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THE PREPARATION OF 5 , 6 , 7 , 8-TETRAHYDRO-INDOLIZIDINES AND 6 , 7 , 8 , 9-TETRAHYDRO-[5H] -PYRROLO[1 , 23 ] -AZEP INES . STUDIES DIRECTED TOWARDS THE SYNTHESIS OF SIMPLE INDOLIZIDINE AND UINOL ZIDINE ALKALOIDS. ptesen e by Jeffrey W. Raggon has been accepted towards fulfillment of the requirements for Ph . D. degree in Chemistry ‘3 é " W/ M Jjor professor . Date April 21, 1986 MS U is an Affirmative Action/Equal Opportunity Institution 0- 12771 MBRARY Michigan State University PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. ll DATE DUE DATE DUE DATE DUE l FT l MSU Is An Affirmative Action/Equal Opponunlty Institution eWuna-m PART I PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. THE PREPARATION OF 5,6,7,8-TETRAHYDRO-INDOLIZIDINES AND 6,7,8,9-TETRAHYDRO-[5H]-PYRROLO[1,2a]-AZEPINES. PART II STUDIES DIRECTED TOWARDS THE SYNTHESIS 0? SIMPLE INDOLIZIDINE AND OUINOLIZIDINE ALHALOIDS. By Jeffrey willism Raggon A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1986 ABSTRACT PART I PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. THE PREPARATION OF 5,6,7,8-TETRAHYDRO-INDOLIZIDINES AND 6,7,8,9-TETRAHYDRO-[5H]-PYRROLO[1,2A]-AZEPINES. PART II STUDIES DIRECTED TOWARDS THE SYNTHESIS OF SIMPLE INDOLIZIDINE AND OUINOLIZIDINE ALKALOIDS. By Jeffrey William Raggon- In Part I of this thesis, Né(epoxya1ky1) pyrroles 8, 9, 10, 11, 12 and 13 are readily prepared either by direct pyrrole N—alkylation with o—iodo-1,2-epoxy alkanes or via alkylation with o-iodo—1,2-a1kanediol acetonides followed by conversion to the corresponding epoxides. The cyclization of these §e(epoxyalky1) pyrroles were examined with five Lewis acids: EtAlClz; EtzAlCl; Ti(O-iPr)aCl; ZnIz; and BFa-OEtz, EtaN providing cyclized products 14, 16, 17, 18, 19, 20 and 21 in moderate to excellent yields. The cyclization products 14, 16 and 20 are formally the products of ”anti-Markovnikov” attack on the less-substituted epoxide terminus. In Part II, carbinol amides 21, 24, 28, 31, 35, 38, 42 and 45, derived from Mitsunobu coupling of either succinimide 17 or glutarimide 18 and the appropriate furyl alcohol followed by reduction, were employed as N- acyliminium ion precursors. 'Treatment of the precursors with a two-phase mixture of formic acid and cyclohexane resulted in facile cyclization to 5,6; 6,6; 5,7 and 6,7- membered, fused-ring systems in the electronically favored 3-to-2-fury1 closure and 5,6- and 5,7-membered rings only in the 2-to-3-furyl closure. In similar fashion, carbinolamides 61 (n=1) and 64 (n=2) prepared by Mitsunobu coupling of succinimide 17 or glutinimide 18 and 2-(5- methyl-Z-furyl) ethanol 58 followed by reduction, provided, under the standard cyclization conditions (HCOzR, c-Csflz) 2 to 3 minutes, the diones 62 (n=1) and 65 (n=2), respectively. The chemical manipulations of the furyl residue necessary to transform indolizidine precursor E! and quinolizidine precursor 65 into the bioactive alkaloids elaeokanine A 12 and lipinine 15 or epi-lupinine 16, respectively, are described. TO MY LOVING PARENTS, JOHN AND NORMA RAGGON. ii ACENONLEDGEMENTS The author wishes to express his sincerest gratitude to Dr. Steven ”Han with hair of fire” Tania for his patience, support, guidance, friendship, and many excellent parties throughout this project. The author also wishes to acknowledge the members of the faculty and staff for their assistance and advice throughout this work. Special thanks are extended to my fellow workers in the Tania lab for their advice, companionship, and ability to withstand various personalities trapped within my body (1;e. Marlon Brando, Dr. Zachary Smith, Herb Alpert, etc.). In particular, the author wishes to thank Ricky ”Cleanhead” Olsen for performing mass spectrometric analysis and Mark "Sehvenia" McMills for his friendship and editorial assistance in the preparation of this thesis. Finally, the author wishes to thank Michigan State University for its support in the form of a graduate assistantship and the National Institute of Health for a grant supporting the latter part of the research performed herein. ' iii TABLE OF CONTENTS Page LIST 0’ TABL'S - PART Is a s s e e s a s s s e a s s V LIST OF FIGURES - PARTS I AND II a s s e e s e e a a V1 LIST OF EQUATIONS - PARTS I AND II . . . . . . . . . V11 LIST OF SCHEMES “ PART II. . . . . . . . . . . . . . V111 PART I.“ PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. TRE PREPARATION OF 5.6.7.8- TETRARYDRO‘INDOLIZIDINES AND 8.7.8.9- TETRARYDRO“[5R]-PYRROLO[I,Ell-AZEPINES. . . 1 INTRODUCTION 0 a e s s s s e s e s s e s s s e a s a 1 DESIGN AND SYNTRESISS OE CYCLIZATION SUDSTRATES . . . 3 CYCLIZATION STUDIES. . . . . . . . . . . . . . 9 EXPERIMENTAL e a e e s a a e e e s e e a s e s e a e 18 LIST OP REFERENCES . . . s . . . . . . . . . . . . . 50 PART II ' STUDIES DIRECTED TOWARDS THE SYNTHESISS OP SIMPLE INDOLIZIDINE AND OUINOLIZIDINE ALKALOIDSs e s e e s s e a e s e s e a s e 55 INTRODUCTION e a s e s e e s e a s s s s s e s s s s 55 DESIGN AND SYNTHESISS OE CYCLIZATION SUDSTRATES . . . 60 NURAN NANIPULATIONS ‘ THE PREPARATION OF ALEALOID PRECURSORS s s s s s s s e a e e s s s e e e s a e s 66 EXPERIMENTAL s a a e a e s s ~e e e e e e e o a s e s 79 LIST 0’ REFERENCBS s s e a s e s e s a s s s s e e e 107 iv EAR! I Table I Table II LIST OF TABLES Cyclization Substrates and Possible Praduct.. O O O O O O O O O O O O O Cyclization Results . . . . . . . . um Figure I Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 LIST OF FIGURES The Synthesis of §r(8poxyalky1)- Pyrroles 8, 10, 12 and 13. . . . . . . N-acyliminium Ion 1. . . . . . . . . . N-acyliminium Ion Skeletal Types . . . 3-Substituted-to-2-fury1 and 2- , substituted-to-S-furyl Terminated N- acyliminium Ion-Initiated Cyclisations Leading to Indolisidine and Quinolizidine Alkaloid Precursors. . . Indolizidines and Quinolizidines . . . Oxidation of 2,3—Disubstituted Furans. vi 55 59 60 62 67 (1) (3) (3) PAR (1) (2) <3) (4) (5) (8) (7) (8) (9) (10) I LIST OF EQUATIONS Cyclisation Sequence. . Products. . . . . . . . Alkylation Sequence Providing grepoxyalkyl Pyrroles 9 and 11 . . i The Tscherniac-Einhorn Reaction. . . . Electrochemical Oxidation of Amides. The pH-Controlled Sodium Borohydride Reduction of Cyclic Imides . N-acyliminium Ion with Closure. . . . . . . . . N-acyliminium Ion with Closure. . . . . . . . . a 3-to-2-furyl a 2-to-3-furyl Preparation of Cyclised Substrates 22 and Preparation of Cyclised Substrates 2D and Preparation of Cyclised Substrates 36 and Preparation_of Cyclized Substrates 43 and Ketalization of l! (n=1) and 65 (n=2). vii 'Synthetic Equivalents of fl,e-dialkyl Pyrrole 56 57 57 60 60 63 63 63 63 74 EAST—LL Scheme I Scheme II