ( E)-2-(4-phenyl-6-(p-tolylethynyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate : Compound IV-45ss (24.6 mg, 0. 1 mmol) was subject to general procedure of dihydropyran synthesis to provide 33.7 mg ( 94% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.45 -7.39 (2H, m), 7.37 -7.30 (2H, m), 7.28 -7.23 (3H, m), 7.18 -7.13 (2H, m ), 5.72 (1H, d, J = 3.5 Hz), 5.63 (1H, s), 4.16 -4.05 (2H, m), 3.73-3.64 (2H, m), 3.17 -3.07 (1H, m), 2.37 (3H, s), 1.24 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 167.1, 165.5, 142.2, 139.3, 135.1, 131.7, 129.2, 128.7, 127.3, 127.0, 118.5, 114.0, 99.8, 89.5, 82.0, 59.7, 36.2, 30.3, 21.6, 14.3 ppm. IV-48s: Ethyl ( E)-2-(4-phenyl-6-((E)-1-phenylprop-1-en-2-yl)-3,4-dihydro-2H-pyran-2-ylidene)acetate: Compound IV-48ss (24.8 mg, 0. 1 mmol) was subject to general procedure of dihydropyran synthesis to provide 11.2 mg ( 31% yield) of the pure product as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.40 -7.31 (6H, m), 7.29 -7.26 (4H, m), 7.15 (1H, s ), 5.69 (1H, s), 5.50 (1H, d, J = 3.5 Hz ), 4.16 -4.08 (2H, m), 3.77 -3.69 (2H, m), 3.16 -3.05 (1H, m), 2.03 (3H, d, J = 1.0 Hz) 1.26 (3H, t, J = 7.0 Hz) ppm; 13C NMR (125 MHz, OPhCO2EtIV-45s OPhPhCO2EtIV-48s !))'!CDCl3) ! 167.4, 166.6, 150.5, 143.2, 137.4, 129.4, 128.7, 128.7, 128.2, 127.3, 126.9, 126.8, 126.8, 105.3, 98.8, 59.6, 36.1, 30.9, 14.3, 14.0 ppm. IV-50s: Ethyl ( E)-2-(4-methyl -6-(phenylethynyl) -3,4-dihydro-2H-pyran-2-ylidene)acetate : Compound IV-50ss (34.0 mg, 0. 2 mmol) was subject to general procedure of dihydropyran synthesis to provide 21.1 mg ( 37% yield) of the pure product was isolated as a yellow oil; 1H NMR (500 MHz, CDCl 3) ! 7.50 -7.47 (2H, m), 7.36 -7.31 (3H, m), 5.60 (1H, d, J = 1.0 Hz), 5.53 (1H, d, J = 4.0 Hz), 4.16 (2H, ddd, J = 1.0, 7.0, 7.0 Hz), 3.46 (1H, ddd, J = 0.5, 1.5, 15 Hz), 2.70 (1H, ddd, J = 1.0, 8.5, 15 Hz), 2.55-2.46 (1H, m), 1.28 (3H, t, J = 7.5 Hz) 1.11 (3H, d , J = 7.0 Hz) ppm; 13C NMR (125 MHz, CDCl3) ! 167.4, 166.5, 133.9, 131.7, 128.9, 128.3, 121.8, 117.3, 99.3, 88.8, 82.7, 77.3, 77.0, 76.8, 59.7, 29.6, 25.2, 20.2, 14.3 ppm. IV-52: Ethyl ( Z)-2-(6-acetyl -5-methyl -4-phenyl-2H-pyran-2-ylidene)acetate: Quantitative yield of the pure product was isolated as a dark red crystal. m.p: 75 ¼C ; OCO2EtPhIV-50s OOPhCO2EtIV-52 !))