THE AROMATIC 3-AZA-COPE REARRANGEMENT AND AZA-ANNULATION REACTION AS SYNTHETIC TOOLS FOR THE CONSTRUCTION OF NITROGEN HETEROCYCLES By Lars Guenter Beholz A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY College of Natural Science Department of Chemistry 1994 ABSTRACT THE AROMATIC 3-AZA-COPE REARRANGEMENT AND AZA-ANNULATION REACTION AS SYNTHETIC TOOLS FOR THE CONSTRUCTION OF NITROGEN HETEROCYCLES By Lars Guenter Beholz Conditions for the aromatic 3-aza-Cope rearrangement were developed for which the reaction occurred at a reasonable rate, at practical temperatures and with adequate reproducibility and regiospecifity. The catalyst systems BF3-Et20 in toluene, ZnC12 in xylenes, and AlCl3 in xylenes efficiently accelerated the 3-aza-Cope rearrangement of N- allylaniline substrates accessing a convenient method for CC bond formation between N- alkyl substituents and an o-aromatic ring carbon. This versatile rearrangement yielded products which could potentially act as precursors to a variety of indole alkaloids substituted in the indole 6-membered ring portion. Stereochemically complex hydroxylated piperidine alkaloids were efficiently accessed through use of the aza-annulation. The G4 and C-5 substituent pattern was determined through initial substrate preparation. After aza-annulation, the stereochemistry at these positions could then be controlled through choice of reduction conditions. Trans stereochemistry at C-4 relative to OS was efficiently incorporated to an extent of >98:2 through use of the Baeyer-Villiger oxidation. Stereospecific cis hydroxylation at the C-2 and C-3 positions was then accessed through selenation followed by oxidation with 0804. D-mannonolactam and deoxymannojirimycin were prepared from propargyl alcohol using this methodology. ' The aza-annulation was then shown to constitute a quick and efficient method of building up highly functionalized 6-membered nitrogen heterocycles for potential use in the preparation of peptide mimics. DDQ oxidation of these functionalized heterocycles provided the corresponding functionalized pyridone ring systems. This methodology thus may provide a rapid and efficient route into the formation of peptide mimics with functionalization possible at the C-2, C-4, and 05 positions. To my parents Joan and Guenter ACKNOWLEDGEMENTS I would like to express my great appreciation to Dr. Stille for his dedication to the field of chemistry and for all he has taught me throughout my graduate career. I would also like to thank those on my graduate committee, Drs. Reusch, Allison, and Dunbar. Furthermore, I would like to extend my appreciation to all those individuals without whom my graduate career would have incomprehensibly more difficult: the NMR staff - Drs. Long and Jackson, Kermit, Dennis, Bev at the Mass Spec Facility, Lisa, Beth, Cathie, and Katherine, Tom from electronics, and all those in the glass shop. I would also like to thank Dr. Goetz for his wisdom, and companionship. I would like to extend my deepest thanks to Elizabeth, for her spiritual as well as financial support, her love, understanding and sacrifice. I would also like to thank my parents, family, and close friends: Andy and Niki, Tim and Michelle, and Dud and Lorna. I would especially like to thank those members of my group for their friendship and comradeship. I will especially miss Petr and Subramani. I have already said farewell to the California crowd: Art, Greg, and Paul. Finally, I would like to thank all those outside my family who have touched and changed my life in the most significant ways, and whom I think of daily: Mr. and Mrs. Calkins, Opa, all my friends over sea and Dr. O'Keeffe. iv RI TABLE OF CONTENTS LIST OF TABLES ........................................................................... vi LIST OF FIGURES ......................................................................... vii LIST OF SCHEMES ........................................................................ viii CHAPTER I. REFINEMENT OF THE LEWIS ACID-PROMOTED 3-AZA- COPE REARRANGEMENT OF N-ALKYL-N- ALLYLANILINES: A VERSATILE ROUTE TOWARD THE PREPARATION OF INDOLES SUBSTITUTED IN THE BENZENE RING PORTION. Introduction .......................................................................... 1 Aromatic-B-aza-Cope-Rearrangement ........................................ 4 Aza-annulation of N-Allylindoles ............................................. 8 Results and Discussion ............................................................. 10 Conclusion ........................................................................... 26 Experimental ......................................................................... 27 References ........................................................................... 41 CHAPTER II. AZA-ANNULATION AS A ROUTE TO HYDROXYLATED ALKALOIDS: THE TOTAL SYNTHESIS OF D- MANNONOLACTAM AND DEOXYMANNOJIRIMYCIN. Introduction .......................................................................... 43 Results and Discussion ............................................................. 45 Conclusion ........................................................................... 56 Experimental ......................................................................... 59 References ........................................................................... 71 CHAPTER III. AZA-ANNULATION AS A ROUTE TOWARD THE PREPARATION OF PEPTIDE MIMICS. Introduction .......................................................................... 73 Results and Discussion ............................................................. 76 Conclusion ........................................................................... 85 Experimental ......................................................................... 86 References ........................................................................... 94 REPRINTS OF PUBLICATIONS Table I-l Table I-2 Table I-3 Table [-4 Table I-S Table I-6 Table I-7 Table I-8 Table I-9 Table I- 10 Table I-ll Table I- 12 Table I-13 Table I- 14 Table I-15 Table 11-1 Table 11-2 Table 11-3 Table 11-4 LIST OF TABLES Study of Acid Catalyzed Rearrangements of I-31 ................ Effect of Varying ZnC12 Molarities on Maximum % I-77 in the Reaction Mixture in the Rearrangement of [-49 ................... Results of the Acid Catalyzed Rearrangement of I-49 ............ Effect of Solvent Reflux Temperature on the Rearrangement of I-49 ..................................................................... Effect of Varying Equivalents of A103 on the Rearrangement of I - 4 9 ..................................................................... Optimized Yields for the Rearrangement of I-49 .................. Results of the Acid Catalyzed Rearrangement of [-53 ............ Results of the Acid Catalyzed Rearrangement of [-50 to I-87.. Results of the Acid Catalyzed Rearrangement of I-55 ............ Results of the Acid Catalyzed Rearrangement of [-57 ............ AlCl3 Catalyzed Rearrangements of Various Nitrogen and Aromatic Substituted Anilines ....................................... ZnC12 Catalyzed Rearrangement of Various Nitrogen and Aromatic Substituted Anilines ....................................... BF3-etherate Catalyzed Rearrangement of Various Nitrogen and Aromatic Substituted Anilines ....................................... o-Allyl Regioisomer Product Ratios for the N-Substituted m- Methoxy Substrates Under Conditions of Various Acid Catalysts ................................................................. Competitive Lewis Acid-Promoted 3-Aza-Cope Rearrangement of I-49 and 1-67 ...................................................... Baeyer-Villiger Oxidation Studies on cis II-l3 .................... Baeyer-Villiger Oxidation Studies on trans II-l3 ................. Various Conditions Used in the Palladium Mediated Reduction of 11-12 to II-l3 ..................................................... Continued Baeyer-Villiger Oxidation Studies on 11-13 ........... 13 13 14 17 18 18 18 19 19 21 22 22 23 24 47 48 49 49 Figure I-1 Figure I-2 Figure I-3 Figure I-4 Figure 11-1 Figure 11-2 Figure 11-3 Figure 11-4 Figure 11-5 Figure III-l Figure III-2 Figure III-3 Figure III-4 Figure III-5 LIST OF FIGURES Transition State of N-Allylindole (I-59) Rearrangement. ........ Substrates Prepared for Acid Catalyzed Rearrangement ........... N-Substituted-p-methoxy Substrates ................................ N-Substituted-m-methoxy Substrates ............................... Hydroxylated Piperidine Alkaloids and Stereochernically Similar Sugars ................................................................... Alkaloid Precursor Target ............................................. Epimerization of Model Compound II- 13 .......................... DQ-COSY Spectra of 11-6 ............................................ DQ-COSY Spectra of II-7 ............................................ Several Important Peptide Mimics ................................... Example of Peptide Surrogate Design ............................... B-Turn Mimic ........................................................... Piperidone Peptide Mimic ............................................. Aza-annulation B-Amino Acid Analogs ............................. 11 11 ll 45 50 57 58 73 74 75 75 77 Scheme 1-1 Scheme 1-2 Scheme 1-3 Scheme 1-4 Scheme 1-5 Scheme 1-6 Scheme II-l Scheme 11-2 Scheme 11-3 Scheme 11-4 Scheme 11-5 Scheme 11-6 Scheme 11-7 Scheme 11-8 Scheme 111-1 Scheme III-2 Scheme 111-3 Scheme III-4 Scheme III-5 Scheme 111-6 Scheme 111-7 Scheme III-8 Scheme 111-9 Scheme 111- 10' LIST OF SCHEMES Retrosynthetic Analysis of Substituted Indole Preparation ' from Substituted Anilines ......................................... Possible Transition State Conforrnations for o-Substituted- N-allylanilines......; ............................................... Preparation of N-Benzyl-N-allyl-m-methoxyaniline .......... Possible Mechanism for the Formation of 1-78 from I-49.. Ring Closure of 1-7 7 ............................................. Synthesis of N-Methyl-p-allylaniline ............................ Preparation of II-6 and 11-7 from Sugar Analogs ............ Preparation of Initial Precursor Analog II-lS ................. Oxidation of Achiral Substrate Surrogate ....................... Preparation of Alkaloid Precursor II-24 ....................... Preparation of Alkaloid Precursor II-31 ....................... Alternate Route to Alkaloid Precursor Preparation ............ Use of Alternate Route to Introduce Chiral Center ............ Preparation of II-6 and II-7 from Alkaloid Precursor ....... General Strategy for Functionalized Pyridone Formation... ' Aza-annulation of B-Ketoester III-25 .......................... Aza-annulation of B-Enaminoester III-29 ..................... Preparation of B-Ketoamide Substrates ......................... Aza-annulation of B-Ketoamide III-33 ........................ Aza-annulation of B-Ketoamide III-34 ........................ Aza-annulation of Acetylenic Ester III-43 ..................... Aza-annulation of Acetylenic Ester II-45 ...................... Aza-annulation of Acetylenic Ester III-48 ..................... Hydrolysis of 111-28 and III-31 ............................... 4 12 1 5 20 26 45 50 51- 52 53 54 55 76 78 78 79 8O 81 82 83 83 84 Ac Bn BuLi (rt-BuLi) C6H6 DBU DDQ DMSO Et . G. C. hr (s) LHMDS IDA M m IVE m-CPBA (MCPBA) Ts (Tos) p-TsOH LIST OF ABBREVIATIONS Acetyl Benzyl n-Butyllithium Benzene 1,8-Diazabicyclo[5.4.0]undec-‘7-ene 2,3-Dichloro-5,6-dicyano-l,4—benzoquinone Dimethylsulfoxide Ethyl Gas Chromatography Hour (5) Lithium Bis(u'imethylsilyl)amide Lithium Diisopropylamide Molar Meta Methyl m-Chloroperoxybenzoic Acid Generalized Lewis Acid N-Bromosuccinimide Nuclear Overhauser Effect Ortho Generalized Protecting Group Para Pyridinium Chlorochromate Phenyl Room Temperate Tetrahydrofuran Trimethylsilyl Thin Layer Chromatography p-Toluenesulfonyl p-Toluenesulfonic Acid CHAPTER I. REFINEMENT OF THE LEWIS ACID-PROMOTED 3-AZA-COPE REARRANGEMENT OF N-ALKYL-N-ALLYLANILINES: A VERSATILE ROUTE TOWARD THE PREPARATION OF INDOLES SUBSTITUTED IN THE BENZENE RING PORTION. Introduction. Indoles substituted in the benzene ring portion occupy an important role in indole alkaloid synthesis. Examples of these alkaloids are serotonin (1-1) and oxypertine (1-2). H3C HO W I N W2 1v E] If H H N 1.. Serotonin Oxypertine (a neurotransmitter) (a tranquilizer) I-l I-2 Preparation of these types of indoles have been executed by a variety of methods.1 Many of these methods began with various o-substituted anilines (eqs. 1-3).2'4 Preparation of these o-substituted anilines was also approached via a wide variety of methodologies (eqs. 4 and 5).5’6 CH32.2 eq. BuLi H2 PhCOzEt , - I (32%) (1) NIH Hume N " THE-78°C If Ph he has H -5 L3 L4 I 5% PdC12(MeCN)2 = | (15%) (2) quinone N mrxlllHanM CH3 H3 C /|\CH3 Ac - AeOH ; O _A_°°_, (63%) (3) N IS IS I-9 I-10 + > 49% 4 O H3CJ\S/\/OAC 2) Et3N 0 OAc ( ) () NH: 1-11 1-12 1-13 Br Br H3 1) Br ,hv,C 1) Fe, HOAc 2 C14 > \ > \ (5) 2) PPh3 2) TsCl, Py No2 3) 0120,5th N02 NH 1. 1-14 1-15 1-16 The major disadvantages of these methods are either low overall yields from aniline to indole or lack of aniline substituent availability. A compromise between the benzene portion substituent pattern of the indole and overall yield of reaction is particularly evident in the synthesis outlined in equation 6.7 Yields for this synthesis range from 40% to 45% not including the formation of the endo-peroxide pyrrole (1-17). it h( re.- C0 1111 R2 TMSCI R2 02CH3 R3 \ CHO —_’ R3 / / —-> Eth, ZnClz ms 1- 1 7 R2 I I ’ l 9 1 3 C02CH3 I- l 8 I- 20 In order to ascertain a more efficient route toward the formation of substituted indole frameworks, the aromatic 3-aza—Cope rearrangement (aromatic-amino-Claisen rearrangement) for the o-allylation of anilines has been examined. Specifically, it was hoped that conditions for the 3-aza-Cope reaction could be developed so that the reaction would occur at a reasonable rate, at practical temperatures and with adequate reproducibility and regiospecifity. These improved conditions would allow for the convenient and versatile preparation of indoles substituted in the benzene ring portion as illustrated retrosynthetically in Scheme [-1. Scheme I-l. Retrosynthetic Analysis of Substituted Indole Preparation from Substituted Anilines \ \ \ \ \ \ |/ |=|/ |=¢I// d|// dl/ Rr/ If R/ NH R1 If R1 NHR R1 NHZ R R R I-23 I-24 I-25 I-26 I-27 R represents any appropriate N-protecting group and R1 represents any desired substituent. Aromatic 3-aza-Cope rearrangement. The aromatic 3-aza-Cope rearrangement, a [3,3]-sigmatropic rearrangement of N- allyl-N-arylamines, has received less attention than its counterpart, the aromatic-Claisen rearrangement, probably because of the drastic conditions required and the tendency toward side reactions.8 Thermal rearrangements of N-allylaniline occur at 200 - 350°C with cleavage to arylamines sometimes being the dominant reaction.9 Analogous rearrangements of the oxygen counterparts occur in the temperature range of 150 - 225°C.8 The nature of the rearrangement was examined extensively by Jolidon and Hanson and found to be similar to the aromatic oxy-Claisen rearrangement.9 Futhermore, in rearrangements using mixtures of deuterated and non-deuterated reactants (one reactant with the aromatic ring deuterated at the m-positions and the other with the terminal allyl positions deuterated), the formation of cross products was not observed. Also in this study, the [3,3] nature of the reaction was examined through steric interactions arising in the rearrangement of o-substituted-N-allylanilines. Scheme 1-2 gives the possible transition state conformations of a [3,3]-type process. As substituents of increased bulk were used, steric interaction between them and the crotyl methyl group increased in the cis-chair transition state conformation (top). A corresponding decrease in the amount of I-29 resulted. Evidence that the Lewis acid catalyzed rearrangement follows the same mechanism is available.11 Extensive studies of Lewis acid catalyzed rearrangements were executed by Abdrakhmanov, et alum-13 In one study, the rearrangement of N-(a- methylcrotyl)aniline (1-31, eq. 7) was monitored by Gas Chromatography (G. C.) relative to an internal standard. The results of this study are shown in Table I-l. Scheme I-2. Possible Transition State Conformations for o-Substituted-N-allylanilines NH2 CH3 . R C / if/ H ‘N / I-29 R ———-—. t O Na I-31 I-32 I-33 I-34 I-35 Table 1-1. Study of Acid Catalyzed Rearrangements of 1-3112 Entry Acid Catalyst/ Solvent Time (min.) % I- % I- % I- % I- Equivalents (130°C) 90% conv. 320 33a 34a 35a 1 Aniline-HCI / 1:1 Aniline 360 87 11 0 NA 2 Aniline-HCI/ 1:1 1-Octanol 200 74 3 12 NA 3 Aniline-HCI/ 1:1 DMSO 180 40 6 6 NA 4 Aniline-HCI/ 1:1 C6Hs-NOz 180 62 4 8 20 5 Aniline-HCI/ 1 2 C6H5-N02 260 68 4 11 15 6 Aniline-HCI/ 1.3 C6H5-N02 380 72 3 12 12 7 ZnClz/ 1:10 C6H5-N02 60 90 7 0 1 8 A1C13/ 1:10 C6H5-N02 25 68 3 18 5 9 CoClz/ 1:10 C5115-N02 30 55 6 13 15 10 SnCl4/ 1:10 C6H5-N02 10 62 12 0 10 11 TiC14 / 1:10 C6H5-N02 6O 48 4 O 17 12 BF3-ctherat6/ 1:10 C6H5-N02 20 68 10 O 9 13 ZnClz/ 1:1 C6H5-Cl 20 75 5 O 10 14 ZnClz/ 1:1 xylene 60 65 7 O 10 a Values represent G.C. yields relative to an internal standard. Inconsistencies exist between the results of Abdrakhmanov and those reported by Jolidon and Hansen. In particular, the recovery of 1-34 and I-35 by Abdrakhmanov indicated bond cleavage prior to bond making, a less [3,3]-like process. Furthermore, explanation as to how more 1-34 than I-35 could be formed in some cases was difficult since the second substituent on I-34 had to have come from I-31, 1-32, or 1-33. Decomposition mechanisms have been postulated. 14 One sequence is shown in equation 8. (8) I-36 I-37 I-38 I-39 Substituent effects on the aromatic portion of the substrate have also been examined in some depth. For the rearrangement of o- and m-substituted anilines, the amount of resulting p-product (similar to I-33) was found to be significantly higher.15 For example, in m-toluidines (m-methylanilines), the ratio of o- to p-rearrangement products was found to be 2.5 : 1 as opposed to 7 : 1 in the unsubstituted case. For 0- chloroaniline, the ratio was 3 : 1. The only exception to this trend was m-anisidine (m- methoxyaniline) which yielded the o-product only. Reaction rates for all substituted anilines were reported slower. Rates of reaction of p-substituted-N-allylanilines in H2804 at 60°C were as follows: p-H (kl-51:1), p-CH3 (krel=0-5). p-Cl (kl-31:05), p- OCH3 (krel=0-2)- With the p-CN substituent, cleavage was the principle reaction. Krowicki, et al., also studied the effects of substituents on the aromatic ring.15 For the rearrangement of N-methyl-N-(a-methylallyl)aniline under conditions of refluxing ethanol / water with an HCl catalyst for 8 hours the following isolated yields were obtained: p-H (95%), p-CH3 (95%), p-OCH3 (92%), m-CH3 (45%), m-OCH3 (24%). Under conditions of 180 - 230°C in concentrated HCl, N-allylanisidines simply decomposed.l7 N-Substitution has been reported to give increased yields and faster rates of rearrangement under milder conditions.15 Rates of reaction for both the thermal and acid catalyzed rearrangements increased in the order of N-H < N-CH3 , N-t-butyl.9 Rearrangement yields vary greatly depending on the reaction conditions and substituent pattern of the migrating group. The most favorable conditions were reported by Krowicki et al.1 and Abdrakhmanovlzv13 although yields reported by Abdrakhmanov were by G. C. only. The fact that the yields given were by G. C. only was significant in that isolated yields have sometimes been found to be far less than G. C. yields (for example: 70% yield by G. C. vs. 29% isolated for the Bronsted catalyzed rearrangement of N-methyl-N- (a-methylallyl)aniline and 88% G. C. vs. 57% isolated for a similar rearrangement of N- allylaniline).9 To exemplify the variety of yields obtained in seemingly similar reactions, the following illustrations have been included. Reported yields for ZnC12 catalyzed rearrangements range from 42% isolated for N-allylaniline in refluxing xylenes for 3 Au rear 0Vt: achi hours with 0.7 equivalents of catalyst to 23% isolated for 1-32 under conditions of 1 equivalent of ZnClz in refluxing xylenes.18 For the rearrangement of 1-31 to 1-32 the yields range from 65% under conditions of 1.1 equivalent of ch12 in xylenes at 130°C for 1 hour by G. c.13 to 97% with 1.1 equivalents of ZnC12 at 130°C in nitrobenzene by G. C. The highest overall yield found for an acid catalyzed rearrangement was for the reaction shown in equation 9.19 This reaction, which was run with a "large excess" of aniline, was reported to have provided a 100% isolated yield of 1-42 after 4 hours at 120°C or 3 hours at 184°C. The authors attributed the high yield to the catalytic activity of aniline-HCl, checking their hypothesis by running the reaction without excess aniline (no reaction) and then adding aniline-HCl which gave 100% isolated yield. For analogous reactions run without excess aniline and under conditions of thermal and acid catalysis, the authors obtained 20 - 40% yields. CH3 NH2 H\ NH CH3 Cl N | + W ——> a O H3C H3 H3 0 1 H3 excess I-35 I-40 I-41 I-42 Aza-annelation of N-Allylindolee. The [3,3]-rearrangement of N-allylindoles is far less studied than the [3,3]- rearrangement of N-allylanilines. This is probably due to the higher energy required to overcome the strained transition state and the variety of other methods available to achieve the same transformation (eqs 10-12).20‘22 /\/Br I O | I (10) N N V I E820, 20°C I MgBr 11 I-43 I-44 CH3 / B/\/‘\CH3 ‘ D I I (11) If HOAc, NaOAc, RT 1? H30 H3 H H I-4S 1-46 CC [C is: eff pI'C on< ind Rir 310 C01] pn'r syst ' Wm, I (12) = N02 N N I C6136 I H H 1-45 I-47 Thermal rearrangements of N-allylindole (I-S9) to 3-allylindole (I-44) occur at elevated temperatures (405 - 470°C).23 The requirement for higher temperature is consistent with the greater strain the transition state (1-48) must endure (Figure 1-1). Under conditions of 1 equivalent of AlCl3 in refluxing benzene for 2 hours, 1-59 rearranged to I-44 in 58% isolated yield while the crotyl analog rearranged in 43% isolated yield.24 Figure I-l. Transition State I-48 I-48 There exists support for use of the aromatic 3-aza-Cope rearrangement as an efficient synthetic tool in the preparation of o-substituted anilines. This same [3,3]- process may then be used in the 3-allylation of indoles from 1-59. In the former case, once the o-allylaniline is formed, ring closure may be executed to form the corresponding indole oxidatively via aldehyde formation followed by acid catalyzed ring closure.25 Ring closure may also be affected directly using Hg(OAc)226 or light16 followed by aromatization with Mn(II)27 or DDQ.28 The 3-aza-C0pe rearrangement could thus constitute an efficient route to indole alkaloids substituted in the benzene portion. The primary obstacles that must be overcome are: finding a general and efficient catalyst system, improving reaction yield reproducibility, and increasing overall reaction yield. Ann 5 Dr .Irqlllll mm.» .. .11"! 66 an fol be 150 am 10 Results and Discussion. Substrates for the aromatic 3-aza-Cope rearrangement were cleanly prepared by N-alkylation through the methodology of Tweede and Allabashi.29 Since previous rearrangements were executed using only a small variety of spectator (protective) N- substituents, a variety of substrates (Figure 1-2, I-3, and L4) were synthesized. Preparation of these substrates were as indicated in Scheme H. The protecting group or equivalent was added to the aniline or aniline derivative and the product then isolated. The protected aniline was then allowed to react with the alkyl bromide to provide the N- allylanilines. The specific syntheses were as follows: N-methyl-N-allyl aniline (1-49) was prepared in 91% yield by allylating N-methyl aniline. N-Allyl-N-benzyl aniline (I- 50) was prepared in 3 steps from 1-35 by condensation first of 1-35 with benzaldehyde to form N-benzylidine aniline (I-Sl) which was subsequently reduced to N-benzyl aniline (1-52) with LiAlH4. Substrate I-52 was allylated to give I-50 in 54% overall yield. N- tosyl-N-allyl aniline (1-53) was prepared by the reaction of 1-35 with tosyl chloride to yield the N-tosyl aniline (1-54) which was then allylated to provide I-53 in 40% overall yield. N-allyl acetaniline (I-SS) was prepared via preparation first of acetaniline (1-56) from I-35, followed by allylation in 50% overall yield. Preparation of 1-57 in 20% overall yield from m-nitro aniline was accomplished by methylation of 1-74 to give N- methyl-m-nitroaniline (1-58) which was then allylated to provide I-57. Preparation of I- 59, by allylation of 1-45, was accomplished in 75% yield. The p-methoxy substrates were prepared in similar fashion from p-anisidine (Figure 1-3). N-Methyl-N-allyl-p-methoxy aniline (I-60) was prepared in 42% overall yield via N-methyl-p-methoxy aniline (I-61). N-Benzyl-N-allyl-p-methoxy aniline (1-62) was prepared in 28% overall yield in 3 steps by preparation first of N-benzylidine-p- methoxy aniline (I-63), reduction of I-63 to N-benzyl-p-methoxy aniline (I-64) followed by allylation. The m-methoxy substrates (Figure 1-4) were prepared from m-methoxy aniline (I- 66), which was prepared as outlined in Scheme 1-3.30 N-methyl-N-allyl-m-methoxy aniline (1-67) was prepared by formation first of N-methyl-m-methoxy aniline (1-68) followed by alkylation in 50% overall yield. N-benzyl-N-allyl-m-methoxy aniline (1-69) was prepared in similar fashon via N-benzyl-m-methoxy aniline (1-70) or via N- benzylidine-m-methoxyaniline (I-7l) followed by alkylation in 72% overall yield. N- isobutyl-N-allyl-m-methoxy aniline (1-72) was prepared via N-isobutyl-m-methoxy aniline (1-73) in 62% overall yield. 11 Figure 1-2. Substrates Prepared for Acid Catalyzed Rearrangement Ham “W an O 0 0 I-49 I-50 I-53 train/W “sew/W 0 v I-55 I-57 I-59 Figure 1-3. N-Substituted-p-methoxy Substrates item/WI MAN/WI 0 O OCH3 OCH: 1-60 1-62 Figure 1-4. N-Substituted-m-methoxy Substrates “sew/W awn/W “scram“ 0' 0 .. in. oils I-67 I-69 L7 2 12 Scheme 1-3. Preparation of N-Benzyl-N-allyl-m—methoxyaniline. N02 N02 N02 1) Nam)2 Mel, Na2C03 O 2) Cu(NO3)-3H26 0 H20, EtOH ' O NH2 Cu20 OH (94%) OCH3 (33%) I-74 I-75 I-76 TiC14 lNaBH4 (113C0CH2)2 (7 5%) “‘AN I allylbromide AN’H benzylbmmme NH“ N32C03 O 7 H20,EtOI-1 H20, EtOH 0% (33%) OCH. (48%) OCHs I-69 I-70 I-66 Acid catalyzed rearrangement of the substrates 1-49, 1-50, I-53, I-55, I-57, and I- 59 were then explored with emphasis being placed on the rearrangement of 1-49 (eq 13). Initial studies of the rearrangement of 1-49 focused on the optimization of conditions using the well studied catalyst ZnClz. ZnC12 molarities were varied from 0.36 to 3.0 M under conditions of refluxing xylenes (140°C) and 1.2 equivalents of catalyst. Rearrangement of I-49 to the o-allyl product (1-77) occurred in 45% isolated yield at 0.5 M (Table 1-2). Compound 1-49 was then subjected to rearrangements using a variety of acid catalysts. These catalysts exhibited a wide range of activities as indicated in Table 1- 3. H3C\ H3C ,H N’m MLn ‘N O O m) I I-49 L77 1! 13 Table 1-2. Effect of Varying ZnClz Molarities on Maximum % 1-77 in the Reaction Mixture in the Rearrangement of I-49 Entry znc120 Time % of molarity (hours) I-77b 1 0.36 16 27 2 0.5 16 52 3 1.0 16 51 4 2.0 16 37 5 3.0 40 17 0 Reactions were executed using 1.2 equiv of catalyst relative to 1-49. b Values represent % of the reaction mixture as 1-77, as indicated by G.C. without an internal standard. Table 1-3. Results of the Acid Catalyzed Rearrangement of 1-49 Entry Catalyst“ Time (hours) % yield Of 1.77" 1 TiCl4 20 46 2 MgBrz 44 38 3 HBF4 48 33 4 bis-t-Cl-AlMeC 24 28 5 bis-d-Ph-AlMed 72 27 6 FeCl3 4 24 7 AlMezCl 24 22 8 H2804 24 17 9 MeAlC12 44 16 10 EtAlClz 14 8 1 1 HCl No rxn! O 12 AIMCZCI No an! 0 13 SnCl4 No rxn.‘ 0 14 F6373 Dest of SMf. 0 a Reactions were executed using 1.2 equiv of catalyst relative to 1-49. ’7 Values represent G.C. yields relative to an internal standard. c bis-t-Cl-AlMe represents bis-(2,4,6-trichlorophenoxy)methylaluminum. d bis-d-Ph-AlMe represents bis-(2,6-diphenylphenoxy)methy[aluminum. e No rxn. indicates that less than 2% of the starting material was consumed over 48 hours. f Dest of SM indicates complete destruction of starting material with less than 2% yield of any single isolable product. In 14 Table 1-4. Effect of Solvent Reflux Temperature on the Rearrangement of I-49 Entry Catalyst“ Solventb Time (hours) % yield 0f L770 1 A1C13 xylene 8 88 2 AlC13 toluene 24 52 3 BF3-Et20 xylene 24 49 4 BF3-Et20 toluene 44 79 5 ZnC12 decalin 16 0d 6 ZnClz xylene 16 52 7 ZnC12 toluene 24 17 8 I-IBF4 xylene 2 l 1 9 HBF4 toluene 48 33 10 FeC13 xylene 4 24 1 1 FeCl3 toluene 4 2 12 HCl decalin 24 9 13 HCl xylene No rxne 0 14 HCl toluene No pm; 0 15 F6313 xylene Dest of SW 0 16 FeBr3 toluene 8 3 a Reactions were executed using 1.2 equiv of catalyst relative to 1-49. b Temperatures at reflux for the solvents used were: 190°C for decalin, 140°C for xylene and 111°C for toluene. 0 Values represent G.C. yields of I-77 relative to an internal standard. 4 Product 1-78 was formed. See text and Scheme IV for explanation. ‘ No rxn. indicates that less than 2% of the starting material was consumed over 48 hours. f Dest of SM indicates complete destruction of starting material with less than 2% yield of any single isolable product. 15 Scheme 1-4. Possible Mechanism for the Formation of I-78 from 1-49 Hm X) l'€ of ho f0] Zn p0 pro loll the folll SOdi the 1 yielc yiclc SYSte Catal; indie: 16 The effect of temperature was examined by running similar reactions in refluxing xylenes (140°C), toluene (111°C) or decalin (190°C) as indicated in Table 1-4. These results indicated that, in general, xylenes exhibited the optimum solvent conditions for the catalysts examined. Notable exceptions were those of BF3-etherate, which provided an increase in yield from 49% at 24 hours in xylenes to 79% at 40 hours in toluene, and of I-IBF4 which provided an increase in yield from 11% at 2 hours in xylenes to 33% at 48 hours in toluene. Another interesting result obtained from these experiments was the formation of 1,2-dimethylindole (1-78) as the sole product in 30% isolated yield from ZnClz catalyzed reaction of I-49 under conditions of refluxing decalin for 16 hours. A possible mechanism for this conversion is indicated in Scheme 1-4. Since AlCl3 in xylenes gave the highest yield of 1-77, the next variable explored was the equivalents of A1C13 relative to 1-49 (Table I-5). These experiments yielded interesting results in that lower equivalents of AlCl3 tended to promote cyclization to the 1,2-dimethyl-2,3-dihydroindole (1-85) and even aromatization to I-78. Decomposition to N-methylaniline (1-86) was also noted (eq. 14). Although G.C. yields for the rearrangement of I-49 to 1-77 were extremely promising, isolation of 1-77 proved to be challenging as expected from the results of Jolidon and Hanson.9 Products of the test reactions were generally isolated by quenching the acid in situ with an excess of 15% aqueous sodium hydroxide. Quenching was followed by repeated washing with 15% aqueous sodium hydroxide, saturated aqueous sodium chloride and water. Solvent removal was then affected by rotary evaporation, and the resulting product mixture chromatographed on silica with petroleum ether. Isolated yields of I-77 for the three most effective acid catalysts are given in Table I-6. Reaction yield consistency remains problematic at times, especially for the A1C13 catalyzed systems. Rearrangements of I-50, I-53, and 1-55 were also examined using a variety of catalysts. For the other substrates, a more limited number of catalysts was examined as indicated (Tables 1-7 - I-9). 