Scheme III IV Scheme Scheme V Several Methods LIST OF SCHEMES of N-acyliminium Ions. Desilylation of N—acyliminium Ion Precursor 5” (n=2) Upon Cyclization to 25 (n=2). Preparation of Diones 5! (n=1) and 65 (n=2). for the Generation Proposed Synthesis of Lupinine 15 or Bpi-lupinine 15. Proposed Synthesis of Elaeokanine A viii Page 70 71 74 76 INTRODUCTION PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. THE PREPARATION OF 5,6,7,8-TETRAHYDRO-INDOLIZIDINES AND 5,7,8,9-TETRAHYDRO-[5H]-PYRROLO[1,2A]-AZEPINES. INTRODUCTION The alkaloids present a multitude of skeletal and structural types providing a broad spectrum of potent and interesting biological activities.1 A common skeletal arrangement displayed by a number of the bioactive alkaloids is a five-membered nitrogen-containing ring fused to a five-, six-, or seven-membered carbocycle. The Nrcontaining heterocyclic moiety, in the pyrrole or pyrrolidine oxidation state, is an integral part of such molecules as the pyrrolizin-l-one 12; from the hairpencil secretion of the male Monarch butterfly Lycorea cares cares; the haepatotoxic pyrrolizidine alkaloid heliotridine 2"; the Dendrobatjd alkaloid pumiliotoxin B 3‘; the potent abmannosidase inhibitor swainsonine 45; and 'the insecticide, tuberostemonine 5.5 LO Alkaloids 1-5 exhibit an N—a attachment of the fused ring system, as opposed to an a,p-fused array which is indicative of the indole class of alkaloids. As a result of our success in preparing fused-ring systems via furan- _terminated cationic-cyclizations’, we became intrigued by the possibility of preparing the fused-ring systems of compounds 1-5 by a pyrrole-terminated cationic cyclization. In principle, the pyrrole nucleus should be a more effective terminator in cationic recyclizations than a furan, owing to pyrrole’s greater nucleophilic character.8 The general sequence (Eq. 1) for preparing the N-a fused system consists of cyclizing an N-alkyl substituted pyrrole 6, possessing a latent electrophilic site at a well-defined location in the alkyl chain. Compound 7 would result after activation of th DU 89 eq: in BM ROI. fun PTO the benign electrophile, electrophilic attack at the more nucleophilic e—position, and rearomatization. The resulting flea—dialkyl pyrrole 7, obtained from the cyclization of 6, establishes the pyrrole nucleus as the operational equivalent of the hypothetical pyrrolyl dianion illustrated in Equation 2. Variation of the distance between the active and latent electrophilic centers of the alkyl chain (Eq. 2) would provide compound 7 in which the size of the formed ring could be easily altered. In addition, the residual functionality resulting from the cyclization initiator might provide sufficient synthetic ”handles” for the completion of a complex synthesis. 05 —-' GIGS —_—* Cb "’ E. Z. R ‘ R _ ‘~(3 ‘0 - A Z. Desi n and S nthesis of thggCyclization Substrates. Cationic s—cyclization, in the construction of carbocyclic ring systems, has been the object of intense study since 1950.7'9'“n A classic example is the biomemetic a: P? th u re] Do} It“ polyene cyclisations which have yielded a variety of naturally occurring steroids and other natural products with remarkable stereoselectivity at ring Junctions and remote stereocenters in the polycyclic frameworkJ":u For a polyene cyclization to succeed, a suitably electrophilic cyclization initiator and a sufficiently nucleophilic terminator-functionality are imperative. During the course of previous investigations of cationic cyclisations, a wide variety of initiator and terminator functions have been examined. Some commonly utilised nucleophilic terminators include simple olefins“, aromatic rings13, acetylenes“, allyl- and propargyl silanesu and allenes." Other terminator. functions that are used with less regularity are vinyl ethers” or heteroaromatics, such as thiophenen and furan.7 Conspicuously 1 missing are numerous examples in which pyrrole has been used as a successful cyclization- terminator function.3v""' The lack of precedent in this area is undoubtedly due to the reactivity of the N-alkyl pyrrole starting materials and the enhanced sensitivity of the derived gee-dialkyl pyrrole products. This is expected as pyrrole and simple alkyl substituted pyrroles have been reported to react readily with oxygen and acids, providing polymeric materials." The range of electrophilic-initiator functions has been studied to a much greater extent. A wide variety of functional groups have been used to ”trigger” cyclization M De 'Y reactions. Some of the common initiators are simple olefins30; epoxides’kail‘lai; allylic alcohols7kt’0'1‘; and their oxidation products, a,p-unsaturated ketones.13'-° Additionally, Johnson has shown that acetals can be used to initiate cationic cyclisations and that chiral acetals have the ability to transfer chirality to the . resulting cyclization products.33 Recently, attention has been directed towards the use of N-acyliminium ions as cationic cyclization initiators culminating in the syntheses of several alkaloid skeletal types.""'M . Our earlier work with furan-terminated cationic cyclisations’ and the excellent studies of othersi'hl‘il'ni1 has deEonstrated the utility of the epoxide function as a cyclisation initiator. A wide variety of Lewis acids were examined in that study and successful cyclization to acid labile 2,3-disubstituted furans was observed when the Brdnsted acidity of the reaction medium was moderated. These relatively mild conditions, coupled with the ease of epoxide introduction, either insertion intact or as the corresponding diol acetonide, made the epoxide the initiator of choice. Another equally important aspect of this study was to assess the effbctiveness of the sensitive pyrrole nucleus as a terminator function in cationic sbcyclisations. The cyclization substrates examined were designed to permit entry into five-, six-, or seven-membered ring systems. In all of the cases examined, the substitution rea: intr inta undo nucL the Equat ether preps 0121’ Yield. PYrrol ePOxy. the about the oxirane was biased to favor one mode of C-0 bond polarization over the alternative bond."°'13v1° Furthermore, we have examined placing the initiator function within the ring being formed (endocyclic) or outside the forming cycle (exocyclic).23 The requisite N-epoxyalkyl pyrroles and possible reaction products are illustrated in Table I. R’ KOtOu R R3 6 .= . 2: ~ e \ NH IJ n EtO CMCH): (3’ £31533: EE’ 2 III H it g: 4‘5‘ ’21 3 Ms H H L'. 