(!HRMS (ESI) Calculated Mass for C 18H18O4: 299.1283 ([M+H] +), Found 299.1283 ([M+H] +). IV-5.4. General procedure B for the synthesis of enones IV -44ss to IV -47ss and IV -50ss:79 To a solution of alkyne (1.0 equiv) in THF, n-BuLi (1.1 equiv) was added dropwise at -78 ¼C. The solution was left to stir for 10 min , allowed to warm up to room temperature and kept for another 30 min. It was then cooled down to -78 ¼C, and enal (1.0 equiv) in THF was added . The reaction was warmed to room temperature and kept for another 4 hours. After the reaction was completed (followed by TLC detection), saturated NH 4Cl was added and the product was extracted with EtOAc. The combined organic layer s were washed by brine and dried over Na 2SO4, filtered , and concentrated under reduced pressure . The crude product was used for the next step without further purification. The crude enol from the last step was dissolved in DCM, and MnO 2 (25.0 equiv) was added, and the mixture was stirred at room temperature for 24 hours. The solution was filtered and concentrated, followed by purification by silica gel column chromatography to provide the enones using ethyl acetate and hexanes as the eluent. HR1OR2R1OR21) n-BuLi (1.1 equiv) THF, -78 ¡C 2)(1.0 equiv) -78 ¡C to rt 3) MnO 2 (25 equiv) rt, overnight !))"! IV-47ss: Phenylacetylene (102.1 mg, 1. 0 mmol) and cinnamaldehyde (132.2 mg, 1.0 mmol) were subject to general procedure B to provide 178.9 mg (71% yield) of the pure product as a yellow crystal . m.p: 56 ¼C ; 1H NMR (500 MHz, CDCl 3) ! 7.92 (1H, d, J = 16.5 Hz), 7.68 -7.64 (2H, m), 7.64 -7.60 (2H, m), 7.51 -7.41 (6H, m), 6.88 (1H, d, J = 16.5 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 178.2, 148.3, 134.0, 132.9, 131.2, 130.6, 129.1, 128.7, 128.7, 128.5, 120.2, 91.5, 86.6 ppm. IV-46ss: Phenylacetylene (102.1 mg, 1.0 mmol) and p-methyl cinnamaldehyde (146.2 mg, 1.0 mmol) were subject to general procedure B to provide 160.1 mg ( 65% yield) of the pure product as a brown solid. m.p: 50 ¼C ; 1H NMR (500 MHz, CDCl 3) ! 7.9 0 (1H, d, J = 16 .0 Hz), 7.68 -7.64 (2H, m), 7. 52-7.49 (2H, m), 7. 48-7.45 (1H, m), 7.45 -7.39 (2H, m), 7.26-7.22 (2H, m), 6.84 (1H, d, J = 16.5 Hz) , 2.40 (3H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 178.3, 148.5, 141.9, 132.9, 132.1, 131.3, 130.5, 129.8, 128.7, 128.6, 128.3, 127.6, 120.3, 91.3, 86.6, 21.6 ppm. PhOPhIV-47ss OPhIV-46ss !)))! IV-45ss: 4-Ethynyltoluene (116.2 mg, 1.0 mmol) and cinnamaldehyde (132.2 mg, 1.0 mmol) were subject to general procedure B to provide 209.4 mg ( 85% yield) of the pure product as a yellow crystal. m.p: 67 ¼C ; 1H NMR (500 MHz, CDCl 3) ! 7.91 (1H, d, J = 16.0 Hz), 7.64 -7.59 (2H, m), 7.57 -7.54 (2H, m ), 7.47 -7.41 (3H, m), 7.25 -7.20 (2H, m), 6.87 (1H, d, J = 16.5 Hz), 2.41 (3H, s) ppm; 13C NMR (125 MHz, CDCl 3) ! 178.3, 148.1, 141.3, 134.1, 130.0, 129.1, 128.7, 128.6, 117.0, 92.2, 86.4, 21.8 ppm. IV-44ss: (Triisopropylsilyl )acetylene (182.4 mg, 1.0 mmol) and cinnamaldehyde (132.2 mg, 1.0 mmol) were subject to general procedure B to provide 240.5 mg ( 77% yield) of the pure product as a yellow oil ; 1H NMR (500 MHz, CDCl 3) ! 