17 + AIC133© (14) 3”“ gin, tn, 1-49 1-77 1-78 Table I-S. Effect of Varying Equivalents of AlCl3 on the Rearrangement of I-49 Entry Equivalents of Time (hours) % % % % AlCl3“ I-77b I-85b I-78b I-86b 1 1.5 2 38 0 0 0 2 1.5 4 22 0 0 0 3 1.5 8 9 0 0 0 4 1.2 4 49 0 0 0 5 1.2 8 88 0 0 2 6 1.2 24 7 l 0 0 3 7 1.2 30 66 0 0 5 8 0.75 2 58 0 0 0 9 0.75 4 68 l 0 0 10 0.75 8 70 6 0 0 1 1 0.75 24 23 32 5 0 12 0.75 48 4 37 9 1 13 0.75 72 1 42 12 3 14 0.5 2 36 0 0 0 15 0.5 4 51 2 0 0 16 0.5 8 72 6 0 4 17 0.5 24 3 71 9 5 18 0.25 2 18 0 0 0 19 0.25 4 33 1 0 0 20 0.25 8 55 l 1 0 0 21 0.25 24 9 56 9 0 22 0.25 48 3 40 13 0 23 0.25 72 2 29 22 0 a Reanangements were run 0.5 M of 1-49 with 1.2 equiv. of Lewis acid at reflux in xylenes. b Yieldswele determined by G.C. analysis of the cnlde reaction mixture relative to an internal standard. 18 Table 1-6. Optimized Yields for the Rearrangement of 1-49 Entry Catalyse: % yield of 1.77 % yield of 1.77 by G. C.b isolated 1 A103 88 46 2 BF3-etherate 79 58 3 ZnC12 52 45 a Rearrangements were run 0.5 M of substrate with 1.2 equiv. of Lewis acid at reflux in toluene (111°C, Et20-BF3) or xylenes (140°C ZnClz). b Yields were determined by G. C. analysis of the crude reaction mixture relative to an internal standard. Table 1-7. Results of the Acid Catalyzed Rearrangement of 1-53 Entry Catalyst“ Solvent Time (hours) % o-prodb (at reflux) 1 A1C13 xylenes 1 33 2 ZnC12 xylenes No me 0 3 BF3-etherate toluene Dest of SMd O 4 AlMezCl xylenes 24 1 1 a Rearrangements were run 0.5 M of 1.53 with 1.2 equiv. of Lewis acid. ’0 Yields were determined by G. C . analysis of the crude reaction mixture relative to an internal standard. C No reaction indicates that less than 2% of the starting material had been consumed over 48 home. d Dest. of SM indicates complete destruction of starting material with less than 2% of any single product formed. Table I-8. Results of the Acid Catalyzed Rearrangement of 1-50 to 1-87 Entry Catalyst“ Solvent Time ‘ % o-prod (at reflux) (hours) 1.8711 1 A1C13 xylenes 2 75 2 AlMezCl xylenes 2 0 3 BF3-etherate toluene 24 0 4 HF xylenes 72 13 5 H3PO4 xylenes 24 O a Rearrangements were run 0.5 M of 1-50 with 1.2 equiv. of Lewis acid. b Yields were determined by G. C. analysis of the crude reaction mixture relative to an internal standard. 19 Table 1-9. Results of the Acid Catalyzed Rearrangement of 1-55 Entry Catalyst“ Solvent Time % o-prodb (at reflux) (hours) 1 A1C13 xylenes 2 1 2 BF3-etherate toluene 2 10 3 ZnClz xylenes No rxnC 0 4 TiCl4 xylenes No rxn O 5 A1Me3 xylenes 2 8 6 A1Me2Cl xylenes No rxn 0 7 H2804 xylenes No rxn O 8 bis-d-Ph-AlMed/ xylenes N0 rm 0 a Reanangements were run 0.5 M of I-55 with 1.2 equiv. of Lewis acid or 0.1 - 0.3 equiv. using the Lewis acid TiCl4. b Yields were determined by G. C. analysis of the crude reaction mixture relative to an internal standard. C Bis-d-Ph-AlMe represents the bis-(2,6-diphenylphenoxy) methylaluminum. d No rxn indicates that less than 2% of starting material had been consumed within 48 hours. Results of the acid catalyzed rearrangements of 1-59 were particularly promising in lieu of the strained transition state. Isolated yields of I-44 along with the corresponding G. C. yields are indicated in Table I-10. Table I-10. Results of the Acid Catalyzed Rearrangement of 1-57 Entry Catalyst“ Solvent Time (hours) %yield 1.44b % iSCI yield of -44 1 AlCl3 xylenes 8 88 54 2 ZnC12 xylenes No me O - 3 BF3-etherate toluene 4 5 - 4 AlMezCl xylenes 24 30 20 5 TiCl4 xylenes 8 3 - 6 AlMeClz xylenes 24 23 5 7 “3-41-1311- AlMeb xylenes No rxn 0 - 8 FeC13 toluene No rxn 0 - a Reanangements were run 0.5 M of 1-57 with 1.2 equiv. of Lewis acid or 0.1 - 0.3 equiv using the Lewis acid TiCl4. b Ratios were determined by G. C. analysis of the crude reaction mixture relative to an internal standard. c Bis-d-Ph-AlMe represents bis-(2,6-diphenylphenoxy)methylaluminum. d No rxn. indicates that less than 2% of the substrate had been consumed within 48 hours. 20 At this time, several initial attempts to achieve ring closure of 1-7 7 were attempted. Photocyclization (Hg arc lamp, C6H5)15 yielded the desired I-85 in 50% yield as determined by G. C. (a portion isolated for analysis by preparative TLC). Ring closure initiated by action of Hg(OAc)2 gave 10% isolated yield of the same product (Scheme 1- 5).26 Scheme 1-5. Ring Closure of 1-77 Irv, 450 nm C6H6_ RT, 3.5 hrs 50% by G.C., portion isolated by TLC H C H 3 \N’ for analysis D I “3 1'77 1) Hg(OAc)2, RT, 1 hr 1'35 2) NaBH4 /NaOH 10%2 A potentially promising route to ring closure could be through the use of KMnO4 / NaIO4,31 Subsequent aromatization could then be achieved using Mn(11)27 or DDQ.28 To determine the scope and generality of the aromatic aza-Cope rearrangement, several other aniline substrates were examined: 1-60, 1-62, 1-67, 1-69 and 1-72 (eq 14, 15). Results for rearrangement of I-49, I-50, 1-53, I-57, 1-60, I-62, I-67, I-69, I-72 and I- 81 using the most favorable catalyst conditions are indicated in the summary tables 1-11 - 1-13: 21 R‘ R‘ ,H N’\“ MLn N = (14) [O 0 | R' R' 1-50 R = CHzPh, R' = H 1-87 R = CHzPh, R' = H 1-60 R = Me, R' = OMe I-88 R = Me, R‘ = OMe 1-62 R = CHzPh, R' = OMe 1-89 R = CHzPh, R' = OMe Rs N/\“ R.N.H R‘N,H MLn (15) 0 *0 I + O I OCH, OCH, H,Co 1-67 R = Me 1-90 R = Me 1-91 R = Me 1-69 R = CHzPh 1-92 R = CH2Ph 1-93 R = CHzPh 1-72 R = iBu I-94 R = iBu 1-95 R = iBu Table I-ll. AlC13 Catalyzed Rearrangements of Various Nitrogen and Aromatic Substituted Anilines“ ring N-isobutyl N-methyl N-benzyl N-tosyl substitution hrs. G.C. [isob hrs. G.C. [isob hrs. G.C./isob hrs. G.C./isob unsubstituted 08 88 / 68 02 35/ 15 48 33 / 0 p-methoxy 04 0 / 0 01 ll [Cnic 04 0 / Dsmd m-methoxy 04 0 / dsm 24e 0 / Dsm 016 18 / Cni 08‘ O/ Dsm m-nitro O4 0 / Dsm a Rearrangements were run 0.5 M of substrate with 1.2 equiv. of Lewis acid at reflux in toluene (111°C, Etzo-BF3) or xylenes (140°C ZnClz). b Yieldswere determined by G.C. analysis of the crude reaction mixture relative to an internal standard. CCni indicates no isolable products. d Dsm indicates destruction of starting material. e Yield is inclusive of both o-regioisomers formed. 22 Table I- 12. ZnC12 Catalyzed Rearrangement of Various Nitrogen and Aromatic Substituted Anilines“ ring N-isobutyl N-methyl N-benzyl N-tosyl substitution hrs. G.C./iso. hrs. G.C.b/iso. hrs. G.C.b/iso. hrs. G.C.b/iso. unsubstituted 16 52/ 45 24 30/ 15 48 0/ No rxne p-methoxy 16 66/58 24 57 / 53 48 0/ Dsm” m-methoxy 064 98/ 98 08" 77/70 24" 64/ 57 48 0 / Dsm m-nitro 48 0 / No rxn a Rearrangements were run 0.5 M of substrate with 1.2 equiv. of Lewis acid at reflux in toluene (111°C, Et20-BF3) or xylenes (140°C, ZnClz). b Yields were determined by G.C. analysis of the crude reaction mixture relative to an internal standard 6 Dsm indicates destruction of starting material 4 Yields are inclusive of both o-regioisomers formed. e No rxn indicates no reaction. Table 1-13. BF3-etherate Catalyzed Rearrangement of Various Nitrogen and Aromatic Substituted Anilinesa ring N-isobutyl N-methyl N-benzyl N-tosyl substitution hrs. G.C./iso. hrs. G.C.IL/ iso. hrs. G.C.b 1 iso. hrs. G.C.b/iso. unsubstituted 48 79 / 58 24 0 / Cnic 48 0 / Dsmd p-methoxy 72 61 /55 48 42 / 35 48 O / Dsm m-methoxy 24c 89/ 80 48‘ 99/99 48‘ 47 I 38 48C 0 / Dsm m-nitro 24 O / Dsm a Rearrangements were run 0.5 M of substrate with 1.2 equiv. of Lewis acid at reflux in toluene (111°C, Et20-BF3) or xylenes (140°C ZnClz). b Yields were determined by G.C. analysis of the crude reaction mixture relative to an internal standard 0 Chi indicates no isolable products. 0' Dsm indicated destruction of starting material. 9 Yields are inclusive of both o-regioisomers formed. For the 1-67, 1-69, and 1-72, rearrangement resulted in the formation of o-allyl regioisomers (Table 1-14). Rearrangement to the position para to the m-methoxy group was always preferred. HCl catalyzed rearrangement in refluxing ethanol according to the method of Krowicki2 yielded regioisomer ratios of 2.1 : 1.0 for 1-72 after 60 hours (78% 23 conversion), 2.8 : 1.0 for 1-67 after 60 hours (26% conversion) and 2.7 : 1.0 for the I-69 after 60 hours (22% conversion). Table 1-14. O-Allyl Regioisomer Product Ratios for the N-Substituted m- Methoxy Substrates Under Conditions of Varying Acid Catalysis. Lewis Acid Catalyst product ratio ZnClg BF3-etherate 1-95 : 1-94 2.7 : 1.0 2.6: 1.0 1-91 :1-90 1.8: 1.0 1.9: 1.0 1-93 : I-92 2.5 : 1.0 2.6 : 1.0 For the nitrogen substituents examined, the rearrangement appears to be promoted by bulky N-substituents (probably through ground state destabilization). This finding correlates well with previous work.” Rearrangement in the presence of the benzyl substituent is retarded though, and the N-tosyl substrate (1-53) did not rearrange. Substituents on the aniline aromatic ring promoted rearrangement in the order of m- methoxy > p-methoxy > unsubstituted >> m-nitro. This supports the notion of greater ring reactivity being associated with electron releasing substituents. For regioisomers obtained where m-substituted anilines underwent rearrangement, the two o-allyl products were generally obtained in the ratio of 2.0-3.0 : 1.0. Bulkier N- substituents promoted somewhat greater selectivity than non bulky substituents. This correlation was opposite that observed under conditions of HCl catalysis described earlier. Also, HCl catalyzed reactions did not go to completion after 84 hours. Comparison of relative rearrangement rates of the non-activated substrate 1-49 (eq 13) vs the activated 1-67 (eq 15) was carried out through direct competition of 1.0 equiv of each substrate with 1.8 equiv of Lewis acid (Table 1-15). Results of this study ' indicated that 1-67 reacted approximately 1.5 times faster when the rearrangement was promoted by Et20-BF3 and approximately 3.0 times faster when promoted by ZnClz. 24 Table I-15. Competitive Lewis Acid-Promoted 3-Aza-Cope Rearrangement of 1-49 and 1-67 product formationb (%) condnsa (I-90 + I-91) : catalyst (time (hours)) I-90 + 1-91 I-77 I-77 Et20-BF3 2.0 24 15 62:38 4.0 33 22 60:40 6.0 49 30 62:38 8.0 55 33 63:37 ZnC12 0.5 17 7 71:29 1.0 36 10 78:22 1.5 47 15 76:24 2.0 55 18 75:25 a Rearrangements were run 0.5 M of substrate with 1.5 equiv. of Lewis acid at reflux in toluene (111°C, EtzO-BF3) or xylenes (140°C ZnClz) with 1.8 equiv of Lewis acid. b Yields were determined by G. C. analysis of the crude reaction mixture relative to an internal standard. In order to establish a potential route to methoxy-substituted natural products, the rearrangement of several substrates containing unsymmetrical allylic substituents was examined. N-((E)-2-Hexen-1-yl)-N-methyl-m-methoxyaniline (1-100) and N-((E)-2- hexen-1-y1)-N-methyl-p-methoxyaniline (1-97) were prepared by standard procedures in 72 and 73% yields from their respective methoxy substituted-N-methyl anilines and 1- bromo-2-hexene (I-98). Bromination of 2-hexene-l-ol with NBS provided 1-98 in 68% yield.32 3 H, o H,Ce MLn O \ > NH \ 3 (16) If CH, CH, I-97 I-99 25 Rearrangement of 1-97 provided 1-99 in 50% yield with ZnClz in xylenes at 140°C and in 79% yield with BF3-Et20 at 111°C (eq 16). For the meta-substituted aniline substrate (1-100), a mixture of regioisomers was obtained (eq 17). CH, CH3 1-100 1-101 I-102 H,C Selectivities for the rearrangement of I-100 under conditions of BF3-Et20 and ZnC12 were higher than for 1-67, as was expected based on the bulkier allyl substituent. For the BF3-Et20 promoted system, a regioselectivity of 75:25 was obtained for I- 101 and 1-102. For the ZnClz system, a regioselectivity of 83:17 was obtained for the same products. Yields for these reactions were 75% and 70% respectively. Another product isolated from both of these reactions in 11% was 1-103. H,C NH H3 I- 103 To determine whether any N-methyl-p-allylaniline (I- 104) was formed during the aromatic 3-aza-Cope rearrangement of I-49, I-104 was prepared by standard methodologies. The preparation of 1-104 was executed by Grignard reaction of bromobenzene with allylbromide to provide allylbenzene (1-105).33 The alkene was then masked using Br2 in diethyl ether at -78°C to give 1-106 in 92% overall yield. Nitration of 1-106 gave I-107 (72% yield), and debromination gave p-allylnitrobenzene (I-108) with some o-product present (69% yield).33o 34 The nitro group was then reduced to the corresponding amine using acid activated iron to give I-109 in 95% yield.35 The o-, and p-isomers were then separated by chromatography and the p-isomer N-methylated to give the desired product, I-104 (Scheme 1-6).29 Overall yield for the conversion of bromobenzene to I-104 was 16%. 26 Scheme 1-6. Synthesis of N-Methyl-p-allylaniline. Br Br Br MgBr \ G M8 Br BIZ ‘ 5120 E120 A 92%, 3 steps I-105 I-106 HONO, H2804 72% Br \ \ \ Br Ansepamfion / I 4 1130.136 / I < N31 / | (4.011110) 2) Mel, Na2C03, \\NH c611, \\ EtOH \ Noz‘s‘m’ H20, EtOH 2 N02 69% mum-13) 95% 37% MM I-l09 I-108 I-107 It was determined that in no rearrangement of 1-49 to 1-104 occurred in greater than 2%. Conclusion. It was hoped that conditions for the 3-aza-Cope reaction could be developed under which the 3-aza-Cope rearrangement would occur at a reasonable rate, at practical temperatures and with adequate reproducibility and regiospecifity. The catalyst systems BF3-Et20 in toluene and ZnClz, and A103 in xylene efficiently accelerated the 3-aza- Cope rearrangement of N-allylaniline substrates accessing a convenient method for C-C bond formation between N-alkyl substituents and an ortho aromatic ring carbon. This versatile rearrangement yields products which may potentially act as precursors to a variety of indole alkaloids substituted in the benzene ring portion. 27 Experimental Section. General Methods. All reactions were carried out using standard inert atmosphere techniques to exclude moisture and oxygen, and reactions were performed under an atmosphere of nitrogen. Benzene, toluene and diethyl ether were distilled from sodium/benzophenone immediately prior to use. Xylenes and decalin were heated over calcium hydride for a minimum of 12 hr and then distilled prior to use. LiA1H4 (1 M in THF) was obtained from Aldrich Chemical Co. Unless specified, concentration of mixtures was performed using a Btichi rotary evaporator. Gas chromatographic (G. C.) analyses were carried out on one of two instruments. For lower molecular weight compounds gas chromatographic analysis was carried out isothermally on a Perkin-Elmer 8500 instrument using a 50 meter RSL-200 capillary column (5% methylphenyl silicon) and an FID detector at 200 °C oven temperature, 220 °C injector temperature, and 300 °C detector temperature. Helium gas pressure was set at 15 psi with a flow rate of 2 mL/min. For higher molecular weight compounds, gas chromographic analysis was carried out on a Hewlett-Packard 5880A series gas chromatograph fitted with a 30 meter silica capillary column and a flame ionization detector. For these analysis injector and detector temperatures were set at 250 °C and the column oven temperature was programmed: 40 °C, 2 min., 10 °C/min. ramp to 200 °C. All reactions were monitored by G. C. and the reactions terminated either when the starting material had been consumed or no further reaction appeared to continue. For reactions in which a Dean-Stark trap was used, the trap was filled with molecular sieves to a level below that of returning solvent turbulence. These were changed during reactions in which additional reagent was added after the reactions initiation. Molecular sieves were activated by heating in a 150 °C oven for at least 24 hours prior to use. NMR spectra were obtained on a VXR-300 spectrometer using CDCl3 with 0.1% TMS as an internal standard 5 (0.00 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept = septet), integration and coupling. Infrared spectra were recorded on a Nicolet 42 FT-IR instrument. Formation of l-Bromo-Z-hexene (1-98). 2-Hexene-1-ol (2.00 g, 20 mmol) and triphenylphosphine (6.29 g, 24 mmol) were added to 60 mL of CH2C12 and cooled to 0°C. Using a solids addition funnel, NBS (4.27 g, 24 mmol) was slowly added over a period of 1 h. The reaction was allowed to warm to room temperature. After 14 h, the solvent was removed and the solid mass extracted with low boiling petroleum ether (10 X 50 mL) with vigorous mixing. Solvent removal gave a clear, colorless oil (2.23 g, 68% 28 yield); 1H NMR (300 MHz, CDC13) 5 0.90 (t, J = 7.3 Hz, 3H), 1.41 (sext, J = 7.3 Hz, 2H), 2.04 (q, I = 6.7 Hz, 2H), 3.94 (d, J = 6.0 Hz, 2H), 5.60-5.80 (m, 2H); 13C NMR (75 MHz, CDC13) 5 13.49, 21.90, 33.40, 33.99, 126.40, 136.26; IR (oil/NaCl) 3032, 2961, 2874, 1661, 1464 cm'1 General Method for N-Alkylation of primary anilines. The aniline (2.0-50 mmol, 4.0 equiv) and the alkyl bromide or alkyl iodide (1.0 equiv) were taken up in a 4:1 ethanol/water mixture (0.5 M relative to the aniline) along with Na2CO3 (0.6 equiv). After stirring at room temperature for 14 h, the EtOH was removed under reduced pressure and the crude oil purified by flash column chromatography (silica, 230-400 mesh; eluent - 5:95 Et20:low boiling petroleum ether). The solvents were evaporated and the mono- and dialkylated aniline by-products isolated. N-Tosylaniline (1-54). ( 30% Yield, mp 101 - 103 °C); 1H NMR (300 MHz, CDC13) 5 2.32 (s, 3H), 7.14 (m, 7H), 7.65 (s-br, 1H), 7.73, (d, J = 8.4 Hz, 2H); 13C (75 MHz, CDC13) 5 21.41, 121.19, 124.98, 127.21, 129.15, 129.53, 129.58, 135.83, 136.59. 143.77; IR (KBr) 3052, 3059, 2899, 1483, 1339, 1159, 914, 756 cm'l. N-Methyl-m-nitroaniline (1-58). (20% yield); 1H NMR (300 MHz, CDC13) 5 2.89 (d, J = 2.7 Hz, 3H), 4.19 (s-br, 1H), 6.86 (ddd, J = 8.4, 2.7, 0.9 Hz, 1H), 7.26 (t, .I = 8.1 Hz, 1H), 7.36 (t, J = 2.4 Hz, 1H), 7.50 (ddd, J = 8.1, 2.1, 0.6 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 30.42, 105.67, 111.65, 118.40, 129.55, 149.39, 149.95; IR (oil/NaCl) 3410 (broad), 3000, 2800, 1541, 1343, 1094, 779, 729, 667 cm'l. N-Methyl-p-methoxyaniline (1-60). (65% yield); 1H NMR (300 MHz, CDC13) 5 2.73 (s, 3H), 3.44 (bs, 1H), 3.70 (s, 3H), 6.50-6.56 (m, 2H), 6.74-6.80 (m, 2H); 13C NMR (75 MHz, CDC13) 5 31.30, 55.55, 113.39, 114.68, 143.59, 151.82; IR (oil/NaCl) 3405 (broad), 3058, 2988, 2832, 2811, 1620, 1514, 1466 cm'l. N-Methyl-m-methoxyaniline (I-68). (73% yield); 1H NMR (300 MHz, CDC13) 5 2.74 (s, 3H), 3.67 (bs, 1H), 3.73 (s, 3H), 6.12 (t, J = 2.4 Hz, 1H), 6.18 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 6.25 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 7.06 (t, J = 8.1 Hz, 111); 13C NMR (75 MHz, CDC13) 5 30.44, 54.82, 98.08, 102.07, 105.42, 129.70, 150.65, 160.68; IR (oil/NaCl) 3413 (broad), 2994, 2836, 2811, 1617, 1499 cm’l. N-Benzyl-m-methoxyaniline (1-70). (87% yield); 1H NMR (300 MHz, CDC13) 5 3.70 (s, 3H), 4.01 (bs, 1H), 4.25 (s, 2H), 6.15 (t, J = 2.4 Hz, 1H), 6.21 (ddd, J = 7.8, 2.4, 0.6 Hz, 1H), 6.26 (ddd, J = 8.4, 2.4, 0.9 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 7.20-7.38, (m, 5H), 13C NMR (75 MHz, CDC13) 5 48.14, 54.90, 98.74, 102.52, 105.84, 127.10, 127.38, 128.51, 129.87, 139.25, 149.45, 160.70; IR (oil/NaCl) 3416 (broad), 3029, 2836, 1615, 1495 cm'l. 29 Formation of N-Benzylidene aniline (1-51) from the Condensation of Aniline and Benzaldehyde. To benzene (100 mL) were added aniline (9.31 g, 100.0 mmol), benzaldehyde (1.10 g, 100.0 mmol) and p-toluenesulfonic acid (0.33 g, 1.7 mmol). The reaction flask was fitted with a Dean-Stark trap containing 4 A molecular sieves, and the solution heated at reflux for 14 h. After cooling the mixture, the volatiles were removed under reduced pressure and the imine recrystallized from low boiling petroleum ether to give N-benzyliminaniline (16.60 g, 92.0 mmol) in 92% yield. (mp 50-52 °C); 1H NMR (300 MHz, CDC13) 5 7.15-7.22 (m, 3H), 7.31-7.45 (m, 5H), 7.84-7.90 (m, 2H), 8.39 (s, 1H); 13C NMR (75 MHz, CDC13) 5 120.77, 125.81, 128.63, 128.69, 129.03, 131.22, 136.14,151.98, 160.15; IR (KBr) 3061, 2892, 1626, 1591, 1451 cm-1. Reduction of N -Benzylidene-aniline (LE 1) to Benzylaniline (I-52). To a suspension of LiAlH4 (10.36 g, 280.0 mmol) in Et20 (56 mL) at 0 °C, was slowly added I-Sl (5.00 g 27.6 mmol). The mixture was heated at reflux for 72 h, after which the solution was cooled to 0 °C and quenched by the addition of water (10 mL), followed by 15% aqueous NaOH (10 mL), and water (30 mL). After stirring for 2 h, the solution was filtered through Nags O4 and the solvent removed under reduced pressure at room temperature. The resulting oil was purified by flash column chromatography (silica, 230. 400 mesh; eluent - 10:90 Etzozlow boiling petroleum ether). The solvents were evaporated to give I-52 (7.92 g, 210.0 mmol) in 75% yield: (mp 34-37 °C); 1H NMR (300 MHz, CDC13) 5 3.77 (bs, 1H), 4.09 (s, 2H), 6.46 (dd, J = 8.4, 0.9 Hz, 2H), 6.63 (tt, J = 7.2, 0.9 Hz, 1H), 7.10-7.18 (m, 2H), 7.20—7.35 (m, 5H); 13C NMR (75 MHz, CDC13) 5 48.15, 112.72, 117.42, 127.10, 127.39, 128.51, 129.15, 139.34, 148.03; IR (oil/NaCl) 3420 (broad), 3027, 2843, 1603, 1507, 1453 cm'l. Formation of N-Benzylidene-p-methoxyaniline (I-63) from the Condensation of p-Methoxyaniline and Benzaldehyde. To 100 mL of benzene were added p- methoxyaniline (1.79 g, 14.6 mmol), benzaldehyde (1.54 g, 14.6 mmol) and p- toluenesulfonic acid (0.05 g, 0.1 mmol). The reaction flask was fitted with a Dean-Stark trap containing 4 A molecular sieves, and the solution was heated at reflux for 14 h. After cooling the mixture to room temperature, the volatiles were removed under reduced pressure, and the imine purified by flash column chromatography (silica, 230-400 mesh; eluent - 10:90 Etzozlow boiling petroleum ether). The solvents were evaporated and the solvents removed under reduced pressure to give 1-63 ( 2.30g, 10.9 mmol) in 75% yield: (mp 707 1 °C); 1H NMR (300 MHz, CDC13) 5 3.79 (s, 3H), 6.87-6.95 (m, 2H), 7.18-7.26 (m, 2H), 7.40-7.47 (m, 3H), 7.83-7.91 (m, 2H), 8.45 (s, 1H); 13C NMR (75 MHz, CDC13) 5 55.38, 114.29, 122.13, 128.49, 128.63, 130.93, 136.38, 144.79, 158.23; IR (KBr) 3054, 2955, 2879, 2838, 1622, 1507 cm‘l. 30 Reduction of N -Benzylidene-p-methoxyaniline (I-63) to N -Benzyl-p- methoxyaniline (L64). To a suspension of LiA1H4 (4.04 g, 109.1 mmol) in Et20 (20 mL) at 0 °C, was slowly added I-63 (2.30 g, 10.9 mmol). The mixture was heated at reflux for 72 h, after which the solution was cooled to 0 °C and quenched by the addition of water (10 mL), 15% aqueous NaOH (10 mL), and water (30 mL). After stirring for 2 h, the solution was filtered through Na28 O4 and the solvent removed under reduced pressure. The oil was then purified by flash column chromatography (silica, 230-400 mesh; eluent - 20:80 Et20:low boiling petroleum ether). The solvents were evaporated and the aniline distilled under vacuum to give I-64 (1.63 g, 7.8 mmol) in 71% yield.(mp 46-49 °C); 1H NMR (300 MHz, CDC13) 5 3.70 (s, 3H), 3.75 (bs, 1H), 4.24 (s, 2H), 6.53- 6.60 (m, 2H), 6.72-6.79 (m, 2H), 7.20-7.37 (m, 5H); 13C NMR (75 MHz, CDC13) 5 49.08, 55.66, 113.98, 114.78, 127.04, 127.42, 128.47, 139.60, 142.34, 152.04; IR (KBr) 3376 (broad), 2998, 2950, 2832, 1514 cm'l. Formation of Acetanilide (I-56) from Aniline and Acetic anhydride. To an acidified 50 °C aqueous solution of aniline (0.91 g, 9.7 mmol, 0.3 M) was rapidly added acetic anhydride (1.38 g, 13.5 mmol) followed immediately by addition of sodium acetate (2.25 g, 1.1 mmol) in water (60 mL). The mixture was cooled to 0 °C for 15 min and the white crystals collected by vacuum filtration. The crystals were then dissolved in methylene chloride, dried and the solvent removed under reduced pressure to give (1.10 g, 8.3 mmol) 85% of the desired I-56.(mp 113-115 °C); 1H NMR (300 MHz, CDC13) 5 2.12 (s, 3H), 7.07 (td, J = 7.3, 1.2 Hz, 1H), 7.27 (td, J = 8.4, 1.8 Hz, 2H), 7.51 (dd, J = 7.3, 1.2 Hz, 2H), 8.37 (s-br, 1H); 13C NMR (75 MHz, CDC13) 5 24.24, 120.13, 124.15, 128.76, 147.91, 169.04; IR (KBr) 3295, 3195, 3059, 1665, 1599, 1557, 1435, 1323, 760, 694 cm'l. General Method for the N-Allylation of Secondary Anilines. The aniline (2.0- 50.0 mmole, 1.0 equiv) and the alkyl bromide or alkyl chloride (1.2-4.0 equiv) were taken up in a 4:1 ethanolzwater mixture (0.5 M relative to the aniline) along with Na2C03 (0.6 equiv). After stirring at room temperature for 14 h the ethanol was removed under reduced pressure and the crude oil purified by flash column chromatography (silica, 230- 400 mesh; eluent 5:95 Etzozlow boiling petroleum ether). The solvents were evaporated and the di-alkylated anilines distilled under vacuum. N-AllyI-N-methylaniline (1.49). (91% yield, bp 107-110°c <1.5 mmHg): 111 (300 MHz, CDC13) 5 2.78 (s, 3 H), 3.76 (dt, J = 5.0, 1.7 Hz, 2H), 5.05 (dq, J = 17.0, 1.7 Hz, 1H), 5.07 (dq, J = 10.4, 1.7 Hz, 1H), 5.73 (ddt, J = 17.0, 10.4, 5.0 Hz, 1H), 6.60- 6.68 (m, 3H), 7.11-7.19 (m, 2H); 13C (75.5 MHz) (CDC13) 5 37.57, 54.86, 112.16. 31 115.70, 116.17, 128.82, 133.60, 149.81; IR (oil/NaCl) 3063, 3027, 2980, 2897, 2815, 1644, 1599, 1449 cm‘l- N-Allyl-N-benzylaniline (L50). (85% yield); 1H NMR (300 MHz, CDC13) 5 3.85-3.91 (m, 2H), 4.43 (s, 2H), 5.10 (dq, J = 10.5, 1.8 Hz, 1H), 5.12 (dq, J = 17.4, 1.8 Hz, 1H), 5.78 (ddt, J = 17.4, 10.5, 4.8 Hz, 1H), 6.59-6.68 (m, 3H), 7.06-7.24 (m, 7H); 13C NMR (75 MHz, CDC13) 5 52.81, 53.76, 112.24, 116.06, 116.43, 126.41, 126.63. 128.40, 128.99, 133.52, 138.76, 148.73; IR (KBr) 3062, 3028, 2862, 1599, 1509 cm'l. N-Allyl-N-tosylaniline (L53). (87% yield, mp 66-68 °C); 1H NMR (300 MHz, DCD13) 5 ,2.41 (s, 3H), 4.17 (dt, J = 6.3, 1.4 Hz, 2H), 5.04 (sext, J = 0.9 Hz, 1H), 5.06 (dq, J = 17.1, 1.4 Hz, 1H), 5.73 (ddt, J = 17.1, 10.2, 6.3 Hz, 1H), 7.04 (m, 5H), 7.26 (m, 5H), 7.48 (dt, J = 8.7, 2.1, 1H); 13C NMR (75 MHz, CDC13) 5 21.46, 53.43, 118.68. 127.62, 128.76, 129.35, 132.74, 135.32, 139.02, 143.36; IR (KBr) 3068, 2928, 1493, 1183, 1038, 918, 696, 670 cm'l. N-AllyI-N-acetanilide (L55). (75% yield, mp 44-46 °C); 1H NMR (300 MHz, CDC13) 5 1.86 (s, 3H), 4.38 (d, J = 6.3 Hz, 2H), 5.04 (s, 1H), 5.10 (d, J = 7.8 Hz, 1H), 5.87 (ddt, J = 17.1, 10.2, 6.3 Hz, 1H), 7.17 (d, J = 6.9 Hz, 2H), 7.36 (m, 3H); 13C NMR (75 MHz, CDC13) 5 22.47, 51.77, 117.53, 127.64, 127.86, 129.34, 132.95, 142.78; IR (KBr) 3009, 2938, 1645, 1593, 1501, 1399, 1277, 1009, 939, 916, 708 cm'l. N-AllyI-N-methyl-m-nitroaniline (LS7). (99% yield); 1H NMR (300 MHz, CDC13) 5 3.01 (s, 3H), 3.97 (dt, J = 4.8, 1.8 Hz, 2H), 5.13 (dq, J = 16.8, 1.8 Hz, 1H), 5.17 (dq, J =17.1,1.8 Hz, 1H), 5.81 (ddt, J =17.1, 10.5,1.8 Hz, 1H), 6.93 (ddd, J = 8.1, 2.4, 0.6 Hz, 1H), 7.28 (tt, J = 8.4, 1.2 Hz, 1H), 7.48 (m, 2H); 13C NMR (75 MHz, CDC13) 5 38.17, 54.81, 106.02, 110.55, 116.54, 117.56, 129.47, 132.25, 149.31, 149.74; IR (oil/NaCl) 3088, 2909, 2826, 1530, 1375, 1348, 1003, 735, 673 cm'l. N-Allyl-N-methyl-p-methoxyaniline (L60). (66% yield, bp <4 mmHg 80-86 °C); 1H NMR (300 MHz, CDC13) 5 2.83 (s, 3H), 3.72 (s, 3H), 3.80 (dt, J = 5.3, 1.7 Hz, 2H), 5.14 (dq, J = 10.5, 1.7 Hz, 1H), 5.16 (dq, J = 17.4, 1.7 Hz, 1H), 5.82 (ddt, J = 17.4, 10.5, 5.3 Hz, 1H), 6.67-6.73 (m, 2H), 6.77-6.84 (m, 2H); 13C NMR (75 MHz, CDC13) 5 38.54, 55.55, 56.44, 114.54, 114.59, 116.26, 134.20, 144.38, 151.64; IR (oil/NaCl) 3077, 2936, 2832, 2809, 1642, 1516 cm’l. N-Allyl-N-benzyl-p-methoxyaniline (L62). (75% yield, bp <4 mmHg 128-139 °C); 1H NMR (300 MHz, CDC13) 5 3.72 (s, 3H), 3.92 (dt, J = 5.1, 1.8 Hz, 2H), 4.46 (s, 2H), 5.16 (dq, J = 10.2, 1.8 Hz, 1H), 5.17 (dq, J = 17.2, 1.8 Hz, 1H), 5.87 (ddt, J = 17.2, 10.2, 5.1 Hz, 1H), 6.64-6.71 (m, 2H), 6.74-6.80 (m, 2H), 7.18-7.33 (m, 5H); 13C NMR (75 MHz, CDC13) 5 53.78, 54.82, 55.66, 114.35, 114.63, 116.33, 126.71, 126.80, 128.46, 134.17, 139.25, 143.61, 151.53; IR (oil/NaCl) 3085, 2934, 2832, 1512 cm'l. 32 N-Allyl-N-methyl-m-methoxyaniline (L67). (68% yield, bp <4 mmHg 83-87 °C); 1H NMR (300 MHz, CDC13) 5 2.91 (s, 3H), 3.76 (s, 3H), 3.88 (dt, J = 5.1, 1.8 Hz, 2H), 5.13 (dq, J = 10.8, 1.8 Hz, 1H), 5.14 (dq, J = 17.1, 1.8 Hz, 1H), 5.82 (ddt, J =17.1, 10.8, 5.1 Hz, 1H), 6.22-6.29 (m, 2H), 6.30-6.36 (m, 1H), 7.07-7.15 (m, 1H); 13C NMR (75 MHz, CDC13) 5 37.96, 54.95, 55.16, 98.90, 101.09, 105.50, 116.01, 129.66, 133.66, 150.79, 160.65; IR (oil/NaCl) 3085, 2998, 2938, 2836. 1609, 1503 cm'l. N-Allyl-N-benzyl-m-methoxyaniline (L69). (83% yield, bp <4 mmHg 130-137 °C); 1H NMR (300 MHz, CDC13) 5 3.68 (s, 3H), 3.96 (dt, J = 4.8, 1.8 Hz, 2H), 4.50 (s, 2H), 5.16 (dq, J = 10.5, 1.8 Hz, 1H), 5.17 (dq,J =17.1, 1.8 Hz, 1H), 5.85 (ddt, J =17.1, 10.5, 4.8 Hz, 1H), 6.22-6.35 (m, 3H), 6.32 (ddd, J = 8.4, 2.1, 0.8 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 7.17-7.31 (m, 5H); 13C NMR (75 MHz, CDC13) 5 53.03, 53.89, 54.88, 98.91, 101.19, 105.46, 116.21, 126.46, 126.71, 128.48, 129.71, 133.50, 138.77, 150.26, 160.63; IR (oil/NaCl) 3085, 3936, 2836, 1612, 1501, 1453 cm“. N-Allyl-N-isobutyl-m-methoxyaniline (L72). (80% yield, bp <4 mmHg 35-36 °C); 1H NMR (300 MHz, CDC13) 5 0.92 (d, J = 6.6 Hz, 6H), 2.06 (sept, J = 6.6 Hz, 1H), 3.06 (d, J = 7.2 Hz, 2H), 3.73 (s, 3H), 3.91 (dt, J = 4.8, 1.8 Hz, 2H), 5.09 (dq, J = 16.8, 1.8 Hz, 1H), 5.10 (dq, J =11.1, 1.8 Hz, 1H), 5.78 (ddt, J =16.8, 11.1, 4.8 Hz, 1H), 6.18- 6.32 (m, 3H), 7.04-7.11 (m, 1H); 13C NMR (75 MHz, CDC13) 5 20.33, 27.30, 53.96, 54.82, 58.93, 98.83, 100.27, 105.39, 115.82, 129.51, 133.82, 149.98, 160.58; IR (oil/NaCl) 2955, 2870, 2836, 1611, 1576, 1499 cm'l. N-(E-Z-hexene)-N-methyl-p-methoxyaniline (L97). (73% yield); 1H NMR (300 MHz, CDC13) 5 0.86 (t, J = 7.4 Hz, 3H), 1.36 (sext, J = 7.4 Hz, 2H), 1.98 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H), 3.70 (s, 3H), 3.73 (bd, J = 5.4 Hz, 2H), 5.43 (dtt, J = 15.3, 5.7, 1.1 Hz, 1H), 5.56 (dtt, J = 15.3, 5.7, 1.1 Hz, 1H), 6.67-6.73 (m, 2H), 6.76-6.82 (m, 2H); 13C NMR (75 MHz, CDC13) 5 13.46, 22.29, 34.22, 38.21, 55.41, 55.78, 114.41, 114.81, 125.66, 132.91, 144.55, 151.60; IR (oil/NaCl) 2957, 2932, 2872, 2832, 1620, 1562, 1464 cm'l. N-(E-z-hexene)-N-methyl-m-methoxyaniline (L100). (72% yield); 1H NMR (300MHz, CDC13) 5 0.86 (t, J = 7.4 Hz, 3H), 1.36 (sext, J = 7.4 Hz, 2H), 1.98 (q, J = 7.4 Hz, 2H), 2.85 (s, 3H), 3.74 (s, 3H), 3.81 (dd, J = 5.4, 0.9 Hz, 2H), 5.42 (m, 1H), 5.55 (m, 1H), 6.21-6.28 (m, 2H), 6.31-6.36 (m, 1H), 7.09 (td, J = 8.0, 0.7 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 13.48, 22.29, 34.20, 37.57, 54.41, 54.80, 98.91, 100.97, 105.58, 125.18, 129.55, 132.63, 150.88, 160.59; IR (oil/NaCl) 2959, 2872, 2836, 1607, 1503, 1456 cm'l. Formation of N-Isobutyl-m-methoxyaniline (L72) by a Modified N-alkylation Procedure. The aniline (4.00 g, 35.5 mmol) and isobutyl bromide (2.22 g, 16.2 mmol) were taken up in a 4:1 ethanolzwater mixture (65 mL) along with Na2CO3 (1.02 g, 9.7 33 mmol). After stirring at reflux for 48 h the ethanol was removed under reduced pressure and the crude oil purified by flash column chromatography (silica, 230-400 mesh; eluent - 10:90 Ethdow boiling petroleum ether). The solvents were evaporated and product distilled under vacuum to give (1.21 g, 6.3 mmol) 78% yield of the L72. 