34% As previously mentioned, the propensity of pyrroles to readily react with oxidizing agents necessitates the introduction of the epoxide, or its synthetic equivalent, intact. Standard olefin epoxidation Eethodology" would undoubtedly result in destruction of the sensitive pyrrole nucleus. Therefore, we envisioned the most direct route to the requisite epoxy pyrroles 8-13 to be that described in Equation 3. Treatment of pyrrole with EOtéBu and lB-crown-G ether followed by the addition of epoxy-iodide 22, which is prepared from the commercially available 3-methy-3-buten-l- 013‘, provided grepoxyalkyl pyrrole 9 in a very modest 40* yield. Similarly, iodo-epoxide 2335 led to epoxyalkyl pyrrole 11 in a disappointing 34x yield. The low yields of 'epoxy-pyrroles 9 and 11 forced us to consider introducing the epoxide function in a protected form, as the . 5., 5‘61 7‘91:; TABLE I: Cyclizotton Statutes and Possible Predicts M' notion EpoxyolkyI-Pyrrols Possifls Products franc/Sande G. \ N mo 8 I3 is ~ CC 8? )9‘ NH )8: corresponding dial-acetonide, in order to complete the synthesis of R, 10, 12, and 13 (See Figure l). .J=~= 2.315: gt 2 HH, £5 2 HMs g. 3 HH ’33, 4 HH 1|; 1|? IL? 3|? 1x: I 1|? ll i fit tiflblhrH H link H H H H H fith H H H H H fith it 2a a onoanorololols 283 Figure 1 : The Synthesis of flr(EpOXYllk¥ll-P¥rr°l¢5 Qo L2-.L%v “"d LE- As is illustrated in Figure l, the alkylation (SOL-Bu, 180-6, EtzO) of pyrrole with o—iodo diol acetonide 243‘ yielded the corresponding pyrrole-fl-alkyl diol acetonide 25 in a much improved 952 yield after chromatography. Careful hydrolysis with pyridinium prtoluenesulfonate27 in methanol provided diol 32 (R4=R5=E, 892) which was converted to the tl (E in of car he ring labil 'enai Carefl Drila, Profou Path“J c"Feet glycol monotosylate (stCl, pyridine) 32 (R4=27Ts, Rs=R) in 912 yield. Closure to the oxirane, with carefully chosen reaction conditions, (xogrsu, TRF, -78°C) gave the desired N—(epoxyalkyl) pyrrole S (902) in 692 overall yield from pyrrole. In similar fashion, alkylation of pyrrole with e- iodo diol acetonides 263°, 28", and 3030 provided the requisite !r(epoxyalkyl) pyrroles 10, 12 and 13 in 252, 572 and 722 overall yields, respectively. With the exception of the mono-tosylation of the highly hindered diol 33 (R4=Rs=R), all yields were 2 782 per step. Although initially disappointed with the low yield for the tosylation of diol 33 (Rs=Rs=H), the remainder of the reaction mixture consisted of unreacted starting material (552) which could be readily recovered and resubmitted to the reaction conditions, thus providing an acceptable yield of 33 (R4=R, Rs=p-Ts). Cyclization Studies With the desired cyclization substrates available, the ring closing sequence was then examined. Given the acid lability of the pyrrole terminator-function and the enhanced sensitivity of the resulting product, fi,s—dialkyl pyrroles, careful consideration of the reaction conditions are of primary concern. The choice of Lewis acid should have a profound effect in determining the preferred reaction pathway of the cyclization substrates. It was our hope that correct conditions could be found which would maximize the 10 pathway leading to fruitful cyclization and minimise the formation of unwanted side products. In addition to the standard EFs'OEta, which has seen considerable use in inducing cationic s-cyclisations°"351°, four other Lewis acids were selected (See Table _II) after considering two factors: (1) the ability to readily modify the potency of a group of Lewis acids with a common metal center and (ii) the possibility of moderating the Er5nsted acidity of the medium through choice of Lewis acid. Extraneous protic acid might be scavenged by Lewis acids, such as the alkyl aluminum halides81 which possess a protonolysable carbon-metal bond, forming an alkane. Alternatively, with the proper choice of metal, the product metal-alcohol complex should be a much weaker Br5nsted acid compared to a SFa-alcohol complex. Snider has reported the successful application of alkyl aluminum halides as Lewis acids in acid-sensitive cyclizations. The alkyl aluminum halides cover a wide range of Lewis acidity’l, from the very potent AlCls, .to the barely acidic MeeAl. It is this range in Lewis acidity, together with their ability to scavenge protic acids, which might make these Lewis acids appropriate choices for initiating epoxy-pyrrole_cyclisations. Further modification of aluminum-centered Lewis acids is possible, as demonstrated by Boeckman in his use of activated alumina as «>wrm _~ nan..~mn‘e: ”sundae was.m >nia . m.fi€§.§3-€33 52$: 3; 253;: 2.. 2.38:» 2.. 393:9.“ 3.. EN: 3.. a $28. $8: $33 $23 $33 a SE: SE: SE: ....... S35 $ 52: 583 $2: 5:: as: u .5. $5: $85 $3.5 $253 53: am $83 $33. $35 $3.: $325 £23. £22: $883 $ 323 Bag £33. £25: £23.95 +~.a Loaoskas‘: £§§2~8 +59“ .oaoskas‘: 0C th 95': fit ac; Pro 12 a catalyst for epoxide-initiated vinyl ether-terminated cationic cyclisations.u Titanium tetrachloride is a strong Lewis acid which has been observed to react with epoxides to provide '- chlorotitanates.33 The oxophilicity of titanium and the relative acidity of the Ti-alcohol complex can be tempered by replacing chloride by alkoxy groups, such as isopropoxy. The titanium tetraalkoxides have been shown to be effective in catalyzing aldol condensations" and p-hydroxyl epoxide- initiated olefin-terminated cyclisations.n Furthermore, Stork” has demonstrated the use of the closely related 2r(O-iPr)4 in promoting intramolecular Michael additions, leading to angularly methylated trans-hydrindenones. Finally, zinc iodide:N was selected to catalyse epoxy- initiated cyclizations based on the assumption that the intermediate Zn-alcohol complex, generated in the cyclisation step, would be a weak protic acid. This assumption is substantiated by Marshall’s successful closure of an acid-sensitive diene-aldehyde in 'his synthesis of occidentaldol.°" For our particular study, we examined the ability of the following five Lewis acids to promote epoxy-initiated pyrrole-terminated cationic cyclization: EtAlClz; EtaAlCl; Ti(OirPr)sCl; ZnIa; and BFs-OEta/TEA. The first four Lewis acids had provided poor to excellent yields of cyclized products during our furan-terminated cyclization studies"; N de‘ 0x1 13 however, the aluminum-based Lewis acids afforded considerable quantities .of allylic alcohol by-products. From our initial experiments, we discovered that standard BF3~OEta conditions generally used to catalyse epoxy- initiated cyclisations had to be modified. Tempering the Lewis acidity of BFa-OEts was accomplished with ethereal solvents (EtsO, TEF) and tertiary amine bases, such as triethylamine. Raving considered the requirements for the Lewis acids in this study, we began our examination with the moderated lFe-OEta (R20, EtaN) reaction conditions. g-(epoxyalkyl) pyrrole S was treated with BFa-OEts (1 equiv.), EtaN (1 equiv.) in TRF at -45°C to provide a single product 14 in 702 yield (See Table II). Examination of the spectroscopic data (IR, 1R NMR, EI/MS) obtained for product 14 revealed the nature of the product. Indolizidine precursor 14 resulted from an unanticipated 6-endocyclic ring closure. The observation of cyclisation exclusively at the less-substituted terminus of the epoxide was unforeseen in light of our experiences with a similar iG-exo/S-endo furan-terminated cyclization" and the prior studies of van Tamelen.