7.93 (1H, d, J = 16.5 Hz), 7.56-7.53 (2H, m), 7.45 -7.40 (3H, m), 6.79 (1H, d, J = 16.5 Hz), 1.16 (18H, d, J = 5.0 Hz), 1.22-1.15 (3H, m) ppm; 13C NMR (125 MHz, CDCl 3) ! 178.1, 149.0, 134.1, 131.2, 129.1, 128.7, 128.6, 128.6, 102.6, 96.2, 18.6,18.6, 11.1 ppm. IV-5.5. General procedure C for the synthesis of e nones IV -48ss, IV-74ss and IV -75ss:80,81 PhOIV-45ss PhOSi( i-Pr)3IV-44ss !))*! To a stirred solution of benzaldehyde (1.0 equiv) and 2 -butanone (2.0 equiv) in acetic acid ( 1.25 mM), conc entrated H 2SO4 (0.95 equiv) was added slowly at room temperature. The reaction was allowed to stir for 20 h. T he mixture was neutralized with 25% aqueous NaOH solution. The residue was extracted with EtOAc and the combined organic layers were separated and dried over Na 2SO4, and concentrated under reduced pressure . The crude was purified by silica gel column chromatography to provide the enones using ethyl acetate and hexanes as the eluent. A solution of diisopropylamine (1.01 equiv.) in THF at -78 ¡C was treated with n-BuLi (1.0 equiv.) for 30 min , and the enone (1.0 equiv.) was added. After 30 min, aldehyde (2.0 equiv.) was added at the same temperature. After another 60 min, the reaction was quenched by addition of HOAc -H2O (1:1 v/v) at -78 ¡C. The flask was warmed up to room temperature, followed by separation of the two phases. The aqueous phase was extracted with Et2O. The combined organic phase s were washed with saturated NaHCO 3 and brine, and dried with anhydro us Na 2SO4. The crude aldol product was used for the next step without further purification. The aldol production was dissolved in pyridine (12.4 equiv.) at 0 ¡C and methanesulfonyl chloride (1.22 equiv.) was added. The solution was kept at room CHOOH2SO4, CH3CO2Hrt, 24 h PhO1) LDA (1.1 equiv) THF, -78 ¼C 2) RCHO (1.0 equiv) -78 ¼C to rt 3) CH 3CO2H/H2OPhOROH1) MsCl (2.3 equiv) pyr (23.2 equiv) 0 C to rt, 12 h 2) Et 3N (15 mM) PhOR(2.0 equiv) !))+!temperature overnight and H 2O was added. The mixture was extracted with Et2O and the combined phase was washed by saturated CuSO 4 and brine. The organic layer was dried over anhydrous Na 2SO4, concentrated under reduced pressure, and redisposed in Et 2O. Et3N (15 mM ) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched by addition of water, followed by extraction with Et 2O. The combined organic layers were washed with cold 1% HCl, saturated NaHCO 3, and then water. The organic phase was dried over MgSO 4, then filtrated and concentrated under reduced pressure to a crude oil , which was purified by silica gel column chro matography to deliver the asymmetric dienone using ethyl acetate and hexanes as the elue nt. IV-48ss: Benz aldehyde (106.1 mg, 1.0 mmol) was subject to general procedure C to provide 119.2 mg ( 48% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl3) 7.71 (1H, d, J = 16.0 Hz ), 7.66-7.57 (3 H, m), 7.50-7.34 (9H, m), 2.20 (3H, d, J = 1.0 Hz) ppm; 13C NMR (125 MHz, CDCl 3) ! 