1H NMR (300 MHz, CDC13) 5 0.96 (d, J = 6.7 Hz, 6H), 1.86 (nonet, J = 6.7 Hz, 1H), 2.89 (d, J = 6.7 Hz, 2H), 3.72 (bs, 1H), 3.77 (s, 3H), 6.14 (t, J = 2.4 Hz, 1H), 6.18-6.26 (m, 2H), 7.05 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 20.40, 27.95, 51.72, 54.94, 98.50, 101.95, 105.81, 129.83, 149.93, 160.80; IR (oil/NaCl) 3407 (broad), 2957, 2870, 2836, 1617, 1497 cm‘l. General Method for N-Alkylation of Indole and Acetanilide. The indole or acetanilide (10.0 mmol, 1.0 equiv) was added to a previously prepared mixture of crushed KOH (40.0 mmol, 4.0 equiv) in DMSO (20 mL) and allowed to stir 45 min at room temperature. After cooling the mixture in an ice bath for several minutes, the alkyl bromide or alkyl iodide (20.0 mmol, 2.0 equiv) was then added. After stirring at room temperature for 1 h, a large excess of water was added and the product mixture extracted with Et20. The Et20 was then removed under reduced pressure and the crude oil purified by flash column chromatography (silica, 230-400 mesh; eluent - 5:95 EtzOzlow boiling petroleum ether). The solvents were evaporated and the alkylated anilines distilled under vacuum or recrystallized. N-Allylacetanilide (L55). (75% yield, mp 44-46 °C); 1H NMR (300 MHz, CDC13) 5 1.86 (s, 3H), 4.30 (d, J = 6.3 Hz, 2H), 5.04 (s, 1H), 5.10 (d, J = 7.8 Hz, 1H), 5.87 (ddt, J = 17.1, 10.2, 6.3 Hz, 1H), 7.17 (d, J = 6.9 Hz, 2H), 7.36 (m, 3H); 13C NMR (75 MHz, CDC13) 5 22.47, 51.77, 117.53, 127.64, 127.86, 129.34, 132.95, 142.78; IR (KBr) 3008, 1645, 1593, 1501, 1399, 1277, 1009, 916, 708, 662 cm'l. N-Allylindole (L59). (73% yield); 1H NMR (300 MHz, CDC13) 5 4.87 (dt, J = 7.0, 1.5 HZ, 2H), 5.43 (dq, J = 17.1, 1.5 Hz, 1H), 5.57 (dq, J = 10.5, 1.5 Hz, 1H), 6.29 (ddt, J = 21.0, 10.5, 5.3 Hz, 1H), 7.08 (dd, J = 3.0, 0.8 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.74 (m, 3H), 8.25 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 48.13, 101.07, 109.40, 116.49, 119.18, 120.68, 121.23, 127.52, 128.48, 133.22, 135.83; IR (oil/NaCl) 3086, 2859, 1645, 1511, 1465, 1316, 1259, 1013, 992, 924, 737, 718 cm'l. m-Nitroanisole (L76). (54% yield, mp 35-38 °C); 1H NMR (300 MHz, CDC13) 5 3.88 (s, 3H), 7.32 (ddd, J = 8.4, 2.7, 0.9 Hz. 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.73 (t, J = 2.4 Hz, 1H), 7.82 (ddd, J = 7.2, 2.1, 1.2 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 55.83, 108.15, 115.75, 121.27, 121.36, 129.93, 121.01, 149.27, 160.16; IR (KBr) 2832, 1530, 1352, 1250, 1042, 801, 739, 671 cm'l. 34 Formation of m-Nitrophenol (L75) from m-Nitroaniline. To a stirred mixture of m-nitroaniline (2.87 g, 20.8 mmol) in 35% aqueous sulfuric acid (50 mL), 50 g of ice was added followed by sodium nitrite (1.70 g, 25.0 mmol) in water (20 mL). After 5 min several crystals of urea were added and the mixture then allowed to continue stirring for an additional 5 min. A solution of cupric nitrate (466.50 g, 2050 mmol) in water (900 mL), and cupric oxide (2.80 g, 19.6 mmol) were then added and the solution allowed to warm to room temperature. After 1 h the dark green mixture was extracted with Et20 (15 X 50 mL). The solvent was removed under reduced pressure and the solid recrystallized from Et20/low boiling petroleum ether to give a yellow solid (2.40 g, 20.1 mmol) in 83% yield. (mp 95-97 °C); 1H NMR (300 MHz, CDC13) 5 7.21 (dd, J = 8.1, 1.8 Hz, 1H), 7.40 (t, J = 9.0 Hz, 1H), 7.63 (m, 2H), 9.21 (s-br, 1H); 13C NMR (75 MHz, CDC13) 5 110.64, 115.02, 122.71, 131.07, 149.98, 158.86, 207.29; IR (KBr) 3391 (broad), 1522, 1350, 1300, 1078, 818, 739, 673 cm'l. Formation of m-Nitroanisole (L76) from m-Nitmphenol (L75) Using K2CO3 in Acetone. m-Nitrophenol (0.50 g, 3.6 mmol) and methyl iodide (0.27 g, 7.2 mmol) were added to a stirred mixture of K2CO3 (1.02 g, 7.2 mmol) in dry acetone (7.2 mL). After stirring for 14 h at room temperature, the mixture was filtered and the solvents removed under reduced pressure. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 10:90 Et20:10w boiling petroleum ether). The solvents were evaporated to give the desired product (0.32 g, 0.3 mmol) in 58% yield. Spectroscopic data was identical to that reported for the product obtained by the general N-alkylation of Indole and Acetanilide procedure. Formation of m-Nitroanisole (L76) from m-Nitrophenol (L75) Using Na2CO3 in Aqueous Ethanol. m-Nitrophenol (0.50 g, 3.6 mmol) and methyliodide (2.04 g, 14.4 mmol) were taken up in 7.2 ml. of a 4:1 ethanol/water mixture along with Na2C03 (0.76 g, 7.2 mmol). After stirring at room temperature for 14 h the ethanol was removed under reduced pressure, the crude oil purified by flash column chromatography (silica, 230-400 mesh; eluent - 5:95 Et20:1ow boiling petroleum ether). The solvents were evaporated to give m-nitroanisole (0.54 g, 3.5 mmol) in 98% yield. Spectroscopic data was identical to that reported for the product obtained by the general N—alkylation of Indole and Acetanilide procedure. Formation of m-Methoxyaniline (L70) from m-Nitroanisole (L76). To a mixture of TiCl4 (1.19 mL, 11.0 mmol) and NaBH4 (1.25 g, 33.0 mmol) in dimethoxyethane (40 mL) was slowly added a solution of m-nitroanisole (1.53 g, 10.0 mmol) in dimethoxyethane (10 mL) at 0 °C. After 14 h at room temperature the reation mixture was cooled to 0 °C and quenched by carefuu addtion of excess water. Extraction 35 of the reaction mixture with Et20 followed by solvent removal at reduced pressure afforded a crude oil which was purified by flash column chromatography (silica, 230-400 mesh; eluent - 5:95 Et20:low boiling petroleum ether). The solvents were evaporated to give m—methoxyaniline (1.84 g, 15.0 mmol) in 75 % yield. 1H NMR (300 MHz, CDC13) 5 3.66 (s-br, 2H), 3.74 (s, 3H), 6.21 (t, J = 2.4 Hz, 1H), 6.29 (dddd, J = 15.9, 8.4, 2.4, 0.9 Hz, 2H), 7.05 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 54.95, 100.93, 103.79, 107.79, 129.99, 147.74, 160.63; IR (oil/NaCl) 3372 (broad), 3002, 2838, 1603, 1496, 1461, 1208, 1173, 1159, 1037, 739, 689 cm‘l. In a separate reaction acetone was allowed into the reaction mixture during quenching affording N—isopropyl-m-methoxyaniline. 1H NMR (300 MHz, CDC13) 5 1.18 (d, J = 6.0 Hz. 6H), 3.47 (s-br, 1H), 3.85 (p, J = 6.3 Hz, 1H), 3.74 (s, 3H), 6.13 (t, J = 2.1 Hz, 1H), 6.18 (dd, J= 8.1, 2.7 Hz, 1H), 6.23 (dd, J: 8.1, 2.7 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 22.88, 44.09, 54.89, 99.02, 101.83, 106.28, 129.85, 148.80, 160.75; IR (oil/NaCl) 3395 (broad), 2967, 2872, 2836, 1617, 1512, 1497, 1211, 830, 756, 689 cm‘l. Alternate Method for the Formation of N-Tosylaniline (L54) from Aniline and Tosyl Chloride. Aniline (2.50 g, 26.9 mmol) and tosyl chloride (5.65 g, 29.6 mmol) were added to chlorobenzene (54 mL) and heated at reflux for 18 h. After cooling, the solvent was removed under reduced pressure to give a solid. Recrystallization of the solid from Et20/low boiling petroleum ether under aspirator vacuum gave N-tosylaniline (4.40 g, 17.7 mmol) in 66% yield. Spectroscopic data was identical to that reported for the LS4 obtained by the general N-alkylation procedure. General Method for the Lewis Acid Catalyzed Rearrangement of N-Allyl-N- alkylanilines. The aniline (0.5-2.0 mmol, 1.0 eq) and the catalyst (0.6—2.4 mmol, 1.2 eq) were added to dry xylenes or toluene (0.5 M relative to the aniline) at -78 °C along with an internal standard of decalin. The reaction was heated to the appropriate temperature and allowed to react as described in the text. The reaction was then quenched at 0 °C by addition of a 15% aqueous NaOH solution and the organics concentrated. The crude products were isolated and purified by flash column chromatography (silica, 230-400 mesh; eluent, 5:95 Et20:10w boiling petroleum ether). Formation of N -Methyl-o-allylaniline (L77) by Acid Catalyzed Rearrangement of N-Allyl-N-methylaniline (L49). (45% yield): 1H NMR (300 MHz) (CDC13) 5 2.83 (s, 3 H), 3.26 (bd, J = 6.1 Hz, 2H), 3.73 (bs, 1H), 5.08 (dq, J = 16.7, 1.8 Hz, 1H), 5.10 (dq, J = 10.4, 1.8 Hz, 1H), 5.93 (ddt, J = 16.7, 10.4, 6.1 Hz, 1 H), 6.63 (d, J = 8.2 Hz, 1H), 6.70 (td, J = 7.4, 1.1 Hz, 1H), 7.03 (dd, J = 7.4, 1.1 Hz, 1H), 7.12 (td, J = 7.4, 1.6 Hz, 1H); 13C (75.5 MHz) (CDC13) 5 30.54, 36.21, 109.73, 115.97, 116.93, 36 123.39, 127.59, 129.47, 135.95, 147.22; IR (oil/NaCl) 3436 (broad), 3075, 2978, 2894, 2815, 1634, 1605, 1514, 1466 cm’l. Formation of o-Allyl-N -benzylaniline (L87) by Acid Catalyzed Rearrangement of N-Allyl-N-benzylaniline (L50). 1H NMR (300 MHz, CDC13) 5 3.34 (bd, J = 6.3 Hz, 21-1), 4.10 (bs, 1H), 4.34 (s, 2H), 5.07 (dq, J = 16.8, 1.7 Hz, 1H), 5.11 (dq, J = 10.5, 1.7 Hz, 1H), 5.95 (ddt, J = 16.8, 10.5, 6.3 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 6.70 (td, J = 7.4, 0.9 Hz, 1H), 7.06 (dd, J = 7.4, 1.2 Hz, 1H), 7.12 (td, J = 7.4, 1.5 Hz, 1H), 7.22-7.37 (m, 5H); 13C NMR (75 MHz, CDC13) 5 36.50, 48.13, 110.69, 116.29, 117.34, 123.49, 127.12, 127.35, 127.68, 128.57, 129.78, 135.93, 139.41, 146.11; IR (oil/NaCl) 3440 (broad), 3031, 2888, 2843, 1633, 1603, 1510 cm'l. Formation of o-Allyl-N-methyl-p-methoxyaniline (L88) by Acid Catalyzed Rearrangement of N-Allyl-N-methyl-p-methoxyaniline (L60). 1H NMR (300 MHz, CDC13) 5 2.81 (s, 3H), 3.25 (dt, J = 6.0, 1.7 Hz, 2H), 3.37 (bs, 1H), 3.74 (s, 3H), 5.07 (dq, J = 17.1, 1.7 Hz, 1H), 5.12 (dq,J = 10.2, 1.7 Hz, 1H), 5.93 (ddt, J = 17.1, 10.2, 6.0 Hz, 11-1), 6.58 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.76 (dd, J = 8.7, 3.0 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 31.37, 36.31, 55.70, 110.96, 112.02, 116.23, 116.50, 125.45, 135.76, 141.65, 151.81; IR (oil/NaCl) 3422 (broad), 2938, 2832, 2808, 1638, 1514, 1464 cm'l. Formation of o-AIlyl-N-benzyl-p-methoxyaniline (L89) by Acid Catalyzed Rearrangement of N-Allyl-N-benzyl-p-methoxyaniline (L62). 1H NMR (300 MHz, CDC13) 5 3.29 (dt, J = 6.0, 1.5 Hz, 2H), 3.72 (s, 3H), 3.78 (bs, 1H), 4.28 (s, 2H), 5.06 (dq, J = 17.1, 1.5 Hz, 1H), 5.11 (dq,J = 10.5, 1.5 Hz, 1H), 5.94 (ddt, J = 17.1, 10.5, 6.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 3.0 Hz. 1H), 6.66-6.73 (m, 1H), 7.21-7.37 (m, 5H); 13C NMR (75 MHz, CDC13) 5 36.46, 48.89, 55.65, 111.94, 112.02, 116.39, 116.55, 125.50, 127.05, 127.39, 128.51, 135.69, 139.67, 140.34, 151.93; IR (oil/NaCl) 3430 (broad), 3063, 2936, 2832, 1636, 1509, 1466 cm'l. Formation of N-Methyl-2-allyl-3-methoxyaniline (Minor Isomer, L90) and N- Methyl-Z-allyl-S-methoxyaniline (Major Isomer, L91) by Acid Catalyzed Rearrangement of N-Allyl-N-methyl-m-methoxyaniline (L67). Minor Isomer: 1H NMR (300 MHz, CDC13) 5 2.84 (s, 3H), 3.38 (dt, J = 6.0, 1.9 Hz, 2H), 3.78 (bs, 1H), 3.80 (s, 3H), 5.02 (dq, J = 17.4, 1.8 Hz, 1H), 5.03 (dq, J = 9.3, 1.8 Hz, 1H), 5.88 (ddt, J = 17.4, 9.3, 6.0 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 27.90, 31.04, 55.78, 100.66, 103.68, 114.76, 125.90, 127.67, 136.05, 148.70, 157.60; IR (oil/NaCI) 3438 (broad), 3077, 2939, 2836, 2815, 1601, 1591, 1478 cm'l. Major Isomer: 1H NMR (300 MHz, CDC13) 5 2.82 (s, 3H), 3.21 (dt, J = 6.0, 1.8 Hz, 2H), 3.77 (bs, 1H), 3.79 (s, 3H), 5.05 (dq, J = 16.8, 1.8 Hz, 37 1H), 5.08 (dq, J = 10.8, 1.8 Hz, 1H), 5.91 (ddt, J = 16.8, 10.8, 6.0 Hz, 1H), 6.19-6.27 (m, 2H), 6.93 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 30.62, 35.69, 55.10, 97.19, 100.74, 115.79, 116.31, 130.17, 136.53, 148.51, 159.83; IR (oil/NaCl) 3438 (broad), 3077, 2938, 2834, 2809, 1617, 1520 cm'l. Formation of N-Benzyl-Z-allyl-3-methoxyaniline (Minor Isomer, L92) and N- Benzyl-Z-allyl-5-methoxyaniline (Major Isomer, L93) by Acid Catalyzed Rearrangement of N-Allyl-N-benzyl-m-methoxyaniline (L69). Minor Isomer: 1H NMR (300 MHz, CDC13) 5 3.42 (dt, J = 6.0, 1.8 Hz, 2H), 3.79 (s, 3H), 4.16 (bs, 1H), 4.34 (s, 2H), 5.01 (dq, J = 16.8, 1.8 Hz, 1H), 5.02 (dq, J = 11.0, 1.8 Hz, 1H), 5.89 (ddt, J = 16.8, 11.0, 5.4 Hz, 1H), 6.32 (bd, J = 8.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 7.21-7.36 (m, 5H); 13C NMR (75 MHz, CDC13) 5 28.02, 48.35, 55.77, 100.81, 104.50, 114.97, 127.06, 127.30, 127.65, 128.55, 128.62, 135.93, 139.61, 147.43, 157.90; IR (oil/NaCl) 3440 (broad), 2936, 2836, 1634, 1599, 1476 cm'l. Major Isomer: 1H NMR (300 MHz, CDC13) 5 3.25 (dt, J = 6.0, 1.8 Hz, 2H), 3.72 (s, 3H), 4.13 (bs, 1H), 4.31 (s, 2H), 5.05 (dq, J = 17.1, 1.8 Hz, 1H), 5.09 (dq, J = 10.5, 1.8 Hz, 1H), 5.93 (ddt, J = 17.1, 10.5, 6.0 Hz, 1H), 6.19-6.27 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 7.20-7.37 (m, 5H); 13C NMR (75 MHz, CDC13) 5 35.82, 48.12, 55.04, 97.96, 101.16, 115.95, 116.22, 127.15, 127.38, 128.57, 130.32, 136.41, 139.21, 147.22, 159.68; IR (oil/NaCl) 3438 (broad), 3063, 2834, 1617, 1586, 1520, 1466 cm'l. Formation of N-Isobutyl-2-allyl-3-methoxyaniline (Minor Isomer, L94) and N -Isobutyl-2-allyl-5 -methoxyaniline (Major Isomer, L95) by Acid Catalyzed Rearrangement of N-Allyl-N-Isobutyl-m-methoxyaniline (L72). Minor Isomer: 1H NMR (300 MHz, CDC13) 5 0.97 (d, J = 6.6 Hz, 6H), 1.89 (nonet, J = 6.6 Hz, 1H), 2.92 (d, J = 6.6 Hz, 2H), 3.39 (dt, J = 5.7, 1.8 Hz, 2H), 3.79 (s, 3H), 3.83 (bs, 1H), 5.03 (dq, J = 10.8, 1.8 Hz, 1H), 5.06 (dq, J = 16.8, 1.8 Hz, 1H), 5.88 (ddt, J = 16.8, 10.8, 5.7 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 20.57, 28.00, 28.13, 51.89, 55.76, 100.17, 104.03, 110.84, 114.91, 127.58, 136.30, 147.90, 157.67; IR (oil/NaCl) 3430 (broad), 3076, 2959, 2870, 2836, 1635, 1601, 1476 cm‘l. Major Isomer: 1H NMR (300 MHz, CDC13) 5 0.98 (d, J = 6.7 Hz, 6H), 1.91 (nonet, J = 6.7 Hz, 1H), 2.91 (d, J = 6.7 Hz, 2H), 3.24 (dt, J = 6.3, 1.8 Hz, 2H), 3.79 (s, 3H), 3.83 (bs, 1H), 5.06—5.16 (m, 2H), 5.93 (ddt, J = 17.7, 9.6, 6.3 Hz, 1H), 6.17-6.24 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 20.58, 27.84, 36.14, 51.59, 55.12, 97.42, 100.43, 115.88, 116.08, 130.33, 136.82, 147.74, 159.79; IR (oil/NaCl) 3432 (broad), 3079, 2957 , 2870, 2834, 1617, 1588, 1520 cm’l. Formation of N-Methyl-Z-(2-vinylpentane)-3-methoxyaniline (Minor Isomer, L102), N-Methyl-Z-(Z-vinylpentane)-5-methoxyaniline (Major Isomer, L101) as well 38 as N-Methyl-3-methoxy-4-(2-E-hexene)-aniline (E-Isomer, L103) by Acid Catalyzed Rearrangement of N-trans-Z-Hexene-N-methyl-m-methoxyaniline (L100). Minor Isomer: 1H NMR (300 MHz, CDC13) 5 0.87 (t, J = 7.2 Hz, 3H), 1.07-1.37 (m, 2H), 1.70- 1.89 (m, 2H), 2.77 (s, 3H), 3.77 (s, 3H), 3.98-4.17 (m, 2H), 5.07 (dt, J = 6.6, 2.4 Hz, 1H), 5.12 (d, J = 2.4 Hz, 1H), 6.11 (m, 1H), 6.30 (bd, J = 8.1 Hz, 2H) 6.37 (bd, J = 8.1 Hz, 1H), 7.10 (t, J = 8.1 Hz, III); 13C NMR (75 MHz, CDC13), 5 14.18, 21.11, 31.06, 32.49, 37.58, 55.78, 100.89, 104.45, 113.37, 114.28, 127.58, 141.64, 148.91, 158.10; IR (oil/NaCl) 3426 (broad), 2919, 2848, 1588, 1476 cm'l. Major Isomer: 1H NMR (300 MHz, CDC13) 5 0.92 (t, J = 7.4, 3H), 1.21-1.48 (m, 2H), 1.62-1.81 (m, 2H), 2.82 (s, 3H), 3.15 (bq, J = 7.4 Hz, 1H), 3.79 (s, 3H), 3.87 (bs, 1H), 5.01 (dt, J = 11.7, 1.4 Hz, 1H), 5.06 (dt, J = 10.5, 1.4 Hz, 1H), 5.81(ddt, J = 17.7, 10.5, 7.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 6.28 (dd, J = 8.4, 2.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H); 13c NMR (75 MHz, CDC13) 8 14.09, 20.75, 30.80, 35.48, 43.19, 55.04, 97.49, 100.92, 114.13, 120.41, 127.59, 141.76, 148.28, 159.31; IR (oil/NaCl) 3438 (broad), 3077, 2959, 2930, 2872, 2836, 2807, 1615, 1586, 1463 cm'l. E-Isomer: 1H NMR (300 MHz, CDC13) 5 0.88 (t, J = 7.4 Hz, 3H), 1.37 (sext, J = 7.4 Hz, 2H), 1.97 (bq, J = 7.4 Hz, 2H), 2.82 (s, 3H), 3.20 (d, J = 7.4 Hz, 2H), 3.62 (bs, 1H), 3.79 (s, 3H), 5.43 (dtt, J = 15.0, 6.5, 1.4 Hz, 1H), 5.43 (dtt, J = 15.0, 6.5, 1.4 Hz, 1H), 6.13-6.20 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 13.69, 22.69, 31.03, 32.21, 34.66, 55.25, 96.26, 104.09, 118.56, 129.13, 130.07, 130.70, 149.03, 158.03; IR (oil/NaCl) 3413 (broad), 2957, 2930, 2872, 2836, 1618, 1516, 1464 cm'l. Formation of N-Methyl-Z-(z-vinylpentane)-4-methoxyaniline (L99) by Acid Catalyzed Rearrangement of N-Methyl-N-(trans-Z-hexene)-p-methoxyaniline (L97). 1H NMR (300 MHz, CDC13) 5 0.92 (t, J = 7.4 Hz, 3H), 1.22-1.48 (m, 2H), 1.62-1.81 (m, 2H), 2.80 (s, 3H), 3.26 (bq, J = 7.4 Hz, 2H), 3.47 (bs, 1H), 3.75 (s, 3H), 5.02 (dt, J = 17.1, 1.4 Hz, 1H), 5.06 (dt, J = 10.2, 1.4 Hz, 1H), 5.81 (ddd, J = 17.1, 10.2, 7.4 Hz, 1H), 6.57-6.66 (m, 1H), 6.71-6.76 (m, 2H); 13C NMR (75 MHz, CDC13) 5 14.03, 20.65, 31.54, 35.52, 43.50, 55.61, 111.10, 111.38, 114.24, 114.49, 129.87, 141.09, 141.35, 152.04; IR (oil/NaCl) 3413 (m-broad), 3077 , 2957, 2872, 2832, 2809, 1647, 1510, 1458 cm‘l‘. Formation of l,2-Dimethyl-2,3-dihydroindole (L85) by Photochemical Ring Closure of o-AllyI-N-methylaniline (L77). o-Allyl-N-methylaniline (0.12 g, 0.82 mmol) and Argon degassed thiophene free benzene (41 mL) were placed in a pyrex tube and subjected to a 450 Watt medium pressure Hg lamp. After 3.5 h the solvent was removed under reduced pressure. The reaction had gone 50% to completion by G.C. The resulting oil was separated by preparative TLC (silica) to give the desired product. 1H NMR (300 MHz, CDC13) 5 1.32 (d, J = 6.3 Hz, 3H), 1.71 (s, 3H), 2.59 (dd, J = 15.3, 10.5 Hz, 1H), 39 3.08 (dd, J = 15.3, 8.1 Hz, 1H), 3.39 (qt, J = 2.4, 1.5 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.65 (td, J = 7.4, 0.9 Hz, 1H), 7.06 (m, 2H); 13C NMR (75 MHz, CDC13) 5 18.7, 33.7, 37.4, 62.8, 107.1, 117.8, 124.0, 127.3, 129.2; IR (oil/NaCl) 3073, 2921, 2815, 1605. 1586, 1514, 1466, 1312, 1264, 1065, 914, 748, 648 cm'l. Formation of l,2-Dimethyl-2,3-dihydroindole (L85) by Hg(OAc)z Catalyzed Ring Closure of o-Allyl-N-methylaniline (L77). o-Allyl-N-methylaniline (1.42 g, 9.66 mmol) was added to anhydrous methanol (48.3 mL) followed by addition of Hg(OAc)2 (3.69 g, 11.59 mol) at room temperature. After 1 h the reaction mixture was cooled to 0 °C and reduced by careful addition of NaBH4 (2 equiv, 0.5 M solution) in NaOH (2 N ). After 20 h the reaction mixture was extracted repeatedly with Et20 and the organics concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 1:99 EtzOzlow boiling petroleum ether). The solvents were evaporated to give the desired product (0.14 g, 0.9 mmol) in 10% yield. Formation of 2,3-Dibromopropylbenzene (L106). To Mg turnings (15.29 g, 636.94 mmol) in dry Et20 (40.0 mL) was slowly added a solution of bromobenzene (10.00 g, 63.69 mmol) in dry Et20 (23.7 mL). The Grignard reagent was allowed to form over an hour at room temperature (the solution turned dark brown). The solution was transfered via cannula to a dry flask. The temperature was lowered to 0°C and allylbromide (9.35 g, 76.43 mmol) was added dropwise via syringe. The reaction was allowed to warm to room temperature. After 14 h the reaction was quenched by addition of water. The organics were collected and the aqueous layer washed with 4 portions of ether (20.0 mL). The organics were dried, collected and cooled to -78°C. To this mixture was added Br2 (12.23 g, 76.43 mmol) dropwise. The solution was allowed to stirr for 1 h and remained red. Solvent removal under reduced pressure gave an orange oil. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent -5:95 Et20:low boiling petroleum ether). The solvents were evaporated to yield the desired product as a clear oil (16.28 g, 92% yield); 1H NMR (300 MHz, CDC13) 5 3.13 (dd, J = 14.5, 8.3 Hz, 1 H), 3.51 (dd, J = 14.5, 4.8 Hz, 1 H), 3.63 (dd, J = 10.5, 8.9 Hz, 1 H), 3.85 (dd, J = 10.3, 4.2 Hz, 1 H), 4.37 (m, 1 H), 7.24-7.37 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 36.02, 42.00, 52.39, 127.18, 128.48, 129.48, 136.83; IR (oil/NaCl) 3106, 3031, 2938, 1497, 1431, 1252, 1219, 1142 cm'l. Formation of 2,3-DibromopropyI-p-nitrobenzene (L107). To a mixture of 70% I-INO3 (26.6 mL) and 98% H2804 (33.7 mL) was added 2,3-Dibromopropylbenzene (16.28 g, 58.58 mmol) dropwise at -15°C. The reaction was then allowed to warm to 0°C 40 over 45 min. After an additional 15 min the reaction was cooled again to -15°C and quenched by partitioning between water and ether. The organics were collected, dried and the solvent removed under reduced pressure to give oils. The crude oils were purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20:low boiling petroleum ether). The solvents were evaporated to give the desired pure product. (13.66 g, 72% yield); 1H NMR (300 MHz, CDC13) 5 3.21 (dd, J = 14.6, 8.6 Hz, 1 H), 3.62 (t, J = 10.2 Hz, 1 H), 3.67 (dd, J = 14.6, 4.2 Hz, 1 H), 3.90 (dd. J = 10.7, 4.2 Hz, 1 H), 4.37 (m, 1 H), 7.42-7 .51 (m, 2 H), 8.14-8.24 (m, 2 H); 13C NMR (75 MHz, CDC13) 5 35.31, 41.42, 50.74, 123.58, 130.38, 135.91, 144.13; IR (oil/NaCl) 3079, 2973, 2855, 1607, 1520, 1435, 1346, 1250 cm'l. Formation of p-Allylnitrobenzene (L 108). To a solution of 2,3-dibromopropyl- p-nitrobenzene (3.00 g, 9.28 mmol) in EtOH (92.8 mL) was added NaI (2.78 g, 18.58 mmol) as a single portion at room temperature. The reaction was heated at reflux for 1.5 h. NaI (2.78 g, 18.58 mmol) was again added in small portions. After 6 h total, the reaction was allowed to cool to room temperature and stir for 14 h. The solvent was removed under reduced pressure and the residue partitioned between CHC13 and aqueous 50% saturated sodium bicarbonate solution. The organics were collected, dried and the solvent removed under reduced pressure to give an oil. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - low boiling petroleum ether). The solvents were evaporated to yield the desired product as a clear oil (1.05 g, 6.43 mmol) in 69% yield. 1H NMR (300 MHz, CDC13) 5 3.49 (d, J = 6.6 Hz, 2 H), 5.12 (dq, J = 16.9, 1.6 Hz, 1 H), 5.16 (dq, J = 10.2, 1.6 Hz, 1 H), 5.94 (ddt, J = 16.9, 10.2, 6.6 Hz, 1 H), 7.32-7.37 (m, 2 H), 8.10-8.70 (m, 2 H); 13C NMR (75 MHz, CDC13) 5 39.86, 117.37, 121.28, 123.64, 129.35, 135.44, 147.77; IR (oil/NaCl) 3081, 2853, 1640, 1605, 1518, 1346 cm‘l. Preparation of p-Allylaniline (L109). To a solution of p-allylnitrobenzene (0.55 g, 3.37 mmol) in benzene (20.0 mL) was added activated Fe (5.00 g, 89.28 mmol) and water (2.0 g, 111.11 mmol). The reaction was brought to reflux. After 2 h a trace of HCl was added to the reaction along with a several drops of water. After 12 h the reaction was quenched by partitioning between water and EtzO. The organics were separated, dried and the solvents removed under reduced pressure to yield an oil. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20:low boiling petroleum ether). The solvents were evaporated to yield the desired product as an oil (0.43 g, 95% yield); 1H NMR (300 MHz, CDC13) 5 3.28 (d, J = 6.6 Hz, 2 H), 3.56 (s- br, 2 H), 5.02 (dq, J = 10.3, 1.7 Hz, 1 H), 5.04 (dq, J = 17.1, 1.7 Hz, 1 H), 5.94 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H), 6.61-6.65 (m, 2 H), 6.95-7.00 (m, 2 H); 13C NMR (75 MHz, 41 CDC13) 5 39.36, 115.06, 115.25, 129.34, 130.02, 138.18, 144.45; IR (oil/NaCl) 3436 (broad), 3355 (broad), 3218 (broad), 3077, 3004, 2897, 1624, 1516, 1435, 1273 cm'l. Formation of N-MethyI-p-allylaniline (L104). The p-allylaniline (0.20 g, 1.50 mmol) and Mel (0.05 g, 0.38 mmol) were taken up in a 4:1 ethanol:water mixture (3.0 mL) along with N a2CO3 (0.02 g, 0.22 mmol). After stirring at room temperature for 14 h the ethanol was removed under reduced pressure and the crude oil purified by flash column chromatography (silica, 230-400 mesh; eluent - 5:95 Et20:low boiling petroleum ether). The solvents were evaporated to give a clear colorless oil. (0.06 g, 37% yield); 1H NMR (300 MHz, CDC13) 5 2.82 (s, 3 H), 3.28 (d, J = 6.9 Hz. 2 H), 3.60 (s-br, 1 H), 5.01 (dq, J = 10.2, 1.7 Hz, 1 H), 5.04 (dq, J = 16.8, 1.7, 1 H), 5.95 (ddt, J = 16.8, 10.2, 6.9, 1 H), 6.54-6.59 (m, 2 H), 6.99-7.03 (m, 2 H); 13C NMR (75 MHz, CDC13) 5 30.96, 39.37, 112.58, 114.93, 128.69, 129.29, 138.37, 147.69; IR (oil/NaCl) 3413 (broad), 2977, 2893, 2813, 1615, 1522, 1318, 1264, 1063 cm'l. References. l) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry, Vol. 4; Pergamon Press: 1984. 2) Smith, A. 3., III; Visnick, N.; Haseline, J. N.; Spanger, P. A. Tetrahedron, 1986, 42, 2959. 3) Harrington, P. 1.; Hegedus, L. 8.; Mc Daniel, K F. J. Am. Chem. Soc. 1987, 109, 4335. 4) Murai, Y.; Masuda, G.; Inoue, S.; Sato, K. Heterocycles, 1991, 32, 1377. 5) Murai, Y.; Masuda, G.; Inoue, S.; Sato, K. Heterocycles, 1991, 32, 1377. 6) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. 7) Muratake, H.; Natsume, M. Heterocycles 1989, 29, 783. 8) Lutz, R. Chem. Rev. 1984, 84, 205. 9) Jolidon, S.; Hansen, H.-J. Helv. Chim. Acta. 1977, 60, 978. 10) Prater, G.; Habish, A.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta. 1969, 52, 335. 11) Schmid, M.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta. 1973, 56, 105. 12) Abdrakhmanov, I. B.; Sharafutdinov, V. M.; Tolstikov, G. A. Zhur. Org. Chem. 1984, 163. 13) Abdrakhmanov, I. B.; Fakhretdinov, R. N.; Khusnutdinov, R. N .; Dzhemilev, U. M. Zhur. Org. Chem. 1982, 2325. 14) Hurd, C. D.; Jenkins, W. W. J. Org. Chem. 1957, 22, 1418. 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25) 26) 27) 28) 29) 30) 31) 32) 33) 34) 35) 42 Abdrakmanov, I. B.; Sharafutdinov, V. M.; Nigmatullin, N. G.; Sagitdinov, I. A.; Tolstikov, G. A. Zhur. Org. Chem. 1982, 1278. Krowicki, K; Paillous, N.; Riviere, M.; Lattes, A. J. Hetero. Chem. 1976, I3, 555. Bader, A. R.; Bridgwater, RJ.; Freeman, P. R. J. Am. Chem. Soc. 1961, 83, 3319. Takamatsu, N.; Inoue, S.; Kishi, Y. Tetrahedron Lett. 1971, 48, 4661. Abdrakhmanov, I. B.; Sharafutdinov, V. M.; Sagitdinov, I. A.; Tolstikov, G. A Zhur. Org. Chem 1978, 2350. Brown, J. B.; Henbest, H. B.; Jones, E. R. H. J. Chem. Soc. 1952, 3172. Casnati, G.; Francioni, M.; Guareschi, A.; Pochini, A. Tetrahedron Lett. 1969, 29, 2485. Bitchi, G.;Mak, C.-P. J. Org. Chem. 1977, 42, 1784. Jolidon, S.; Hanison, H.-J. J. Org. Chem. 1974, 39, 846. Inada, S.; Nagai, K; Takayanagi, Y.; Okazaki, M. Bull. Chem. Soc. Jpn. 1976, 49, 833. Aristoff, P. A.; Johnson, P. 0.; Harrison, A. W. J. Am .Chem. Soc. 1985, 107, 7967. Katayama, I-I.; Tachikoma, Y.; Takatsu, N.; Kato, A. Chem. Pharm. Bull. 1983, 31, 2220. Ketcha, D. Tetrahedron Lett. 1988, 29, 2151. Tao, X.; Nichiyama, S.; Yamamura, S. Chem. Lett. 1991, 1785. Tweedie, V.; Allibashi, J. J. Org. Chem. 1960, 26, 3676. (a) Cohen, T.; Dietz Jr., A. G.; Miser, J. R. J. Org. Chem. 1977, 42, 2053. (b) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169. (c) Kano, S.; Tanaka, Y.; Sugino, B.; Satsoshi, H. Synthesis 1980, 695. Aristoff, P. A., ° Johnson, P. D., ' Harrison, A. W. J. Am. Chem. Soc. 1985, 107, 7967. Bose, A. K; Lal, B. Tetrahedron Lett. 1973,33, 3937. (a) Hobbs, C. F.; Hamman, W. C. J. Org. Chem. 1970,35, 4188. (b) Gough, R.G.; Dixon, J. A. J. Org. Chem. 1968, 33, 2148 Robertson, G. R. Org. Syn. 1932, I, 389. Hazlet, S. B.; Dornfield. C. A. J. Am. Chem. Soc. 1944, 60, 1781. 43 CHAPTER II. AZA-ANNULATION AS A ROUTE TO HYDROXYLATED ALKALOIDS: THE TOTAL SYNTHESES OF D-MANNONOLACTAM AND DEOXYMANNOJIRIMYCIN Introduction. Naturally occurring piperidine alkaloids exhibit a wide variety of biological activities.1 Although found in a number of organisms, these alkaloids possess alike stereochemical arrays similar to those found in simple sugars such as glucose (II-l), D- mannose (II-2), and fucose (II-3) (Figure II-l). For example, deoxymannojirimycin (II- 4), with stereochemistry similar to 1L2, is an inhibitor of both bovine a-L—fucosidase and mannosidase I for glycoprotein processing. D-mannonolactam (II-7) inhibits both a-D- mannosidase and 01-D-glucosidase.2 Deoxynojirimycin (II-4), stereochemically similar to II-l, has exhibited selective inhibition of a-glucosidases I, and II without effective inhibition of a-mannosidase.3 The more lipophilic alkaloids, prosopinine (II-5) and cassine (II-8) are also very biologically active.4 A convergent route to these alkaloids would thus be beneficial. While compounds IL6 and IL7 have been prepared from their sugar analogs,5 an efficient and convergent synthesis of these compound types from simple organic molecules has not been previously reported (Scheme II-l). Key to the preparation of any of the aforementioned alkaloids is the construction of the piperidine ring of the type represented by II-ll (Figure II-2). In II-ll, particular attention to the stereochemistry of C—4 relative to GS is critical. Protected hydroxyl functionality at C-4 and C-6 must also be incorporated. Further stereochemical features at C-2 and 03 must then be incorporated efficiently and specifically relative to the first two. Adding the tether to C—1 could then be executed if desired. It is the objective of this work to use the aza-annulation in the design of a convergent route toward the preparation of these highly active compounds. Figur: 110, H0 110,, (deoxyl H0 44 Figure II-l. Hydroxylated Piperidine Alkaloids and Stereochemically Similar Sugars OH HO”. .“OH OH HO O II-l (glucose) OH HO,“ “(OH OH ’1 H II-4 (deoxynojirimycin) OH HO ‘“OH OH 0 If H IL7 (D-mannonolactam) OH 9H HO .“OH HO ' ‘¢OH OH I) ' 0, HO O HO O ’1 II-2 IL3 (D-mannose) (fucose) O “(OH MM “' OH ‘ N I H II-S (prosopinine) OH HO .“OH OH N I H I I - 6 (deoxymannoj irimycin) OH ‘7‘ O H 11-8 (cassine) 45 Scheme ILl. Preparation of IL6 and IL7 from Sugar Analogs OH OH HO “OH ° , HO .“OH OH ' 0 v H02CHO ‘o”/0H H IL7 II-9 OH OH HO “OH ‘ , HO ‘“OH OH ' N HOHfiI I HO CHO H IL6 IL10 Figure II-2. Alkaloid Precursor Target “‘0? IkOP 0 t P I-ll III Results and Discussion. The initial piperidine ring system was prepared via aza-annulation.5 Desired substitution at 05 as well as at C-4 was incorporated at the onset, in the preparation of the initial B-diketone, B—ketoester, or acetylenic ester. In the simplest instance, benzylamine was added to acetoacetone to form the enamine which was annulated with acryloyl chloride to give II-12 in 94% yield (Scheme II-2). Reduction of II-12 to II-13 was afforded in 81% yield using Pd/C and H2. Baeyer-Villiger oxidation of IL 13 (epimerized to an equilibrium 24:76 ratio of cis:trans isomeric products) yielded II-l4 in 45% yield. Subsequent hydrolysis of II-14 provided IL15 in 89% yield. Of particular interest were the development of predictable conditions for cis-hydrogenation of II-12 and development of an efficient method for the oxidation of II-13 to IL14. Optim 11.12 Condj 46 Scheme II-2. Preparation of Initial Precursor Analog II-lS 1) BilNHz. C6H6. 