°'b In the analogous epoxide initiated-furan terminated cyclization, the ring-opened allylic alcohol was formed to the complete exclusion of closure to form the five-membered ring." The failure to form a five-membered ring is likely the result of poor overlap between the developing cationic center at the internal carbon of the oxirane with the s-system of the pyrrole nucleus. Lack of 0t 09 th to: on ”in "It! 14 flexibility in the Iralkyl side chain which possesses but two sp3-carbon atoms precludes this overlap from occurring. Indeed, by analogy to the work of Storka'F, we anticipate that 'Markovnikov” attack of the nucleophilic pyrrole-a- carbon upon the more substituted carbon of the Lewis acid complexed epoxide would result in a severe bond angle distortion. Furthermore, van Tamelea has examined a polyene cyclization with an identical orientation of the Ibsystem nucleophile relative to the mono-substituted epoxide and has obtained the ”anti—Markovnikov” cyclization product, albeit in 22 yield.“'” Our observation of exclusive ”anti— Markovnikov” attack on grepoxyalkyl pyrrole I to give 14 in 702 yield is indeed noteworthy. A In a similar fashion, Slwas subjected to EtAlCla (2 equiv., 022012, -78°C), EtaAlCl (2 equiv., CRsCla, ~78°C), Ti(0;rPr)eCl (3 equiv., CR2012, O°C-25°C) and ZnIa ((3 equiv., PhR, 25°C) to provide 14 in 232, 322, 452 and 332 yields, respectively. It should be noted that these and other cyclization yields determined in this study are for optimised reaction conditions and represent virtually all of the recovered material. !r(epoxyalkyl) pyrrole 9, which has been further biased toward C-O bond cleavage at the internal carbon of the oxirane, was treated with BFa-OEta in THE containing an equivalent of TEA to yield exclusively the 6-endo product 15 in 322 yield; none of the possible by-products associated with epoxide opening were detected. The alkyl aluminum All it 15 halides; EtAlCla, EtaAlCl and ZnIa, yielded only 15 in 422, 442 and 672 yields, respectively. Surprisingly, the generally mild Ti(OirPr)sCI afforded an intractable mixture of unstable products which apparently did not contain 15. Epoxy-pyrrole 10, which was expected to yield only 6- endo product 17 by analogy to our earlier work in the furan area", was treated with moderated BFs-OEta (TEA, TRF) providing a single cyclized alcohol 17 in an excellent 912 yield as a white crystalline solid (mp = 79-8100). Good to excellent yields were obtained (60-742) with the remaining Lewis acids used in this study (See Table II). Similarly, !r(epoxyalkyl) pyrrole 11 led to uniformly high (72-812) yields of the expected S-exo product 15 after treatment with the Lewis acids shown in Table II. The next substrate examined was the gr(epoxyalkyl) pyrrole 12 which is the precursor to the 6-exo 19 and the 7- endo cyclised alcohol 25. An analogous 5-(3-furyl)-l,2- epoxy pentane provided only the corresponding 6-exo cyclised product with a variety of Lewis acids." Therefore, we anticipated similar behavior when the furyl moiety was replaced with pyrrole as the terminator. In the event, treatment of'12'with BFe-OEta (TEA, TEF) afforded the 6-exo product 19, albeit in only 202 yield. However, treatment of 12‘with EtAlCla (032012, -78°C) yielded a mixture of two compounds, the expected fire-dialkyl pyrrole product 19 (352) and the previously unobserved 7-endo alcohol 25 (452). The isolation of the 7-endo product as the maJor cyclised Pr be (e 16 material suggests that the more nucleophilic pyrrole terminator coupled with the relatively mild reaction conditions are conspiring to yield the product of an assisted 823 substitution at the less sterically encumbered oxirane carbon.33 The final cyclization precursor 13 provided the expected 7-exo alcohol 21 (See Table II) as the only cyclised product with the five Lewis acids studied. The yield of 21 ranged from a disappointing 212 using moderated BFa-Olts (TEA, TRF) to an excellent 852 using Ti(OiPr)3C1 (See Table II). Exposure of 13 to 2nIs provided, 1: addition to cyclised product 21, the corresponding iodohydrin in a yield which was dependent upon the reaction solvent (PhR, 212; EtaO, 492). These results demonstrate the pyrrole moiety to be an excellent cationic cyclization terminator in epoxide- initiated cyclisations. In general, the ring size obtained is predictable, providing mixtures only in the case of 5: (epoxyalkyl) pyrrole 12. In addition, it is interesting to note that the 7-endo mode of closure can compete effectively with the expected 6-exo pathway leading to 12. It is particularly noteworthy that the exclusive products obtaineo from epoxy-pyrroles 5 and 9 are the ”anti-Markovnikov” cyclised materials. Finally, the yields of cyclised products obtained ranged from moderate to excellent; ' however, closer scrutiny of Table II does not reveal any general trends which would assist in the selection 0: 17 ”optimum” reaction conditions. The most favorable reaction conditions must be determined on an individual basis. -__ EXPERIMENTAL PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. THE PREPARATION OF 5,6,7,8-TETRAHYDRO-INDOLIZIDINES AND 6,7,8,9*TETRAHYDRO-[5H]-PYRROLO[1,2A]-AZEPINES. EXPERIMENTAL SECTION General. Tetrahydrofuran (TEF) and benzene were dried by distillation under argon from sodium benzophenone ketyl; methylene chloride was dried by distillation under argon from calcium) hydride; triethylamine (TEA) was dried by distillation under argon from calcium hydride; t-butanol was dried by distillation under argon from sodium; pyridine was dried by distillation under argon from calcium hydride. Boron trifluoride etherate (BFe-OEtz) was dried by distillation at .reduced pressure from calcium hydride. Petroleum ether refers to 35-60°C boiling point fraction of petroleum benzin. Diethyl ether was purchased from Columbia Chemical Industries, Inc., Columbus, Wisconsin, and was used as received. Osmium tetraoxide was purchased from Aldrich Chemical Company, Milwaukee, Wisconsin and prepared as a 0.5M solution in t-butanol. Ethylaluminum dichloride and diethyl aluminum chloride were purchased as hexane solutions from Alfa Products, Denvers, Massachusetts, and .used as received. All other reagents were used as received unless otherwise stated; all reactions were performed under argon with the rigid exclusion of moisture from all reagents and glassware unless otherwise mentioned. 