192.7, 143.4, 138.7, 138.5, 136.0, 135.1, 130.2, 129.7, 128.9, 128.5, 128.5, 128.2, 121.9, 13.8 ppm. IV-74ss: 4-Bromobenz aldehyde (185.2 mg, 1.0 mmol) was subject to general procedure C to provide 147.2 mg (45% yield ) of the pure product as a light yellow solid. m.p: 85 ¼C; PhOIV-48ss PhPhOIV-74ss Br!))$!1H NMR (500 MHz, CDCl 3) 7.63 (1H, d, J = 16.0 Hz ), 7.59-7.34 (11H, m), 2.19 (3H, d, J = 1.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 192.4, 142.0, 138.9, 138.5, 135.8, 134.0, 132.1, 129.8, 129.7, 129.6, 128.6, 128.5, 124.4, 122.4, 13.8 ppm. IV-75ss: p-tolualdehyde (120.2 mg, 1.0 mmol) was subject to general procedure C to provide 65.6 mg (25% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl3) 7.74-7.32 (9H, m ), 7.25-7.16 (2 H, m), 2.38 (3H, s), 2.19 (3H, d, J = 1.5 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 192.8, 143.6, 143.5, 140.7, 138.6, 138.4, 138.4, 136.0, 132.3, 129.7, 129.7, 129.6, 128.5, 128.4, 128.3, 128.3, 120.9, 120.9, 21.5, 13.9 ppm. IV-5.6. General procedure D for the s ynthesis of adduct s IV-54 and IV-55: To a solution of pyran (1.0 equiv) in toluene (0.12 mM), maleic anhydride (2.0 equiv) was added. The solution was heated and kept refluxing for 6 h. T he solvent was removed by a stream of N2 gas. The crude was purified by silica gel column chro matography to deliver the adduct using ethyl acetate in hexanes (5-20%) as the eluent. PhOIV-75ss OR2CO2EtR1OOOToluene, reflux 6hOR2CO2EtR1OOO(2.0 equiv) !))%! IV-54: IV-44 (25.0 mg, 0.06 mmol) was subject to general procedure D to provide 4.2 mg (14% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) 8.31 (1H, d, J = 2.0 Hz), 7.67 -7.58 (2H, m), 7.49 -7.43 (3H, m ), 6.52 (2H, s), 6.31 (1H, d, J = 2.0 Hz), 4.70 -4.61 (1H, m), 4.23 (2H, ddd, J = 7.5, 7.5, 3.0 Hz), 3.23 (1 H, d d, J = 1 0.5, 19.0 Hz) , 2.93 (1H, dd, J = 6.5, 19.0 Hz), 1.31 (3H, t, J = 7.5 Hz), 1.12 -1.06 (21H, m) ppm; 13C NMR (125 MHz, CDCl 3) ! 170.8, 163.0, 154.6, 144.8, 136.1, 136.0, 132.0, 130.1, 129.1, 126.3, 114.6, 105.9, 96.2, 60.7, 36.6, 24.7, 18.6, 18.6, 14.0, 10.9, 1.02 ppm; HRMS (ESI) Calculated Mass for C 30H39O6Si: 523.2516 ([M+H] +), Found 523.2529 ([M+H] +). IV-55: IV-46 (16.0 mg, 0.045 mmol) was subject to general procedure D to provide 5.2 mg (25% yield ) of the pure product was isolated as a light yellow oil; 1H NMR (500 