80°C 3‘ 2) acryloyl chloride, THF 0 66°C (94%) :1) DBU, THF, RT IL 14 (trans:cis, .99: 1) 2) CF3C02H, MCPBA, (45 %) \NaOH, H20 (89%) o N 1'31. “-15 O N Bn II-12 1 atm H2, Pd/C, Na2C03. EtOH (81%) O N 1.. IL 13 (trans:cis, 10:90) Examination of a variety of oxidation conditions had been initiated prior to optimization of the hydrogenation conditions.7 A series of oxidations were attempted using IL12, which was a mixture of isomers at the reduced double bond (trans:cis, 10:90). Conditions and percent reaction mixture as product are given in Table II- 1. 47 Table II-l. Baeyer-Villiger Oxidation Studies on cis II-l3 Entryaeo Conditions“ time (hours) % rxn. mix as prod}? 17a MCPBA, NaOAc, CHC13, reflux 96 4 27b FezCO3, benzaldehyde, C6H6, 02, RT 96 1 37c H202, Aczo, N aOAc, 0°C to RT 120 0 47d- 7° MCPBA, NaHCO3, CH2C12, RT 120 8 57f MCPBA, CH2C12, RT 120 18 678 MCPBA (2.6 eq), CF3COOH, CH2C12, RT 120 35 77h MCPBA, glacial HOAC, CH2C12, RT 120 33 878 MCPBA (2.6 eq), CF3COOH, CH2C12, reflux 72 51 978 MCPBA (5.2 eq), CF3COOH, CH2C12, reflux 72 60 1078 MCPBA, H2804, HOAC, CH2C12, reflux 48 12 1178 t—BuOH, CF3COOH, CH2C12, RT 24 0 1278 t-BuOH, CH2C12, reflux 24 0 1378 MCPBA (10.4 eq), CF3COOH, CH2C12, reflux 24 34 a Starting material was a mixture of isomers with a cis:trans ratio of 90:10. b The percent reaction mixture as product was determined by G. C. without an internal standard. Si prepared more dil: Again, a 5' under sim ammo Be Strics of n f01mm (I the WM) srudiets. S reSuits [0‘ 48 Since none of these sets of conditions yielded satisfactory results, and since all prepared IL13 had been consumed, more II-12 was reduced. Reduction of IL 12 under more dilute conditions resulted in a product isomer ratio of 24:76 cis:trans (Table IL3). Again, a series of oxidations was attempted. These yielded greatly improved results, even under similar conditions (Table II-2). Table II-2. Baeyer-Villiger Oxidation Studies on trans Substrate II-l3 Entryfief) Conditions“ Time (hours) % rxn. as prodb(iso) 178 MCPBA (5.2 eq), CF3COOH, CH2C12, reflux 24 86 (41%) 278 MCPBA (5.2 eq), CF3COOH, CH2C12, reflux 10 75 (45%) 378 MCPBA (2.6 eq), CF3COOH, CH2C12, reflux 7.5 66 (43%) 478 MCPBA (2.6 eq), CF3COOH, CH2C12, reflux 10 67 (20%) 578 MCPBA (5.2 eq), CF3COOH, CHC13, reflux 14 89 (18%) 678 MCPBA (5.2 eq), CF3COOH, CH2C12, reflux 24 52 (22%) a Starting material was a mixture of isomers with a cis:trans ratio of 24:76.b The percent reaction mixture as product was determined by G. C. without an internal standard. Because it appeared that the primarily trans substrate yielded superior results, a series of reduction conditions were examined to try to maximixe the portion of trans II-l3 formed (Table IL3). The greatest percentage trans achieved was 76%. This represented the approximate thermodynamic product distribution, as exhibited by several equilibration studies. Several other sets of oxidation conditions were then attempted but yielded inferior results to those indicated in Table II-2 (Table II-4). Table Enrv —_I-—- Ta! £110in 172 272 “'1 then 0X11 49 Table IL3. Various Conditions Used in the Palladium Mediated Reduction of II-12 Entry 5 Pd : mmol reactant Molarity (substrate) II-l3 cis:trans ratio“ 1 1.0: 1 0.25 61 :39 2 0.2: 1 0.50 83 : 17 3 0.1: 1 0.50 69:31 4 0.1 :1 0.10 24 :76 5 0.1 : 1 0.05 32:68 b The cis to trans product ratio was determined by 1H NMR. Table II-4. Continued Baeyer-Villiger Oxidation Studies of II-l3 to II-l4 End-W“) Ratio Conditions Trrne % rxn. as cis : trans (hours) proda(iso) 17g 28 : 72 MCPBA (5.2 eq), CF3COOH, CHzClz, RT 24 62 (41%) 278 54 : 46 . MCPBA (5.2 eq), CF3COOH, CH2C12, RT 24 63 (32%) 37i 24 : 76 MCPBA (5.2 eq), NazHPO4, CH2C12, RT 36 23 471' 24 : 76 MCPBA (5.2 eq), stOH, CH2C12, RT 84 88 (18%) 57k 24 : 76 MCPBA (5.2 eq), NaHCO3, CH2C12, RT 12 9 671 24 : 76 MCPBA (5.2 eq), Li2C03, CH2C12, RT 84 30 77i 24 : 76 MCPBA (5.2 eq). NazHPO4, CH2C12 84 16 871 53 : 47 MCPBA (5.2 eq), stOH, CH2C12, reflux 60 68 a The percent reaction mixture as product was determined by G. C. without an internal standard. To further indicate the role substrate structure might have been responsible for the relatively low oxidation yields, compound II-l6 was reduced to II- 17 (62% yield) and then oxidized to II-18 (Scheme IL3). Yield of the oxidan'on was 67%. 1 mixture th oxidation stereochen' the final pr Ex1 IndicaiCd dcpmiOna 50 Scheme IL3. Oxidation of Achiral Substrate Surrogate O O O I 1 atm H2, Pd/C fik CF3C02H, MCPB A17 1K ' To N N I I Bn Bn 0 N EtOH (67%) o (89%) Bn II-l6 II-l7 IL18 Efficient base catalyzed equilibration of cis II-13 to trans IL13 yielded a product mixture that was consistently 30% cis to 70 % trans (Figure IL3). Baeyer Villiger oxidation yielded only trans II-14 as detectable by NMR. Confirmation of stereochemistry was achieved by comparison to known compounds8 and by comparison of the final products to purchased standards. Figure IL3. Epimirization of Model Compound ILl3 o 0 fl baseeatalyzed equilibration _ «K N (7le tin Bn II-l3 (cis) II-l3 (trans) 69% cis : 31% trans LHMDS. THF. ~78°C - RT. 12 hrs 28% cis : 72% trans 61% cis : 39% trans DBU. THF. -78°C - RT. 12 hrs 30% cis : 70% trans Extension of this methodology toward the preparation of compounds of the type indicated by structure II-ll was then executed. Initially, propargyl alcohol was deprotonated and protected using benzyl bromide to afford II-18 in 90% yield. Deprotonation of the alkyne using BuLi, followed by reaction with II-20, gave the alcohol II-21. Oxidation of IL21 with PCC provided IL22 in 54% yield.9 Aza-annulation of II-22 in the usual manner provided IL23 in 33% yield. Hydrogenation of II-23 provided II-24 in 67% yield (Scheme II-4). 51 Scheme IL4. Preparation of Alkaloid Precursor IL24 1) BuLi, THF 2) OHCVOBn OH Bno/ > OBI] (77%) BnO é II-l9 IL21 PCC. CH2C12 (54%) O O l OBI: 1) BnNHz. THF. RT \/u\/0Bn 0 N OB“ 2) acryloyl chloride BnO / ' (33%) Bn II-23 II-22 1 atrn H2. Pd/C. EtOI-I (67%) O OBn OBn ° ’7‘ Bn II-24 A more efficient route toward compounds of the type indicated by II-ll was initiated by acylation of II-l9 with ethylchloroformate by action of BuLi to provide II-25 in 88% yield. Aza-annulation of II-25 provided II-26 in 35% yield using acryloyl chloride and in 62% yield using freshly prepared acrylic anhydride. Reduction of II-26 afforded II-27 in 80% yield and in a cis to trans ratio of 98:2. To prepare IL28 for use in the Baeyer-Villiger oxidation, 81 modified Grignard reaction was used. Epimerization at the position or to the ketone of cis IL28 with DBU afforded IL28 in a cis to trans ratio of 17:83. Overall yield for the 2 steps was 61%. Oxidation of IL28 provided IL29 in 56% yield. Subsequent hydrolysis gave II-30 in 85% yield. Protection of II-30 was executed using benzyl bromide to provide IL31 in 84% yield (Scheme II-5).lo 52 Scheme II-S. Preparation of Alkaloid Precursor IL31 O 1) BuLi, THF, -78°C 3110/ = / 0E1 2) ClCOzEt BnO / (88%) II-19 II-25 1) BnNHg, THF. 66°C 2) acrylic anhydride, THF, 66°C v (62%) COzEt COzEt 1 atm H2, Pd/C, N82CO3, EIOH l OBn ‘fi OBn O N O N Bn (80%) Bn II-27 II-26 NEt3, MeMgBr O O 0 N OB" (68%, 2 steps from IL27) O N OB" l I Bn Bn IL28 (cis) IL28 (trans) CF3C02H, MCPBA (55%) “(OH “(O KOH, H20 \n/ O N OBn < O N O I (85%) I Bn Bn OBn IL30 IL29 KOH, BnBr (84%) “\OBD mOBn O N l Bn IL31 53 An alternative route to the preparation of IL31 could be accessed from tetronic acid (Scheme IL6). Annulation of tetronic acid using benzylamine and acrylic anhydride afforded IL32 in 71% yield. Reduction of IL32 provided II-33 in 83% yield. Use of the modified Grignard procedure to open the lactone yielded IL34 in 27% yield. Protection of the C-6 alcohol using benzyl bromide was executed in 71% yield providing II-28 as a mixture of cis and trans isomers in the ratio of 20:80 respectively. Scheme IL6. Alternate Route to Alkaloid Precursor Preparation O O 1) BnNHz. CeHe. 80°C m = O I O 2) acrylic anhydride, THF 0 N H0 (71%) t Bu IL32 1 atrn H2, Pd/C, EtOH (70%) 0 0 N33, MeMgBr : O OH O N (27%) O N Bn Bn II-34 II-33 “OH, BnBr O (7 1%) . ,\\u\ 11,08“ 0 N I Bn II-28 This alternate route was significant in that it could possibly allow access to a variety of natural products with stereochemistry incorporated at C—6 (Scheme H-7). Alkylation of II-35 (prepared from the respective carboxylic acid) provided II-36 in 80% yield. The tetronic acid derivative, IL37, was then prepared in 35% yield.11 Aza-annulation of II- 37 in the usual fashion using acryloyl chloride afforded II-38 in 29% yield. Reduction of II-38 provided IL39 in 70% yield as a mixture of isomers in the ratio of 70:30 . 54 Scheme IL7. Use of Alternate Route to Introduce Chiral Center 0 (I) 0 mo = pyridine (73%) 50% O O II-35 IL36 LDA, THF (35%) 0 0 l) BnNHz, C5H6, 80°C I O t 2) l 1 hi °d THF I O acryoy c on e, 0 If (29%) H0 Bn II-38 II-37 1 atrn H2, Pd/C. EIOH (70%) o O 0 i Bn II-39 As a synthetic equivalent to ILl 1, IL31 proved to be a versatile substrate for the preparation of alkaloids. For example, the preparation of 1L5 from IL31 was executed in 29% overall yield.10 Preparation of IL6, and IL7 were then executed from IL31 as outlined in Scheme II-8. Selenation of IL31 followed by NaIO4 oxidation provided II- 40 in 78% yield.12 Stereospecific cis-dihydroxylation of IL40 using OsO4 in NMO gave IL41 in 64% yield.13 Attempted protection of IL41 with benzyl bromide using KOH afforded II-42 as the sole product. Direct reduction of the diol using LiAlH4 provided II- 43 in near quantative yield. Reductive removal of the protecting groups from II-43 using Pd/C, H2, and with a trace of acid afforded IL6 in 52% yield. 14 Preparation of IL7 from IL41 was executed smoothly by Li/NH3 reduction in 44% yield.15 Yields for the preparation of IL5, IL6, and IL7 from II-18 were 3% overall for each (Scheme II-8). DQ-COSY spectra of IL6 and IL7 are shown in Figure II-4 and Figure II-5, respectively. 55 Scheme IL8. Preparation of IL6 and IL7 fom Alkaloid Precursor .603" 1) LDA / “(OBn 2) PhSeCl OBn = OBn o N o N Bn (78%) Bn IL31 IL40 0804, NMO (64%) 0H OH HO MOB“ 1) LiA1H4 HO “(OBn OBn 2) NaOH, H20 0 N OBn N (>98%) I B“ Bn IL43 IL41 1 atrn H2, Li/NH3 Pd/C, MeOH (44%) (52%) 0H OH HO “(OH “(OH 0H 0H ’t‘ ‘7‘ H H IL6 IL7 56 Conclusion. Stereochemically complex hydroxylated piperidine alkaloids can be efficiently accessed through use of the aza-annulation. The O4 and C—5 substituent pattern may be incorporated at the onset by aza-annulation substrate manipulation. The stereochemistry at these positions may then be controlled through choice of reduction conditions. Trans stereochemistry at 04 relative to 05 may be efficiently incorporated to an extent of >98:2 through use of the Baeyer-Villiger oxidation. Subsequent incorporation of cis stereochemistry at the C-2 and C-3 positions may then be accessed through use 0s04 cis hydroxylation. Comparison of IL6 with a purchased standard of the same compound showed that all four stereocenters were incorporated as initially predicted from asymmetric starting materials. 57 Figure IL4. DQ-COSY Spectra of IL6 Mort OH g 5 2 2 III IIII IIII IIII IIII IIII'IIIIIIIII‘IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII I l I I 3.1 3.3 ’1 (PM) 58 Figure II-S. DQ-COSY Spectra of IL7 m ’0‘! z i 8 "I it- its { ITIT'I'ITPTI l’ [TTT‘ITT'ITI'I'TTT l WTWUNWW TITIIIImIIIIIIIIIII—ITIII'V IIIIIIIIIIIIIIIIIIIII'IIIIIIIII'IIIIIIITIIIIIITfl?III 1 Iv to «0 av «N v *9 O N at «I «l v v 1v v I v O I c \fib :C O 2.3: I I O HO 4.2 4.0 3.8 3.6 3.4 3.2 4.4 4.6 F1 (P93) 59 Experimental Section. General Methods. All reactions were carried out using standard inert atmosphere techniques to exclude moisture and oxygen, and reactions were performed under an atmosphere of nitrogen. Benzene, toluene and ether were distilled from sodium/benzophenone immediately prior to use. Xylenes and decalin were heated over calcium hydride for a minimum of 12 h and then distilled prior to use. LiAlH4 (1 M in THF) was obtained from Aldrich Chemical Co. Unless specified, concentration of mixtures was performed using a Buchi rotary evaporator. For reactions in which a Dean—Stark trap was used, the trap was filled with molecular sieves to a level below that of returning solvent turbulence. These were changed during reactions in which additional reagent was added after the reactions initiation. Molecular sieves were activated by heating in a 150 °c oven for at least 24 h prior to use. Formation of II-12. To 2,4-pentanedione (25.00 g, 250.00 mmol) in C5H5 (500.0 mL) was added benzylamine (47.50 g, 250.00 mmol) and a catalytic amount of p- TsOH at room temperature. The reaction was fitted with a Dean - Stark trap, filled with molecular sieves to a level below that of returning solvent turbulence, and heated at reflux. After 12 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. THF (500.0 mL) and acryloyl chloride (38.45 g, 425.00 mmol) were then added and the reaction again heated at reflux. After 14 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230—400 mesh; eluent - 90:10 Et20:petroleum ether). The solvents were evaporated to give a clear, colorless oil (54 g, 94% yield); 1H NMR (300 MHz, CDC13) 5 2.21 (s, 3 H), 2.24 (s, 3 H), 2.53-2.68 (m, 4 H), 5.00 (s, 2 H), 7.12 (bd, J = 2.0, 2 H), 7.16-7.34 (m, 3 H); 13C NMR (75 MHz, CDC13) 5 15.72, 21.81, 29.33, 30.84, 44.22, 116.95, 125.65, 126.67, 128.28, 137.08, 145.83, 170.11, 198.32; IR (oil/NaCl) 3031, 2969, 2843, 1669, 1590, 1383, 1275, 1186 cm'l. Formation of II-l3. To IL12 (10.00 g, 56.50 mmol) in EtOH (565.0 mL) was added Na2C03 (20.96 g, 197.74 mmol) and 10% Pd/C (5.65 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (8.19. g, 81% yield, 90: 10 cis:trans). 1H NMR (300 MHz, CDC13) (cis isomer) 5 1.07 (d, J = 6.6 Hz, 3 H), 2.06 (s, 3 H), 1.92-2.17 (m, 4 H), 2.48 (ddd, J = 18.3, 10.4, 8.0 Hz, 1 H), 2.61 (ddd, J = 18.3, 7.4, 2.0 Hz, 1 H), 2.79 (dt, J = 12.6, 4.2 Hz, 1 H), 3.84 (m, l H), 3.96 (d, J = 15.2 Hz, 1 60 H), 5.31 (d, J = 15.2 Hz, 1 H), 7.22-7.36 (m, 5 H); 13C NMR (75 MHz, CDC13) (cis isomer) 5 14.52, 17.33, 28.08, 29.96, 47.74, 51.03, 51.14, 127.04, 127.36, 128.28. 136.97, 168.67, 206.25; IR (oil/NaCl) 2975, 1713, 1640, 1163 cm‘l; HRMS calcd for C15H19N02 mlz 245.1416, found mlz 245.1415. Isomerization of IL13. To IL13 cis (0.20 g, 1.12 mmol) in THF (2.24 mL) was added DBU (0.09 g, 0.56 mol) at room temperature. After 16 h the reaction was terminated by addition of an equal volume of water. The organics were seperated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.20 g, >99% yield, 72% trans); 1H NMR (300 MHz, CDC13) (trans isomer) 5 1.22 (d, J = 6.6 Hz, 1 H), 1.89 (s, 3 H), 1.91-2.12 (m, 3 H), 2.35-2.63 (m, 3 H), 3.82 (m, 1 H), 4.01 (d, J = 15.2 Hz, 1 H), 5.23 (d, J = 15.2 Hz, 1 H), 7.22-7.34 (m, 5 H); 13c NMR (75 MHz, CDC13) (trans isomer) 5 19.53, 19.86, 27.47, 29.39, 46.98, 51.14, 52.26, 126.93, 127.78, 128.10, 136.97, 168.87, 207.05; IR (oil/NaCl) 2975, 1713, 1640, 1163 cm‘l. Formation of II-l4. To IL13 (76% trans) (1.00 g, 5.60 mmol) in CH2C12 (11.2 mL) was added m-CPBA (5.00 g, 29.20 mmol) and CF3C00H (0.60 g, 5.60 mol) at room temperature. The reaction was heated at reflux. After 14 h, the reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting slurry was brought up in a minimum amount of Et20 and purified by flash chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (4.5 g, 41% yield, 100% trans) (mp = 66-67 °C); 1H NMR (300 MHz, CDC13) 5 1.24 (d, J = 6.7 Hz, 3 H), 1.89 (s, 3 H), 1.97 (m, 1 H), 2.16 (dddd, J = 14.7, 11.4, 7.5, 2.7 Hz, 1 H), 2.51 (ddd, J = 18.3, 7.5, 2.1 Hz, 1 H), 2.66 (ddd, J = 18.3, 11.4, 7.5 Hz, 1 H), 3.46 (qt. J = 6.7, 2.0 Hz, 1 H), 3.80 (d, J = 15.3 Hz, 1 H), 4.88 (dt, J = 3.9, 2.1 Hz, 1 H), 5.46 (d, J = 15.3 Hz, 1 H), 7.207.37 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 17.80, 20.75, 21.03, 26.81, 47.18, 54.38, 70.07, 127.19, 127.72, 128.32, 136.95, 168.57, 169.89; IR (oil/NaCl) 2975, 2942, 1736, 1634, 1482, 1246, 1179 cm'l; HRMS calcd for C15H19N03 mlz 261.1365, found m/z 261.1363. Formation of IL15. To II-14 (0.10 g, 0.56 mmol) in water (0.6 mL) was added crushed NaOH (0.04 g, 1.12 mol) at room temperature. The reaction was heated at approximately 50°C. After 12 h, the product was extracted from the reaction mixture with 6 portions of CHC13 (1.0 mL each). The organics were combined, dried, and the solvent removed under reduced pressure. the product was recrystallized from Et20zlow boiling petroleum ether giving white crystals. (0.06 g, 89% yield) (mp = 110-113 °C); 1H NMR (300 MHz, CDC13) 5 1.18 (d, J = 6.6 Hz, 3 H), 1.88 (m, 1 H), 1.95-2.12 (m, 2 61 H), 2.42 (ddd, J = 18.0, 7.3, 2.8 Hz, 1 H), 2.71 (ddd, J = 18.0, 10.8, 7.3 Hz, 1 H), 3.34 (m, 1 H), 3.83 (dt, J = 4.8, 2.8 Hz, 1 H), 3.95 (d, J = 15.2 Hz, 1 H), 5.35 (d, J = 15.2 Hz, 1 H), 7.20-7.35 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 18.37, 24.05, 26.92, 47.42, 57.96, 68.45, 127.23, 127.78, 128.56, 137.33, 169.42; IR (oil/NaCl) 3289, 3023, 2890, 1609, 1453, 1175, cm]; HRMS calcd for C13H17N02 mlz 219.1259, found mlz 219.1245. Formation of IL17. To II-16 (0.24 g, 1.05 mmol) in EtOH (10.5 mL) was added Na2CO3 (0.39 g, 3.67 mmol) and 10% Pd/C (0.10 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.15 g, 62% yield); 1H NMR (300 MHz, CDC13) 5 1.79-1.94 (m, 2 H), 2.14 (s, 3 H), 2.49 (ddd, J = 16.8, 10.4, 6.4 Hz, 1 H), 2.59 (ddd, J = 17.8, 6.4, 4.4 Hz, 1 H), 2.79 (tdd, J = 9.9, 5.3, 3.8 Hz, 1 H), 3.29 (ddd, J = 12.6, 5.3, 1.4 Hz, 1 H), 3.41 (dd, J = 12.3, 9.3 Hz, 1 H), 4.47 (d, J = 14.7 Hz, 1 H), 4.73 (d, J = 14.7 Hz, 1 H), 7.22-7.36 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 23.79, 28.01. 30.96, 46.58, 47.17, 50.07, 127.40, 128.05, 128.52, 136.70, 168.63, 207.21; IR (oil/NaCl) 3032, 2932, 2876, 1713, 1642, 1495, 1455, 1262, 1167, cm'l. Formation of IL18. To IL17 (0.10 g, 0.43 mmol) in CH2C12 (0.86 mL) was added m-CPBA (0.39 g, 2.25 mmol) and CF3C00H (0.05 g, 0.43 mol) at room temperature. The reaction was heated at reflux. After 14 h, the reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting slurry was brought up in a minimum amount of Et20 and purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.07 g, yield = 67%); 1H NMR (300 MHz, CDC13) 5 2.01 (s, 3 H), 2.02-2.08 (m, 2 H), 2.52 (ddd, J = 17.9, 6.0, 5.3 Hz, 1 H), 2.67 (ddd, J = 17.9, 9.6, 7.1 Hz, 1 H), 3.26 (ddd, J = 13.2, 3.9, 1.3 Hz, 1 H), 3.43 (dd, J = 13.2, 3.9 Hz, 1 H), 4.49 (d, J = 14.7 Hz, 1 H), 4.71 (d, J = 14.7 Hz, 1 H), 5.12 (dq, J = 3.9, 3.6 Hz, 1 H), 7.21-7.36 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 20.97, 25.49, 27.86, 49.80, 50.46, 66.17, 127.49, 127.99, 128.60, 136.56, 168.73, 170.18; IR (oil/NaCl) 3063, 2959, 2873, 1738, 1646, 1491, 1365, 1421, 1238, 1182, 1075 cm‘l. Formation of 22. To II-19 (0.43 g, 2.95 mmol) in THF (8.56 mL) was added BuLi (1.41 mL, 2.5 M) at -78 °C). After stirring for 10 min, IL20 (0.53 g, 3.53 mmol) was added, and the reaction allowed to warm to room temperature. After 10 min at room temperature, the reaction was quenched by addition of water. The reaction was extracted 62 with EtOAc (5 X 10 mL) and the organics dried and concentrated. The resulting oil was brought up in a minimum amount of Et20 and purified by flash chromatography (silica, 230-400 mesh; eluent - 1:1 petroleum ether:Et20). The solvents were evaporated to give IL21 as a clear, colorless oil.(0.67 g, 77% yield). To IL21 (0.43 g, 1.45 mmol) in CH2C12 (14.50 mL) was added PCC (0.63 g, 2.91 mol) at room temperature. After 14 h, the reaction was repeatedly extracted with Et2O and the organics combined and concentrated. The resulting oil was brought up in a minimum amount of Et20 and purified by flash column chromatography (silica, 230-400 mesh; eluent - 1:1 petroleum ether:Et20). The solvents were evaporated to give IL22 as a clear, colorless oil.(0.23 g, 54% yield). 1H NMR (300 MHz, CDC13) 5 4.19 (s, 2 H), 4.28 (s, 2 H), 4.56 (s, 2 H), 4.61 (s, 2 H), 7.25-7.78 (m, 10 H); 13C NMR (75 MHz, CDC13) 5 56.72, 56.75, 71.97, 73.24, 75.49, 83.12, 90.58, 127.80, 127.90, 127.92, 127.95, 128.33, 136.51, 136.77, 184.23; IR (oil/NaCl) 3065, 1694, 1455, 1352, 1211, 1173, 1028 cm‘l. Formation of II-23. To IL22 (0.60 g, 2.04 mmol) in THF (4.0 mL) was added BnNH2 (0.19 g, 2.04 mol) at room temperature. The reaction was heated at reflux. After 12 h the reaction was cooled to room temperature and acryloyl chloride (0.31 g, 3.47 mmol) added. The reaction was again heated at reflux. After 14 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230-400 mesh; eluent - 10:90 Et20:petroleum ether). The solvents were evaporated to give a clear, colorless oil (0.30 g, 33% yield); 1H NMR (300 MHz, CDC13) 5 2.48-2.61 (m, 4 H), 4.21 (s, 2 H), 4.31 (s, 2 H), 4.54 (s, 4 H), 5.08 (s, 2 H), 6.98 (dd, J = 7.5, 1.5 Hz, 2 H), 7.18-7.37 (m, 13 H); 13C NMR (75 MHz, CDC13) 5 21.53, 30.78, 44.47, 63.68, 72.72, 73.41, 74.46, 119.82, 126.08, 127.78, 127.91, 127.96, 128.04, 128.15, 128.43, 128.50, 128.65, 136.91, 137.59, 137.72, 144.55, 170.53, 198.97; IR (oil/NaCl) 3031, 1678, 1605, 1497, 1455, 1306, 1277, 1068 cm'l- Formation of IL24.To IL23., (0.15 g, 0.34 mmol) in EtOH (3.4 mL) was added Na2C03 (0.13 g, 1.19 mmol) and 10% Pd/C (0.034 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.10 g, 67% yield); 1H NMR (300 MHz, CDC13) (isomer ratio 70:30) 5 (major isomer, diagnostic peaks) 3.12 (dt, J = 12.9, 3.9 Hz, 1 H), 3.88 (d, J = 16.2 Hz, 1 H), 4.00 (d, J = 16.2 Hz, 1 H), 5.25 (d, J = 15 Hz, 1 H), (minor 63 isomer, diagnostic peaks) 3.26 (dt, J = 6.6, 4.8 Hz, 1 H), 3.63 (d, J = 16.8 Hz, 1 H), 3.81 (d, J =16.8 Hz, 1 H), 5.19 (d, J =15 Hz, 1 H), ; 13C NMR (75 MHz, CDC13) 5 17.54, 20.03, 29.85, 30.09, 44.08, 45.81, 48.17, 49.13, 55.15, 55.74, 67.64, 69.91, 73.03, 73.06, 73.16, 73.22, 73.77, 74.74, 127.30, 127.35, 127.54, 127.64, 127.69, 127.70, 127.73, 127.78, 127,85, 127.90, 128.16, 128.29, 128.34, 128.36, 128.43, 128.50, 136.81, 137.03, 137.08, 137.25, 137.33, 169.44, 170.21, 206.33, 207.68; IR (oil/NaCl) 3031, 1717, 1645, 1453, 1100 cm'l. Formation of IL25. To benzyl protected propargyl alcohol (1.20 g, 8.19 mmol) in THF (16.38 mL) was added BuLi (3.28 mL, 2.5 M in Hexane) at -78°C. After 10 min ethyl chloroformate (0.89 g, 8.19 mmol) was added dropwise. The reaction was slowly warmed to 0°C (until a deep red color began to form) and was promptly quenched by addition of water. The organics were separated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - petroleum ether). The solvents were evaporated to give a clear, colorless oil (1.61 g, 91% yield); 1H NMR (300 MHz, CDC13) 5 1.29 (t, J = 7.2 Hz, 3 H), 4.22 (q, J = 7.2 Hz, 2 H), 4.25 (s, 2 H), 4.59 (s, 2 H), 7.22-7.40 (m, 5 H); 13c NMR (75 MHz, CDC13) 5 13.78, 56.53, 61.90, 71.81, 78.07, 82.94, 127.87, 127.90. 128.29, 136.59, 152.87; IR (oil/NaCl) 3032, 2984, 2872, 2236, 1713, 1248 cm‘l. Formation of IL26. To IL25 (1.61 g, 7.37 mmol) in THF (14.74 mL) was added BnNH2 (0.70 g, 7.37 mol) at room temperature. The reaction was heated at reflux. After 12 h the reaction was cooled to room temperature and acryloyl chloride (0.70 g, 7.74 mmol) added. The reaction was again heated at reflux. After 14 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230-400 mesh; eluent - 10:90 Et20:petroleum ether). The solvents were evaporated to give a white solid (1.61 g, 35% yield) (mp = 84 - 87 °C); 1H NMR (300 MHz, CDC13) 5 1.27 (t, J = 7.0 Hz, 3 H), 2.49-2.58 (m, 2 H), 2.62-2.71 (m, 2 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.57 (s, 2 H), 4.60 (s, 2 H), 5.12 (s, 2 H), 6.97-7.03 (m, 2 H), 7.16-7.39 (m, 8 H); 13C NMR (75 MHz, CDC13) 5 14.16, 21.69, 30.82, 44.51, 60.76, 63.56, 72.65, 113.54, 126.06, 126.97, 127.93, 128.07, 128.42, 128.63, 137.61, 137.90, 146.08, 166.71, 170.92; IR (oil/NaCl) 2984, 1682, 1636, 1269, 1130 ch HRMS calcd for C23H25N04 mlz 379.1784, found m/z 379.1777. Formation of IL27. To IL26 (2.50 g, 6.85 mmol) in EtOH (68.50 mL) was added Na2C03 (2.54 g, 23.97 mmol) and 10% PdlC (0.69g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude oil was purified by flash 64 column chromatography (silica, 230-400 mesh; eluent - 70:30 Et20:petroleum ether). The solvents were evaporated to give a clear, colorless oil (1.66 g, 66% yield, 90: 10 cis:trans). 1H NMR (300 MHz, CDC13) (cis isomer) 5 1.13 (t, J = 7.2 Hz, 3 H), 2.03 (m, 1 H), 2.21 (ddt, J = 9.9, 7.8, 12.9 Hz, 1 H), 2.49 (ddd, J = 18.3, 10.0, 8.3 Hz, 1 H), 2.59 (ddd, J = 18.3, 7.8, 1.8 Hz, 1 H), 2.79 (dt, J = 15.0, 9.0 Hz, 1 H), 3.53 (d, J = 5.4 Hz, 2 H), 3.88-4.08 (m, 3 H), 4.15 (d, J = 15.2 Hz, 1 H), 4.37 (s, 2 H), 5.23 (d, J = 15.2 Hz, 1 H), 7.17-7.37 (m, 10 H); 13C NMR (75 MHz, CDC13) (cis isomer) 5 13.82, 19.18, 30.07, 42.40, 49.16, 56.17, 60.65, 68.62, 73.15, 127.19, 127.44, 127.59, 127.67, 128.19, 128.42, 137.22, 137.31, 169.56, 171.06; IR (oil/NaCl) 2959, 2870, 1734, 1645, 1173 cm'l; HRMS calcd for C23H27N04 mlz 381.1940, found mlz 381.1988. Formation of II-28. To MeMgBr (2.27 mL, 3.0 M in THF) in C6H5 (19.1 mL) was added NEt3 (2.06 g, 20.44 mol) at 0°C. After 10 min H-27 (1.25 g, 3.41 mmol) in C6H5 (5.0 mL) was added with vigorous stirring. After 3 h at 0°C the reaction was quenched by addition of an equal volume of 3 M aqueous HCl. The organics were separated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.56 g, 61% yield); 1H NMR (300 MHz, CDC13) (cis isomer) 5 1.87 (m, 1 H), 2.02 (s, 3 H), 2.12 (m, 1 H), 2.32-2.64 (m, 2 H), 2.71 (dt, J = 13.2, 4.1 Hz, 1 H), 3.42 (dd, J = 9.9, 7.5 Hz, 1 H), 3.50 (dd, J = 9.9, 4.1 Hz, 1 H), 3.94 (m, 1 H), 4.05 (d, J = 15.0 Hz, 1 H), 4.30 (d, J = 1.8 Hz, 2 H), 5.28 (d, J = 15.0 Hz. 1 H), 7.16-7.36 (m, 10 H); 13C NMR (75 MHz, CDC13) (cis isomer) 5 18.07, 28.30, 29.82, 48.85, 49.63, 55.82, 67.89, 72.90, 127.12, 127.34, 127.49, 128.03, 128.11, 128.29, 136.91, 137.04, 169.23, 205.36; IR (oil/NaCl) 3088, 2924, 1713, 1644, 1161, 1101 cm'l; HRMS calcd for C22H25N03 mlz 351.1835, found mlz 351.1818. Isomerization of trans IL28. To cis IL28 (0.2 g, 0.74 mmol) in THF (1.48 mL) was added DBU (0.06 g, 0.37 mol) at room temperature. After 16 h the reaction was terminated by addition of an equal volume of water. The organics were separated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.20 g, >99% yield, 83% trans); 1H NMR (300 MHz, CDC13) (trans isomer) 5 1.89 (s, 3 H), 1.95 (m, 1 H), 2.04 (m, 1 H), 2.44 (dt, J = 17.7, 6.5 Hz, 1 H), 2.58 (ddd, J = 17.7, 7.5, 6.5 Hz, 1 H), 2.95 (dt. J = 6.5, 4.8 Hz, 1 H), 3.42-3.52 (m, 2 H), 3.94 (m, 1 H), 4.10 (d, J = 15.0 Hz, 1 H), 4.37 (d, J = 1.5 Hz, 2 H), 5.14 (d, J = 15.0 Hz, 1 H), 7.16-7.36 (m, 10 H); 13C NMR (75 MHz, CDC13) (trans isomer) 5 19.93, 27.27, 29.58, 47.78, 47.98, 55.17, 69.36, 72.81, 127.01, 65 127.30, 127.45, 127.53, 127.82, 128.12, 136.91, 137.15, 169.86, 207.06; IR (oil/NaCl) 3088, 2924, 1713, 1644, 1161, 1101 cm'l. Formation of II-29. To IL28 (83% trans) (1.15 g, 4.24 mmol) in CH2C12 (8.48 mL) was added MCPBA (3.66 g, 21.22 mmol) and CF3C00H (4.24 g, 0.48 mol) at room temperature. The reaction was heated at reflux. After 14 h, the reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting sltn'ry was brought up in a minimum amount of Et20 and purified by flash chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.60 g, 60% yield, 100% trans); 1H NMR (300 MHz, CDC13) 5 1.88 (s, 3 H), 1.94 (m, 1 H), 2.17 (dddd, J = 13.8, 10.8, 7.8, 3.0 Hz, 1 H), 2.51 (ddd, J = 18.3, 7.6, 2.7 Hz, 1 H), 2.63 (ddd, J = 18.3, 10.8, 7.6 Hz, 1 H), 3.45-3.60 (m, 3 H), 3.92 (d, J = 15.3 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 5.16 (m, 1 H), 5.39 (d, J = 15.3 Hz, 1 H), 7.18-7.40 (m, 10 H); 13C NMR (75 MHz, CDC13) 5 20.86, 22.30, 27.00, 48.12, 58.52, 67.97, 68.74, 73.31, 127.37, 127.63, 127.92, 128.01, 128.44, 128.50, 136.91, 137.31, 169.72, 169.96; IR (oil/NaCl) 3063, 2934, 2869, 1738, 1647, 1240, 1181 cm'l; HRMS calcd for C22H25NO4 mlz 367.1784, found mlz 367.1768. Formation of IL30. To IL29 (0.30 g, 1.05 mmol) in water (1.05 mL) was added crushed KOH (0.2 g, 0.52 mmol) at room temperature. The reaction was heated at approximately 50°C. After 12 h, the product was extracted from the reaction mixture with 6 portions of CHC13 (2 mL each). The organics were combined and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.22 g, 85% yield); 1H NMR (300 MHz, CDC13) 5 1.81 (m, 1 H), 2.00 (dddd, J = 12.6, 9.9, 6.9, 3.0, 1 H), 2.37 (ddd, J = 18.3, 6.9, 4.8 Hz, 1 H), 2.64 (ddd, J = 16.8, 9.3, 6.9 Hz, 2 H), 3.39 (m, 1 H), 3.40 (s, 1 H), 3.51 (m, 1 H), 4.07 (d, J = 15.3 Hz, 1 H), 4.10 (bs, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 12 Hz, 1 H), 5.18 (d, J = 15.3 Hz, 1 H), 7.16 - 7.38 (m, 10 H); 13C NMR (75 MHz, CDC13) 5 25.16, 27.37, 48.09, 62.13, 65.65, 69.42, 73.27, 127.15, 127.58, 127.71, 127.86, 128.45, 128.46, 137.23, 137.44, 170.28; IR (oil/NaCl) 3364 (broad), 3063, 2928, 1617, 1453, 1181, 1101 cm'13 HRMS calcd for C20H23N03 mlz 325.1678, found m/z 325.1666. Formation of IL31. To IL30 (0.50 g, 2.05 mmol) in Et20 (4.10 mL) was added crushed KOH (0.23 g, 4.10 mmol) and molecular sieves (0.40 g) at room temperanlre. After 5-10 min of stirring BnBr (0.39 g, 2.26 mmol) was added. After 3 h the reaction was quenched by addition of excess water. The reaction mixture was extracted 66 with 10 portions of Et20 (4 mL each), the organics combined and solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a white solid (0.57 g, 84% yield) (mp = 60 - 63 °C); 1H NMR (300 MHz, CDC13) 5 1.91-2.02 (m, 2 H), 2.40 (ddd, J = 18.0, 6.2, 3.9 Hz, 1 H), 2.69 (ddd, J = 18.0, 10.4, 8.5 Hz, 1 H), 3.39 (dd, J = 9.9, 7.2 Hz, 1 H), 3.52 (dd, J = 9.9, 3.9 Hz, 1 H), 3.65 (m, 1 H), 3.83 (dd, J = 6.2, 3.9 Hz, 1 H), 3.99 (d, J = 15.3 Hz, 1 H), 4.26 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 5.36 (d, J = 15.3 Hz, 1 H), 7.14-7.36 (m, 15 H); 13C NMR (75 MHz, CDC13) 5 22.18, 27.22, 47.69, 58.37, 69.16, 69.77, 71.79, 73.03, 126.87, 127.07, 127.28, 127.37, 127.56, 127.65, 128.05, 128.21, 128.26, 137.06, 137.36, 137.85, 169.93; IR (oil/NaCl) 3088. 