18 th 8e C0 19 Melting points were determined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Pye-Unicam SP-1000 infrared spectrometer or a Perkin-Elmer Model 167 spectrometer with polystyrene as standard. Proton magnetic resonance spectra (la-NMR) were recorded on a Farian T-60 at BOMEz, a Varian OFT-20 at EOMEz, or a Druker HM-250 spectrometer at 250MHz as mentioned in deuteriochloroform unless otherwise indicated. Chemical shifts are reported in parts per million (0 scale) from internal standard tetramethylsilane. Data are reported as followed: chemical shifts (multiplicity: s = singlet, hrs 8 broad singlet, dd a doublet of doublets, d = doublet, t = triplet, q = quartet, m = multiplet, coupling constant (Hz), integration). Electron impact (EI/MS, 70eV) mass spectra were recorded on a Finnigan 4000 with an INCOS 4021 data system. Exact Mass Mass Spectrometry is presently being performed at the University of Chicago under the direction of Professor David G. Lynn. Flash column chromatography was performed according to the procedure of Still“ et. al. by using the Nhatman silica gel mentioned and eluted with the solvents mentioned. The column outer diameter (o.d.) is listed in millimeters. 20 General Procedure for the N-Alkzlatiog of Pyrroles with e- Iodo Epoxides. g-Methyl-5-(Aprrrolyl)-l,2-epoxypentane 11. To anhydrous ether (40mL) at room temperature under argon was added 18-crown-6 ether (0.53g, 2.0mmol) and potassium t-butoxide (2.58g, 23.0mmo1) followed immediately by pyrrole (1.34g, 1.39mL, 20.0mmol). The resulting off- white suspension was stirred for 15 minutes. To this mixture was added a solution of 23'" (5.20g, 23.0mmol) in ether (18mL) over 15 minutes. The mixture was stirred at room temperature for 20h, diluted with 220 (100mL) and cast into ether (100mL) and E20 (100mL). The aqueous layer was. separated and washed with ether (2 x 80mL). The combined ether layers were washed with brine (200mL), dried (NazSOs) and concentrated in vacuo to afford a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 200g, 60mm o.d., ether-petroleum ether 30:70, 60mL fractions) using the flash technique. Fractions 24-32 provided 1.13g, 342, of 11 as a pale yellow, free-flowing liquid. 1 1E-NMR (250MHz, Gene): 6 = 6.45 (m, 2), 6.35 (m, 2), 3.29 (t, J=6Ez, 2), 2.10 (s, 2), 1.38 (m, 2), 1.10 (m, 2), 0.93 (s, 3); IR (neat): 3100, 3040, 2920, 1290, 1090, 720 cm‘l; EI-MS (70eV): 165 (M’, 73.3), 148 (37.7), 134 (38.7), 120 (60.5), 81 (53.5), 80 (base), 68 (60.7). Anal. C, H, N. 2“ 21 g-Methzl-4-(g-pyrrolyl[-1.2-fipoxzbutage 9. According to the general procedure for fi-alkylation of pyrroles with e—iodoepoxides, the reaction of 0.34g (5mmol) of pyrrole with EOtDu (0.56g, 5mmol) and l8-crown-6 ether (44mg, 0.17mmol) in benzene (8mL) followed by the addition of e—iodoepoxide 227v35 gave 0.302g (402) of 9 after purification by chromatography on a column of silica gel. 1E-NMR (60MEz): 5 = 6.43 (t, J=1.5Ez, 2), 5.90 (brt, J=1.5Rs, 2), 3.88 (t, J=6.5Ez, 2), 2.3 (m, 2), 1.85-2.20 (m, 2), 1.22 (s, 3); IR (neat): 3100, 3020, 2930, 2870, 1500, 1450, 1380 (br), 1285, 1090, 905, 800, 730 cm'l; EI—MS (70eV); 151 (M’, 68), 120 (33), 106 (14), 95 (12.8), 80 (base). Anal. C, H, N. -Eenz o -4- e 1- ent-3-ene. To a suspension of oil-free Nan (1.42g, 59mmol) in dry TEF (100mL), chilled in an ice-820 bath to 0°C, was added 4- methyl-pent-3-en-1-ol3° (5.78g, 57.8mmol) over 30 min. The mixture was warmed to 25°C, stirred for 30 min, then a catalytic amount of tetrabutylammonium iodide (214mg, 0.578mmo1) was added followed by the addition of a solution of benzyl bromide (9.99g, 58.4mmol) in TRF (lOmL) over 40 min. The resulting suspension was stirred at 25°C for 5h, quenched by cautiously adding water (100mL) and extracted with EtaO (3 x 100mL). The combined Et20 layers were washed 22 with brine (300mL), dried (MgSOs) and concentrated in numb to 11.0g, 1002, of the benzyl ether as a pale yellow liquid which was used without further purification. 1E-NMR (60MEz): 6 = 7.38 (s, 5), 5.10 (m, l), 4.45 (s, 2), 3.48 (t, J=8Ez, 2), 2.50-2.0 (m, 2), 1.70 (s, 3), 1.63 (s, 3); EI-MS (70eV): 190 (n+, 1.05), 175 (1.97), 147 (1.48), 132 (8.50), 107 (26.6), 91 (base), 69 (76.7), 41 (76.0). 1- enz lox -4- et 1 entan-3 4-diol. To'a solution of benzyl ether (3.85g, 20.26mmol) and N- methylmorpholine N—oxide hydratea’ (3.56g, 26.34mmol) in acetone (13mL) and water (5.0mL) was added at room temperature a solution of osmium tetraoxide°° (2.02mL, 1.01mmol, 0.5M) in t-butanol. The resulting deep purple solution faded within minutes to a light maroon color where it remained for 15 minutes before returning to a deep purple’ cast. The mixture was stirred at room temperature for 24h. A major portion of the solvents were removed at reduced pressure and the aqueous residue was acidified with cold 2N aqueous ECl followed by the addition of 102 aqueous sodium bisulfite (lOmL). The aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (6 x 50mL). The combined organic phases were washed with 102 aqueous sodium bisulfite (300mL), brine (300mL), dried (MgSOa) and concentrated invacuoto provide 4.03g of a pale yellow, A viscous liquid. The crude product was purified by chromatography on a column of silica gel (60-230 mesh, 200g, 17 84 23 60mm o.d., ethyl acetate, 75-100mL fractions) using the flash technique to provide 3.50g, 772, of mono-protected triol as a water-white viscous liquid which was immediately converted to the corresponding acetonide. 1R-NMR (60MRz): 5 = 7.30 (s, 5), 4.50 (ha, 2), 3.70 (t, J=6Ez, 2), 3.50 (m, l), 3.15 (s, 2), 2.0-1.56 (m, 2), 1.23 (s, 3), 1.15 (s, 3); EI-MS (70eV): 224 (M*, 0.20), 206 (0.18), 188 (0.44), 178 (0.65), 165 (1.32), 148 (0.87), 123 (8.25), 107 (15.1), 91 (base). 1- Eens lox -4-Meth 1-3 4-Di-O-Iso ro li ene- entane-3 4- Biol. To a solution of the O-Denzyldiol (3.50g, 15.62mmol) in dry acetone (50mL) was added two drops of concentrated sulfuric acid and solid sodium sulfate (4.0g). The. mixture was stirred at room temperature overnight then quenched by suspending solid sodium bicarbonate in the reaction mixture for 15 min. The mixture was then filtered through a pad of celite topped with a layer of anhydrous magnesium sulfate and concentrated in vacuo to give 4.0g, 972, of the desired acetonide as awater-white viscous liquid. 