MHz, CDCl3) 8.31 ( 1H, d, J = 1.5 Hz), 7.56-7.50 (4H, m), 7.44 -7.38 (2 H, m), 7.38-7.33 (1H, m), 7.29-7.27 (1H, m), 7.11 (1H, d, J = 16.0 Hz), 6.69 (1H, d, J = 16.0 Hz), 6.38 (1H, d, J = 1.5 Hz), 4.79-4.70 (1H, m), 4.24 (2H, ddd, J = 7.0, 7.0, 1.5 Hz), 3.32 (1H, dd, J = 10.5, 19.0 Hz) , 2.98 (1H, dd , J = 7.0 , 19.0 Hz), 2.41 (3H, s), 1.32 (3H, t , J = 7.0 Hz) ppm ; 13C OPhCO2Et(i-Pr)3SiIV-54 OOOOCO2EtPhIV-55 OOO!))#!NMR (125 MHz, CDCl3) ! 170.9, 163.2, 144.6, 140.6, 135.2, 133.0, 129.8, 129.4, 129.0, 127.3, 126.2, 119.5, 113.6, 106.4, 95.9, 60.6, 21.4, 14.1, 1.0 ppm; HRMS (ESI) Calculated Mass for C 28H25O6: 457.1651 ([M+H] +), Found 457.1688 ([M+H] +). IV-5.7. General procedure E for the s ynthesis of carbocyclic !Ðamino ester: To a solution of dihydropyran (1.0 equiv) and amine (1.1 equiv) in toluene, pyridine (cat.) was added. The solution was kept refluxing overnight. T he solvent was removed under N 2 flow. The crude was purified by silica gel column chro matography to deliver the adduct using ethyl acetate and hexanes as the eluent. IV-55: IV-32 (32.0 mg, 0. 1 mmol) and 4 -methoxybenzy lamine (27.4 mg, 0.2 mmol) were subject to general procedure E to provide 35.6 mg (81% yield ) of the pure product as a light yellow oil; 1H NMR (500 MHz, CDCl 3) 9.73 (1H, t, J = 6.0 Hz), 7.32-7.22 (11H, m), 7.17-7.13 (2H, m), 6.89-6.84 (2 H, m), 5.56 (1H, d, J = 3.5 Hz), 4.42 (2H, ddd, J = 15.5, 15.5, 6.0 Hz), 3.84-3.73 (2H, m), 3.80 (3H, s ), 3.63 (1H, dt, J = 4.5 , 13 .0 Hz ), 2.80 (1H, dd, J = 5.5, 16 .0 Hz), 2.55 (1H, dd , J = 14.0, 16 .0 Hz), 0.62 (3H, t, J = 7.0 Hz ) ppm; 13C NMR (125 MHz, CDCl 3) ! 169.4, 163.0, 158.9, 144.2, 144.0, 140.0, 130.0, 128.6, 128.1, OR1R2CO2EtR2R3H2NNHR3pyridine (cat.) toluene reflux, overnight CO2EtR1(1.1 equiv) PhCO2EtPhNHOIV-72 ab !))&!127.7, 127.6, 126.6, 126.2, 126.0, 121.0, 114.2, 93.4, 58.6, 55.3, 46.7, 40.2, 34.7, 29.7, 13.3 ppm. !)*'! APPENDIX !"#$! OPhPhCO2EtIV-37 !"#%! OPhPhCO2EtIV-37 !"#"! OHPhPhCO2EtIV-37i !"##! OHPhPhCO2EtIV-37i !"#&! OCO2EtIV-38 BrBr!"#'! OCO2EtIV-38 BrBr!"#(! OHCO2EtIV-38i BrBr!"#)! OHCO2EtIV-38i BrBr!"#*! OCO2EtIV-39 BrBr!"&+! OCO2EtIV-39 BrBr!"&$! OHCO2EtIV-39i BrBr!"&%! OCO2EtIV-41 !"&"! OCO2EtIV-41 !"&#! OHCO2EtIV-41i !"&&! OHCO2EtIV-41i !"&'! OCO2EtIV-42 ClCl!"&(! OCO2EtIV-42 ClCl!"&)! OHCO2EtIV-42i ClCl!"&*! OHCO2EtIV-42i ClCl!"'+! OCO2EtIV-43 OO!"'$! OCO2EtIV-43 OO!"'%! OPhCO2EtIV-44 (i-Pr)3Si!"'"! OPhCO2EtIV-44 (i-Pr)3Si!"'#! OPhCO2EtIV-45 !"'&! OPhCO2EtIV-45 !"''! OPhCO2EtIV-46 !"'(! OPhCO2EtIV-46 !"')! OPhPhCO2EtIV-47 !"'*! OPhPhCO2EtIV-47 !"(+! OPhPhCO2EtIV-48 !"($!OPhPhCO2EtIV-48 !"#$!Crystal Structure: !!! OPhIV-52 OCO2Et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