3030, 2867, 1642, 1453, 1096 cm‘l; HRMS calcd for C27H29N03 mlz 415.2148, found mlz 415.2142. Formation of IL32 Using Acryloyl Chloride. To tetronic acid (2.00 g, 20.00 mmol) in C6H5 (40.0 mL) was added benzylamine (1.95 g, 18.18 mmol) and a catalytic amount of p-TsOH at room temperature. The reaction was fitted with a Dean - Stark trap and heated at reflux. After 12 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. THF (40.0 mL) and acryloyl chloride (2.80 g, 30.91 mmol) were then added. The reaction was again heated at reflux. After 14 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a white solid (3.08 g, 70% yield) (mp = 121-124°C); 1H NMR (300 MHz, CDC13) 5 2.58 (bt, J = 8.1 Hz, 2 H), 2.80 (bt, J = 8.1 Hz, 2 H), 4.65 (t, J = 2.0 Hz, 2 H), 4.78 (s, 2 H), 7.16-7.21 (m, 2 H), 7.24-7.36 (m, 3 H); 13C NMR (75 MHz, CDC13) 5 15.54, 30.26, 45.58, 64.98, 102.21, 126.53, 127.77, 128.73, 135.25, 159.97, 169.18, 170.94; IR (solid/KBr) 3071, 2961, 2869, 1738, 1698, 1665, 1437, 1277, 1138 cm‘l; HRMS calcd for C14H13N03 m/z 243.0896, found m/z 243.0880. Formation of IL32 Using Acrylic Anhydride. To tetronic acid (2.00 g, 20.00 mmol) in C5H5 (40.0 mL) was added benzylamine (1.95 g, 18.18 mmol) and a catalytic amount of p-TsOH at room temperatme. The reaction was fitted with a Dean - Stark trap and heated at reflux. After 12 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. THF (40.0 mL) and acrylic anhydride (3.15 g, 30.91 mmol) (Acrylic anhydride was prepared immediately prior to use by adding NaH (1.8 equiv) to acrylic acid (1.2 equiv) at -78°C and allowing the mixture to warm to room temperantre followed by the addition of acryloyl chloride (1.0 equiv) and allowing the 67 mixture to stir for 1 h. This mixture was transfered via cannula.) were then added. The reaction was again heated at reflux. After 14 h the reaction was cooled to room temperauue and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a white solid (3.13 g, 71% yield). Formation of IL33. To H-32 (0.46 g, 1.96 mmol) in EtOH (30.0 mL) and MeOH (15.0 mL) was added Na2CO3 (0.72 g, 6.86 mmol) and 10% Pd/C (0.40 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude solid was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a white solid (0.38 g, 79% yield, >98:2 cis:trans). 1H NMR (300 MHz, CDC13) (cis isomer) 5 2.01 (m, 1 H), 2.30 (m, 1 H), 2.41 (m, 1 H), 2.52 (m, 1 H), 2.98 (m, 1 H), 4.18-4.30 (m, 4 H), 5.13 (d, J = 15.0 Hz, 1 H), 7.14-7.42 (m, 5 H); 13C NMR (75 MHz, CDC13) (cis isomer) 5 19.88, 29.68, 37.85, 47.94, 55.20, 71.23, 127.93 (2), 128.97, 136.15, 169.49, 176.09; IR (solid/KBr) 3071, 2961, 2862, 1738, 1698, 1665, 1437, 1277, 1196 cm'l. Formation of IL34. To MeMgBr (1.77 mL, 3.0 M in THF) in C6H5 (3.0 mL) was added NEt3 (1.61 g, 15.92 mol) at 0°C. After 10 min H-33 (0.65 g, 2.65 mmol) in C5H5 (2.3 mL) was added with vigorous stirring. After 3 h at 0 °C the reaction was quenched by addition of an equal volume of 3 M aqueous HCl. The organics were separated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 95:5 Et2O:Me0H). The solvents were evaporated to give a clear, colorless oil (0.17 g, 25% yield, >98:2 cis:trans); 1H NMR (300 MHz, CDC13) (cis isomer) 5 1.90 (m, 1 H), 1.91 (s, 3 H), 2.10 (m, 1 H), 2.40 (dt, J = 17.7, 6.8 Hz, 1 H), 2.54 (dt, J = 17.7, 6.8 Hz, 1 H), 3.03 (dt, J = 6.6, 4.8 Hz, 1 H), 3.57 (dd, J = 11.6, 3.8 Hz, 2 H), 3.65 (dd, J = 11.4, 6.3 Hz, 1 H), 3.82 (m, 1 H), 3.92 (bs, 1 H), 4.08 (d, J = 15.0 Hz, 1 H), 5.19 (d, J = 15.0 Hz, 1 H), 7.21 (bd, J =-- 7.8 Hz, 2 H), 7.20-7.34 (m, 3 H); 13C NMR (75 MHz, CDC13) (cis isomer) 5 20.11, 25.58, 29.86, 47.49, 48.03, 57.15, 61.87, 127.45, 127.91, 128.54, 136.91, 171.06, 207.88; IR (oil/NaCl) 3374, 3088, 2942, 1711, 1613, 1455, 1256, 1169 cm'l. Formation of Preparation of Ethyl 2(S)-acetoxypropanoate (II-36). To a solution of S-ethyl lactate (2.0 g, 16.96 mmol) in pyridine (14.75 mL), was added acetic anhydride (1.88 g, 18.42 mol) at 0 °C. The reaction was allowed to stirr at room temperature. After 12 h the reaction was poured into a mixture of crushed ice (100 mL) 68 and HCl (‘7 mL). The mixture was extracted with Et20, and the ether extracts washed with water followed by brine. The organics were dried, and the solvent removed under reduced pressure to give a colorless oil. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20:low boiling petroleum ether). The solvents were evaporated to give the product pure as a clear oil (5.2 g, 44.44 mmol) in 80% yield. 1H NMR (300 MHz, CDC13) 5 1.27 (t, J = 7.2 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H), 2.11 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 5.03 (q, J = 7.2 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 13.66, 16.46, 20.14, 60.85, 68.29, 169.82, 170.38; IR (oil/NaCl) 2990, 2878, 1744. 1451, 1373, 1240, 1134, 1101, 1020, 735 cm'l. Formation of 4-Hydroxy-5(S)-methyl-2-furanone((S)-y- Methyltetronic Acid) (II-37). To a solution of lithium bis(trimethylsi1yl)amide (15 mmol, 1M in THF) in THF (40 mL) was added Ethyl 2(S)-acetoxypropanoate (II-36) (1.00 g, 6.29 mmol) in THF (40 mL) at -78 °C. The reaction was kept at -78 °C for 1 h and then poured into 2 M HCl (60 mL). The two layers were separated and the aqueous layer washed with EtOAc. The combined organics were dried and the solvents removed under reduced pressure. The oil was brought into CH2C12, dried and the solvent removed to provide a solid. The solid was then recrystallized from EtOAc-low boiling petroleum ether to yield the desired product pure (0.25 g, 2.2 mmol) in 35% yield. (mp. 108-111 °C); 1H NMR (300 MHz, CDC13) 5 1.54 (d, J = 7.2 Hz. 3H), 4.93 (q, J = 6.8 Hz, 1H), 5.09 (s, 1H), 11.92 (bs, 1H); 13C NMR (75 MHz, CDC13) 5 17.33, 77.32, 88.18, 178.13. 185.04; IR (oil/NaCl) 2942, 2708, 1709, 1599, 1279, 1238, 909 cm'l. Formation of II-38. To IL37 (2.00 g, 20.00 mmol) in C6H5 (40.0 mL) was added benzylamine (1.95 g, 18.18 mmol) and a catalytic amount of p-TsOH at room temperauue. The reaction was fitted with a Dean - Stark trap and heated at reflux. After 12 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. THF (40.0 mL) and acryloyl chloride (2.80 g, 30.91 mmol) were then added. The reaction was again heated at reflux. After 14 h the reaction was cooled to room temperature and the solvent removed under reduced pressure. The reaction mixture was then chromatographed (silica, 230—400 mesh; eluent - Et20). The solvents were evaporated to give pure IL38 in 29% yield; 1H NMR (300 MHz, CDC13) 5 1.49 (d, J = 6.7 Hz, 3H), 2.51-2.71 (m, 2H), 2.72-2.91 (m, 2H), 4.50 (d, J = 16.2 Hz, 1H), 4.86 (qd, J = 6.7, 1.4 Hz, 1H), 5.25 (d, J = 16.2 Hz, 1H), 7.14 (d, J = 6.3 Hz. 2H), 7.27-7.39 (m, 3H); 130 NMR (75 MHz, CDC13) 5 15.78, 19.42, 30.85, 45.87, 73.19, 103.99, 126.25, 128.03, 129.11, 135.48, 142.26, 163.78, 169.98; IR (KBr) 2982, 2853, 1748, 1669, 1451, 1424, 1319, 1148, 1038, 773 cm'l. MeOl reacti atmos; scinter nude 5 Et20). MHz, 1 (<1 1 = = 6.6, = 6.9 I = 9.9, 1 20.04, 80.41, added E (0.51 g, °C Aft mixture Concent (16.028. diluted‘ (10.0 11) 1383851113 P“ the MHz, ( H). 4.0( H14.3: 5-37 (d. H)» 7.11 69 Formation of IL39. To IL38 (0.46 g, 1.96 mmol) in EtOH (30.0 mL) and MeOH (15.0 mL) was added Na2C03 (0.72 g, 6.86 mmol) and 10% Pd/C (0.40 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude solid was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give pure IL39 in 70% yield. 1H NMR (300 MHz, CDC13) (diagnostic peaks for the two isomers are designated A and B) 5 (A) 1.31 (d, J = 6.6 Hz, 3H), 2.58 (m, 1H), 3.08 (m, 1H), 3.58 (d, J = 15.0 Hz, 1H), 4.58 (qd, J = 6.6, 1.8 Hz, 1H), 4.01 (d, J = 15.0 Hz, 1H), 5.37 (d, J = 15.6 Hz, 1H), (B) 1.44 (d, J = 6.9 Hz, 3H), 2.52 (m, 1H), 2.01 (m, 1H), 3.79 (dd, J = 8.7, 1.8 Hz, 1H), 4.28 (dd, J = 9.9, 6.9 Hz, 2H), 5.67 (d, J = 15.0 Hz, 1H); 13C NMR (75 MHz, CDC13) 5 16.49, 20.04, 20.33, 21.80, 29.57, 30.60, 37.21, 38.69, 47.73, 49.06, 56.05, 60.54, 78.95, 80.41, 127.95, 128.92, 128.96, 135.97, 169.50, 170.82, 175.95, 176.05. Formation of IL40. To IL31 (1.00 g, 2.41 mmol) in THF (16.1 mL) was added BuLi (1.06 mL, 2.5 M in THF) at -78 °C. After 10 min, phenylselenium chloride (0.51 g, 2.65 mmol) in THF (8.0 mL) was added and the reaction allowed to warm to 0 °C. After 3 min the reaction was quenched by addition of an equal volume of water. The mixture was extracted with 4 portions of Et20 (10.0 mL) and the organics dried and concentrated under reduced pressure. The residue was brought up in MeOH:THF:HOH (16.0:8.0:1.0 mL) and NaIO4 (1.55 g, 7.23 mmol) added. After 14 h the reaction was diluted with an equal volume of water and the mixture extracted with 10 portions of Et20 (10.0 mL). The organics were separated, dried, and the solvent removed under reduced pressure. The resulting crude solid was purified by recrystallization from Et20:10w boiling pet ether to give white crystals. (0.78 g, 78% yield) (mp = 98-99 °C); 1H NMR (300 MHz, CDC13) 5 3.34 (t, J = 9.2 Hz, 1 H), 3.48 (dd, J = 9.6, 5.0 Hz, 1 H), 3.84 (m, 1 H), 4.00 (d, J = 15.5 Hz, 1 H), 4.08 (dd, J = 5.9, 1.4 Hz, 1 H), 4.27 (d, J = 12.0 Hz, 1 H), 4.33 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 5.37 (d, J = 15.5 Hz, 1 H), 6.15 (d, J = 9.6 Hz, 1 H), 6.47 (ddd, J = 9.6, 5.9, 1.1 Hz, 1 H), 7.10-7.15 (m, 2 H), 7.19-7.38 (m, 13 H); 13C NMR (75 MHz, CDC13) 5 48.07, 57.40, 68.07, 68.60, 70.11, 73.24, 127.32, 127.52, 127.69, 127.75, 127.87, 128.04, 128.24, 128.29, 128.44, 128.51, 134.59, 136.91, 137.40, 137.52, 162.29; IR (oil/NaCl) 3088, 2870, 1669, 1611, 1455, 1262, 1146, 1092 cm'l. Formation of IL41. To IL40 (0.10 g, 0.24 mmol) in t-BuOH (1.4 mL) was added NMO (excess) and 0804 (0.96 mL, 0.05 M in t-BuOH) at room temperature. After 3 h the reaction was quenched by addition of excess Na2SO3. Solvent was removed under reduced purified 50:50 Et were eve MHz, C H), 3.97 4.41 (s, 5.27 (d, MHz, C 127.65, 171.20 E calcd for I and Li 1] the reac‘ was the: was ext] through a solid V Chromat e"21130171 MHZ. C 041: 4'20 (d. 71.94, 1 1032 Cu 1 added e Slow ad filtered, Was Pur Soil/ems (300 Ml HZ, 1 H H), 3.55 = 10.4, ‘ 70 reduced pressure till the reaction color began to turn grey. The resulting mixture was purified by repeated flash column chromatography (silica, 230-400 mesh; eluent - Et20 to 50:50 Et20:Et0H) till the resulting product fractions were clear and colorless. The solvents were evaporated to give a white solid (0.07 g, 64% yield) (mp = 95-98 °C); 1H NMR (300 MHz, CDC13) 5 2.96 (d, J = 1.8 Hz, 1 H), 3.61-3.78 (m, 3 H), 3.84 (d, J = 1.2 Hz, 1 H), 3.97 (t, J = 3.1 Hz, 1 H), 4.32 (d, J = 15.6, 1 H), 4.37 (td, J = 3.6, 2.1 Hz, 1 H), 4.41 (s, 2 H), 4.42 (m, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 5.27 (d, J = 15.6 Hz, 1 H), 7.11-7.21 (m, 4 H), 7.21-7.39 (m, 11 H); 13C NMR (75 MHz, CDC13) 47.56, 58.98, 68.11, 68.85, 69.57, 71.48, 73.13, 75.21, 127.39, 127.55, 127.65, 127.74, 127.83, 128.23, 128.35, 128.41, 128.53, 136.83, 137.19, 137.43, 171.20 5 ; IR (oil/NaCl) 3409, 3088, 3031, 2869, 1645, 1455, 1250, 1074 cm‘l; HRMS calcd for C27H29N05 mlz 447.2046, found mlz 447.2046. Formation of IL7. To IL41 (0.06 g, 0.13 mmol) was added NH3 (3.9 mL) and Li metal at -78°C, until the solution turned a persistent deep blue. After 3 h at reflux the reaction was cooled to -7 8°C and quenched by the addition of NH4C1. The reaction was then allowed to warm to room temperature allowing for NH3 removal. The reaction was extracted with 10 portions of a solution of CHCl3zMe0H (2:1, 2.0 mL) and filtered through cotton. Solvent removal under reduced pressure then under flat vacuum resulted in a solid which was dissolved in a minimum amount of MeOH and purified by flash column chromatography (silica, 230-400 mesh; eluent - 90:10 CHCl3zMe0H). The solvents were evaporated to give a white solid (0.01 g, 44% yield) (mp = 163-168 °C); 1H NMR (300 MHz, CDC13) 5 3.23 (td, J = 6.3, 3.9 Hz, 1 H), 3.59 (dd, J = 11.9, 5.9 Hz, 1 H), 3.68 (dd, J = 11.7, 5.1 Hz, 1 H), 3.72 (t, J = 6.2 Hz, 1 H), 3.89 (dd, J = 5.7, 3.9 Hz, 1 H), 4.20 (d, J = 3.9 Hz, 1 H); 13C NMR (75 MHz, CDC13) 57.30, 61.11, 67.20, 68.14, 71.94, 173.17 5 ; IR (oil/NaCl) 3287, 3063, 2941, 2890, 2834, 1609, 1453, 1281, 1175, 1032 cm'l. Formation of IL43. To IL41 (0.07 g, 0.16 mmol) in Et20 (1.6 mL) was added excess LAH at room temperature. After 3 h the reaction was quenched at 0°C via slow addition of 15% NaOH until all visible LAH had been consumed. The reaction was filtered, dried and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230—400 mesh; eluent - Et20). The solvents were evaporated to give a clear, colorless oil (0.07 g, >99% yield); 1H NMR (300 MHz, CDC13) (cis isomer) 5 2.21 (dd, J = 12.2, 1.5 Hz, 1 H), 2.38 (dt, J = 8.7, 2.6 Hz, 1 H), 2.82 (s-broad, 2 H), 2.91 (dd, J = 12.2, 4.4 Hz, 1 H), 3.27 (d, J = 12.9 Hz, 1 H), 3.55 (dd, J = 8.4, 3.3 Hz, 1 H), 3.64 (t, J = 8.6 Hz, 1 H), 3.73 (m, 1 H), 3.76 (dd, J = 10.4, 2.6 Hz, 1 H), 3.83 (dd, J = 10.4, 2.6 Hz, 1 H), 4.16 (d, J = 13.2 Hz, 1 H), 4.45 (s, l 13c N) 78.42, 138.52. for C37 added 1 and the room te under rtl white scI (ddd, J 3.0 Hz, J = 6.8 Refere 1) (a) I. 33 Le 2) Ev l9. 3) (a) W. 19. 4) (a) An. Co 71 (s, 1 H), 4.56 (d, J = 11.1 Hz, 2 H), 4.90 (d, J = 11.1 Hz, 1 H), 7.20-7.40 (m, 15 H); 13C NMR (75 MHz, CDC13) 5 54.71, 56.67, 64.76, 66.87, 68.10, 73.26, 74.61, 75.90, 78.42, 127.16, 127.65, 127.74, 127.79, 127.97, 127.99, 128.40, 128.94, 137.85. 138.52, 138.60; IR (oil/NaCl) 3422, 3063, 2923, 1495, 1453, 1098 cm-l; HRMS calcd for C27H31N04 mlz 433.2253, found m/z 433.2253. Formation of IL6. To IL43 (0.08 g, 0.18 mmol) in EtOH (1.8 mL) was added 10% Pd/C (0.18 g) and cone HCl (1.8 mL). The reaction flask was purged with N2 and then flushed with and maintained under an atmosphere of H2 and allowed to stir at room temperature. After 14 h the reaction mixture was filtered and the solvent removed under reduced pressure. The crude solid was recrystallized from Me0H:Et20 to give a white solid. (0.01 g, 33% yield) (mp = 184-186 °C); 1H NMR (300 MHz, CDC13) 5 3.00 (ddd, J = 9.9, 6.6, 3.0 Hz, 1 H), 3.10 (dd, J = 13.8, 1.3 Hz, 1 H), 3.27 (dd, J = 13.8, 3.0 Hz, 1 H), 3.55 (dd, J = 9.6, 3.0 Hz, 1 H), 3.70 (dd, J = 12.3, 6.0 Hz, 1 H), 3.74 (t, J = 6.8 Hz, 1 H), 3.85 (dd, J = 12.3, 3.5 Hz, 1 H), 4.10 (m, 1 H). References. 1) (a) Fairbanks, A. J.; Carpenter, N. C.; Fleet, G. W. J.; Ramsden, N. G.; de Bello, I. C.; Winchester, B. G.; Al-Daher, S. S.; Nagahashi, G. Tetrahedron 1992, 48, 3365. (b) Sharon, N. Lis, H. Sci. Amer. 1993, 82 (c) Fuhrmann, U.; Bause, E.; Legler, G.; Ploegh, H. Nature 1984, 307, 755. 2) Evans, 8. V.; Fellows, L. E.; Shing, T. K. M.; Fleet, G. W. J. Phytochemistry 1985, 24, 1953. 3) (a) Truscheit, E.; Frommer, W.; Junge, B.; Muller, L.; Schmidt, D. D.; Wingender, W. Angew. Chem. Int. Ed. Engl. 1981, 20, 744. (b) Fellows, L. E. Chem. Ber. 1987 , 23, 842. 4) (a) Fr. Patent; FR 1524395, [CA 71 :91733w]. (b) Bourrinet, P.; Quevauviller, A. Ann. Pharm. Fr. 1968, 26, 787, [CA 71 : 29012g]. (c) Bourrinet, P.; Queviller, A. Compt. Rend. Soc. Biol. 1968, 162, 1138, [CA 70:95233k]. 5) (a) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45, 319. (b) Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45, 327. 6) Paulvannan, K; Stille, J. R. J. Org. Chem. 1992, 57, 5319. 7) (a) Daniewski, A. R.; Kiegiel, J. Synthesis 1987, 70, 5. (b) Murahashi, S-I.; Oda, Y.; Naota, T. Tetrahedron Lett. 1992, 33 , 7557. (c) Daniewski, A. R.; Warehol, T. Liebigs Ann. Chem. 1992, 965. (d) Miki, Y.; Ohta, M.; Hachiken, H.; Takemura, S. Synthesis 1989, 312. (e) Wender, P. A.; Tebbe, M. J. Synthesis 1991, 1089. (1) Conversations with Paulvannan, K. (g) Canan, Koch, S. S.; —--m 14) 15) 8) 9) 10) ll) 12) 13) 14) 15) 72 Chamberlin, R. Synth. Commun. 1989, I9, 829. (h) Hassal, C. H. Organic Reactions 1943, 3, 73. (i) Wilson, S. R.; Di Grandi, M. J. J. Org. Chem. 1991, 56, 4766. (j) Siginome, H.; Yamada, S. J. Org. Chem. 1985, 50, 2489. (k) Baxter, A. J. C.; Holmes, A. B. JCS Perkin I 1977, 2343. (l) Warasaki, K; Sakakura, T.; Uchimura, T.; Guedin-Vuong, D. J. Am. Chem. Soc. 1984, 106, 2954. Paulvannan, K; Stille, J. R. Tetrahedron Lett. 1993, 34, 6673. (a) Kurth, M. J.; O'Brian, M. J.; Hope, H.; Yanuck, M. J. Org. Chem. 1985, 50, 2626. (b) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647. Cook, G. R.; Beholz, L. G.; Stille, J. R. Tetrahedron Lett. 1994, 35 , 1669. (a) Fryuk, M. D.; Dosnich, B. J. Am. Chem. Soc. 1978, 100, 5491. (b) Brandage, S.; Flodman, L.; Norberg, A. J. Org. Chem. Soc. 1984, 49, 927. (a) Clive, D. L. J. Tetrahedron 1978, 34, 1049. (b) Reich, H. J. Acc. Chem. Res. 1979, 12, 22. (a) Nishiyama, S.; Yamamura, S.; Hasegawa, K; Sakoda, M.; Harada, K. Tetrahedron Lett. 1991, 32, 6753. (b) Guillerm, G.; Varkados, M.; Auvin, S.; Legoffis, F. Tetrahedron Lett. 1987, 28, 535. The physical data for IL6 were consistent with those reported, 5b The physical data for IL7 were consistent with those reported, 5a Introc these 0 PrOCCS: €11 Zym aJIOthe (Figuh agents 73 CHAPTER III AZA-ANNULATION AS A ROUTE TOWARD THE PREPARATION OF PEPTIDE MIMICS Introduction. There has recently been increased interest in the preparation of peptide mimics, as these compounds have been used in the modification of an increasing number of biological processes. Compounds such as A58365A (III-1) act as effective angiotension converting enzyme (ACE) inhibitors, effective for the treatment of hypertension.1 L-696,229 (III-2), another peptide mimic, constitutes one of the latest in HIV-reverse transcriptase inhibitors (Figure III-1).2 Other peptide mimics have been implicated for use as potential anti-cancer agents.3 Figure III-l. Several Important Peptide Mimics OH H02C O C02H III-l (A58365A) (Is-696,229) memq but dif desirec' HI-Zl.‘ them p HA” H,N COmm Units 1 Any 51 An Ex: 74 In the design of a peptide mimic, a known peptide possessing some function acts as the target for the design. A peptide surrogate is then designed to mimic the original peptide but differ from it significantly enough to disrupt normal enzyme function and elicit some desired response. An example of this method of design was executed by Rapoport (Figure III-2).4 In this work, several dipeptides were targeted and 5-membered ring analogs of them prepared. In each instance, the first amino acid side chain was tethered into the ring. Figure III-2. Examples of Peptide Surrogate Design H H I I H N C0211 N C0211 I HZN HZN N C0211 HZN o o 0 5 III-3 III- III-7 (Val-Ala) (Ile-Ala) (Leu-Ala) a: r .. T “T2 O O O III-4 III-6 III-8 Extremely important to peptide function is the peptides secondary structure. One common structural unit is the B-turn. In natural peptides, the B-turn is four amino acid units long. In B-tum mimics, the turn can be comprised of a variety of structural units. Any structure that effectively mimics the topography of the targeted B-tum may be used. An example of a conformationally restricted B-turn mimic is presented in Figure III-3.5 mimi. as fix confc infon TCSII‘iI 75 Figure III-3. B-Tum Mimic R‘ko HII- H / 0 N ‘N/ ‘H RIN I'OV-‘R R . a H ’H a 7‘“ 0 HR NH H 0 HR III-9 III-10 (B-turn) (B-turn mimic) Many conformationally restricted B-amino acids have also been prepared as peptide mimics.6'8 Generally, these peptide surrogates are resistant to enzymatic cleavage as well as fixed in geometry, making them effective probes of enzyme function. Incorporation of conformationally restricted B-amino acid segments into linear bioactive peptides can give information concerning the linear peptides active conformation.7 Further, conformationally restricted B-amino acids may be highly biologically active without further modification. An example of a piperidinone B-tum mimic is shown in Figure III-4.8 When incorporated into short peptides, the B-amino acid adopts the conformation shown at the right. Pyridinone B—amino acids and their derivatives, such as III-l, would exhibit significantly altered external topography, thus potentially inhibiting enzyme function. These pyridinone B—amino acids are also very stable. Figure III-4. Piperidinone Peptide Mimic III-11 (3-D conformation) annula mimic indicat SCOpe The ] COITCE ResU positi These comp mIXe‘ oxida Used alani] Selim rePl‘e benb Oxida 29 w, 76 The objective of the current work was to examine ways to employ the aza- annulation as a tool for accessing conformationally restricted 6-membered-ring peptide mimics.6 The general strategy for approaching functionalized pyridinone systems is indicated in Scheme III-1. Scheme III-l. General Strategy for Functionalized Pyridinone Formation 0 Y \ O\ Y = i = \ 1 N ‘ .Nc H3C N R2 H R2 H O III-12 III-l3 III-l4 To this end, a variety of substrates were prepared and annulated, exploring the scope and generality of the aza-annulation methodology toward peptide mimic formation. The prepared piperidinone B-amino acid mimics were then oxidized yielding the corresponding pyridinone B-amino acids. Results and Discussion. As precursors of pyridones substituted at the 04 position and especially the C-5 position, functionalized B—ketoesters, B—ketoamides, or acetylinic esters were prepared. These reacted with benzylamine or the amine salt of phenyl glycine ethyl ester to provide compounds with a structure similar to III-14.10 These were then annulated using the mixed anhydride of 2-acetamidoacrylic acid, accessing structures similar to III-13.9 DDQ oxidation of these compounds provided compounds similar to III-12.11 The amino acids used as models for preparation of the B-amino acid analogs by aza-annulation were: alanine (III-15), proline (III-16), aspartic acid methyl ester (III-l7), benzyl protected serine (III-18), and phenylalanine (III-19). The aza-annulated derivative types are represented by structures III-20 - III-24 (Figure III-5). Initially, the B-ketoester III-25 was annulated. Reaction of III-25 with benzylamine and 2-acetamidoacry1ic acid cleanly afforded III-27 in 91% yield. DDQ oxidation provided III-28 in 73% yield (Scheme III-2). Annulation of enaminoester III- 29 with 2-acetamidoacry1ic acid provided III-30 in 77% yield. Oxidation of III-30 with DDQ gave III-31 in 73% yield (Scheme III-3). 77 Figure III-5. Aza-annulation B-Amino Acid Analogs 78 Scheme III-2. Aza-annulation of B-ketoester III-25 o\ 0Et o\ 0Et BnNH2. C6H6. reflux CH3 ,— \ CH3 . N x O H Bn III-25 III-26 2-acetamido- acrylic acid, NaH, Et02CCl. THF (91% from III-25) DDQ L ‘ toluene, reflux (73 %) o OEt 0\ CB \ 2-acetamidoacrylic acid, \ = o \ NaH, Et02CCl, THF JL N H,N (77%) H3C N H O III-29 III-30 DDQ toluene, reflux (73 %) with dikete reactit amine 17ch gave, ] 31111112 as a m in 559 III-39 34 Wil 79 Several B-ketoamide substrates were smoothly prepared by reaction of diketene with benzyl amine or the amine salt of glycine ethyl ester (Scheme III-4). Reaction of diketene with benzyl amine, using NaHC03 as a base, provided III-33 in 81% yield while reaction with the amine salt of glycine ethyl ester provided III-34 in 98% yield. Scheme III-4. Preparation of B-keto amide substrates Cl'+H3N/\C02Et BnNH2, NaHC03 NaHC03 C6H6 C6146 (81%) (98%) i i erh NVCOZEt CH3 3 0 O III-33 III-34 Aza-annulation of III-33 and III-34 were executed as described7 using benzyl amine or the amine salt of phenylglycine ethylester (Scheme III-5 and III-6). Oxidation provided the corresponding peptide analog types. Annulation of III-33 with benzyl amine gave III-35 in 90% yield. Subsequent oxidation with DDQ afforded III-36 in 76% yield. Similar reaction of III-33 with the amine salt of phenylglycine ethylester provided III-37 as a mixture of diastereomers in a ratio of 51:49 in 87% yield. DDQ oxidation gave III-38 in 55% yield. For the annulation substrate III-34, reaction with benzyl amine provided III-39 in 95% yield. DDQ oxidation afforded III-40 in 78% yield. Annulation of III- 34 with the protected phenylglycine salt gave III-41 as a mixture of diastereomers in a ratio of 51:49 in 86% yield. Oxidation of III-41 provided III-42 in 60% yield. 80 Scheme III-5. Aza-annulation of B-ketoamide III-33 Ii NvPh H3 0 III- 33 “N112. 1) Eh C1-+H,N ACOZEt (361-1 6 r Ph 2) 2-acetamido— 2) 2-acetamido— acrylic acid, acrylic acid, 0\ N‘H NaH, ElOzCCl NaH, E102CC1, THF THF CH3 (90%) (87%) i H,C N H III-35 DDQ, toluene, reflux (76%) Ph H CH3 0 BH HachN 81 Scheme III-6. Aza-annulation of B-ketoamide III-34 CH3 0 III-34 1) BnNH2. 1) 5" C H5 ' 6 Cl'*H3N AC0,EI COzEt COHO COzEI I/ 2) 2-acetamido- 2) 2-acetarnido- r acrylic acid, acrylic acid, . 0\ N< H NaH, EtO2CCl NaH, EtOzCCl, THF THF CH, (95%) (86%) i N CO Et H,C N 2 H 0 Ph III-39 III-41 DIEQ, toluene, DDQ, toluene, re ux reflux (78%) (60%) C02Et I/CO,Et H O\ N‘H CH, 0 CH, JL I N C0212; Bn H,C N H 0 Ph 82 To effect placement of functionality at the C-5 position, aza-annulation using acetylenic esters was executed (Scheme III-7, III-8, and III-9). Annulation of III-43 with benzyl amine gave III-48 in 71% yield. Subsequent DDQ oxidation gave III-45 in 71% yield. Ethyl ester II-45 (prepared as described in chapter H) was annulated in 83% yield providing III-46. DDQ oxidation of III-46 failed, giving recovery starting material.11 Substrate III-49 (prepared in similar fashon to II-25 in 94% yield) was annulated using benzyl amine to provide III-50 in 61% yield. The stereochemical conformation about the double bond was determined using NOE.12 The expected isomer comprised 8% of the product mixture. Scheme III-7. Aza-annulation of Acetylenic Ester III-43 OMe 1) BnNH2, THF. \ OMe reflux OMe 2) 2-acetamido- JL acrylic acid, H C N Bn 0 NaH, THF 3 u (71%) H 0 III-43 83 Scheme III-8. Aza-annulation of Acetylenic Ester II-45 OEt 1) BuLi, THF \OBn = O 2) EtOzCCl % 03,, (88%) II-52 II-45 1) BnNH2, THF, reflux 2) 2-acetamido— acrylic acid, NaH, THF v (83%) O OEt O OBn Jk N. H3C N Bn III-47 III-46 Scheme III-9. Aza-annulation of Acetylenic Ester III-49 OEt 1) BuLi, THF \/ Ph = 2) EtOgCCl 0 % Pb (94%) III-48 III-49 l) BnNH2, THF, reflux 2) 2-acetamido- acrylic acid, NaH, THF ll (61%) O\ OEt O / Jk N. H3C III Bn H O 84 Hydrolysis of III-28 and III-31 prepared the substrates for acylation of the amine or alkylation of the carboxylic acid. Treatment of III-28 with aqueous KOH cleanly hydrolyzed the ester leaving the amide intact to provide III-51 in 83% yield. Hydrolysis of III-31 under similar conditions provided III-49 in 82% yield. To deprotect the amine of III-28, KOH in 30% H202 was used to give III-53 in 75% yield (Scheme III-10). Scheme III-10. Hydrolysis of III-28 and III-31 KOH H20 (33 %) H3C KOH N H2O H3C If (82%) HZN KOH H20 (68%) 85 The versatility of compounds such as III-52 was demonstrated by alkylation of the free carboxylic acid. Alkylation of III-52 with phenylglycine ethyl ester provided III-S4 in 78% yield (eq 18). Ph YCOZEt 1) NaH, 2) 15102ch H = CH3 (18) 3) phenylglycine O ethylester i (78%) H3C N Bn III-52 Hydrogenation of III-50 under conditions of Pd/C, Na2C03, and H2 at one atmosphere resulted in the formation of III-55 as a mixture of diastereomers in a ratio of 96:4 in 94% yield (eq 19). Attempted DDQ oxidation of III-50 failed.9 OEt 0 Ph 0 OEt / Pd/C, N32CO3, H2 JL N\ EtOH, 14h, 1 atm JL N\ H3C til Bn (94%) H3C If Bn H O H O III-50 III-55 Conclusion. The aza-annulation constitutes a quick and efficient method of building up highly functionalized 6-membered nitrogen heterocycles. Oxidation of these heterocycles provide the corresponding functionalized pyridone ring. The aza-annulation methodology thus constitutes a rapid and efficient route for the formation of peptide mimics with functionalization possible at the C-2, C-4, and 05 positions. In the current work, the aza- annulation methodology was used to prepare a series of extended, 6-membered ring amino acid analogs. 14 These analogs constitute conformationally modified protein segments that may be incorporated into peptide mimics. 86 Experimental Section. General Methods. All reactions were carried out using standard inert atmosphere techniques to exclude moisture and oxygen, and reactions were performed under an atmosphere of nitrogen. Benzene, toluene and ether were distilled from sodium/benzophenone immediately prior to use. Xylenes and decalin were heated over calcium hydride for a minimum of 12 h and then distilled prior to use. LiAlH4 (1 M in THF) was obtained from Aldrich Chemical Co. Unless specified, concentration of mixtures was performed using a Buchi rotary evaporator. Gas chromatographic (GC) analyses were carried out on one of two instruments. For lower molecular weight compounds gas chromatographic analysis was carried out isothermally on a Perkin-Elmer 8500 instrument using a 50 meter RSL-ZOO capillary column (5% methylphenyl silicon) and an FID detector at 200 °C oven temperature, 220 °C injector temperature, and 300 °C detector temperature. Helium gas pressure was set at 15 psi with a flow rate of 2 mL/min. For higher molecular weight compounds, gas chromographic analysis was carried out on a Hewlett-Packard 5880A series gas chromatograph fitted with a 300 meter silica capillary column and a flame ionization detector. For these analysis injector and detector temperatures were set at 250 °C and the column oven temperature was programmed: 40 °C, 2 min., 10 °C/min. ramp to 200 °C. All reactions were monitored by GC and the reactions terminated either when the starting material had been consumed or no further reaction appeared to continue. For reactions in which a Dean-Stark trap was used, the trap was filled with molecular sieves to a level below that of returning solvent turbulence. These were changed during reactions in which additional reagent was added after the reactions initiation. Molecular sieves were activated by heating in a 150 °C oven for at least 24 hours prior to use. NMR spectra were obtained on a VXR-BOO spectrometer using CHC13 with 0.1% TMS as an internal standard 5 (0.00 ppm), CD3OD, Acetone-d5, or DMSO-d6, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet), integration and coupling. Infrared spectra were recorded on a Nicolet 42 FT—IR instrument. General Method for the Formation of B-Ketoamides. Diketene (5.0-30.0 mmol, 1.0 equiv) and the amine or amine hydrocloride salt (1.0 equiv) were taken up in benzene (0.5 M relative to the amine) along with an excess of NaHCO3 (2.0 equiv) at 0 °C. After stirring at room temperature for 14 h, the reaction mixture was filtered and the solvent removed under reduced pressure to yield the product as a solid. Recrystallization from Et20/CHC13 yielded the product as white leaflets. 87 III-34: (1.74 g, 9.35 mmol, 99% yield); mp 52-53 °C; 1H NMR (300 MHZ, CDC13) 5 1.28 (t, J = 7.1 HZ, 3 H), 2.28 (S, 3 H), 3.50 (S, 2 H), 4.04 (d, J = 5.4 HZ, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 7.61 (bs, l H); 13C NMR (75 MHZ, CDC13) 5 13.84, 30.36, 41.11, 49.63, 61.13, 166.16, 169.41, 203.54; IR (KBr) 3353, 2986, 1754, 1715, 1673, 1543, 1418, 1401, 1321, 1175 cm'l; HRMS for C3H13NO4 m/z 187.0845, found m/z 187.0844. III-33: (3.59 g, 18.80 mmol, 81% yield); mp 100—102 °C; 1H NMR (300 MHz, CDC13) 5 2.24 (S, 3 H), 3.42 (s, 2 H), 4.44 (d, J = 6.0 HZ, 2 H), 7.25-7.40 (m, 6 H); 13C NMR (75 MHZ, CDC13) 5 30.90, 43.46, 49.56, 127.42, 127.62, 128.62, 137.88, 165.38. 