1R-NMR (60MRz): a = 7.32 (s, 5), 4.58 (s, 2), 3.69 (m, 3), 1.80 (m, 2), 1.43 (s, 3), 1.37 (s, 3), 1.28 (s, 3), 1.10 (s, 3); EI-MS (70eV): 264 (M’, 0.85), 249 (base), 206 (18.8), 175 (4.46), 147 (25.4), 123 (38.2), 107 (13.8), 91 (73.3), 84 (16.7). [CD l'." he 18 at ove to ext Vitl aClue m, 24 4-Met 1-3 4-Di-0-Iso ro lidene- entane- 3 4-triol. A solution of benzylether-acetonide '(4.00g, 15.2mmol) in ethanol (60mL) was. hydrogenated at 65 psi over 102 palladium on charcoal (0.98g) for 24h. The catalyst was removed by filtration and the solution was concentrated in mumm»to afford 2.54g, 982, of the deprotected triol as a water-white viscous liquid. . 1R-NMR (60MEz): 0 = 7.33 (s, 5), 4.55 (s, 2), 3.64 (m, 3), 1.78 (m, 2), 1.41 (s, 3), 1.32 (s, 3), 1.25 (s, 3), 1.10 (s, 3); IR (neat): 3480, 2950, 1460, 1370, 1100, 750, 700 cm'l; EI-MS (70eV): 174 (M*, 1.05), 159 (19.3), 117 (14.6), 99 (34.8), 85 (50.8), 71 (23.4), 59 (61.4), 43 (base). General Procedure for the Tosylgtiog of e-gydroxy Acetonides. 2-Meth 1-2 3-Di-0-Iso ro lidene- entane- 3 5-tr o -5- - Toluenesulfgnate. To a solution of the e-hydroxy acetonide (2.54g, 14.60mmol) in dry pyridine (8mL), chilled in an ice-water bath, was added p-toluenesulfonyl chloride (3.48g, 18.25mmol) in one portion. The reaction mixture was stirred at 0°C for 2h and then placed in a freezer (-20°C) overnight. The cooled reaction mixture was allowed to come. to room temperature, cast into ice-conc. RCl (50g/50mL), and extracted with ether (100mL). The ether layer was washed with 12 aqueous ECl (100mL), water (100mL), saturated aqueous sodium bicarbonate (100mL), brine (100mL), dried (NazSOs) and concentrated in mumm>to give 4.57g, 952, of 25 the acetonide tosylate as a pale yellow, viscous liquid which was used without further purification. General onceduge for the Iodination of Acetonide-Iosylates. To a solution of the corresponding acetonide-tosylate (8.22g, 25.06mmol) in acetone was added anhydrous sodium iodide (4.25g, 27.68mmol). The resulting yellow-brown mixture was heated under reflux for 5h, cooled to room temperature, filtered, and the filtrate taken up in ether (l50mL). The organic layer was washed with 102 aqueous sodium bisulfite (2 x l50mL), water (l50mL), saturated aqueous sodium bicarbonate (l50mL), brine (l50mL), dried (NazSOs) and concentrated .in vacuo to provide 6.0g (842) of 25 as a pale yellow, freeeflowing liquid. The crude product was purified by bulb-to-bulb distillation: bps.o = 89°C, to yield 5.69g, 802, of 25 as a water-white, free-flowing liquid. 1E-NMR (60MEz): 6 = 3.45 (m, 1), 3.32 (m, 2), 2.10 (m, 2), 1.50 (s, 3), 1.40 (s, 3), 1.29 (s, 3), 1.18 (s, 3); IR (neat): 2940, 1450, 1400, 1230, 1060, 830 cm'l; EI-MS (70eV): 284 (M’, 2.57), 269 (70.5), 239 (5.08), 227 (30.5), 212 (20.5), 127 (4.38), 99 (34.8), 71 (23.4), 59 (61.5), 43 (base). IA 26 A solution of the corresponding ePhydroxy acetonide3° (8.42g, 57.7mmol) in dry pyridine (30mL), cooled to 0°C in an ice-water bath, was reacted with p-toluenesulfonyl chloride (14.66g, 76.9mmol) according to the general procedure for tosylation of ePhydroxy acetonides to yield 15.0g, 872, off the tosylate acetonide as a pale yellow, viscous liquid which was used in the next step without further purification. A solution of the tosylate acetonide (15.0g, 50mmol) in acetone (dried over CaClz, 200mL) was reacted with anhydrous sodium iodide (8.25g, 55mmol) according to the general procedure. The crude iodo acetonide 24 'was purified by bulb-to-bulb distillation, E.P.o.1 = 52°C, to provide 10.1g, 792, of 24 as a water-white, free-flowing liquid. 1R-NMR (60MEz, 0014): 6 = 4.08 (m, 2), 3.60 (m, l), 3.22 (t, J=BRz, 2), 2.02 (m, 2), 1.38 (s, 3), 1.31 (s, 3); IR (neat): 2980, 2940, 2880, 1370, 1230, 1160, 1060, 840 cm’l; EI-MS (70ev): 256 (M’, 0.87), 241 (base), 218 (6.79), 199 (9.66), 181 (30.9), 101 (13.7), 72 (22.0), 59 (18.7), 43 (95.3). 5-deroxz-l,2-Di-O-Isopropylidene-pentane-l,2-Diol. To a solution of the 1,2,5-Pentanetriolz° (4.13g, 34.4mmol) in acetone (50mL, dried over CaCla) at room ll (7 10 H h in was 23. 85: Via: (fine; Prov; 27 temperature was added two drops of conc. RCl together with anhydrous NaaSOs (6.0g). The reaction mixture was stirred for 3h at room temperature then solid NaECOa was suspended in the mixture and stirring was continued for an additional 25 min. The reaction mixture was filtered and concentrated in ammo to 4.98g, 902, of the hydroxy acetonide as a slightly cloudy, viscous liquid which was purified by distillation: bpo.1 = 70°C. A 1E-NMR (60MRz, CDaCN): a = 4.10 (m, 2), 3.53 (m, 3), 2.80 (hrs, 1), 1.60 (m, 4), 1.4 (s, 3), 1.32 (s, 3); EI-MS (70eV): 160 (M’, 1.00), 145 (6.39), 117 (6.27), 99 (24.5), 101 (15.7), 83 (18.9), 59 (60.1), 43 (base). 1,2-Di-0-Isopropylidene-pentane-l,2-Diol—p-Toluenesulfonate. A solution of the hydroxy acetonide (2.85g, 17.8mmol) in dry pyridine (lOmL), chilledsto 0°C in an ice-water bath, was reacted with p-toluene sulfonyl chloride (4.52g, 23.7mmol) according to the general procedure to yield 4.08, 852, of the acetonide-tosylate as a cloudy, pale yellow viscous liquid which was used without further purification. 5-Iodo-l 2-Di-0-Iso ro lidene- entane-l 2-Diol 25 . A solution of the tosylate acetonide (4.23g, 13.43mmol) in acetone (50mL, dried over CaClz) was ireacted with anhydrous sodium iodide (2.32g, 15.44mmol) according to the 'general procedure for iodination of tosylate acetonides to provide 2.94g, 762, of 25 as a pale yellow, free-flowing 28 liquid. The crude product was purified by Eugelrohr distillation, E.P.0.01 = 68-70°C, to yield a colorless free- flowing liquid. In-uus (sauna): a = 4.1 (m, z), 3.45 (m, 1), 3.20 (t, J=SEz, 2), 2.15 (I, 2), 1.60 (I, 2), 1.35 (I, 3), 1.30 (I, 3); IR (neat): 2960, 1370, 1230, 1180, 1080, 850 Cl‘l; EI-MS 1,2-Di-0-Isopropzlidene-hexane-S-p-Toluenesulfonate. A solution of the hydroxy acetonide3° (11.12g, 63.9mmo1) in dry pyridine (33mL), chilled to 0°C in an ice- water bath, was reacted with p-toluenesulfonyl chloride (16.2g, 85mmol) according to the general procedure to give 18.95g, 902, .of the tosylate acetonide as a colorless viscous liquid which was used without further purification. 6-Iodo-1,2-Di-0-Isopropylidene-hexane-l,2-diol (30). A solution of the tosylate acetonide (18.84g, 57.44mmol) in acetone (180mL, dried over CaClz) was reacted with anhydrous sodium iodide (9.48g, 63.2mmol) according to the general procedure. The crude iodo-acetonide 30 was purified by bulb-to-bulb distillation: bpo.oi = 87°C, to give 15.17g, 932, of 30 save water-white 1iquid., In-unn (song): a = 4.08 (m, 2), 3.50 (m, 1), 3.20 (t, 1:732, 2), 1.90 (m, 2), 1.60 (m, 2), 1.42 (s, 3), 1.39 (s, 3); IR (neat): 2920, 1450, 1370, 1225, 1170, 1060, 850 cm'l; EI-MS (70eV): 284 (M’, 11.9), 269 (base), 227 (8.85), 209 (22.6), 127 (4.38), 101 (13.5), 81 (76.3), 72 (37.8), 43 (89.3). 29 Gener l P ocedure for the N-Al 1 tin of P rroles wit Iodo Acetonides. 1 2-Di-0-Iso ro lidene-6- N- rrol l hexane-l 2-diol 31 . To anhydrous ether (60mL) at room temperature under argon was added 18-crown-6 ether (0.793g, 3.0mmol) and potassium t-butoxide (3.82g, 34.0mmol), followed immediately by pyrrole (2.08mL, 30.0mmol). The -resulting off-white suspension was stirred at room temperature for 15 min. A solution of 30 (9.37g, 33.0mmol) in ether (22mL) was then added over 20 min. The reaction mixture was stirred at room temperature for 24h, diluted with 220 (100mL) and cast into ether (100mL) and water (50mL). The aqueous layer was separated and washed with ether (2 x 75mL). The combined other layers were washed with brine (200mL), dried (NazSOa), and concentrated in vacuo to provide a yellow liquid. The crude product was purified by chromatography on a column of silica'gel (60-230 mesh, 120g, 50mm o.d., ether-petroleum ether 1:1, 75mL fractions) using the flash technique. Fractions 7-14 yielded 6.56g, 982, of 31 as a pale yellow, free-flowing liquid. 1R-NMR (250MHz, Cans): 6 = 6.46 (t, J=1Rz, 2), 6.34 (t, J=le, 2), 3.70 (m, 2), 3.27 (m, l), 3.25 (t, J=8Rz, 2), 1.42 (s, 3), 1.32 (s, 3), 1.65-0.9 (m, 6); IR (neat): 2940, 1370, 1240, 1060, 720 cm‘l; EI-MS (70eV): -223 (M*, 26.1), 30 208 (8.21), 165 (18.6), 148 (55.2), 81 (base), 72 (35.3), 43 (53.5). Anal. C, R, R. General Procedure for the Deprotection of the Pyrrole Acetonides. 6- N- rrol 1 exa e-l 2-diol 35 . To a solution of the pyrrole-acetonide 31 (1.045g, 4.69mmol) in methanol (250mL) at 25°C was added p- toluenesulfonic acid (0.95lg, 0.50mmol). The mixture was allowed to stir for 2h then quenched by suspending solid NaRCOa for 5 min. in the reaction mixture. The mixture was filtered and concentrated In vacuo to provide a yellow viscous liquid together with some solid NaRCOe. The crude diol was purified by chromatography on a column of silica gel (60-230 mesh, 100g, 50mm o.d., EtOAc, 75mL fractions) using the flash technique. Fractions 7-15 yielded 0.775g, 902, of 35 as a yellow viscous liquid. 1R-NMR (250MHz, Cst): 6 = 6.51 (t, J=ZEz, 2), 6.35 (t, J=23z, 2), 3.81 (brs, l), 3.55 (m, 2), 3.41 (m, 1), 3.35 (t, J=7Rz, 2), 3.34 (t, J=7Rz, 2), 3.30 (hrs, 1), 1.25 (m, 6); IR (neat): 3360 (br), 2920, 1280, 1070, 730 cm"; EI-MS (70eV): 183 (M’, 44.4), 166 (7.34), 152 (12.3), 134 (15.2), 81 (base), 80 (78.2), 41 (44.3). 31 General Procedure for the Mono-Tosylation of the Pyrrolyl- 1. 2-2101.e Pre aration of 6- N- rrol l hex ne-l 2-dio -l- — Tol enesulfonate 35 R = Ts R =R . To a solution of diol 35, R4=Rs=H (0.75g, 4.10mmol) in dry pyridine (18mL), chilled in an ice-water bath, was added in one portion pétoluenesulfonyl chloride (0.90g, 4.72mmol) and a crystal of 4,4-dimethylaminopyridine. The resulting deep-red colored mixture was stirred at RT for 48h. The mixture was then cast into ice-cone. ECl (100g/100mL) and extracted with ether (l50mL). The ether layer was washed with 1N aqueous RCl (100mL), water (100mL), brine (100mL), dried (NazSOa), and concentrated in vacuo to provide a green viscous liquid (1.4g). The crude tosylate was purified by' chromatography on a column of silica gel (60-230 mesh, 100g, 50mm o.d., EtOAc, 40mL fractions) using the flash technique. Fractions 3-7 yielded 1.28g, 932, of 35 as an orange viscous liquid. 1R-NMR (60MRz, Cst): 0 = 7.70 (d, J=ERz, 2), 6.70 (d, J=SRz, 2), 6.40 (m, 2), 6.27 (m, 2), 3.95 (bra, 1), 3.74 (m, 2), 3.30 (m, 3), 1.89 (s, 3), 1.08 (m, 4); IR (neat): 3500, 3100, 2920, 1600, 1360, 1180, 970, 730 cm'l; EI-MS (70eV): 337 (M*, 0.81), 182 (lr43), 166 (5.20), 165 (19.7), 134 (10.2), 122 (16.7), 107 (20.5), 91 (46.9), 81 (base). 32 General Procedure for the Pornation of the Pzrrolyl Bpoxides. 6- N- rrol 1 -l 2-e ox hexane l3 . To a suspension of potassium t-butoxide (0.775g, 6.91mmo1) in dry TRF (40mL), cooled in a dry ice-0014 bath to -23°C, was added dropwise over 15 min. a solution of 35 (2.025g, 6.01mmo1) in dry TRF (20mL). The resulting magenta-colored mixture was stirred at -23°C for 15 min., warmed to RT, diluted with water (24mL), and cast into ether (200mL) and water (100mL). The organic layer was separated, washed with brine (200mL), dried (NazSOo), and concentrated in vacuo to yield a pale yellow, free-flowing liquid. The crude product was purified by chromatography on a column of silica gel (so-230 mesh, 1003, 50mm o.d., BtzO-petroleum ether 30:70, 50mL fractions) using the flash technique. Fractions 7-13 provided 0.87g, 88$, of 13 as a pale yellow, free-flowing liquid. 1R-NMR (250MHz): 6 = 6.61 (t, J=le, 2), 6.10 (t, J=le, 2), 3.85 (t, J=682, 2), 2.75 (m, 1), 2.69 (t, J=3Rz, l), 2.40 (m, l), 1.78 (m, 2), 1.45 (m, 4); IR (neat): -3100, 3050, 2920, 1500, 1290, 1100, 730 cm‘l; BI-MS (70eV): 165 (M’, 15.5), 147 (1.98), 134 (13.2), 120 (13.8), 106 (14.6), 94 (15.9), 81 (base), 80 (78.6), 53 (40.1). Anal. 0, H, N. 33 1,3-0i-0-Isopropzlidene- -(N-Pyrrolyl)butane-1,2—diol (25). A mixture of pyrrole (1.38mL, 20mmol), 18-crown-6 ether (0.53g, 2.0mmol) and potassium t-butoxide (2.58g, 23mmol) in anhydrous ether (40mL) was stirred at room temperature for 30 min. To the suspension was added a solution of 24 (5.76g, 22.5mmol) in anhydrous ether (15ml) over 15 min. The reaction mixture was stirred at room temperature for 18h and worked up according to the general procedure for the preparation of pyrrole acetonides. Flash chromatography on a column of silica gel provided 3.73g, 95:. of 25 as a pale yellow liquid. ln—NMR (60M82,_ 0014): a = 6.41 (t, J=282, 2), '5.87 (t, J=2Rz, 2), 3.83 (m, 4), 3.28 (m, 1), 1.80 (m, 2), 1.28 (s, 3), 1.20 (s, 3); IR (neat): 3100, 2980, 294-, 2880, 1500, 1370, 1290, 1250, 1220, 1160, 1090, 1065, 860, 730 cm'1; BI- MS (70eV): 196 (M’l, 2.97), 195 (M’, 24.4), 180 (1.17), 137 (10.4), 120 (43.0), 106 (4.34), 94 (30.1), 81 (base), 80 (73.9), 43 (36.0). 4-(N-errolzl )butane-l , 2-diol (32, R5 =R§ =11) . A solution of 25 (0.14g, 0.77mmol) in methanol (20mL) was stirred with pyridinium-p-toluenesulfonate (0.015g, 0.06mmol) at room ‘temperature for 32b and was worked up according to the general procedure for the deprotection ‘of pyrrole acetonides. Flash chromatography on a column of 34 silica gel gave 0.10g (898) of pyrrole-dial 32 as a pale yellow, viscous liquid. 1H-NMR (BOMHz, 0014): 5 = 6.38 (t, J=282, 2), 5.83 (t, J=282, 2), 3.89 (t, J=7Rz, 2), 3.50 (m,_ 2), 3.26 (m, 3), 2.62 (m, 2); IR (0014): 3400, 2930, 2870, 1500, 1280, 1240, 1090, 1060, 720 cm'l; RI-MS (70eV): 156 (M’l, 4.24), 155 (M’, 38.3), 137 (1.78), 124 (4.17), 120 (5.60), 106 (2.44), 94 (6.40), 81 (base), 80 (80.0), 68 (15.1), 53 (22.2). 4-(N-Pyrrolyl)butane-l,2-diol-l-p-Toluenesu1fonate (32, R = T R =8 . A solution of 0.098g (0.632mmol) of 32 (R4=Rs=R) in dry pyridine (4mL), chilled to 0°C in an ice-water bath, was reacted with p-toluenesulfonyl chloride (0.132g, 0.692mmol). The mixture was stirred overnight and worked up according to the general procedure for the tosylation of pyrrole diols. Flash chromatography on a column of silica gel yielded 0.177g, 91%, of the glycol mono-tosylate 32 (R4=st, Rs=8) as a pale yellow, viscous liquid. 