204.35; IR (KBr) 3249, 3085, 1715, 1640, 1443, 1410, 1190, 1163 cm'l; HRMS for C11H13NO2 m/z 191.0146, found m/z 191.0982. General Method for the Aza-Annulation of B—Ketoamides and B - Ketoesters. A mixture of the primary amine or primary amine salt (0.5-5.0 mmol, 1.0 equiv) and the B-ketoamide (1.0 equiv) were taken up in benzene (0.5 M relative to the amine) along with BF3-etherate (0.5 equiv) and fitted with a modified Dean-Stark trap which passes returning solvent through molecular sieves. After the reaction had gone to completion, as indicated by 1H NMR, the solvent was removed under reduced pressure and the crude enamine brought up in THF (0.1 M relative to the enamine). The sodium salt of 2-acetamidoacrylic acid (1.3 equiv) was added at -78 °C and the reaction allowed to stir at rt for 14 h, or longer if 1H NMR suggested the reaction not complete. Sat. aq. NaHCO3 (excess) was added, and the mixture was extracted 4 times with EtOAc. The combined organic fractions were dried over Na2803, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica, 230-400 mesh, eluent, Et20:EtOAc:MeOl-I) III-27: (0.56 g, 1.70 mmol, 74% yield); mp 132-135 °C; 1H NMR (300 MHz, CDC13) 5 1.28 (t, J = 7.2 Hz, 3 H), 2.06 (s, 3 H), 2.27 (tq, J = 15.9, 2.6 Hz, 1 H), 2.37 (d, J = 2.1 Hz, 3 H), 3.40 (dd, J = 15.9, 6.3 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.55 (dt, J = 14.7, 6.0 Hz, 1 H), 4.78 (d, J = 16.1 Hz, 1 H), 5.22 (d, J = 16.1 Hz, 1 H), 6.61 (bd, J = 5.1 Hz, 1 H), 7.11 (d, J = 6.9 Hz, 2 H), 7.22-7.36 (m, 3 H); 13C NMR (75 MHz, CDC13) 8 14.14, 16.11, 23.15, 27.69, 45.80, 48.96, 60.51, 109.12, 126.04, 127.41, 127.63, 128.83, 136.73, 147.35, 166.68, 170.12; IR (KBr) 3299, 2986, 1686, 1389, 1248, 1163 cm'l; HRMS for C18H22N2O4 m/z 330.1580, found m/z 330.1572. III-30: (1.27 g, 4.77 mmol, 74% yield); mp 150-151 °C; 1H NMR (300 MHz, CDC13) 5 1.29 (t, J = 7.2 Hz, 3 H), 2.03 (quint, J = 7.3 Hz, 2 H), 2.07 (s, 3 H), 2.29 (tt, J = 15.6, 2.9 Hz, 1 H), 3.16 (td, J = 7.7, 2.1 Hz, 2 H), 3.40 (dd, J = 16.2, 7.5 Hz, 1 H), 3.68 (dt, 88 J = 11.4, 7.3 Hz, 1 H), 3.79 (dt, J = 11.4, 7.2 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.54 (dt, J = 14.4, 7.2, 1 H), 6.39 (d, J = 5.7 Hz, 1 H); 13C NMR (75 MHz, CDC13) 5 14.33, 21.59, 23.17, 27.99, 31.20, 46.17, 49.60, 60.15, 100.82, 152.30, 166.41, 167.89, 170.23; IR (KBr) 3281, 2984, 2849, 1690, 1642, 1545, 1399, 1248, 1173, 1109 cm'l; HRMS for C13H13N204 m/z 266.1267, found m/z 266.1260. III-39: (1.06 g, 2.74 mmol, 95% yield); mp 71-74 °C; 1H NMR (300 MHz, CDC13) 5 1.25 (t, J = 7.1 Hz, 3 H), 2.00 (s, 3 H), 2.16 (d, J = 2.2 Hz, 3 H), 2.46 (btd, J = 15.3, 2.2 Hz, 1 H), 2.96 (dd, J = 15.3, 6.5 Hz, 1 H), 3.95 (dd, J = 18.1, 5.6 Hz, 1 H), 4.04 (dd, J = 18.1, 5.6 Hz, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.59 (dt, J = 15.3, 6.5 Hz, 1 H), 4.67 (d, J = 16.7 Hz, 1 H), 5.13 (d, J = 16.7 Hz, 1 H), 6.91 (t,J = 5.6 Hz, 1 H), 7.05- 7.13 (m, 3 H), 7.19—7.34 (m, 3 H); 13C NMR (75 MHz, CDC13) 5 13.84, 15.79, 22.78, 28.31, 41.18, 45.42, 48.74, 61.09, 111.95, 125.82, 127.12, 128.58, 136.78, 139.74, 168.09, 169.34, 169.69, 170.25; IR (KBr) 3285, 2984, 1744, 1657, 1584, 1543, 1319, 1190 cm‘l; HRMS for C20H25N305 m/z 387.1794, found m/z 387.1789. III-35: (0.78 g, 2.06 mmol, 90% yield); mp 82-85 °C; 1H NMR (300 MHz, CDC13) 5 1.92 (s, 3 H), 2.07 (d, J = 2.3 Hz, 3 H), 2.41 (btd, J = 15.3, 2.3 Hz, 1 H), 2.93 (dd, J = 15.5, 6.4 Hz, 1 H), 4.35 (dd, J = 14.7, 5.5 Hz, 1 H), 4.43 (dd, J = 14.7, 5.5 Hz, 1 H), 4.54 (dt, J = 15.0, 6.4 Hz, 1 H), 4.63 (d, J = 16.4 Hz, 1 H), 5.05 (d, J = 16.4 Hz, 1 H), 6.80 (bt, J = 5.7 Hz, 1 H), 6.98 (bd, J = 6.3 Hz, 1 H), 7.07 (d, J = 6.6 Hz, 2 H), 7.16- 7.30 (m, 8 H); 13C NMR (75 MHz, CDC13) 5 15.87, 22.79, 28.51, 43.44, 45.45, 48.78, 112.45, 125.86, 127.15, 127.57, 128.39, 128.61, 136.82, 138.02, 139.12, 167.80, 169.27, 170.21; IR (KBr) 3289, 3002, 1734, 1659, 1584, 1543, 1321, 1248 cm'l; HRMS for C23H25N3O3 m/z 391.1896, found mlz 391.1895. III-41: (mixed diastereomers, ratio 49:51); (0.52 g, 1.13 mmol, 86% yield); mp 77-80 °C; 1H NMR (300 MHz, CDC13, characteristic peaks) 5 (major isomer) 2.03 (s, 3 H), 2.12 (d, J = 1.5 Hz, 3 H), 2.45 (btq, J = 9.0, 1.5 Hz, 1 H), 2.77 (ddd, J = 7.8, 3.3, 1.5 Hz, 1 H), 5.62 (s, 1 H), 6.17 (bt, J = 2.9 Hz, 1 H), (minor isomer) 2.02 (s, 3 H), 2.24 (d, J = 1.5 Hz, 3 H), 2.33 (btq, J = 9.0, 1.5 Hz, 1 H), 3.10 (ddd, J = 9.0, 3.3, 1.5 Hz, 1 H), 5.68 (s, 1 H), 6.13 (bt, J = 2.9 Hz, 1 H); 13C NMR (75 MHz, CDC13) 5 13.97, 16.29, 16.56, 22.75, 22.98, 28.16, 28.26, 41.35, 41.42, 46.44, 49.04, 59.71, 59.91, 60.78, 61.32, 61.80, 62.35, 100.38, 113.15, 113.52, 167.73, 127.71, 127.77, 127.99, 128.04, 128.09, 128.20, 128.34, 133.26, 134.22, 134.44, 139.46, 139.49, 140.42, 167.92, 168.04, 168.47, 169.04, 169.30, 169.35, 169.40, 169.74, 169.79, 170.22, 170.30, 171.05; IR (KBr) 3277, 2986, 1744, 1655, 1541, 1204 cm‘l; HRMS for C23H29N3O7 m/z 459.2006, found m/z 459.2011. 89 III-37: (mixed diastereomers, ratio 49:51); (0.36 g, 0.80 mmol, 87% yield); mp 83-85 °C; 1H NMR (300 MHz, CDC13, characteristic peaks) 5 (major isomer) 2.01 (s, 3 H), 2.22 (d, J = 1.2 Hz, 3 H), 2.30 (bdt, J = 9.2, 1.5 Hz, 1 H), 5.67 (s, 1 H), 5.92 (m, 1 H), (minor isomer) 2.02 (s, 3 H), 2.10 (d, J = 1.2 Hz, 3 H), 2.43 (btd, J = 9.2, 1.5 Hz, 1 H), 5.59 (s, 1 H), 5.95 (m, 1 H); 13C NMR (75 MHz, CDC13) 5 13.87, 16.22, 16.50, 20.86, 22.78, 28.17, 28.33, 40.42, 43.46, 46.47, 48.94, 59.82, 61.67, 111.05, 113.61, 114.01, 117.30, 126.02, 127.06, 127.17, 127.50, 127.55, 127.71, 127.95, 128.21, 128.37, 128.41, 128.52, 134.26, 134.42, 137.88, 137.95, 138.52, 139.39, 167.46, 167.64, 168.02, 168.43, 169.22, 169.61, 170.13, 170.18; IR (KBr) 3297, 3007, 1742, 1651, 1532, 1217 cm'l; HRMS for C26H29N305 m/z 463.2107, found m/z 463.2150. General Method for the Formation of Acetylenic Esters. To benzyl protected propargyl alcohol (10-50 mmol, 1.0 equiv) in THF (0.5 M relative to the alcohol) was added BuLi (1.0 equiv, 2.5 M in Hexane) at -78 °C. After 10 min ethyl chloroformate (1.5 equiv) was added dropwise. The reaction was slowly warmed to 0 °C (only until a deep red color began to form for the case of II-25, after which time it was promptly quenched) and then to rt. After 14 h, the reaction was quenched by addition of water. The organics were separated and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - petroleum ether). The solvents were evaporated to give a clear, colorless oil. II-ZS: (1.61 g, 7.45 mmol, 91% yield); 1H NMR (300 MHz, CDC13) 5 1.29 (t, J = 7.2 Hz, 3 H), 4.22 (q, J = 7.2 Hz, 2 H), 4.25 (s, 2 H), 4.59 (s, 2 H), 7.22-7.40 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 13.78, 56.53, 61.90, 71.81, 78.07, 82.94, 127.87, 127.90, 128.29, 136.59, 152.87; IR (oil/NaCl) 3032, 2984, 2872, 2236, 1713, 1248 cm‘ 1 III-49: (3.06 g, 16.28 mmol, 94% yield); 1H NMR (300 MHz, CDC13) 5 1.30 (t, J = 7.1 Hz, 3 H), 3.73 (s, 2 H), 4.23 (q, I = 7.1 Hz, 2 H), 7.25-7.40 (m, 5 H); 13C NMR (75 MHz, CDC13) 5 14.00, 24.97, 61.87, 74.84, 86.20, 127.16, 127.99, 128.69, 134.07, 153.67; IR(oil/NaCl) 2984,2238, 1709, 1255 cm'l. General Method for the Aza-Annulation of Acetylenic Esters. A mixture of the primary amine (0.5-5.0 mmol, 1.0 equiv) and the acetylenic ester (1.0 equiv) were taken up in THF (0.5 M relative to the amine) along with BF3-etherate (0.5 equiv) and allowed to heat at rt. After the reaction had gone to completion, as indicated by 1H NMR, the solvent was removed under reduced pressure and the crude enamine brought up in THF (0.1 M relative to the enamine). The sodium salt of 2-acetamidoacrylic acid (1.3 equiv) was added at -78 °C and the reaction allowed to stir at rt for 14 h, or longer if 1H 90 NMR suggested the reaction not complete. Sat. aq. NaHCO3 (excess) was added, and the mixture was extracted 4 times with EtOAc. The combined organic fractions were dried over Na28 O3, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica 230-400 mesh, eluent, Et20:EtOAc:MeOH) III-44: (3.60 g, 10.00 mmol, 71% yield); mp 151-154 °C; 1H NMR (300 MHz, CDC13) 5 2.05 (s, 3 H), 2.34 (dd, J = 16.3, 15.6 Hz, 1 H), 3.42 (dd, J = 16.3, 7.0 Hz, 1 H), 3.67 (s, 3 H), 3.73 (s, 3 H), 4.63 (ddd, J = 15.6, 7.0, 5.6 Hz, 1 H), 4.65 (d, J = 15.6 Hz, 1 H), 4.94 (d, J = 15.6 Hz, 1 H), 6.51 (bd, J = 5.6 Hz, 1 H), 7.16-7.22 (m, 2 H), 7.25-7.36 (m, 3 H); 13C NMR (75 MHz, CDC13) 5 23.07, 26.41, 47.81, 48.43, 52.24, 52.90, 108.95, 127.13, 127.79, 128.56, 135.77, 141.88, 163.32, 165.05, 169.21, 170.14; IR (KBr) 3306, 2953, 1742, 1705, 1634, 1534, 1437, 1248 cm'l; HRMS for C13H20N2O6 m/z 360.1322, found m/z 360.1308. III-46: (3.32 g, 7.61 mmol, 83% yield); mp 97-99 °C; 1H NMR (300 MHz, CDC13) 5 1.26 (t, J = 7.2 Hz, 3 H), 2.03 (s, 3 H), 2.29 (td, J = 16.0, 2.0 Hz, 1 H), 3.39 (dd, J = 16.0, 6.6 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.31 (dd, J = 12.9, 2.0 Hz, 1 H), 4.45 (dt, J = 15.0, 6.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.80 (d, J = 16.5 Hz, 1 H), 5.00 (d, J = 12.9 Hz, 1 H), 5.41 (d, J = 16.5 Hz, 1 H), 6.73 (bd, J = 5.7 Hz, 1 H), 6.98-7.02 (m, 2 H), 7.17-7.38 (m, 8 H); 13C NMR (300 MHz, CDC13) 5 13.97, 22.99, 28.00, 45.62, 48.50, 60.90, 63.07, 72.50, 112.97, 125.91, 127.16, 127.87, 128.32, 128.64, 137.12, 137.39, 145.35, 165.91, 170.07; IR (KBr) 3310, 3011, 2936, 1673, 1632, 1497, 1392, 1372, 1217 cm]; HRMS for C25H23N205 m/z 436.1998, found m/z 436.2064. III-50: (mixed isomers, ratio 92:8); (2.64 g, 6.5 mmol, 61% yield); 1H NMR (300 MHz, CDC13) 5 1.14 (t, J = 7.1 Hz, 3 H), 1.79 (ddd, J = 13.1, 11.1, 6.6, 1 H), 2.03 (s, 3 H), 2.80 (ddd, J = 13.1, 9.4, 7.0 Hz, 1 H), 3.85-4.87 (m, 3 H), 4.47 (dt, J = 11.1, 6.3 Hz, 1 H), 4.77 (d, J = 15.4 Hz, 1 H), 5.23 (d, J = 15.4 Hz, 1 H), 6.46 (s, 1 H), 6.84 (d, J = 5.8 Hz, 1 H), 7.13-7.38 (m, 5 H); 13C NMR (300 MHz, CDC13) 5 13.84, 23.00, 29.05, 40.78, 48.71, 51.43, 61.38, 121.37, 127.32, 127.47, 128.40, 128.51, 128.90, 134.38, 135.82, 137.00, 169.53, 170.00, 171.91; IR (KBr) 3330, 2982, 1734, 1671, 1496, 1410, 1244, 1184 cm'l. General Method for the DDQ Oxidation of Aza-Annulation Products. A mixture of the aza-annulation product (0.5-50.0 mmol, 1.0 equiv) and DDQ (1.5 equiv) were taken up in tolune (0.1 M with respect to the aza-annulation product). After heating at reflux for 14 h the solvent was removed under reduced pressure and the crude product was 91 purified by flash column chromatography (silica, 230-400 mesh, eluent, Et20: EtOAc) or recrystallized (CHCl3zEtOAc). For compounds derived from B-ketoamides, the oxidation was repeated to give the indicated yields. III-28: (0.029 g, 0.088 mmol, 58% yield); mp 176-178 °C; 1H NMR (300 MHz, CDC13) 5 1.37 (t, J = 7.1 Hz, 3 H), 2.19 (s, 3 H), 2.68 (s, 3 H), 4.30 (q, J = 7.1 Hz, 2 H), 5.47 (s, 2 H), 7.09 (d, J = 6.7 Hz, 2 H), 7.26-7.35 (m, 3 H), 8.30 (bs, 1 H), 8.91 (s, 1 H); 13C NMR (75 MHz, CDC13) 5 14.19, 16.91, 24.63, 48.33, 61.15, 110.44, 122.64, 125.77, 126.05, 127.64, 128.94, 135.22, 145.30, 158.40, 165.88, 169.02; IR (KBr) 3308, 2982, 1713, 1638, 1516, 1192 cm'l; HRMS for C13H20N204 m/z 328.1423, found m/z 328.1411. III-31: (0.039 g, 0.150 mmol, 78% yield); mp 225-226 °C; 1H NMR (300 MHz, CDC13) 5 1.33 (t, J = 7.1 Hz, 3 H), 2.18 (s, 3 H), 2.21 (quint, J = 7.7 Hz, 2 H), 3.50 (t, J = 7.7 Hz, 2 H), 4.16 (t, J = 7.7 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 2 H), 8.14 (bs, 1 H), 8.85 (s, 1 H); 13C NMR (75 MHz, CDC13) 5 14.31, 20.99, 24.63, 33.04, 49.43, 60.78, 106.11, 122.55, 126.13, 149.57 156.83, 164.86, 168.80; IR (KBr) 3297, 2982, 2936, 1715, 1684, 1636, 1532, 1196, 1100 cm‘l; HRMS for C13H16N204 m/z 264.1110, found m/z 264.1108. III-40: (0.31 g, 0.15 mmol, 80% yield); mp = 177-180 °C; 1H NMR (300 MHz, Acetone-d6) 5 1.21 (t, J = 7.1 Hz, 3 H), 2.11 (s, 3 H), 2.48 (s, 3 H), 4.10 (d, J = 6.0 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 5.54 (s, 2 H), 7.14-7.17 (m, 2 H), 7.24-7.56 (m, 3 H), 8.01 (t, J = 6.0 Hz, 1 H), 8.54 (s, 1 H), 9.04 (s, 1 H); 13C NMR (75 MHz, Acetone-d5) 8 14.42, 17.22, 24.38, 42.21, 48.85, 61.47, 108.55, 122.56, 127.30, 129.21, 129.52, 129.62, 137.19, 145.59, 158.65, 168.80, 170.10, 170.28; IR (KBr) 3277, 3032, 1748, 1671, 1644, 1512, 1210, 1003 cm‘l; HRMS for C20H23N3O5 m/z 385.1638, found m/z 385.1623. III-36: (0.21 g, 0.56 mmol, 76% yield); mp 180-181 °C; 1H NMR (300 MHz, Acetone- d5) 5 2.10 (s, 3 H), 2.42 (s, 3 H), 4.55 (d, J = 6.0 Hz, 2 H), 5.51 (s, 2 H), 7.12-7.16 (m, 2 H), 7.19-7.56 (m, 8 H), 8.18 (t, J = 6.0 Hz, 1 H), 8.54 (s, 1 H), 8.96 (s, 1 H); 13C NMR (75 MHz, Acetone-d6) 5 17.28, 24.36, 44.20, 48.79, 108.50, 122.42, 127.30, 127.83, 128.13, 128.45, 129.21, 129.51, 129.60, 136.99, 137.25, 145.43, 158.59. 168.47, 169.97; IR (KRr) 3299, 3067, 3034, 2880, 1705, 1634, 1507, 1476, 1248, 1003 cm‘l; HRMS for C23H23N3O3 m/z 389.1739, found mlz 389.1762. III-42: (0.32 g, 0.70 mmol, 60% yield); mp = 204-205 °C; 1H NMR (300 MHz, CDC13) 5 1.24 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 2.17 (s, 3 H), 2.49 (s, 3 H), 4.13-4.29 (m, 6 H), 6.14 (s, 1 H), 6.55 (bs, 1 H), 7.26-7.48 (m, 5 H), 8.32 (s, 1 H), 8.55 (s, 1 H); 13C NMR (75 MHz, CDC13) 5 14.08, 17.53, 24.54, 41.88, 61.74, 92 62.17, 62.65, 112.68, 115.71, 121.15, 126.60, 128.08, 128.59, 128.92, 132.86, 134.72, 140.19, 157.78, 167.40, 167.67, 169.65; IR (KBr) 3314, 2986, 1744, 1645, 1524, 1217, 1082, 1003 cm'l; HRMS for C23H27N307 mlz 457.1849, found mlz 457.1853. III-38: (0.16 g, 0.35 mmol, 55% yield); mp = 155-156 °C; 1H NMR (300 MHz, CDC13) 5 1.24 (t, J = 7.2 HZ, 3 H), 2.18 (S, 3 H), 2.50 (S, 3 H), 4.26 (q, J = 7.2 HZ, 2 H), 4.57 (dd, J = 5.6, 1.7 HZ, 2 H), 6.12 (S, l H), 6.19 (m, 1 H), 7.19-7.43 (m, 10 H), 8.27 (S, 1 H), 8.53 (s, 1 H); 13C NMR (75 MHz, CDC13) 8 14.10, 17.52, 24.67, 44.28, 62.11, 62.69, 116.21, 120.69, 126.86, 127.73, 127.85, 128.15, 128.54, 128.62, 128.85, 133.01, 137.69, 139.77, 140.51, 167.20, 167.38, 169.27; IR (KBr) 3280, 2960, 2920, 1736, 1647, 1516, 1455, 1217 cm‘l; HRMS for C26H27N305 m/z 461.1951, found m/z 461.1901. III-45: (0.21 g, 0.59 mmol, 71% yield); mp = 128-129 °C; 1H NMR (300 HZ, CDC13) 5 2.19 (S, 3 H), 3.79 (S, 3 H), 3.85 (S, 3 H), 5.26 (S, 2 H), 7.19-7.32 (m, 5 H), 8.34 (bs, 1 H), 8.84 (S, 1 H); 13C NMR (75 MHZ, CDC13) 5 24.67, 50.44, 52.62, 53.41, 109.06, 120.06, 127.36, 128.04, 128.61, 128.83, 134.77, 138.14, 157.02, 163.12, 164.18, 169.23; IR (KBr) 3374, 3021, 2955, 1728, 1691, 1645, 1516, 1437, 1215 cm‘l. General Method for the Hydrolysis of Esters and Amides. A mixture of the oxidation product (0.5-2.0 mmol, 1.0 equiv) and KOH (20.0 equiv) were taken up in H20 (for hydrolysis of esters) or 30% H202 (for hydrolysis of amides) (0.1 M with respect to the oxidation product). After 14 to 38 h, the reaction was extracted with CHC13, filtered, neutralizated with HCl, and the carboxcylic acid collected by filtration or the amines collected by solvent removal under reduced pressure followed by extraction with MeOH or acetone. The products were then recrystallized (MeOH:CHCl3 or MeOH:Et20). III-51: (0.48 g, 2.03 mmol, 61% yield); mp >260 °C; 1H NMR (300 MHz, Acetone-d5) 5 2.07 (s, 3 H), 2.70 (s, 3 H), 5.55 (s, 2 H), 7.17 (d, J = 6.9 Hz, 1 H), 7.26-7.35 (m, 4 H), 8.98 (s, 1 H); 13C NMR (75 MHz, Acetone) 5 17.09, 24.32, 48.52, 106.25, 123.00, 127.10, 128.14, 129.62, 130.55, 133.29, 137.24, 158.84, 167.42, 171.53; IR (KBr) 3277, 3031, 1692, 1622, 1603, 1553, 1387, 1190 cm'l. III-52: (0.061 g, 0.314 mmol, 82% yield); 1H NMR (300 MHz, DMSO-d5) 5 2.03 (quint, J = 7.6 Hz, 2 H), 3.25 (t, J = 7.6 Hz, 2 H), 3.95 (t, J = 7.6 Hz, 2 H), 6.91 (s, 1 H); 13C NMR (75 MHz, DMSO-d6) 5 21.09, 32.45, 48.73, 111.03, 128.51, 129.14, 135.41, 143.12, 156.81; IR (KBr) 3364, 1698, 1615, 1536, 1117 cm]. III-53: (0.047 g, 0.183 mmol, 61% yield); mp 205-206 °C; 1H NMR (300 MHz, DMSO-d5) 5 2.46 (s, 3 H), 5.46 (s, 2 H), 7.07-7.54 (m, 5 H), 8.02 (s, 1 H); 13C NMR 93 (75 MHz, DMSO-d6) 5 16.83, 30.74, 115.41, 127.05, 128.34, 129.37, 129.86, 133.98, 135.86, 137.69, 160.60, 169.74; IR (KBr) 2928, 1709, 1640, 1549, 1455, 1256, 1024 cm'l. Formation of III-54: To a solution of II-52 (0.20 g, 0.848 mmol) in THF (8.48 mL) was added NaH (0.92 g, 0.848 mol) at -78 °C. To the reaction was added Et02CCl (0.081 mL, 0.848 mmol) followed by phenylglycine ethyl ester (0.183 g, 0.848 mmol). The reaction was allowed to warm to room temperature and stirr for 2 hr. Sat. aq. NaHCO3 (excess) was added, and the mixture was extracted 4 times with EtOAc. The combined organic fractions were dried over Na28 O3, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica, 230-400 mesh, eluent, Et2OzEtOAczMeOH). (0.29 g, 0.66 mmol, 78% yield); mp 209-210 °C; 1H NMR (300 MHz, CDC13) 5 1.22 (t, J = 7.1 Hz, 3 H), 2.17 (s, 3 H), 2.42 (s, 3 H), 4.17 (dq, J = 10.7, 7.1 Hz, 1 H), 4.25 (dq, J = 10.7, 7.1 Hz, 1 H), 5.38 (s, 2 H), 5.63 (d, J = 7.1 Hz, 1 H), 6.98 (d, J = 7.1 Hz, 1 H), 7.09 (d, J = 6.5 Hz, 2 H), 7.25-7.44 (m, 8 H), 8.37 (s, 1 H), 8.55 (s, 1 H); 13C NMR (75 MHz, CDC13) 5 13.90, 16.88, 24.43, 48.53, 57.22, 61.99, 126.20, 126.31, 127.33, 127.63, 128.49, 128.57, 128.84, 128.96, 135.02, 135.89, 140.32, 157.95, 166.84, 169.61, 170.58; IR (KBr) 3324, 3019, 1736, 1636, 1514, 1217 cm'l. Formation of III-55. To III-50 (0.24 g, 1.05 mmol) in EtOH (10.5 mL) was added Na2C03 (0.39 g, 3.67 mmol) and 10% Pd/C (0.10 g). The reaction vessel was purged with N2 and then flushed with and maintained under an atmosphere of H2. After stirring for 16 h, the reaction mixture was filtered through a fine scintered glass funnel and the solvent removed under reduced pressure. The resulting crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - Et20). The solvents were evaporated to give a white solid which was recrystallized fron EtOAc (mixture of diastereomers, ratio 96:4), (0.23 g, 0.99 mmol, 94% yield). mp 202-205 °C; 1H NMR (300 MHz, CDC13) (major diastereomer) 5 1.16 (t, J = 7.2 Hz, 3 H), 2.00 (s, 3 H), 2.32 (q, J = 13.7 Hz, 1 H), 2.55 (m, 1 H), 2.93 (dt, J = 13.7, 4.4 Hz, 1 H), 3.21 (dd, J = 13.7, 7.4 Hz, 1 H), 3.29 (d, J = 15.2 Hz, 1 H), 3.90 (dq, J = 10.8, 7.1 Hz, 1 H), 4.01 (dq, J = 10.8, 7.1 Hz, 1 H), 4.07 (m, 2 H), 5.24 (d, J = 15.2 Hz, 1 H), 7.00 (dd, J = 7.5, 1.9 Hz, 2 H), 7.12 (d, J = 6.4 Hz, 1 H), 7.21-7.34 (m, 8 H); 13C NMR (75 MHz, CDC13) (major diastereomer) 5 13.92, 22.87, 25.69, 37.30, 42.80, 49.65, 50.81, 58.76, 60.95, 126.77, 127.37, 127.47, 128.51, 128.57, 129.34, 136.80, 138.09, 169.14, 170.45, 170.52; IR (solid/NaCl) 3297, 3067, 3009, 1732, 1642, 1541, 1455, 1217 cm'l. 94 References. 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) Jones, J. H. In Amino Acids and Peptides. The Royal Society of Chemistry, London, 1991, Vol. 22. pp 161-7, and references therein. Houpis, I. N.; Molina, A.; Lynch, J.; Reamer, R. A.; Volante, R. P.; Reider, P. J. J. Org. Chem. 1993, 58, 3176. Liskamp, R. M. J. Angew. Chem. Int. Engl. 1994, 33, 305. Wolf, J.-P.; Rapoport, H. J. Org. Chem. 1989, 54, 3164. Kahn, M.; Chen, B. Tetrahedron Lett. 1987, 28, 1623. Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34, 8197. Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993, 49, 3577. Kemp, D. S.; McNamara, P. E. J. Org. Chem. 1984, 49, 2286. For a sample of other aza-annulation uses see: (a) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1992, 5 7, 5319. (b) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34 , 6673. (c) Cook, G. R.; Beholz, L. G.; Stille, J. R. Tetrahedron Lett. 1994, 35 , 1669. (a) In a procedure developed by Nancy Barta, of Michigan State University, the amine of an amine salt could be freed by mixing it with NaHCO3 in C6H5 followed by filtration or the amine salt could be used directly in the condensation with 0.5 equiv of BF3—etherate as catalyst. (b) In a procedure developed by Carol Walters, of Michigan State University, formation of the mixed anhydride during annulation could be efficiently executed by adding the acrylate salt to the enamine, followed by addition of ethylchloroformate. (a) Sano, T.; Horiguchi, Y.; Tsuda, Y.; Itatani, Y. Heterocycles 1978, 9, 161. (b) Kozikowski, A. P.; Xia, Y.; Rajarathnam Reddy, E.; Tukmantel, W.; Hanin, 1.; Tang, X. C. J. Org. Chem. 1991, 56, 4637. (c) Walker, D.; Hiebert, J. D. Tetrahedron 1966, 153. (d) Modifications on described DDQ oxidation procedure attempted to provide increased yield included: 6 hour addition of DDQ, use of increased equivilants of DDQ, use of dioxane and mixed xylenes as solvent, use of stOH as catalyst in all three solvents, and use of triethyl amine as catalyst in all three solvents. None of these modifications provided an increased yield. (e) Attempted oxidation of III-46 using Pd/C in refluxing diglyme or EtOAc resulted in no reaction. Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317. Attempted oxidation of III-46 using 8e02 with HOAc also yielded no product formation. Nagaoka, H. Schmid, H. Kishi, Y.; Kishi, I. Tetrahedron Lett. 1981, 22, 899. .‘n 0'. 4L: 1'." fl 12) 13) 14) 95 NOE studies on III-50 indicated that the stereochemistry of the double bond of the major isomer was E (NOE enhancements between the vinyl proton and N-benzyl protons were 3.3% and 1.6% when the vinyl proton was irradiated. NOE enhancement between the vinyl proton and the benzylidine protons was 9.7% when the vinyl proton was irradiated). DDQ oxidation of III-50 under optimum conditions (see reference 8 and text) provided a mixture of products consisting of III-50 (20%), the analog of III-50 with the double bond isomerized into the ring (80%), and possibly a u'ace of the fully oxidized analog of III-50. The composition of the reaction mixture was determined by 1H NMR. Characteristic peaks of the double bond isomerized product were: 2.49 (td, J = 15.9, 3.0 Hz, 1 H), 3.55 (dd, J = 15.9, 6.3 Hz, 1 H), 4.63 (dt, J = 15.1, 6.3 Hz, 1 H). Compounds III-27, III-28, III-30, III-35, III-36, III-37, III-39, III-40, III-41, III-44, III-45, III-46, III-54, and III-55 were submitted for biological testing. bumfheJounalelOs-gameO-sistry, ”It“. Societyald M laps-head CopyfigMOMWthaA-sriea-Ch-hl 96 reprint-db, eflhaeapyrighte'ner. Lewis Acid-Promoted 3-Aza-Cope Rearrangement of N-Alkyl-N-allylanilines ImG.BeholzandJohnR.Stille‘ DsparMo/ChaaisayJfiehiganState Unimity,£¢stlnnsing,uidn'genm WWAJM (Raisedflesunen‘ptfleea‘uedlm 18.1%.?) Lewis acid reagents at Ill-140 'C. Systematic studies of this rsactim mpufomedwaamineammbaofnufionmhblmnmhneoneenmfiomtheuoichbmeuy dtbeLewhaddwiththembsmtgtheoptimumtemperatnrefor gandthetypeo! rearrangemen Lewis acid reagent. Ofthe many Lewis acids investigated. ZnCl: (140 'C) and moan (111 'C) methemmtgenenflynmfidmgmflfmpmofingtbeamafica-m-Copenamngemmt W‘rthrespecttombsbatevariatiomthepresenceofamethoaysuhstituentparatotheN-allylgroup slowedtbereaetionslightly, whileametasuhstimentaeeeleratedtherateofmfilrearrangement andproducedmoderatesiteselectivityontheammats‘ering. Misadd-promotedrearrangement ofmumymmeflimflymhsfimudanylmdetyrendudinflfilwuopicmmngementm thel-hexen-3-y1suhstimentonthearomaticring.OveralLbotthlgandthO-Bhwereshown aaa-CopereamngementofN-alkyl-N-aflylanilines («the moffamingamrbon-mrbmhondbetmauwndaryalkylmhsfimtandmamade toeficientlyaeeeleratetheregiospeeificfil— n’ng. Introduction The aromatic 3—aaa-Cope rearrangement ofN-allyl- anilinesuhstrates 1 anthasbeenofinterestforsame timeasaroutetotheformationon-substiurtedaniline andindoleproduets.buttheutilityofthisreactioahas lrssrrgr'satlylimited(e111).1 Theseverseendits’cnstzw- . I x u u a: ¢ —L.. '3' l. M (‘1 tza'css v 8 arm coup. have restricted the utility of this reaction and presented an enormom challenge to synthetic organic chemists.a Appmachestoovereomingtheseharrieuhave toassedarormdonessm-ontheme-ehargeaeeeleration ofthereamngementproeessbyreactionofN-allylaniline substrateswithelectrophilicreagentsthroughgeneration ofa quaternary intermediate Theelectrophilesourcesmasteommonlymedfareharge acceleration of the aromatic 3-aaa-Cope rearrangement havebeenBremtedaddgwhiehtypicallypromotere- t at temperatures of 140-150 'C. Polyphos- phmicacidhasbeemusedtopmmote charge-accelerated m-Copemrrangemennhutefl'eefivemeofthisreagmt mlimitedtotheN-crotylderivatives (R3- Me)dl' (”Fannie-Ithatmdudeadismmiead (”fl-3263793! 1958-5095804W0 andz.‘ NethermvtcnsomeeafiClandI-lfio.m studiedmoremvelyandhavesho'ngreaterveraa- tflityinpromofingthislafilsigmabopicreamngemmt. 'I'heuseot‘HCltopromotetberearrangementofltel wasaehievedbytreatmentoflwitheitherHCPm PhNHrl-ICI.‘ Similarly,thetreatmentof2vith HClalao gavez-allylanilinederivatives.“ tofhoth landzwaspmmoudefleetivelywitthfigsoo" A drawbacktothemeofsu'ongproticacidshasheentha tendencyofthesereagentstoproduceformatimofindole andindolineproduetsfrodehusredua’ngtheoverall efl'ectivaseaaofthisreaction.“" Generationofthe analogmquaternaryammonitnnsaltst‘I-alkyl) producedsimilarchargeaeeeleraficnot‘thearomaticm CoperearrangementatllO'C;however,signifimnt amOtmts of substrate deallylation usually counted.“ TheuseofLewisaddsforehargeaeeelerationofthe 3-aaa-Cope rearrangement appears to be a W altsrnativetothemeofproticaeids. Asearlyas1957.‘ ZnClgwaafmmdtopromotethetl-amformationofltoa. and subsequent examples have produced 37-7896 yislb d3.“ TreatmentwithEtgo-BFgwasalaoaneflectin methodolpromota‘ng [3,3]rearnngementdlat140 97 “8 J. 01. Glen, Vol. 58, No. 19. 193 'C,“J'andthemeolEt¢O-BF.wastheonlyeaampleof a Lewis acid-promoted 3-asa-Cope rearrangement on!“ Other catalysts, such as AlClg, FeClg, SnCh. and 'I‘iCL, wereleaseffectiveatpromotingthercaflangementofl.m AstrikingfeatureofstudiesoftheLewisaeid-promoted rsarrangementofsuhstratethasbeentbevaryingsncceas reportedforverysimilarsubsu-atee. Typially,tbeorigin ofthesedifierencesisasensitivityofthissystemtoone or many of the reaction conditions. Ourremntinvestigationsintbeareaofthealiphatic Sana-Cope management have led to the development dpl’otmruandLewisaddnChMtedW mentofN-alkyl-N—allylenamines attemperattnesranging from 40 to 110 °C. Organoaluminum compleaes were partieularlyeficientandversatileinpromotingthe3—m- Copereanangementandarecentreportofanaromatie Claiaenrearrangementacceleratedbyan ' resgentprovidedadditionaloptimismfortbeahilityof organoaluminum complexes to promote the aromatic 3—ssa-Cope rearrangement.” Herein, we report the sys- tematic investigation of the aromatic 3-ua-Cope rear- Besults andDiscussisn Aninvestigationofantnnberofreactionvariahlsswas performedbysmdyingtheefiectoftherelativeamormt of!awisadd,concentntionofthereaction,reactiontime. andthetemperatureatwhichrearrangementwouldoccur. 'I'henature of the nitrogen ”spectator” substituentonthe N-allylaniline substrate, as well substitution on the aromaticringandtheallylgrwpmereusedtoprobetbe features ofthis reaction. Studieswereinitiatedbymonitoringthereanangement d4a(eq2)inthepresenceofvaryingamotmteofAlC1., acatalystthatwasefl'ectivefortbereamngementofl. “w o;- 3 55* i?" 8?? The3-aaa-Coperearrangementof4agave5ainallcaaes, buttberelativeamormtofAlChwasaiticaltothe selectivity of the reaction (Table 1). Treatment of 4a with 1.5equivofbewisacidproducedrapiddisappearanceof starfingmteriaLlowmwnuofkandfurtherde- structionofSaovertime.“ Withtheuseofl.2equiv,tbe rmcfionwudowedmameftdmmandoptimalgenerafion (1M6uge.C.:Gill.E.W.;MJ.A.J.Om-.Sce.0hem l 74. (11)Cooh.G.EL:Stille.J.RJ. Og.Chera.1991,56.557& Cooh.G.R.;B¢ta.N.S.;Stilh.J.RJ.Om.Cheule57.461. (12) EsmkmucYamamfiTm “22th Mmem‘ «.2: wwmpnfim-ummmm Mm R) BehohandStills Table]. MdthsAmoaasetSflhsathsI-Aaa-Ospa m: 4a yidd'tfi) time producttauatim‘ equiv. (11) 4a 5a 4a 7a 9a 1.5 2 12 38 0 o 0 4 o 22 0 o o 8 o 9 o o 0 1.2 4 50 49 0 o 0 8 8 88 0 o 2 24 6 71 0 o 3 0.75 4 28 68 1 o 0 s 16 70 6 0 0 24 11 23 32 5 o 48 9 4 87 9 1 mmwmmuuuumhmmo'o. ‘Vahwtmmdmwmtrd 10.'chationofnogreaterthan 1% aawmeherved. mun. man-monamu the i-Aaa-Cepslsanaamefh PM by Blanket yieldNfi) (Mk) 4a in Ca 1a h 3.0 1 7 19 35 5 2.0 16 37 18 15 7 1.0 19 51 4 6 5 0.75 fl 52 4 6 4 0.5 23 53 4 4 3 0..” D 27 2 0 0 'Rsarrangemenrswerernnatrennamxylsnsstlw'mforldh. Iaeachcaselcuerreactiontimsspsoducsdlnweryiahh.‘Vahm reprmmtxyisldsmdetsrminadbyGCanabiMIQ¢Pormatim ofnogreatsrthan 1% 8a wasobserved. ofSawasobserved. Problemaaasociatedwithsubquent [3,31rearrangementtotheparapositionwerenoten- countered. Whenleasthanastoichiometricamountcf MCI; was used, significant quantities of byproducts. mnlflngbomcydizafionofimwereproducedduringthe time necessary to drive the rearrangement to >955 completion Examination clotber Lewis acids showed similarpatterns,andineachcase,1.2equivo{Lewisacid wastheoptimum amount ofreagent Anotherhwisacidreportedtopromotetherearrange- mentof1,ZnCl¢,showedagreatersensitivitytoward reactionccnditionsandwasusedtoprobetheefleetof mbstrateccncenn'ationontheproductdistributionfl'able ll). Accelerationofthereanangementwichanat ccncentratiomgreaterthan 1.0Mresultedinthegener- ationofsubstantialquanfifiesoffiaand‘lamndreaetion ccncentrationsfromOétolflMwerefotmdtobeoptimal. Forallsubsequent rearrangementsdescribed,reaetions wereperformedatMMofaubstr-atewithlleqmvoflhe Once general reaction conditions were established, a smey of Lewis acids revealed that AlCh, ZnClg, and Etgo-BFawerethemoetefl’ective reagents forpromoting [M1mmmentof4ato5at’l‘ablefl.1‘reaunent oflawithfiChongBrgproducedccnsumptionofh. butinbotbeasm,6a(10-l2%)and7a (2%)wereformed concunentlyunderthesereactionconditions. Alkylalu- minum complexes, including the methylaluminmn bis- (4—bromo-2,6-di-tert-butylphenoxide) reagent used forthe aromtieClaisenrearrangement.produceddisappointing resultsbyslowcomumptionofhpresmnablytometh- 3-Aaa-CopeRaarrargemsntofN-Alkyl-N-anylanilines roam. dehAddse-thaS-Aaa-Cepa [cannon-tofu condm product {urination rasgant‘ temp (‘0 time (h) la: yield (S) MOB 140 8 88 m 140 13 53 Ergo-BF. 111 44 79 Ego-3P3 140 34 49 not. 140 16 46 “(an 140 w 38 (NOW 140 72 28 m 10 4 34 m 140 24 22 MIC}. 140 44 16 'Raarrangemsntawarerunoasllct’hwithmeqmvdhw'n acidat refluxintobssnetul'Qarxyh-amaw'QJValuss repressmGC myialdsdiaud14).-'Ar0 -4—hcmr>2.8-di-m- butylphmnly. TablsIV. “Add-M2” Wol4aad18 and yield (S) substrate (1.2 equiv) (6nd») isolatsd‘ (00‘ 4a AlCh 8 88 (88) 74:0. 16 45 (52) We 48 53 (79) 4D A“ 2 15 (35) 2nd. 24 15 M) 3608?. 24 13 m 1“ has 16 58 (fl) 860-37. 72 56 (61) 145 ZnCh 24 53 (57) 3.0-BF: 48 35 (4” 'WmmuflduwithUeqniVJIawis acidstreflnaintoluenetlu “amourrylenmdw'am andZnCldJOIerallisclatedyialdsofland 1L‘Rafsrancs 14. ylated and oligomeric products. without genera6on of significant amounts of 5a-8a. In general, these trends were opposite those observed for the aliphatic 3-ara-Cope reanangementinwhichtheorganoaluminumspadcswere thematefficientraagmmandthemetalhalidestypically used for Freidel-Crafts alkylation produced very poor "stilts.” Thetemperature atwhichthearoma6c 3-aaa- Cope rearrangement occurred was also critical to the successoftbereac6m. 'l‘heuseofdecalinum'Qresultad intheformationofcaand'laasthamaiorproductsin pooryieldandtheuseoftoluene (111 °C)didnotprovide ahighenoughtemperatureatrefluxtopromoteconveraion aflatoproducta. Interestingly,theuseofEth-BF.was theoneexcep6on.andrearrangementintolueneatreflux was more efficient than reaction in xylene. The three optimum catalysts, AlCh, anIg. and Etgo-BFgwereeachusedinthesmdieaofsubstrate variability. Undartheop6mumccndi6cnsforrearrange- ment.5awasisolatedfromthereac60nmixturein45— 68% yieldtTahleIV). Thereactionofllewisaeidswith 4b,havinganN-henzylgroupinsteadofanN-methyl mbstituentproducadmuchpoorerremlts. Underaimilar reac60ncondi6ons.a35% yieidwasthebestthatcould beohtainadfromanyofthecatalystswith4h. The disappearance of 4b without forma6on of the desired moductswassuspectadtoresultfromreactionofnucleo- philas at the benzylic posi6on and concomitant displace- mantofaquatemrynitrogenduringthevigorousreaction conditions. Treatment of the analogous allyl acetamide and sulfonamide suhs6-ates with these Lewis acids did notrearltinlafilraarrangementproducts. 98 J. Org. Chem. Vol. 58. No. 19, 1993 son Table V. Lewis Acid-WSW Iceman-sat m coeds" product («mafia (%) nibstrate (1.2 equiv) (time (N) 18:14. yield' (60‘ 12a ZnCl; 8 64:3 70 (77) Ergo-BF. 48 88:34 98 (98) at 2:101; 24 71:29 57 (84) 3.0-BF. 48 72:28 88 (47) 12c Zoo. 8 73:27 8 as) war. 24 72:28 at (O) ‘Rearnngemantawererunullofuwithlzeqnivoflaw‘n addatrefluxintoluene(111‘C,B¢0-BFgorxylenm(140'C.ZnCl.). ‘Ra6osdltl4weredeterminsdhyGCanalya'uofthecndeructiu m Formbsuntmbanderatioswereccnfirmadbyiflm W‘Overalliaolatadyieflmthemixnneofflandu. ‘Rataance 14. Rearrangement of substrates containing a methoxy subs6tuentonthearomatieringprovidedmefulinaight intothenatrneofthisbewisacid—promotedtranaformam (aqs3and4.TablesIVandV). Themostno6ceahle (3) 37%-.836 «4 1213 14 2‘39. a... fill differenceobservedwiththeaesuhstrataswasthatAlCl. producedrapiddisappearanceoffland 12,withoutthe generation of any of the typical [3,3] rearrangement products.” Duetotheslightdeactivationattheposi6on metatothemethoxy substituent, substrate lOrearranged moreslowlythantheanalogous unsubs6tutad substrate 4. However,eventhoughthembs6tuentdeac6vatadthe posi6cnatwhiehcsrbon—arbcnbondformationocctmed, standardcondi60nsfortherearrangementpromotedwith ZnClgandEth-BPalcdtocomparahleorhigherisolatsd yields of 11. Rearrangement of substrate 12, having a methoxy suhs6tuentrnetatotheallylaminesubs6ment,introducsd repoaelac6vitywasonlymoderate,rangingfrom64z36to 73:27 for 13:14, and the product ra6o showed little 99 5498 J. Org. Chem, Vol. 58, No. 19. 1993 Table V1. Competitive Lewis Acid-Promoted 2-Aaa-Cepe Renew e! 4e and 1h "I a", product formatitm‘ (i) mt (time th» 18a + Na 5a (13a + 14a):5a W3 2 24 15 5238 4 33 22 flNO 6 49 N 5238 8 55 33 6:37 ZnClg 0.5 17 7 71:” 1.0 S 10 78:22 1.5 47 15 76:24 2.0 55 18 75:25 'RoarrangsmantewareanfiMolhwitleequivdIawi acidstrofluaintohsmetllh‘c, magnum-nose. ZnCla) withueqnivdlaw'nacid. RetiasworedeterminadbyGCamlya'n clthe crude reaction m'nlture (ref 14) occurinshorterfimeperiodgbuthigherproductyields resultedduetotheincreaeadrateofthetranaforma6on of 126) 13and 14 relative tothecompe66ve forma6on olbyproducts. Aswasobeervedinthereac60nof10,AlCh resulted in consumption of 12 without producing 12 or 14.15 Comparisonofrelativeraactionrateswasobeerved bythedirectcompe6tionof1.0equivaachof4aand12a prmnotedbylfiequivofbewisacid. Resultsfromthis studyahowedthatformationoflhandlhwasappma- imatelyléthnesfasterthanthatofSawhanpromotod byEth-BFaandroughly3.0£asterintheproeenceol7aCk (Table VD.“ Afinalsetofsubstrateswaaaaaminedinorderto determinetheregioeelec6vityofthenarrangementwith an tmsymmetrical allylic subs6tuent, enhance regiose- lectivereactiononthearoma6cring,andestahlisha poten6alroutetoamathoay-substitutedvariatyofnat- urallyoccurringalhaloids. Thesembstrateswereprepared with an unsymmetrical N-(m-2-hexen-l-yl) substituent ontheaniline(eq5). RearrangementoflSwichnClgat “05—- mm 6.33:3: a“: 11 r- 140 'C or ago-BF; at 111 ’C produced 14 m 50% and 79% isolated yields. Compared to the amicgmnrearrangementoflhtheuseonnClgwas similar,whilethereac6onpromotedbyEt40-BF3wasfar moseeficiant. lnbothreacticm,only[3,3]rearrangement wasevidentfromanalysisofthereac60nproducts;carbon— carbonbondforma6onresul6ngfroml131rearrangement ofthesubstratethroughanonconcertedpathwaywasnot observed. Most importantly, these reagents effmiently promoted the regiospecific 3-aaa-Cope rearrangement of N-alkyl-N-allylanilinesandproducad carbon-carbonbond forma6onbetweenanaroma6cringandasecondaryalkyl substituent. The rearrangement of the corresponding substrate havingamethoaysubs6tuentmetatotheamine,17, producedremltssimilartothoseobeervadfortheraar- rangement of 12a and 15a (eq 6). As was observed for (IQMvahIQillmtmtstheprmsI-ceoflhs uneral'troadbutthe acumdthmenhseshsomewhatlimitedbythedifleriuefiasnd. otthmeroactsmn. BdolsandStille «05~-<>:0'€5:.0 Ice-coon ”Dam-cm: 68$ 11 8 12a,amixtmeofregioisomerswasobtained. Inthecaee of 17, however. slightly increased product selec6vi6es of 75:25and83:17 for 18:19 were obtained forrearrangement with Eth-BF; and ZnClg, respec6vely. However, in contrast to previous rearrangement with the N-allyl substituents. further [3.3] Cope rearrangementof 18 and] or 19 in the presence of 211C]: produced 20, which could beseparated from 18and 19 in 11% isolated yield. This product appeared to result from two sequen6al [3.3] rearrangements giving onlythe (D-Z-hexen -l-yl aroma6c substituent. Becauseofthediflerentratesatwhichfl Wm” wasgeneratedfrom18versus18,theregioeelectivityra6o based on the direct obesrva6on ofproduct distribution mightnotdirectlyreflacttheacmalselec6vityofthe relativereac60nrates. Thesimilaritiasinstructureoffl, 18,andl9totheindolealkaloirlsnsuchasatz'ricineOKl -X'-lI,X’-0Me).‘7reeerpinine(X1=OMe,X’=-X‘ IIH),"’ot:hropposinine(X1"X’s BIOMQX’ 11),”and mm1=x==rtxu IIIOMe)”ares6'iking andprovidesomeintriguingpoesihilitiesforfutureap- plicationot‘thismethodology. Summary Systematic studies of the aroma6c 3-an-Cope rear- rangementhavebeenusadtoeaamineanmnbarofreadm variables,andresultshaveshownthatreac60ncondi6ons havingasubstrateconcen6ationof05Mand6-ea6nent withllequivoflewisacidwereop6mtnnforohtaining thedadradproduct. Ofthemanylawisacidsinvesfigated. 211013 (140 ’C) and war. (111 ’C) were the most generallysuccesshrlreagentsforpromotingthea-aas-Cope rearrangement. Thepreeencaofamethoxysubstituent paratotheN-allylgroupslowedthereactionslightly,while a meta substituent greatly accelerated the rate of rear- rangementtotheposi6onorthoorparatothemetboay group. Inthiscase,siteselectivityonthearoma6cring was moderate. Rearrangement of an metrically substitutedallylmoietyresultedinregioaelactivelwl rearrangement to produce a l-hexen-a-yl substituent on thearoma6c ring. OveralLbochnClgandEth-Bfiwere demonstrated to efficiently accelerate the regiospecific Sana-Cope rearrangement of N-alkyl-N-allylanilines for "£7;de m. 114.; WinterfoldtlTotrdsedmaLott. 1”(.181';";ul1.‘l‘.;..Olslia.M.;‘l'adinslii.‘l‘.: mammal unmanmumrummmtsnw. 3-Aaa-Cops Maegan-st of N-Alkyl-N-allylanilinas thepurposeolformingacarbcn-carbonbondbetweena secondaryalkylsubstimantandanaromaticring. ExperimentalSactlon Generallethods. Allroac60nsworecarriedcntpsr5crming techniqusstoaclndemoisnireand from me. Xylenesanddecalinworeheatadovercalcimnhydridefm aminimmnol12handthsndie611edpriortouse. Petroleum ethar(35—Q°Cboiliurange)wmueedwithouthn'tharpuri- fiction. UAll-LQMinMwasobtainedhomAldr-ieh ChemicalCo. 1-Bmo-2-heaene‘andallsecnndary were prepared by literature methods." Compound 8a w. preparodthrouhanmdspendentroute.’ Forreac60minwhichaDean-Starh6apwasueed.the6ap wmfillsdwith4-Amolaaslarsisvestoalevelbelowthetd‘ roactiosninwhichadditionalreqentwasaddeddmutheccmae dthereaction mmmmwmn a150°Covenforatlemt24hpriortonea Unla- ‘ ccncentrationolmixturosaherworhupwasperformedminga Buchirotaryevapcratcr. General Hothod for the NAllylatioa of Secondary Anilines." Theam‘linet2.0-50.0mmal.1.0eqniv)andthealhyl homideoralhylehloride(1.2-4.0oquiv)weretahannpina4:1 BOB/HgOmixtureMMrelan'vetotheaniline)alongwith NqCO.(0.8oquiv). Aflerstirringatrccmtemperatmefcu LtheEtOliwasremovedundarroducedprommeandthecr-ude venom. N-Allyl-N-methylaniline (4a): 91% yield; hp 107-110 'C, 9921) The Harem template provided a means through which the relative stereochemistry of the ring substituents could be controlled in the next stage of this synthesis. Catalytic hydrogenation of 10 was performed in the presence of Na2C03. which prevented the deprotection of the hydroxyl group. to stereoselectively give the reduced 5-1actam 11.6 Transformation of 11 to 12 was accomplished through the use of MeMgBr/NEt3.7 and base catalyzed epimerization at the position a to the ketone produced an equilibrium 83:17 transzcis ratio of 12. The subsequent Baeyer-Villiger oxidation produced only the trans isomer 13 under these conditions. with efficiency of the reaction directly proportional to the original transzcis ratio of 12.8 Hydrolysis of the acetyl group. followed by benzyl protection of the resultant hydroxyl group. gave 14. Scheme 11. Homologation of The Lactam Carbonyl. Lawesson's m Reagent «03" 3020611287 JOB" —————. 0811 0811 6702C 0811 0 ’3 (94%) S '1‘ (81%) 3' Bn 1 4 an 1 s 30 1 6 W .109" um. .108" EtO,C\“.. 0811 /\.~“ 0811 (88%) N (87%) HO N I I (>90:10) 8" 17 8." 16 104 1671 The next segment of this synthesis centered around the homologation of the lactam carbonyl in a stereoselective manner that would accommodate subsequent elaboration of the molecule (Scheme 11). Conversion of 14 to the thiolactam 15.9 followed by alkylation and Eschcnmoser contraction.lo gave the vinylogous carbamate 16. Hydride reduction selectively prodmd 17. with the stereochemical configuration of 1 rather than 3. and 1.iAl114 reduction of the ester functionality gave 18. Preparation of the phosphonium salt 24. required for Wittig coupling with the aldehyde derived from 18. is illustrated in Scheme III. Monobromination of 19 produced 20.” which was oxidiud to the corresponding aldehyde. 21. Addition of EtMgBr. followed by oxidation gave 22. which was subsequently protected as dioxolane 23. Treatment with PPh3 resulted in generation of the corresponding phosphonium salt 24. Scheme 11]. Synthetic Preparation of the Aliphatic Wittig Reagent 1) i. EtMgBr. i. 1430’ PCC WM... __.“8' ”Ma. ——"°° 0w. 2’ : 1 9 (56%) 2 0 (7“) 2 1 (75%) Hoot-120112011 H2504 PP": . MeWBr 7 mW& v 111-Wen». a: (72%) LJ \_J 22 as 24 Extension of the aliphatic chain was performed by Swern oxidation of 18 to 25. followed by Wittig olefuiation to give 26 as an 85:15 mixture ofcis and trans isomeric albenes. respectively. The synthesis of prosopinine was completed by deprorection of the carbonyl followed by hydrogenation of the alkene with concomitant removal of the benzyl protecting groups to give 1 in 3% overall yield from 8.12 Sdieme 1V. Wittig Homologation to Attach the Aliphatic Chain. DMSO. 0001): .1109" MEL .908" 24. n-BuLi HO“... N 080 0146‘“. N 0817 1 1 (55% from 18) 1672 105 Acknowledgment. This project was supported initially by BRSG Grant #2507 RR07049-15 awarded by the Biomedical Research Support Grant Program. Division of Research Resources. National Institutes of Health. Support from the National Institutes of Health (GM44163) is gratefully acknowledged. GRC acknowledges BASF Corporation for a Graduate Research Fellowship. REFERENCES AND NOTES 1. 10 oo 10. 11. 12. (a) Ratle. G.; Monseur. X.; Das. B.; Yassi. 1.; Khuong-Huu. 0.; Goutarel. R. Bull Soc. Chim. Fr. 1966. 2945. [CA 66:1877911]. (b) Bourrinet, P.; Quevauviller. A. C. R. Soc. Biol. 1968. 162. 1138. [CA 70:95233kl. (c) Fr. Patent; FR 1524395101 71:91733w]. (d) Bourrinet. P.; Quevauviller. A. Ann. Pharm. Fr. 1968. 26, 787. [CA 71:29012g]. (e) Khuong-Huu. Q.; Ratle. G.; Monseur. X.; Goutarel. R. Bull. Soc. Chim. Belges 1972. 8!. 425. (f) Khuong-Huu. Q.; Ratle. G.; Monseur. X.; Goutarel. R. Bull. Soc. Chim. Belges 1972. 81. 443. For information on nojirimycin and related hydroxylated piperidines. see the following articles and the references cited within: (a) van den Brock. 1... A. G. M.; Vermaas. D. J.; Heskamp. B. M.; van Boeckel. C. A. A.; Tan. M. C. A. A.; Bolscher. l. G. M.; Ploegh. H. L.; van Kemenadc. F. J.; de Goede. R. E. Y.; Miedema. F. Reel. Trav. Chim. Pays-Ba: 1993. 112. 82. (b) Fairbanks. A. 1.; Carpenter. N. C.; Fleet. G. W. J.; Ramsden. N. G.; de Bello. I. C.; Winchester. B. G.; Al-Daher. S. S.; Nagahashi, G. Tetrahedron 1992. 48. 3365. (6) Fleet. G. W. J.; Fellows. L. B.; Winchester.'B. Plagiarizing Plants: Aminosugars as a Classs of Glycosidase Inhibitors. In: Bioacn‘ve Compounds from Plants. p 112-125. Wiley. Chichester (Ciba Foundation Symposium 154) 1990. (d) Legler, G. Adv. in Corbohydr. Chem. and Biochem. 1990. 48. 3l9. (a) Saitoh. Y.; Moriyama. Y.; Takahashi, T. Tetrahedron Lett. 1980. 21. 75. (b) Saitoh. Y.; Moriyama. Y.; Hirota. H.; Takahashi. T.; KhuongHuu. Q. Bull. Chem. Soc. Jpn. 1981. 54. 488. (c) Holmes. A. B.; Thompson. 1.: Baxter. A. 1. G.; Dixon. 1. J. Chem. Soc.. Chem. Commun. 1985. 37. (d) Ciufolini. M. A.; Hermann. C. W.; Whitrnire. K. H.; Byme. N. E. J. Am. Chem. Soc. 1989. III. 3473. (e) Tadano. K.; Takao. K.; Nigawara. Y.; Nishino. B.; Takagi. 1.; Maeda. K.; Ogawa Synlett 1993. 565. ' Natsume. M.; Ogawa. M. Heterocycles 1981. 16. 973. (a) Paulvannan, K.; Stille. J. R. J. Org. Chem. 1992. 57. 5319. (b) Paulvannan, K.; Schwarz. l. B.; Stille. l. R. Tetrahedron Lett. 1993. 34. 215. (c) Paulvannan, K.; Stille. J. R. Tetrahedron Lett. 1993. 34. 6673. (a) Barth. W.; Paquette. 1... A. J. Org. Chem. 1985. 50. 2438. (b) Kazmicrczak. F.; Helquist. P. J. Org. Chem. 1989. 54. 3988. Kikkawa. 1.; Yorifugi. T. Synthesis 1980. 877. Canan Koch. S. S.; Chamberlin. R. Synth. Commun. 1989. I9. 829. lain. S.; Sujatha. K.; Rama Krishna. K. V.; Roy. R.; Singh. J.; Anand. N. Tetrahedron 1992. 48. 4985. (2) Hart. D. J.; Kauai. K. J. Am. Chem. Soc. 1983. 105. 1255. (b) Hart. D. 1.; Hang. W.-P.; Hsu. L.—Y. J. Org. Chem. 1987. 52. 4665. Kang. S.-K.; Kim. W.-S.; Moon. B.-H. Synthesis. 1985. 1161. The physical data for 1 were consistent with those reported for 1 and 2.13-4 and were as follows: 1H NMR (500 MHz. CDC13) 5 1.05 (t. J = 7.3 Hz. 3 H). 1.23-1.41 (m. 13 H). 1.44-1.61 (m. 5 H). 1.66 (m. l H). 1.74 (m. l H). 2.07 (bs. 3 H). 2.39 (t. J = 7.5 Hz. 2 H). 2.41 (q. I = 7.3 Hz. 2 H). 2.76 (m. 1 H). 2.87 (dt. J = 5.5. 7.7 Hz. 1 H). 3.53 (ddd. J = 4.0. 5.6. 6.9 Hz. 1 H). 3.61 (dd. J = 5.4. 10.5 Hz. 1 n). 3.65 (dd. J = 7.3. 10.5 Hz. 1 H); 13c NMR (75.5 MHz. CDC13) a 7.8. 23.9. 26.3. 27.4. 28.6. 29.2. 29.3. 29.4. 29.6. 33.9. 35.8. 42.4. 49.7. 58.1. 62.3. 68.1. 212.0. (Received in USA 29 November 1993; revised 5 January 1994; accepted 11 January 1994) MSC: iofllll'llk BATCH: 500522 USER: DIV: exyldr/daM/CLSJi/GRPJo/JOB_ O can” i12/DW_J0940171k 106 PAGE: 1 DATE: 04/22/94 Construction of Hydroxylated Alkaloids (:li)-Mannonolaetam. (:e)-Deoxymannojirimyein. and (:1:)-Prosopinine through Ana-Annulation GsegoryRCook.LaraG.Behela.endJohnR.Sti11e' DemoIChemistry. Ariana-am UM.EaulAning.Hiehi'gunm-1322 Mickie-71.1.4. mmdmmmmmmmuw andcenvenientroutet’ortharegioealectivecnnstructionoN-laetams. Thistwo-ste ring-form“ mwmithlmdthebmylmthmubdthuamndemaunormm dditbnmacdmfifiBnNHgfdbndbym-emhfiwwithaaybfiehhrideaaayhcmhydride. Conudhdbythngidhamwmhofthamtumedhummueduedondrmgmhfimuwa accomplishedwithhighrelativestereoaelactivity. '1'heearbony1ftmctiona1ity.whiehwasneemaary todirectthe qioaehctivityoftheurannuhfimraefimwuthentranafmmedmwapm bydmnylmbtituentthroughflaeyu-Villigeroxidation. Theresultantt-Iactamproductwaamed asavaluableintermediateintbesyntheaisofthreenahiralproduets. thisb-lactamgavethenaturally occurring yeimwhflesyntheahotthealhloidltrproaopininewuaemmpl’nhadthmsgh deorymannojirim hemologatienclthalaetammrbonyl. Introduction Hydmaylatadpiperidineelkaloidserefoimdfreqmntly mhvmgsm‘andthewidenngeofpotentpbyei- ologicaleffematemsfromtheirebilitytomimieearbo- byrlratestsbatratesinetrerietyol’enxymatir:process.2 Withthepivotalrolethatearbohydreteapleyinbiologiml procemmnsehaseellreccgnitionanddifl‘erentiatimtheae alkaloids have become important synthetic targets.a Impornnt structure-activity relationships for these mole eculeacenteraroundthestereochemiealconfigurationol‘ hydmrylfimetionalitywhieharefltothenitrogen. Due totheprominenceol'o-glucoeeflhndD-mannoae (31in biological processes. many alkaloids mimic the C-4 and C-6 structural (centres of these carbohydrates (Chart 1). Polyhydrorylated piperidine alkaloids ahibit selective inhibitionof a number of biologically important pathways. including the binding and processing of glycoproteins.‘ For example. compound 4 has been shown to inhibit a-L- fucoaidase. a-D-mannoaidase. and a-D-glucoeidase activ- ity.‘whi1e the analogous lactam 5 inhibited both n-D- -4rcn -— - it E i 5' E g i 3’. p i i 5' § 17.1leiadar.A.R.Nat.Pred.ch.1&7.447.(e1Numata.A.:1buha. T.1n1heAlhaleida:Btui.A.EdeAeademic Vol.31.M6.(0Podm.G.B.:Ccla-nti.3.1n4 AWCher—ical ’ Pallatiar. S.W.. EdeWilay: NewYorh. seathe (muse-inn. Li.H.8ei.Am. 199.168.82.1b1MNsI—ia. HSdemlmmz‘IMchbaa. AMMScilal. 12.285. l4llbia.A.D.Ann.Bee.BiochenL 187.56.497. Chart! . aim "'N um on ‘r‘u’: W on us 3 n1" tW imp-Dem Dix-01.14:” ewe-tem- tux-true“ on on em "tw- “' OH . . NIECOH "M x a a 4W.W ten-coat.” them tan-m.“- :ijf" V‘efi’ofl n o u- :‘u. ":th “til-WWW tafl-W;M mannosidase and a-D-glucoeidase." The piperidine a1- keloithmuhibitedsekctiveinhibitionol’mgluccaidases I and 11 without effective inhibition of mannosidase.” andthisgluccseanaleghespotentialforuseintbetherapy 0022-3263/n/1900-0001804.50/0 0 xxx: American Chaim! Society MSG: 5094017 1k BATCH: 10‘b22 O B J.Org.Chem. derivetiveasuchasN-hutyl-z and N-decyloz show pro- nouncedantiviralactivitythrougbinhibitionolsyneytis iamadoninHIVd.” Naturally comm-in heterocyelic amines with 1mm dsphsficappendagmsuehmthah'osopisaandllend Comicalhalm'ds(12.13.15.and16).haveahobeen reported.1 Thesscompoimdsareioimdthrcughcutthe worldandhsvereceivedmcressingattentionmmsdieinsl sgentsduetothavarietyolpharmacologimlpropertim theyenhibit.” ThaProsopisalhaloids7end8ere pertiailarlyintriguingbecametheycontainablendof physiologicallyiiiipoirtantstructuralfeatures.n Atua end of the molecule is the polar head group with a configtnationot’hydrorylsuhstitusntssimilartotht foimdinZandkwhilealipophilictailpcrtionresemblm thtcfthsmembranelipidsphingoainefi). Similar mistinesofalhylchsin‘tail'endcarbohydrate‘haad" structuralieatiireserelotmdinpenaresidineaAendB. whichdisplsypotentATPme-aetivatingpmpertimend BAYR1W5.whichshowspromiaaiorimmunisationd patisnuwithdet‘eetiveT-lymphoeyteseuchmpatients withAlDS.u Ineachcfthesemoleeuleathealkylchain ssrvesto(1)feei1itatetranaferaerommsmbranes.(2) anehortheaetivecompcimdinthemembrsnewiththe polarportionpmuuding.cr(3linteraetwiththehydro- phobieportionottheenaymestowhichthesecompotmds bind. Omapproaehtothacmtruetimofsevedhydrorylatsd piperidinesutiliasdtheua-snnulationreaetionforef- i'icient construction of nitrogen heterocycle 18 from B-enamino carbonyl derivative 19 (Scheme 1).” The heterocyclewasthenusedasaframsworktocontrolthe relativestereoehemiscyoftheC-4andC-5ringsubstitu- (5)alFuhrmana.U.;Baue.£:1~h.GePloegh.1Ll:lotunl”4. Y.;ltolLJcInooye.S.;Ysmads.Y.;Niida.T.;Nobe.M.:Ogawe.Y.J. Antihioi.tfl4.37.1579.teisveaa.S.V;FellowaLE.;Shisg.T.1Lfls MG. 117.2.th 1245.24. 195:1 (61a)1ahids.N.; KemsgaLKcNiidaT; Hams-malts”? immortals". 43.62.1h11aouye.8.:1‘smueha.‘1‘.; 1to.‘1‘.: Nils: T.Tem 1‘24. 212$. atNiwaT;1nouye.Ss‘1‘suruoha.T.; MY; N‘iids.'1‘.Ap-ie. main“. K.;R-deaN. G.; Jamhic Sellademaeherfl'. W. hoeJVetLAcad. 5a. 0.5.4.1”85.m Museum and effects. (111a! Fr. Pat. FR 15243“: Chen. M. 1”,. 71. 91733! (b) BomrineaP; .AAMPhomfr. 1m. 26. 787: Chem. Abstr. l”.71.2”12g.lc)3.ourrinet.1’.;0uevauvillar.A....CRSoeBioL 1m. 10. 1138: Chem. Abtr.1988.70.95233K. (121s1PenmmidineAend ‘ M.;WelchlillfleYammurLSc Tmnall”!.1135.(b)BAYle we .AagemChem. Int. “M19914”. 1611. usnn: DIV: 0xy1dr/data2/CLS_pi/GRP_jo/JOB_112/D1'V_jo940171k cap” 107 PAGE: 2 DATE: 04/22/94 Cceketsl. Sehemsl. GeaeralAppreachlarFermatlaael J-LaetamsbyAaa-Anaalatien/Bydmtiea Scheme 2. Betseeeyele Formation through Casi-est. Addition/Ana-Aanllafl.‘ tar—«c2? ‘Raqmts-dcsaditieu (a) inmmnimm “marcmsmtnamdmmmoaassmo (DMKI'MJEHQMMthmeMO-wfl. (fl) HCI. (iii) HIGH. ”to (34$). entsinthegenerationol‘17.“ Fromthisversata'le intermediatbenstin'allyoccurringalhloidsltymsn- nonolaetam (5). (”deoxymannojirimycin (4). and (e)- prosopininel‘hwerem Issaltsand Discussion fleshed Development. The use of ketone and mter functionality as electron-withdrawing subctituenn was fotmdtosignifieantlyenhencetheefl'ieienqandselectivity of the era-annulation reaction (Scheme 1; Y I Me. OEt).n However. several key consternation were required to adapt this methodology to the synthesis of hydroxylated alkaloids. Ofinitialimportancewastbeneedforadditional methods of enamine preparation that were compatible withthesubaequentara—annulationreacti'on. Inconjune- tioowiththesestudies.eaa-snnulationwuerploredasa routetolSinwhichR at Me.iollmdbysubsequent stereoaelective introduction of the C-5 substituent. In addition. methods for conversion of the C-4 carbonyl subatituenttoahydrorylgroupsndhomologationoltha resulting lactam carbonyl were required. Oneapproaehtothedesiredl-lactamproduetainvclved thecombinaticncithreeirsgmenmanacetylenieester. aprimaryaminendanacrylateden'vative. toproduce thedesiredheterocycleMScheme 2). Conjugateaddition A variety of reagents. which included MaCuCNLig. Me:- CuCNLingI-‘rOEtg. Me1CuBrLig, and MeCu-BFg. were employed for possible introduction ofe methyl substituent (131a1Paulvannm.K..Sti11aJ.R.J.Org.Cheoi.l”2.57.5319.lbl Paulvannan.K.:Schwaer.B.:Stilla.-1.R rmwrimai. 215.1c1Paulvannsn.K.:Stilla.J. 117' TetrahedronLetcl 19.3.34. “73. lPMKSflkJWfiJOfi 184.59 ”71613.1” K.;Stille..l.tt.R.7'atrehedi-enl.e1.lifl.34 (141mmntimiitthacm'bohydratsaubermsyI-wmmsdin mm-umwium MSC: W017“ BATCH: io$h22 USER: 108 eap69 PAGE: 3 DIV: @xyIdr/data2/CLS_pi/GBP_jo/JOB_112lDIV_jo§40171k DATE: 04/ 22/94 0 HydrosylatsdAlhsloidsthrowhAxa-Annulation Schemea. Fermatisaandeldatlaaofz'I' .01"- —°—— .47“ dun sues °qutsendaditisu www.mnmmm. mm‘QMmwaMJVCMSMhHsu-d Ha. we. ROI! C1311“) Waco)“. WCPBA (Ci). Btotheester.butconjugateadditiontotbevinylogous carbamate”wasnotoliserved.u Inordertoexploremodificationoftbecsrborylsub- stituentatC-4. 21wmrsducedthrougbcatslyu'chydro- Attemptsatoxidativedecarbcrylationwiththsuseof established methods were not sucmssful for selective introductionoftheC-4hydroxylduetotheformationof complssproduamixttnes.“ However.asimilaroxidative procedureforintrcducticnofsnaminogroupresultedin psrtialsuccsm. TreatmentofzawithDPPA/N'Etsin t-BuOH. followed by hydrolysis of the intermediate tert- butylcarhamate. provided amine 24 in low yield." Op- timisation of this tranafonnation was not pursued. Relatedstudieswereperlormedwiththecorresponding methylketonederivstivefl (Scheme 3). HydrolysisonS prodwed the corresponding aldehyde. which was con~ densed with BnNH2 and treated with acryloyl chloride to given. Thelowyieldobtsinedforthisthree-stepprocsss resulted from self-condensation of the intermediate al- dehyde. As foimd for 21. conjugate addition of nuclei» philes to vinylogotn imide 26 did not proceed under established conditions 1‘ BaeyerViIliger oxidation of 27 to28generatedverypromisingresultsfortheintroduction of an oxygen substituent at 04." However. the inability to introduce substituenn at the position 8 to the ester or ketone group required that the C-5 substituent be in place prior to era-annulation. Aspreviotnlyreported.“29wescondemedwitthNH¢ and treated with acryloyl chloride to produce the cor- (151a) (W S.;Oehhchlner. A.C.‘1'etrahedron Lettl”1..‘§.341(bl(hle£u3r1.ioflertx. S.;H.Dabbagh.G. Tetrahedron I.” 45. 425.1clIJpshutx.B. H.5yntheris1m. 325 (d) (MsCu-Bfostmamsso. Y.; Yamamoto. S.; Yet-mail! .;Ishihara. Y... J.Org...Cheni.l972.:B.3440.(c)Berton.DHR.;Coatm.1.H.:Ssmmm. PMGJChenLSor Whale/1972.599 (d)DeueyDB Shell-mi. N. J. Org. Chem. 1945.30. 3700. (171a)Mmowsm.D.: BsheckLC; Chmielswshi.M.Synthesisl9!1. mtbiSatoildexatagirLN TaheyamaKsHirose.M.:Kansho.C. ChrmPhomBulleszlclEaImP fitflaviShsnhar.B.K.: J. omcnm C Schams4. Formatienaadeidatienolfl' .If'” —-—.C.I‘—- mm 'Rmmd add“ (allilmcoflafl'c. (lilacybyl mm. fl’CMfiMbllunthd/QWEOH glzlt (cl DBU: (4) 0:00.11. D-CPBA (“$13“) ma. Boo ). Schemes. Matthews-Carbonyl- W‘Wih}? 2;"? °Remsmssndcsnditimm mum‘srsmmtmfimbllel: (c) (i) PrhlgBr. (ii) W (72% flu-30: (d) (11 We. (ii) NIB“. (‘57s ) 1m 24) responding era-annulation product 30. and catalytic hydrogenationgenerated3lase10:90mixtureoftrans and cis isomers (Scheme 4)." In order toacmssalhsloids 12and16.svarietyofconditionsweretned toaffectthe desired Baeyer-Villiger oxidation of cis-31.” However. 22 was the only acetate derivative generated under these conditions. Epimerization 0131. by treatment with DBU. generated an equilibrium ratio of trans/cis homeric products (76:24). and oxidation of this predominantlytrens substrate mixture resulted in the formation of22 in 45% yield. When compared to the successful oaidation of27. steric constraints imposed by the cis methyl substituent prevented efficient Baeyer-Villiger oxidation of cit-31. while trans-31 wastransformedtothecorrespondingsstsr. Hydrolysisoftheacetateresultedindeprotectionoftbe hydroxyl group to generate 33. The final stage of method development focused on homologation of thelactsmcarbonyl. whichwas necemary inordertoappend lipophilietailsegmentsto theslhsloid portion of these molecules. Initial studies of lactsm carbonyl homologation were performed with 22 (Scheme 5). Lawesson's reagent provided an extremely efficient method forthetransfonnationoiatothiolsctamusnd subsequent S-methylation generated the imidatesaltzs.” Tresunentofzswithacsrbonnucleo- phile. to generate the intermediate iminium species. .JlfiheaddimdN-m ‘ ‘ ' " prevented removslcfthsbsnrylprotsenenethydmrylm “MwMWstLAJHOgM1flflm (bllcssmisrcaaLF; llelqu‘naPmJOrgChml 1M”. _"‘. 0"." U. 1.1.:- MSC: $004017“ BATCH: Mb” 0 D Jar-(.Chem. Schemet. navigable“? —- “mend" 'm a. 'II at mil“ 8 i I "510%!“ 15 : I m G013 n?“ W- W H ..." U see “loam-d“ wum'ommsnmm WJflml’l’hsM). followedbyNaBH.reduction.wasimedmastr-ategyfor homologationofthissystsm. WithtbeuseofPngBr, thereactionconditionsresultedinformationofuastbe only reaction product. In contrut. the addition of an acetylidefollowedhytraatmentwithNaBl-Lgaveflas a63:37ratioofdiastereomersin45% yisld.withthehalancs ofthesuhstratacameraman.a Unfortunately.“ sionofth’nmethodologytothehcmologationofthsmethyl- substitutd derivativellawasnoteffective. Analternativerouteforcarhonylhomologationofsu wmexploredthroughthsEschenmosetcontractioanulfide extrusionprocsdure."3 Thiolactamformationofflband alkylation with ethyl hromoacetate generaud the cor- respondingthioimidatesaltandsuhsequentcontraction/ sulfideextrusionproducedthecorrespondingvinylogous carbamate3NScheme 6). Homologstion of 38athrough thissequenceprovidedanefficientandattractiveroute toflasasingleisomer. Onthebasisofstericconsu'ainte. thisisomerwasdesignatedasthecorrespondingEalkane isomer. Reduction with NaBHgCN transformed 39 to a mixtureofdiastereomusWandflJnaratioofm mentsof40 (8.0% enhancement) and“ (5.6% enhance- ment) were established through NMR NOE techniques oneachisomerhyirradiationoftheHandMesuhstitusnts a to the nitrogen (Scheme 6). ApplicationstoAlkaloid Synthesis. Withthemodel studiescompleteforhothconstructionandelahorationof l7.twoseparateapproachestol7wereexploredinwhich (fl) ain.S;Sa'ptha.K.:Rnaalirhhaa.K.V.;Ray.R-;Siluh.J.:An-d. N. Tam "’2. 48. 435. (21) a) Tabahats. H.: Tahhmhi. IL: Wane. E-C; Yammahi. T. J. CUR-$8..“ 15min”. 1211. (”To-"mas. Y.;ltabs.8.; M A. Tm Lea. 1'7. as. 158. USER: eap69 DIV: G”ldr/datd/CIS_pi/GRP_jo/J03_i12/DIV_jo94017lk 109 PAGE: 4 DATE: 04/22/94 Cooketal. Schems‘l. Synthesisafhteemediate 17‘ 2.4-Dar —' mg" m u inc in man) ‘Raflandcnditis‘ wmwimmmxm mmmmrqmmfienmmmvcmx); (nimdfl.wcuqco.wnieosmdimwr:m nonmememaa-aumcrmucrumsxwxoa. “so (05%): (h) KOH. BnBr (84%). diflerentsubstrateeforenaminsformationwareussdfi'he anhydrideresultsdinam—annulationtogeneratauin 62% yieldforthstwo-stepprocsss.whilethsuseofaayloyl chloride produced is. favorabls results for this trans- formation (35% yield). Catalytic hydrogenation of 44in theprasenceofNagCO,stereosehctivelygenerated45 without deprotection of the hydroxyl gimp." and treat- mentwith NEtafollowedbyMeMgBrgavethecor- raspondingmethylhetone(46)ass2:98ratiooftranslcis products.” Base-catalyzed epimerization changed the trans/cis ratio to 72:28. and Baeyer-Villiger oxidation underoptimisedconditionsgaveflnasinglediastere- omer. Deprotectionofthesecondaryhydroxylgroup. :1" lbyl l . 'l lthed‘ lin l' Analternativeroutetol7involvedcondensationof BnNszithtatronicacidumtoformtherequired a-enamino ester intermediate (Scheme 8). Subsequent ass-annulation with acrylicanhydride (71%) or acryloyl chlon'de(70%)resultedinformationofthecorresponding 6-lactsm49. Catalytic hydrogenation generatedthecis- fusedhicycliceystemsomndconversionoftbelactoneto methylhetoneSl (2998. translcis)wasperfomed under theaameconditionsusedforthetransformationofato 46. Benzylationoftbehydroxylgmpunderbasic conditionsresultedinformationofanequilihriummixttm ‘giuamaaahorswutrmm. ”04.35. (mi-mmdamuylmmuw additmaaanNHginanattsmpttoaocuahyammedhactrome. ganseatadsdstrnafhothpu’hlsd-en-inohetansw (261ihhawa.l.;Yorifui.T.Syathem's mean. MSC: io940171k BATCH: Mb22 O HWWWAn-Aflm I Sch-s8. Csnversisaafatau- N£O;@OL@ -m—p. amen mean ‘Mdm mmmmmnmmb ' THRS‘C (71%):(b) let-dHanIC.NaimaBtOH m (83%): (cl Nita. Height (21%): (d) KOH. Hair (715). 8chems9. Synthesisef Dssnymaaneiirimyolnu) “y. ‘Yot-‘fif; 235.» fitness-dead“ (a) (i) LDA. (ii) PthCl. (iii) mo. (78%): (NM. N340 (94%): (c) Li/NHo (44%): (d) (i) LiAlH. (ii) NaOH. H20 (>305): (e) 1 aim d it. we. HeOH (525). of 45 (”.20. trans/cis). Although methods for a more emcienttransformationoffltoflwerenotfullypuisued. thissyntheticschemeprovidedanalternativeroutato“. and ultimately to l7. (en-Mennonolactam (5) and (¢)-Deoxymannojirl- mycin(4). Theconvereionofl‘ltothetstrahydroxylated derivatives4and5wasaccomplishsdbyintroductionof the cis hydroxyl substituents through OsO. dihydroxyl— ation(Scheme9). Treatmentoftheanionol'l‘lwith PhSeCLfollowedbyperiodateoxidstionandelimination ofselenicacid.producsdthea.B-unsaturatedspecies52.” Dibydroaylationgavefl. whichwmussdforthesyntheses ofboth4and5.” Removalofthehanxylprotectinggroups from53generstsd5in44% yieldafterrecrystallination.’ Stepwisereductionofthelsctsmcarbonylfollowedhy deprotectionwithcatalytichydrogenaticngsve4in5296 Mandwhiteaystallinematerialwasohtainedin33% yieldafterrecrystallizstion.” OveralLthesynthesesof4 and5werebothschievedin3% overallyieldfrom42. (tyProsopinine. Two representative Prosopis alka- loids.7and8.isolatadfromtheleavesoftheAfrican (The)Clive.D. LJ. Tetrahedron 1m34.1049.(h)1leiclLH.J. Ace. Circulalm. 12.22. (muN‘nhiyuaas. Ym54HaasgswLK45ahodafl. Hush. ' LTetrahedroiiLett. 1991. 32.67$&(b)6uillerm.0.; Varhadalh Auvin.S.;LeGdic.P. TetrahedroaLett. 1'1”. 535. (29)hephymmlhtaior weiocom'tantwiththasreoortsd: G. W.J J.;.ltnmdemN G.; Winy..DR.TetrnhedranlU9.45.319 (30lhsphyeicaldstaior9were monument “MW G.W..;J lie-“NMR WittyWDRTeuahedroalfliam user: DIV: @xyldr/dataZ/CIS_pi/GRP_jo/J08_i12/DIV_jo94017lh eap69 110 PAGE: 5 DATE: 04/22/94 J.Org.Chem. E Sch-s19. Wofl‘l' " inn-o 5 ss sex-e in QK’OCD- — O in a 5- as “no“ use :0 I“) micelles e7 as “I”: n Hunts-dad“ (align-en'smmiltfhni) m. mmmmsi mimosaProsopisafricanaTaub.“diflerulyinthe starsochem'ntryofthecarhonatwhichtbsalkylchain andthehetarocyclsareconnectad. Mtbssynthds of7hasnotheenrepmad.syntheticefformhaveresultad urine diningformationofuand41.stereochsmicaloontrolwas sfimctionofthereagentussdforreductionoftheiminimn ion gemrated from 39 (Scheme 6). Homologation of the lactam whonyl of 17 was perb formedintbesamemannerdescribedforflfichemefi)! PormationofthethiolactamJollowedhythsEschmar contractiowwfidsesu'mionprocedure.gave“ingood overall yield (Scheme 10)!3 Hydride reducticnof“ eelsctivelyprodmedflina>90z10ratiooftbstwopomihls diastereomers. with the stereochemistry of the major productsimilartothatof‘l. lncontrasttotheresults woduct selectivity was obtained (67:33. 57158). and sslectivefcrmationofss. theintermediaterelatedin structuretoa.wasnotaccomplished. K. H; Byrne. N. B. J. Are. Tunnel-nu marmukae—SM (mmwmunminiiem MSC: 1094017“ BATCH: 506m USER: O r. J.Org.Cheei. Scheme". Cenversienafflter 0.... ll 1. ll " 1‘ in. '"es c Q” a h 0 \.J I " “lauds-duties (s)(i)l.iAlH..(ii)NaOH(37%):(b) DIlSO.(COCl)..Nlta;(c)II.PPh..n-Bul.i(555 fruflmd) (i) HQHsO.(ii)3mdeanIC.HG(fl%). Sch-s12. Preparatisneffl' a e We: —" —— .../W new. -mum mMmenmmm. (£110. .«mmmms “newsman HeSO. (Scheme 11) Furtberreductionoffl generated”. which wasthenpartiallyoxidixedtothecorrespondingaldehyde 60. Chainextansionof60withthey1ideformsdfrom65 (Scheme 12)gave61asa15:85mixmreoftrans/cisalhene isomers on the alkyl appendage. Deprotection of the carbonyl. followedbyreductionofthealkeneanddeheno zylationduringhydrogenation.gsve7in3% oversllyield from 42.“ Summary. The ass-annulation of 6-enamino ketone and ester substrates in'th either acryloyl chloride or acrylic anhydride has profided an efficient and convenient route for the regiosslective construction of i-lactams. This annulation procedure was performed in tandem with two different methods for enamine generation. through con- jugate addition of BnNH; to an «LB-acetylenic ester or by condensation of BM: with a Boheto ester or ketone to form thedesired l-Iacum. Onceestablished.the6-lactam frameworhwasusedtocontiolthestereochemical prefer- enceofsubstituentsonthering.andtbecarbonyl functionality was transformed into a protected hydroxyl substituent. From Haciam 17. the naturally occurring a-mannosidase inhibitors (dd-mannonolactam and (*)‘ deoxymannojirimycin were prepared. In addition. ho- molcgationofthelactamcarhonylof17alsoprovideda route to the alkaloid (dd-prosopinine. ExperimentalSsction Generalletheds. Allieactionsweremrrisdoutbyper- farming standard inert atmosphere techniques to exclude mandosygmandreactionsweremrrisdoutunderan atmosphereofeithernitrogencr agom‘Assoti-opicremovslof H.0wasam'niadhytheineof3-or4-Amoiecularsieves.‘ln eachcsse. diastereomericproductratiosweredetarminedhy‘H (341hsphyeimlmdmsctrsldatafsr7weeecsm'umtwiththase reporesdfar7and9.II-I eap69 DIV: @xyldr/dataZ/CLS_pj/GRP _jo/JOB_i12/DIV_jo940171h 111 PAGE: 6 DATE: 04/22/94 Coohetal. lamb-£21. BnNH¢(10.72g.1(l)mmol)wasaddsdto asolutionoffl(6.41g.100mmol)in8t¢0(100m1.)at0’C.Aftar thesoliitianwmwermsdtorttbemixturewmstirredforuh. ‘I'hemixtm'ewasthenconeentratadandd-olvedinTHPmm 4.71(s.2H).7.l9-7.35(m.6H):"CM(75.5mCDCU 519.8.30.7.49.8.5L5. 1M memxmxisecme. inimmimmmmrse 1049.1439.1377.184.1254.1104.1121.729 Mark E E i purified «om patrolsamethsrlEhO)togive26(0.517g.23mmol)in23% yhld: mp72-75’C(frompscoleumethsr/Et.0):‘HNMRm mCDCUJZIMsJH).2.55-2.66(m.4Hl.4.76(s.2H).7.15 (s.1H).7.20-7.33(m.5H):"CNhIR(75.5hflIx.CDC1.)416.6. 24.7. m 49.9. 119.4. 127.5. 128.0. 123.9. 13.2. 140.3. 1&3. 1M mmosorz.mmm.m.mmm. 104. imimtmiiummimeISaHtccufluNoan/s 229.1103. found mlz 229.1109. General lethed farths Hydragenatlenef Ina-idesA mixtmsofenamids(1equiv).Na.CO.(3.0equiv).“and 10% Pd oncarbon(0.1g/mmolenamide)inBtOH(0.05-0.2fl)wmstirred imderanatmosphereofH; (l-3stm) for 16-40h. Tbssolids were removed by filtration. the mixture w- cancentrsted. and the crude product was purified by chromatography. 22: 5.23g.21.66mmol.96% yieldleNMR(mOhfl-11.CDCU 41.98(ddt.JI6.0. 13.5.9.61'11. 1 H).2.l2 (13.111). 245(“4. J-6.3.9.6. 173112.! H).2.59(ddd.J-5.2.6.3.17.8Ht. 1H). 270(dddd.J-3.9.5.3.9.9. 1241-12.. 1 H).3.36(ddd.J- 1.1. 53.12.4118. 1H).3.42(dd.JI 8.5. 12.4HL1 H).3.53(8.3H). 4.50 (d. J I 14.7 1'12. 1 H). 4.67 (d.J I 14.7 HI. 1 H). 7.3-7.3 (L5H): ”CMU‘..5MHACDCU423.8.&6.3&9.47.9. 50.0. 52.0. 127.4. 13.0. 128.5. 136.6. 168.8. 1724: IR (neat) aces. m. 3030. 2953. 2875. 1736. 1642. 1495. 1454. 1437. 1381. 1356. 1332. 134. 1204. 1171. 1013. 727. 700 cm“: HRMS cold for CuHI‘INo: ml: 247.1209. found nil: 247.1%. 27: 0.15g.0.65mmol.62% yieldfiHNMRMMHs. 4 1.79-1.94 (m. 2 H). 2.14 (s. 3 H). 2.49 (ddd. J . 16.8. 10.4. 6.4 H11 H).2.59(ddd.J-17.6.6.4.4.4 Hx.1H).2.79(tdd.J- 9.9.5.2.th1 H).3.29(ddd.J- 12.6.5.3. 1.4Hx. 1H).3.41 (dd.J- 12.19.3111. 1 H).4.47(d.J-14.7 Hz. 1 H). 4.73 (d. J- 14.7Hs.1H).7.22-7.$(m.5H):“CNMR(75hfl-lx.CDCh) 4 23.79. 26.01. 30.96. 46.56. 47.17. 50.07. 127.40. 128.05. 128.52. 136.70. 168.63. 207.21: IR (oil/NaCl) 3032. 2932. 2876. 1713. 1642. 1495. 1455. 1262. 1167. cm“: HRMS calcd for Gui-1.1140. ili/e 231.1259. fotmd ml: 232.1251. 31: 8.19 g. 33.4 mmol. 61% yield. 90:10 (cis/trans): 'H NMR (MMI‘InCDCLcisisomerHLOHdJ-Gfiflxal-Ihm (s. 3 H). 1.92-2.17 (m. 4 H). 2.48 (ddd. J I 18.3. 10.4. 5.0 Hz. 1 H). 2.611ddd.J I 18.3. 7.4. 2.0 Hz. 1 H). 179(ko I 12.5. 4.2 Han).3.84(m.1H).3.96(d.J- 152111.1H).5.31 (dc/I (35lormmedetailedgeneralexperimsntalproasdurmfre- fie-thus 1992.57 “Lesa: CootG. RMN S;Stil|s.J. llJ. Org. Gem. MSC: io940171k BATCH: 306m USER: O HydroxylatadAlhaloidsthrowhAa-Annulatiou 15.21lx.1H).7.22-7.3(m.5H):“Cma5m'Is.CDCU(c'n band) 5 14.52. 17.33. nos. 3.“. 47.74. 51.03. 51.14. 121.04. 127.3. 128.28. 13.97. 168.67. 25.25: In (oil/NaCl) 2975. 1713. 1640.1163cm-‘zHlulSmlodforCn1‘lnNOim/r 245.1416.found at]: 245.1415. 46: magma-chin yield.fl:2(chltrarn);‘HM (mmCDCU1c'lbmnsrllL1312-II7JHL3H).2N (n.1H).2.21(ddtJ-93.7.8.129Hx.111).249(ddd.J-18.3. 10.0.8.31hl11).2.59(ddd.J-18.3.7.8.1.8Ht.111).279(dt. J- 15.0.9.0H2111).3.53(d.J-5.4H1.2H).3.80-4.(I(II. 3H).4.15(41.JI 15.21h.1H).4.37(4.2H).5.23(d.JI 15.2 Hxlm.7.17-7.37(m.10H):°CMU5hfl'ls.CDQch'n homes) 4 13.82. 19.18. 81.07. 42.40. 49.16. 56.17. 60.65. 68.62. 73.15. 127.19. 127.44. 127.59. 127.67. 128.19. 128.42. 137.22. 137.31. 189.56. 171.“; IR (oil/Neill) “9. 2870. 1734. 1645. 1173 cm": mmmmuznummusmm 90: Mg.1.48mmol.79%yisld.>flt2(c'lltrem):mpfl-101 'C(hompstrolsmnW):‘HNhlBMlfl-InCDCU (cisismner)4201(m.1H).2fl(m.1H).241(m.1H).252(l. 1H).299(B.1H).4.19-4.3(m.411).5.13(d.JI 15.0th H).7.14-7.42(m.51'1): "CMUSEECDCU (cis’nomer) imamnnnummmmm.mnmu in.u.immwmimw.mzsmxmm 1m. 1451. iota. use as"; units odd for Mum. ails muss. found ails 2451M Bydrelysisefzz. Asolutionof22(3flg.120mmol)and NaOH(0.96g.24.0mmol)inamixtureofm(50mL)andHe0 (“wusmredforzohatrtandtbsmixnuewmadmd topH<3.0hyadditionofconodHCl. Thsmixturewmextrsctsd with3x75mLofCIdCLandti-ecomhinsderganic1ayeeeweee drisd(MgSO.)andeoneentratsdtogive23(252g.10.8mmol) in90$yield= mp156-157'CcfromCHCUEts0):‘1-1NMR(M MCDCUJM(B.1H).2.13(II.1H).250(ddd.JI6-3. 9.3. 17.9Hs.1H).253(dt.J- 17.9.5.5Hs.1H).276(m.1H). 238(dd.J-5.5.125HL1H).3.43(dd.J-&5.125Hx.111). 4.4316“, I 14.6 Hz. 1 H). 4.74 (d.J I 14.6 118. 1 H). 7.16-7.35 (m.5H).11.24(he.1H):°CNNB(75.5h011.CDCL)423.6. 31.4. 36.6. 48.0. 50.5. 127.6. 128.1. 128.7. 131. 170.0. 175.7: 111 (momm.2sso.mmo. 2670. 2492. 1940. 1713.1591. 1455. 1421. 1375. 1302. 1223. 9Q. 752.699ar‘:1-1RMScaldfu CuHisNOe Ill/2 233.1052. found mlz 233.1039. General Procedure for DBU Epimerization. To a 90:10 solutionof cis-31/trens-31 (0.20 g. 1.12 mmollinTHFMmL) wasddedDBU (01350.56mmol).andthemixtiu'ewmstirred atrt. m16h.thereactionwasquenchedhyadditionof3ml. ofHaO. 'I'heorganiclayersweiesepareted.conoentrated.md purifiedbychromambymtgmtogiven. trans-31: 0.20g.0.82mmol.>99% yield.28fl2(dsltram):‘H MMMHLCDCM(u-ansisomer)41.22(d.J-66Hx.1 H). 1&(n3 H). 1.91-2.12 (111.311). 2.35-263 (m.3H).3.82(n. lH).4.01(d.JI 15.21121 H).5.23(d.JI 15.2112. 1 H). 7.22-734(m.5H);"CNMR(75MH¢.CDCh)(transisomer)4 19.53. 19.5. fl.47.29.39.4&$.51.14. 5226. 18.93. 127.78. 128.10. 15.97. 168.87. 207.05: IR (oil/NaCl) 2975. 1713. 1640. 1163 cm“: HRMS calcd for CuHuNO. mlz 245.1416. fotmd In]: 245.1415. trans-46mm: 51): 0350.57mmol.>99% yield. 17:83 (cis! trens):‘HNMR(mhfllx.CDCla)(transisomer)41&(s.3H). 1.95m. 1 H). 204 (m. 1 H).244(dt.J- 17.7.6.51'12. 1 H).258 (ddd.J- 117.756.5111. 1 H).2.95 (dt.J - 6.3.4.8 Hz. 1 H). 3.42-3.52 (m. 2 H). 3.94 (In. 1 H).4.10 (d.J I 15.0 Hz. 1 H). 4.37 (in! I 1.5 Ht. 2 1'1). 5.14 (d.J I 15.0 Hz. 1 H).7.16—7.36 (m. 10 H): I'C NMR (75 MHz. CDCU (trans isomer) 4 19.93. 27.27. 29.58. 47.78. 47.96. 55.17. 69.36. 7281. 127.01. 127.3). 127.45. 127.53. 127.82. 128.12. 136.91. 137.15. 19.86. 207.06: IR (oill NaCl) 366. 2924. 1713. 1644. 1161. 1101 cm": HRMS calcd for CgHgNO. at]: 351.1635. foimd nil: 351.1818. General Procedure for Baeyer-VilligerOxidatiou. Toe sohitionof27(0.10g.0.43mmol)inCHiCli(1mL)wereaddsd m-CPBA(0.39g.225mmol)endCF,COOH (0.05g.0.43mmol) atrtandtbereactionwmhestad atreflux. After14h.ths rmctionwmcooledandconcentratedandtheresultingshnry wmptnifisdhychromatographymtgmtogiveza. 28: 0.069g.0.28mmol.67%yield:‘HNMR(300MHz.CDCla) 8 2.01 (s. 3 11). 202-208 (m. 2 H). 2.52 (ddd. J - 17.9. 6.0. 5.3 Hz. 1 H).267 (ddd.J - 17.9. 9.6. 7.1 Hz. 1 11).“ ((1de- 13.2.3.9. 1.3111. 1H).3.43(dd.J- 132391-121 H).4.49(d. eap69 DIV: Gxy1dr/data2/C1.S_pi/GBP_Jo/JOB_i12/DIV_jo940171h 112 PAGE: 7 DATE: 04/22/94 J.Org.Chem. G J- 14.71121H).4.71(d.J-14.7Hx.1H).5.12(dq.J-3£. flHan).7.21-7.3(m.5H):'CNMR(75hfl-ILCDCU4 20.97. 25.49. 27.5. 49$. 50.46. 66.17. 127.49. 127.99. 128.60. ”168.73.170.18:m(oillNaC1)3163.2959.2573.1738.1646. 1491. 185. 1421. 1238. 1152. 1075 cm“. 32 4.49g.17.2mmol.41% yield:mp66-67°C(hompstrdsum WivummmcncuimuJ-um 3H).18(I.3H).1.97(m.111).216(dddd.J-14.7.1147!» 27H21H).251(ddd.J-I18.3.7.5.21H2111).2.88(ddd.J I16.3.1L4.7.51II.1H).3.46(qt.JI6.7.2.01‘18.11am“. J-15.31121H).4.88(dt.J-3.9.21HI.1H).5.46(¢1.J- 15.3H1.11D.7.m-7.37(m.5H):“CNMR(75hDIx.CDGs)4 17.8). 20.75. 21AM47.18.54.38.70.07. 127.19. 127.72. izssr. 13.95.18357.1MD1(NaC1)2975.2942.1736.1634.1482 MllflmHRHScalodforCanNOimlxxmfound III/s 31.133. 47: 059g.1.63mmo1.0% yieldlemmm-Inm 41.891s.3H).194(m.1H).217(dddd.J-13J.10£.7.&20 111.11D.2.51(ddd.J-163.7.6.27Hs.111).263(ddd.J-I 153.102.75Hn1H).3.45-3.60(m.311).3.92(d.J-15.3Hx. 1H).4.43(4.JI12.0H2.11'1).4.501¢JI12.032.119.516 (n.1H).5.39(d.J-I 15.311a.1H).7.18-7.40(m.10H):“CNIB asmmimmnmuizmmmnsn 73.31.12737.12l&.127.fl.128.01.120.44.128.50.1$.91.13731. 10.72.16.96zm(oillNaC1)m2934...1738.1647.1240. lmlmmllsmlodforwoenlrmammundmh 37.1768. Pee-tisnefa. Toasolutiimof32(0.10g.0.383mmal)in H.0(O.8ml..)wmaddedcrtnhsta0H(0.04g.1.12mmol).and thereactionwmhsatsdatapprosimatelyfl'Cforuh. After with8X1mLofCHCl. Theorganiclayerewerecomhinsdand dried.andthseolventwmremovedunderreducadpr-ure.‘lhs pduaurecryetallieedfromthmpeuoleumethertogivefl Mgmmmolflnfli yield: mp 110-113 ’Clem (mmCDCldiL18(d.J-6.6Hx.3H).1.86(m.lHl. 1.95-212(m.2H).242(ddd.J-I M7.L2.3112.11'1).2.71 (ddd.J-130105741121H).3.34(m.1H).3.83(dt.J-4.8. ”Hle).395(d.J-15.2H21H).5.35(d.J-I 15.21121 H).7.20-7.35(m.5H):“CNMR(75MHs.CDCl.)418.37.2405. 28.92. 47.42. 57.96. 68.45. 127.23. 127.78. 123.56. 137.33. 169.42: IR (oilINsCl) 3299. 3123. 2890. 1609. 1453. 1175. cm“: HRMS calcd for CanNO. ml: 219.1259. found nil: 219.1245. Prepsratienef‘l'hisamides. Law-son‘sreagent(0.5equiv) wesaddedtossolutionofthslactam(1.0equiv)in'1'1'IP(0.4M). andthemixturewesstirrsdfor4-12h. Aftsreveporationofthe solventthenonvolatilemixtinewasdilutsdwithEtOAcGtimes thevolumeofTifi').andthesolutionweswmhsdssquentially with3portionsofsaturatedaqueousNaHCOe0Iathevolumeof EtOAc)followedhy2portimisofsaturatedsqusoinNaG(llg thevolumeofEtOAc). Tbeaqusouslayerswerecombinsdand exuactsdwith2portionsofEtOAc0/atbsvohunsofEtOAc). All organic layers were combined and then dried (NQSOJ. Pinificationhychromatography(3t¢0)afiordedthepurethi- 34: 5.35%.4mmoh995 yield:mp63-65’C(from8te0): 'HNhIR(mmis.CDCh)41.87(ddt.J-I 5.8.13.7.9.1Ht.1 H).2.m (dq,J I 13.7. 5.6112. 1 11). 2.781111. 1 H).2.97 (ddd.! I6.3.3.3.18.2H.2.1H).3.14(d¢.JI 18.25.811an).3.42-3.56 (m.2 H).3.56(s.3 H).5.12 (d.J- 14.5 Hz. 1 H).5.40(d.J- 14.5 Hr. 1 H). 7.16-7.29 (m. 5 H): ”C NMR (75.5 MHz. CDCU 1 23.0. 38.6. 403.500. 520. 57.1. 127.6. 127.7. 128.5. 134.8. 172.0. 199.7; IR (neat) soon. 3030. 2951. 250. 1734. 1514. 1453. 1348. 1200. 1169. 1043. 704 an": HRMS calal for CanNOgS Ills $3.09!). found mlz 263.0962. 391:: 228g.7.82mmol.99% wiummmcnm 5 1.17 (d.JI 6.6112311). 1.18 (LJ I 7.1 H2311). 1%213 (m.2H). 277 (ddd.J-4.7.5.8. 11.5111. 1 H).3.14 («J-8.5. 19.51121H).3.29(ddd.J I 3.3.6.6. 19.5 11.1. 1 H). 3.98190", I5366H11H).4.09(q.J-7.1 111.2H).4.45(d.J- 14.8 Hz. 1 H).6.23(d.J- 14.8Hr..1 H).7.23-7.35(m.5H):“CNMR (75.5 MHz. CDC)» 5 14.0. 14.7. 18.3. 40.0. 43.5. 54.9. 55.8. 61.0. 127.5. 127.7. 128.7. 135.3. 170.8. 199.8: 111(nest) m7. 351. m. 2936. 1732. 1m. 1452. 1348. 1171. 981. 700 cm": HRNS calcd for CuHaNogs mlz 291.1293. found mlz 291.1341. MSC: io940171h BATCH: i06h22 USER: DIV: @xyidr/uuz/CLs_pj/onr_jo/Jon O H J.Org.Clieui. .55: L45g.38mmoL94$yteld:mp61—62'C(fru3110). trimmmcnwiim-wmzmoimma I4..4 6.1.19.0H21H).3.N(ddtl.JI7..1 9.6.19.0H21H). 249(de-6.6.10.2Hr.1H).3.58(dd.J-4.4.10.2Hx.1H). 335(m.11'1).3.91(m.1H).4.24(d.J-11.81-12.1H).4.35(d. JI11.9H21H).4.40-4.50(II.3H).6.45(4.JI151112.111). 7.14-7.40(m. 1511):"CN5411(75.51013.CDCI;)422.7.37.3. 55561.1. 691.700.722.713. 12721274. 12751276. 127.9. 120.2. 128.5. 135.2. 137.1. 137.7. ”148; IR (neat) 31%. m ”I. mmnmnmmun 1073. immerses-t; HRMS mlcd fa 617”“ ml: 431.1919. found ail: 431.1887. GenerallethsdferlschanmssersulndeContractien. Thsthiohctam(1.0eqm'v)andBrCHiCOiEt(1.20quiV)wuo sm-rodinEteO(1M)for24-36h. Afterrernovalofsolventths thioniumssltwasd-olvedinCHflNMM).sndPPh.(L2 oquiv)wmaddod. mmixtirrewmallowedtost‘irfammh. NEt.(1.5equiv)wasadded.endthesolutimiweshsatedtoiefhm. muhthsedidswueremoeedhyfllnatiomandthsr-ilmnt concentrated. 39: umpire-3.179% MMfi-fl’cm mmMi;mmmmwcuii.iriea I6.4Hs.3H).1.18(t.J-7.0Hx.3H).1.24(t.J-7.0Ht.3 H).139-2111m.2H).2&-3.N(m.211).3.62(ddd.J-3.1.6.7. 18.7Hr.1H).3.fl(qtn'nt.J-6.3Ha.lH).3.99(du.JI3-4. 7.0Hx.2H).4.02(dq.J-3.4.7.0Hx.1H).4.14(q.J-7.0Hs. 2H).4.26(d.J-16.51121H).4.55(d.J-16.5H1.1H).4.83 (n.1H).7.17(d.J-7.0H1.2H).7.22-7.37(m.3H):“CNIlR (75.5341'lx.CDCls)414.0.14.5.14.6.17.0.25.4.44.1.54.0.54.8. 562.606.857.134. 127.1.128.6.1$.1.159.8. 168.6. 171.8:111 (neat) 31m.w.m0.2978.820.2870.1734.1682 1561. 11%. 1M0. 1m.%6.791.727.96cm“:1Mca1odfor 0.1-19190. III/r 345.1940. found ails 345.1”. 56: 1.225251mmoL815M‘HmmmInCDC1.) 81.17(t.J-7.1H1.3H).1.85(m.1H).1.95(m.1H).295(dt. J-18.1.6.2Ht.1H).3.41(dd.J-6.7.9.7Hs.1H).3.50(n. 1H).3.51(dd.JI-4.5.9.7l'lx.1H).361(ddd.J-28.4.4.7.1 Ht.1H).3.$(ddd.J-3.0.4.4.6.9Hx.1H).3.98(dq.J-3.8. 7.1Ht.1H).4.01(dq.JI3.8.7.1H21H).4.35(d.J-16.5112. 1 H). 4.41 (8. 2 H). 4.43 (d.J I 14.6 H2. 1 H). 4.52 (d.J I 14.6 H21H).4.53(d.JI16511:.11'1).4.60(4.1H).7.18-7.36(M. 15H):“CNMR(75.5MH;.CDC1.)414.6.22.222.3.53.9.58.2 62.5. 70.1. 70.2. 73.2. 73.3. 64.8. 126.6. 127.0. 127.4. 127.5. 127.6. 127.8. 128.3. 128.4. 128.5. 136.3. 137.6. 138.2. 161.7. 168.9: IR (neat) 31(1). 3”. 331. 2900. 2934. 257. 16a). 1561. 1497. 1455. 1S211421094.1073.735.696cm4:HRMScalcdforCaH.- NO. in]: 485.2567. found mlz 485.2559. Formatienof43. Toesolutionof42(1.20g.8.19mmol)in Tl-fI-‘(16mL)wasaddedBuLi(3.28m1.25Minhexane)at-78 ‘C. Afterthemixturewasstirred for 10 min. ClCO,Et (0.89g. 819mmol)wmaddeddropwisa. 'I'hereectionwasslowlywarmsd toO'C(imtiladeopredcolorbegantofoim)andwmthen prmnptlyquenchedhyadditionofl-lgo. Theorganicphmowas separatedandthssolventwaeremovedunderreducedpremure toproduceacrudsoilwhicbwaspurifiedhychromatography (petroletnnether)togive43(1.61g.7.39mmol)in91% yield: ‘HNMR(MMH:.CDC1;)41.29(t.J-7.2H1.3H).4.22(q. J-7.2Ht.2l-l). 4.25 «.210. 4.59 (s.2H). 7.22—7.40 (m.5H): N: NMR (75 MHz. CDCb) 6 13.78. 56.53. 61.”. 71.81. 78.07. 8294. 127.87. 127.90. 128.29. 136.59. 152.87; 111 (oil/NaC1)3032. 2964. 2872. 2236. 1713. 1248 cm“. Ana-Annulation Procedure for Formation of 44. To a solutiouof43(1.61g.7.37mmol)inT1fi'(15mL)wasaddod BnNH3(0.70g.7.37mmol)strt.andthereactionwasheatodat refluxfor12h. Mterthemixturowascooledtortacrylic anhydride(1.7oquiv)wassdded.andtheroactionwashoatedat refliixforuh.” Thesolutionwasthencooledtortand cucmmudandthecrudeproductwaspurifisdhychroma- mhy (10:90 IMO/petroleum ether) togive44 (1.73 g. 4.56 (37)cryiicanhydridswespreparod immediatsiypriortouaebyaddhig NaH(1.8eqmv)toaaylicacid(1.2eqmv)at-78°Candallowmgths mixturetowarmtoitAcryloylchloride(10equiv)wmthensddod.and *' ‘fi-lhT‘ tothsreactiim vemelisa m (38) erg. 5.41.: Kim. W.-S.; 14cm. 3.41. Synthesis 1'8. 1161. eap69 _112/DIV_jo940171h 113 PAGE: 8 DATE: 04/22/94 Cookout mmol)in62%yield: molt-87'C(frmaEteOl other): ‘HM(mm'lx.CDCU4L27(t.J-7.0HL3H).249-258 (m.2 H). 2.62-2.71 (n.2H). 4.17 (q.JI 7.0 H22H).4.57(8. 2H). 4.60 (s.2H). 5.1.2 (s.2H). 697-703 (m.2H).7.16-7.39 (In. 8H):"CNMR(75WILCDC1;)414.16.21.69.3182.44.51. €176.63.56.7265.113.54.128.06.128.97.127.93.128m.12242. 128.63. 137.61. 137.”. 1464!. 166.71. 170.92: IR (NaCl) nu. reams. m9. immmwruwmm 379.1784. foimd III/r 379.1777. GsnsralPrecsdureforConvereisnofBeeeetoIsthl ”Functionality. ToasolutionofMeMgBrMmLu Uin‘l'HF)inbsmsns(19m1.)wmsddodNBh(2flg.fl.4 mmollatO’C. Aftar10min.asolutionof45(1.25g.3.41mmol) inhemens(5ml.)wmaddodwithvigorousetirrhu.andths mixturowmstirredfor3hat0°c Thereactinwmqt-nmod hyadditioncf25mLof3MaqusomHCl. Thsmganiclayer- ssparatsd and concenm and the resultn' crude oil I. punfisdhychrunatography (31.0)topvo44. “(iris-45): 0.56g.1.fl)mmol.61$yisld:‘HNllRm IGlLCDG.)(c'n'nuer)l1.87(m.1H).2.M(l.3Hl.2.121n. 1H).2.32-264(m.2H).271(dt.J-13.24.1H211D.3.42(dl|. JI9.9.7.5H3.1H).3.50(66.JI9.9.4.1HI.110.3.94(n.1 H).4.06(d.J-15.0H1.1H).4.m(d.J-1.8Hx.211).5.28(d. J-15.01121H).7.16-7x(m.10H):°CNth(75m'lr.CDO.) (cis'nomsr)418.m.28.m.3.82.48.85.49.63.55.82678.72fl. 127.12. 127.34. 127.49. 128%. 128.11. 128.29. WI. 137.04. mammal/macaw 1713. 1644.1161.1101 MIMmlcdforwoi-lsSMfotmd-Ja 351.1818. 51: 0.17g.065mmol.25$yield.>M(dI/txall):‘Hm (”MCDON(cis‘nomer)41.90(m.1H).L91(s.3m.210 (m.1H).2.40(dt.J- 17.7.6.8Hx.1H).2.64(dt.J- 17.7.6.8 Hz.1H).3.03(dt.JI6.6.4.81h.1H).3.57(dd.J-11.6.3.8 H22H).3.65(dd.J-I11.4.6.3Ht.1H).3.82(m.1H).3.92(1I. 1 H).4.06(d.JI l5.01‘12.1H).5.19(d.JI 15.01121 H).7.21 (N.JI7.8HI.2H).7J)-7.34(IL3H):"CNHR(75MHI. CD61.)(cisisomsr)421.11.25.5629.&.47.49.48.03.57.15.61.87. 127.45. 127.91. 128.54. 136.91. 171.06. 207.88: 111 (ciliNaCl) 3374. totem 1711. 1613. 1455. 1256. 1169me?" CuHioNOe mlz 51.1365. found Iii/r 261.1354. ' Per-attend". Tossehrtionof47(0$g.0.flmmol)in HeO(1.1mL)wssaddodcrushedl(OH(0-20g.0.52mmol)atfl. andtheroactionwmhmtodatapproximatelyfl’C. After12 h.ths wesextrsctadfromtheroactionmixturewith6 x2mLofCHCl... Theorganiclayerewerecombinedand concenmmd.andthsresultingcrudeslcobolwmptuifisdhy chromatography(Et.O)togiveanoil(0.22g.0.68mmol)in85% yield: ‘HNMR(MMHI.CDC1¢)41.81(II.1H).2.W(M J I 12.6.9.9. 6.9. 3.0.1H).2.87(ddd.JI 18.3. 6.9.4.8112. l H). 264 ((1de . 16.8.93. 69 112.2 H).3.39 (m. 1 H). 3400. 1H). 3.51 (m. l H). 4.07 (d.J I 15.3118. 1 H). 4.10 (h. 1 H). 4.3716. JI12011.1.1H).4.43(d.JI12H21H).5.18(¢LJI15.3112. 1H). 7.16-7.38 (In. 10 H);“C NMRUS MCDCU‘25J6. 27.37. 48.09. 62.13. 65.65. 69.42 73.27. 127.15. 127.58. 127.71. 127.86. 128.45. 128.46. 137.23. 137.44. 170.28: IR (oil/Nam) 334 (hr). 3W3. 2928. 1617. 1453. 1181. 1101 all": HRMS calcd fa 0.119140, ni/r 325.1678. found ml: 325.1666. ToasdufimofthsalmhdiOéOpZMmdenEhOMml—l were added crushed KOH (0.23 g. 4.10 mmol) and molomln sieves(0.40g)strt. After5-10minofstirring.BnBr(0.39g.226 mmol)wasadded. Theroactionwmqusnchsdafter3hby additionofescsmHgomndthemixturewmextractsdwith 10 X4mLofEtgo. Theorganiclayerswerecomhinadand concentratedandthsresult'mgcrudeoilwaspurif'iedhy chromatography(Et.O)togive17(0.57g.1.37mmol)in84% yield. mp 60-63 ’C (from CHCUEHO): ‘H NMR (3!) MHZ. CDCU4191-202(m.2H).240(ddd.J-18.0.6.2.3.9Hx.1 H). 269 (:1de - 18.0. 10.48.5111. 1H).3.39(dd.J n99.7.2 H21H).3.52(dd.J-9.9.3.9H1.1H).3.65(m.1H).3.83(dd. JI6.2.3.9H2.1H).3.99(d.JI1”H21H).43(¢JI12.0 HLIH).4.35(¢LJI 120H21H).4.37(t1.JI 120112.111). 4.41 (d.J . 120 Hz. 1 H). 5.36 (d. J - 15.3 Hz. 1 H). 7.14-73 (m. 15 H): “C NMR (75 MHLCDCh) l 22.18. 27.22. 47.69. 58.37. 69.16. 69.77. 71.79. 73.03. 126.87. 127.07. 127.28. 127.37. 127.56. 127.65. 128.05. 128.21. 128.26. 137.13.137.36. 137.85. 169.93;“! MSC: 1094017“ BATCH: 506b22 USER: 114 "’69 PAGE: 9 DIV: Oxyldr/detn2/CLS_pi/GRP_jo/JOB_112/D1V_jo940171k DATE: 04/22/94 9 HydmyhtedAlhlddIWAm-Anmhfion (Mm “287.164214531096an‘k1mHSmld1or CaHnNOinl141521431oundn/14122142 Permetieaeflz. Tossolutionofl7(1mr.241mmol)in '1'111‘(16m1.)wessddedBuLi(1.06m1..25Nin‘l'111')st-78 'C. m10min.PhSeCI(0.51x.265mmol)inT111‘(8I-D wmeddedendthermctionmirtnrsallowedtowarmtoO‘Cfc 3mm. mmumumanudap. mdthemisunewmesuaaedwith4x10mhdw.‘l'hs emnhined oreenie layers was cone-named under reduced me. mmumuhmmnmae 8:1.25mL).anst.10.(1.553.7.23mmol)weesdded. Anath- minnow-“huntheresetionwmdihimdwithaml. e111go.endthemi:nnewmertreaedwith10x10m1.dh.0. purified reaynellimtim mmnmnmnmnmunnsw mp Mfi’flMMfiM‘WRJ-uflslfl). 348(fiJIM5011111D.3.84(m.11D.4.m(d.JI15.5 111.111).4.M(dd.JI5.9.1.4111.111).4.21(d.J-120111. 1HL4.33(¢JI1203111D.440(¢J-120111.111).4.45 (d.J-120111.111).5.37(d.JI15.5111.111).6.15(d.J-9.6 38.110.647(“J-“5.3.1.1111.1H).7.10-7.15(I.2H). iii-iamumncmmmcncuawmm. 68.07.68.fl.70.11.73.24.127.32. 127.52. 1270.127.75.127.87. m04. 128.24. 128.3. 1344. 128.51. 134.59. 13.91. 1374“. maimmmmmua.mi.iaamua. tanner-awaitediucoflammcme-m 4 leematienetfl. Tossohitionolnm105014mmobin toBu0111L4mL)werseddedNMO(mo~)snd0004(0.flmL 0.0514'mt-Bu0111etrt. m3h.thereaetionwmquenebd byedditiudeumsolidm Solventwmiemoeedimder redumdprmeuntiltheresotionoolmhemtoturnmyflh renln'nnn'xmrewmpmifiedby by-chrmnetopephytsoleutund ion: MNMMMHHocive5M0m9mQ154mmel) in64$yield: mm€(MMO/mn);|am«m mammammhumunasx-amuamw (d.J-1.2111.111).3.97(1.JI3.1111.111).4.32(d.JI 15.6. 1H).4.37(td.JI3-5.2.1H21H).4.41(4.2H).4.42(1||.1H). 4.44(d.J- 120111. 111).4.50(d..l- 120111.111).5.27(d.J I 15.6 111. 1 11). 7.11-7.21 (in. 4 11). 7.21-7.39 (m. 11 11): l'0 masmcncunsamsau.wam. 71.48. 73.13. 75.21. 127.3. 127.55. 127.65. 127.74. 127.83. 13.23. 128.35. 128.41.12853.1“137.19.137.43.171.206;111(N161)34m. mm1.2fl9.1645.1455.1250.1074em4:111154$ea1od1or W01 ml: «7.1011. {oimd am «72046. Formula“; Toesolutiond53(0.063.0.13mmol)in NHai4mL)wmedded1.imetalst-78°C untilthesolution turnedepers'ntentdeephlue. m3hetn0ntheeolution wmeooledto-78'Candthentheiesctionwsequenchedbythe sdditionotsolidN1LC1. Themixunewsethenallowediowenn tort. OnoeN11.removalweeunnplete.thereectionmixturewee extreetedwith10X2mLoi121solutionofC11Ch/Me011and thenfiltered. Solventremovelimderreduoedpremureproduosd asolid.whichwmdimolvedineminimmnemoimto(hle01iend maymmmmcacumonmmsmmo c. 0.057 mmol) in 44% yield: mp 163-168 'C (from CHCUEtIO); ‘HMiMflLCDCUJM(td.J-6.3.3.9111.111).3.59 (ddd-11.9.5.9111111).3.68(dd.J-11.7.5.1H1.111).3.72 (MI-6.2111111).3.89(dd.J-5.7.3.91l1.111).4.20(d..l- 3.9 111. 1 11): I’C NMR (75 11111. CDCU 57:10. 61.11. 67.20. 68.14. 71.94. 173.17;111(oil/NeC1) 3287.W2941.2890.2834. 16m. 1453. 1281. 1175. 1032 cm“: HRMS calcd for CeHuNO. nil: 177.337. [and Iii/1 176.0481. Permetienetu. Toasolntionot53(0.07¢.0.16mmol)in 311011.6mL1wmsddedmLiAl1Lsti-t. After3h.the reactionwmquenchedetO‘Coi'nslowsdditionotwfi squeoue NeOl-luntilallvieihlemflhhndheenoommned. Theresction wmfdtueddifidandoonoentretedtogiveecrudeoiLwhieh wsepuiifiedbychrometopsphy13110)to¢ive54(0..069¢.016 mmol)in>96%yield: I1'1161.111.(:IX)1111'11.C1)C1i)(cisisotiier) 8221(dd.J-12.2.1.5111.111).238(dt..l- 8.7. 26111.111). 2.82(he.211).2.91(dd..l-12244111111).3.27(d.J-129 111.111).3.55(dd.J-8.4.3.3111.111).3.64(1.J-86111.1 11).3.73(m.111).3.76(dd.J-10.4.26111111).3.83(dd..l- 10.4.2.6H21H).4.10(0.JI13.21121H).4.45(8.1H).4.56 J.Or(.Clieut. 1 (d.J-11.1111.211).4m(d.J-11111111H).7.a>-7.40(m. 1511):"010411 (75111-1:CDO.)154.71.56.67.64.76.66.87. 63.10. 7326. 74.61. 75.2). 78.42. 127.16. 127.65. 127.74. 127.79. 127.97.127.99.128.40.128.94.137.85.138.52138.60:111(eill mmmmwmmmaemmwa CnHaNmn/rmwmm Fee-etienett Toeeolutionof54M3.0.18-nol)in Wflaml.)wmedded10$?donmrhon(0.18¢)endend 11C!(1.8m1.).endthemi:turewmpleoedundaranstmmhme 4(0.014¢.0.094)meciudesolid(52% yield).whiehwm reuyetafliesdtoeivepurumnmmmolnnflfiyield: um—mmmmmnmmmmm 8w(ddd.JI9.9.6.6.3.0111.111).3.10(dd.J-13.8.1.3111. 110.3.2Hdd.J- 13230111111).355(dd.J-9.6.3.0118. 111).370(dd.J-123.60111111).3.74(t.J-6.8111.119. mind-11115111110410m411). GenerallethedfeetheNeBliCNIednd-etlnnl- neeetar's. Toeeolutiaotthsmeminouerunemu'flend Mmitramamounmmenindimtoefinlflfim IOwaeeddedNaBmunequiv). A5Smetheno1ir1101 edditiaoIHClwmm-ietomaintmneyellowooh.'1'hemilm1e ummmmmtsmmmamm. “and41:0.1103.0.318mmol.1m5yie|d.miraneo(40/41 mmvammmcnmummmmm. J-6.91-11.311).1.13(t..l-7.11-11.311).1.14(t.J-7.1111. 3H).1.37(dq.JI5.2.124111.1H).1.56(dq.JI13.2.3.031. 111).1.72-1.921m.211).219(dd.J-7.4.14.8111.111).246 (“J-63.14.8311111.278(dt.J-4.9.11.8111.111).3.22 (dad-4.7.6.931111).3.34(m.111).3.67(1.211).3.93-4.12 (m. 4 11). 7.12-7.31 (m. 5 11): (minor homer) 0.93 (d. J - 7.0 111. 311). 1.191%JI 7.3112311). mun-7.1111311). 1.62-1.77 (m.311).1.84(m.11-l).234(dd.J- 10.3.14.2H1.1H).2.05 Md." I 3.4.14.2 H1. 1 H). 2.73 (m. 1 H). 3.22-3.35 (II. 2 H). 3.75 (1.2H).4.06(q.JI7.3H1.211).4.M(q.J- 7.31122H). 7.17-7.341m.511):°CNMR(75.5M1-11.CDCU6(mejoeie~er) 10.4. 14.1. 212282401. 41.5. 50.7. 51.9.53.260.1. 60.4.1266. 127.8. 12821405. 172.1. 174.1: IR (neat) 3081mm. 2960. 2940. 2874. 2853. 1734. 1495. 1453. 1370. 1200. 1152. 1034. 733. “an": HRMScalod {or 0.11.110. Ill/3 347.2051. found-111 347.2113. 57: 0.619;. 1.27 “1.88% yield.mixtureol salient)”: 10):'11 NMR(&01¢1111.CDC1,)6(majorieomer) 1.17 (1.1-7.2 112.311). 1.53-1.78 (111.311). 1.99 (m.1H). 243 (dd.J I87. 14.2 113.1 H).260(dd.JI5.3. 14.2112111).2.95(d1.JI7.0.4.5 111.1H).3.24(m.1H).3.54(d1.JI4.2.7.5111.11-D.3.71(ll. 3H). 4.113(111.1H).4.04(q.J-7.2111.2H).4.3(1.2H).4.42 (d.J I 11.4 111. 1 H). 4.55 (d.J I 11.4 111. 1 H). 7.16-7.38 (III. 15 H): “C NMR (75.5 M111. CDC13) 8 (mejor homer) 14.1. 24.7. 25.4. 33.9. 527.59.160.2655703. 72.9. 74212851273. 127.4. 127.5. 127.6. 128.0. 128.2. 128.3. 128.4. 138.4. 138.8. 140.7. 172.5: IR (neat) N87. 3163. N31. 2900. 836. 235. 1732. 1495. 1452. 1368. 1290. 1157. 1096. 1028. 737. 696 cm“: 1111148 calcd [or Cal-13,170. Iii/1 487.2723. found mlz 487m Bedoctioao!571059.'1‘ossolutionol57(0.167¢.0.342 mmol)inEt.mesdded1.iAl11.(0.1¢.2.63mmol). endthe mixture was stirred (or 2 h. The reaction wee quenched by addition of 11.0 (0.1 mL).15% aqueous Na011 (0.1 mL). and 1110(0.3m1.). Anathemixunewmnirredfmlhthesolutiim weefiltered.1ndthesolventewereeveporntedtouive59(0.133 3.0.298mmo1)in87%yield: mmmomcncwsmc (m. 1 11). 1.27 (t. 1 11). 1.411111. 1 11). 1.681111. 1 11). 1.94 (m. 1 H). 2.09 (In. 1 H).227 (In. 1 11). 2.91 (m. 1 H).3.40(d1.JI 2.2. 10.5111111).3.48—3.68(m.311).3.62(d.J-1311111111374 (“J-80.931121 H).3.$(dd.JI3.7.9.9HI—1H).L11 (d.J- 133111.111).4.41(d.J-115111.111).4.46(d.J-121 HL1H).4.58(0.JI 12.1HLIH).4.61(¢1.JI 115113.111). 7.20-7.38(m.15H):“CNMR(75.51011.CDCU522.8.”.0. 30.9. 50.6. 54.4. 57.1. 629.68.2704723733. 126.9. 121.3. 127.4. ‘11.”!an ‘ MSC: 3094017“ BATCH: 1051122 USER: 9 J J. Org. Chem. PAGE ET: 9.7 121.6.128.3.129.0.138.2138.7.140.0:111(neet)3405.1l7.m ”3.336.231.1495145511mlmmmcm‘km mlodfior Mommas/2mm. SwernOzidetieeetfltefl. Toesoluu‘onofomiyiehloride (0.057;.045mmol)inC11eCleet-70’Cwesddedesolution olDllSOi0.070;.0.90nnol)inC11eCle(1mL). AMlOfliI. ssoliitionol59(0.1333.0.297mmol)inC11¢CIe(2mL)wm added. ’1'hsmir:nrewmsflowedtostir£or45minst-65'C.and thenNEiemmLUmr-obweesdded. Anathemimmewm stirredior!)minet-65°C.itwmwnrniedtortfor1h. The misunewmmienehsdwithloxsqusomhlaflcogsndthen canardwith3x10mLol’C11as. Thesolventewere eeeporetedandthsahishydewmmsdimmsd'mtelywithout mm mama-errors“. Amistnreoflfluulg. 0.6nnol)andPPhs(0.1573.0.6mmol)wmheamdetreauein tobsneamLHoHML Anorthssduunwmmnhdmmths solvmtwmremovedundsrvsomimmdmamldwmedded. AdemMmMMmLMi-wwm sddsdtothephomhom’umsaitet-fl’Cendthe-ismrewm stirredrorlsminst-‘Is'Csndthenstirredtorlhsti-t. The remitineylidssohtionuoooledto-fl'CendflMe. mmhmuwum Anathema wumedm-45'Covm2hitwmetirredetthttempereunefim anedditi-llhwermsdto0°C1¢3h.sndetirredensdditimial 2hetrt. TliereaetiimwmqumohedwithHeOOOIDeedthen thesolutionextiertedwith3xmmLoIC1-1501. Theoomhined mkyerewmedriedmmandomimntreted. The oilwm ' marinara-mm etherlEteO) toeive61 (010290.163 mmol) 111555 yield (oil tea-85:15):‘11mm1fl11.CDCIs)80.0(t.J-7.4HI. 311).1.fl-1.38(m.811). 1.44-L75(m.611). 1:99-wind!“ 222-2351121112561m.111.tremnomer).2¢(m.111).283 «ltd-7.4.3.8111.11Lm'nomer).3.01(dt.J-7.4.4.3111. 1H).3.54(m.1H).3.50-3.73(B.3H).3.91(1.4H).4.N(¢J I14.0111.111.trens'nomer).4.fl(d.J-13.7111.111).4.39 (12111.4.42idJ-I 115111.111). 4.43th- 11.511111Ltrsm imner).4.55(d.J-11.5H1.1H.tnnsnmner).4.56(d.JI11.5 113.111). 5.21111H).5.34(1I.1H). 7.1G-7.41(m.151'1): "c mnumcnooudsmmi.n7.maon¢ 29.1. 29.2. 29.4. 29.5. 29.6. 29.7. 29.8. 52.5. 55.0. 58.9. 64.9. 68.7. 708.729. 74.6. 1121. 126.4. 127.2. 127.3. 127.4. 127.6. 128.0. 128.3. 128.4. 131.1. 138.4. 138.8. 141.1; (mm homer) 8.1. 235. 25.0. 27.2. 29.1. 29.2. 29.4. 29.5. 29.6. 29.7. 29.8. 524.548. 583.643. 68.7.m729.74.6.1120.13.2.126.9.127.3.127412771218. 128.2. 128.3. 128.4. 131.3. 138.4. 138.9. 141.2: IR (neat) 3100. moo. $29. 293. 2855. 1453. 1075. 733. 696 cm":1111MS cold for CeiHseNO. ml: 625.4131. toimd Ill/2 625.4112 Prepantienet7. Toesoh1tiono€61(0.0993.0.158mmol) inT11Pi8memsdded10$sqneom11CH4mL1 Marthe eep69 DIV: 61y1dr/deta2/CLS_pi/GRP_jo/JOB_112/D1V_Jo940171k 115 PAGE: 10 DATE: 04/22/94 Coohetal. mirturewmetiiredfor2h.eeunetedeqiieom_Na1100.(10mL) wmsdded.end.themixtureweaexu'sctedwithc11101s The MWCEIH).L74(II.1H).2.07(h.3H).2.39(1.JI7.5 £2311). 241(q.J-7.3111.211).2761m.111).2.97(dt.J- :2 3.5;. 5 E E “E g: 5: 2 33.9.35.&42-4.49.7.55.1.533.58. 2123111131113”. 14n1377.1275.1119.1m7flcir‘:1111|6 N-1dw0iml13122540dmmdlil13 312.30. 11 E? inparLbyspanDDR-omwflromtheBiotechnology WMWMMWNs- tionallnetitutesofHealth. Supple-eatery Meter-id Availehle: Experiment-1pm- oeduresfor24.35.37. 49. 63. 64.1nd65andoopimof'11m meetraotalloompounmuithefirpernnentslSeetiont49pe‘m). This meteriel is oonteined in my librarim on miaofiohe. immedisulyfollowsthiserticleinthemia-ofilmvenionotthe journalandcenbsorderedfromtheACSueeuycmrent mmthesdpseeiororderin'inioiinstion. 116 can: pm 1 mm ovum 1111:: iron: on: mama; along WJOB_ mortua- AUTHOR INDEX ENTRIES NSC: jewim BATCH: 506122 VOLUME: 059 ISSUE: 012 CochG.R. BehohltG. 311110.111. "11111111711"11171111111“