1R-NMR (60M8z, 0014): 6 = 7.72 (d, J=8Rz, 2), 6.73 (d, J=883, 2), 6.42 (t, J=282, 2), 6.28 (t, J=282, 2), 3.97 (br s, l), 3.77 (t, J=68z, 2), 3.30 (m, 3), 1.87 (s, 3), 1.32 (m, 2); RI-MS (70eV): 309 (M’, 0.41), 172 (1.08), 155 (2.72), 137 (35.5), 120 (11.3), 106 (2.92), 94 (43.3), 81 (22.2), 80 (base), 68 (9.61), 67 (14.0), 53 (22.2). 35 4- N-P rrol 1 -1 2-e ox butane 8 . To a suspension of potassium t-butoxide (0.076g, 0.68mmol) in dry TRF (8mL), cooled to -78°C in a dry ice-i- PrOR bath, was added a solution of 0.174g (0.567mmol) of 32 (R4=st, Rs=8) in TRF (3mL) over 3 min. The mixture was stirred at -78°C for 10 min and worked up according to the general procedure for the formation of the epoxy-pyrroles. Flash chromatography on a column of silica gel provided 0.070g, 903, of 8 as a pale yellow, free-flowing liquid. 1R-NMR (60MRz): o = 6.62 (t, J=28z, 2), 6.10 (t, J=282, 2), 4.00 (t, J=7Rz, 2), 2.78 (m, 2), 2.37 (m, 1), 1.91 (m, 2); IR (neat): 3040, 2985, 2920, 2860, 1500, 1350, 1285, 1090,. 1065, 910, 720 cm'1; RI-MS (70eV): 137 (M', 48.4), 120 (3.71), 106 (14.0), 94 (12.7), 81 (20.3), 80 (base), 67 (13.9), 53 (29.3), 39 (26.4). Anal. 0, R, N. To anhydrous ether (20mL) at room temperature under argon was added 18-crown-6 ether (0.264g, 1.0mmol), potassium t-butoxide (1.23}. 11.0mmol),' and pyrrole (0.694mL, 10mmol). The resulting suspension was stirred at room temperature for 15 min, and a solution of 28 (3.00g, 10.56mmol) in anhydrous ether (7mL) was then added over 5 min. The mixture was stirred at room temperature for 24h 36 and was worked up according to the general procedure for the preparation of pyrrole acetonides. Flash chromatography on a column of silica gel yielded 2.21g, 998, of 27 as a pale yellow liquid. 1R-NMR (80MB:): 5 = 6.70 (hrs, 2), 6.25 (brs, 2), 4.10 (m, 2), 3.60 (m, l), 1.90 (m, 2), 1.50 (s, 3), 1.38 (s, 3), 1.22 (s, 3), 1.12 (s, 3); IR (neat): 3100, 2980, 2930, 2860, 1500, 1450, 1370, 1280, 1220, 1120, 1000, 730 cm'1; BI-MS (70eV): 224 (n+1, 4.80), 223 (M‘, 17.1), 208 (6.09), 178 (5.65), 166 (14.5), 148 (16.5), 81 (base), 80 (37.8), 59 (13.5), 43 (32.4). 2-Methi1-5-(N-pzrrolzl)pentane-2,3-giol (3B, R4=R§=R). A solution of 27 (1.10g, 4.83mmol) in methanol (250mL) was stirred with p-toluenesulfonic acid (0.0938g, 0.493msol) at room temperature for 24h and worked up according to the general procedure for the deprotection of pyrrole acetonides. Flash chromatography on a column of silica gel yielded 0.708g, 783, of 33 (R4=Rs=8) as a yellow viscous liquid. _ 1R-NMR (60MRz, 0014): 5 = 6.40 (t, J=282, 2), 5.83 (t, J=2Rs, 2), 3.90 (t, J=6Rz, 2), 3.60 (t, J=7Rz, l), 3.20 (hrs, 1), 1.95—1.55 (m, 3), 1.25 (s, 3), 1.15 (s, 3); IR (neat): 3400, 2940, 2860, 1500, 1450, 1370, 1280, 1110, 1050, 720 cm'l; EI-MS (70eV): 166 ("-17, 6.86), 165 (M-18, 33.8), 150 (49.8), 148 (14.6), 121 (21.8), 106 (21.6), 81 (base), 80 (52.7), 59 (36.0), 43 (28.1). 37 2-Meth -5- N- rrol l entane-2 3-diol-3- -Toluenesulfonate (33, R4=H, R§=st). A solution of 0.708g (3.87mmol) of 33 (R4=Rs=8) in dry pyridine (17mL), chilled to 0°C in an ice-water bath, was reacted with p-toluenesulfonyl chloride (0.848g, 4.45mmol). The mixture was stirred for 1h at 0°C and overnight at room temperature, then was worked up according to thegeneral procedure for the tosylation of pyrrole-dials. Flash chromatography on a column of silica gel gave 0.522g, 402, of 33 (R4=R, R6=st) as an orange viscous liquid. .389g, 55x, of 33 (R4=Rs=R) was recovered unreacted. lR-NMR (60MRz, 0604): a = 7.68 (d, J=888, 2), 6.73 (d, 1566:, 2), 6.53 (t, J=2Rz, 2), 6.20 (t, J=2nz. 2), 4.50 (t, J=4Rz, l), 3.82 (t, J=SRz, 2), 2.39 (hrs, 1), 1.92 (?, 3), 1.70 (m, 2), 1.00 (s, 3), 0.98 (s, 3); RI-MS (70eV): 337 (M’, 1.12), 182 (2.95), 165 (63.8), 150 (100), 132 (9.49), 121 (44.6), 106 (40.8), 80 (34.4). 2-Meth 1-5- N- rrol 1 -2 3-e ox entane l . To a suspension of potassium t-butoxide (0.049g, 0.44mmo1) in dry TRF (4mL), cooled to -78°C in a dry ice-if PrOR bath, was added a solution of 0.125g (0.371mmol) of 33 (R4=8, Rs=st) in TRF (1mL). The mixture was stirred at - 78°C for 15 min and worked up according to the general ' procedure for the preparation of epoxy pyrroles. Flash 38 chromatography on a column of silica gel provided 0.053g, 868, of 10 as a pale yellow, free-flowing liquid. 1R-NHR (60M82): 5 = 6.52 (t, J=282, 2), 6.02 (t, J=ZRz, 2), 4.12 (t, 3:782, 2), 2.82 (t, J=7Rz, 2), 1.70 (brs, 1), 1.10 (s, 3), 0.99 (s, 3); IR (0014): 3050, 2980, 2920, 2860, 1500, 1280, 1090, 910, 720 cm‘l; BI-MS (70eV): 166 (M’l, 4.70), 165 (M’, 36.9), 150 (47.3), 135 (5.40), 121 (25.7), 106 (63.6), 94 (21.3), 81 (50.6), 80 (88.7), 71 (32.0), 68 (45.3), 43 (base). Anal. 0, R, N. To anhydrous ether (20mL) at room temperature was added 18-crown-6 ether (0.264g, 1.0mmol) potassium tébutoxide (1.29g, 11.5mmol) and pyrrole (0.69mL, lOnmol). The suspension was stirred at room temperature for 15 min then a solution of iodo-acetonide 28 (2.85g, 10.56mmol) in anhydrous ether (7.1) was added over 10 min. The mixture was stirred at room temperature for 19h and worked up according to the general procedure for the preparation of pyrrole-acetonides. Flash chromatography on a colunn .of silica gel gave 1.82g, 873,, of 29 as a pale yellow, free- flowing liquid. lfl-NMR (60MRz, 0014): 5 = 6.52 (t, J=2Rz, 2), 6.00 (t, J=2Rz, 2), 3.88 (m, 4), 3.38 (n, 1), 2.15-1.50 (m, 4), 1.32 (s, 3), 1.25 (s, 3); IR (0014): 3100 2880, 2940, 2870, 1500, 39 1450, 1380, 1280, 1230, 1160, 1060, 850, 730 cm'l; BI-MS (70eV): 210 (M’l, 3.91), 209 (M’, 26.4), 194 (2.41), 166 (0.55), 151 (24.5), 134 (53.0), 93 (36.7), 81 (base), 80 (62.4), 72 (30.2), 43 (54.4). 5- N-P rrol 1 enta e-l 2-diol 34 R =R :8 . A solution of 29 (1.00g, 4.78mmol) in methanol (l30mL) was stirred with pyridinium-p-toluenesulfonate (0.12g, 0.478mmol) at room temperature for 32h and worked up according to the general procedure for the deprotection of pyrrole-acetonides. Flash chromatography on a column of silica gel provided 0.735g, 912, of 34 (R4=Rs=R) as a pale yellow, viscous liquid. In-Nun (sounz): 5 = 6.67 (t, 3:262, 2), 6.15 (t, J=znz, 2), 3.94 (t, J=7Rz, 2), 2.72 (t, J=4Rz, 2), 2.43 (n, 1), 2.12- 1.20 (m, 4); IR (neat): 3360, 2920, 2860, 1500, 1450, 1280, 1090, 1060, 730 cn-I: RI-Ms (70eV): 170 (n+1, 8.20), 169 (M*, 85.5), 152 (10.2), 149 (12.6), 138 (10.9), .134 (11.8), 120 (54.1), 95 (25.7), 85 (45.1), 81 (99), 80 (base), 68 (64.1), 53 (27.4), 43 (45.8). 5-(N-Pzrrolzl)pentane-l,2-di01:1-p-toluenesulfonate (34, R = Ts R =8 . A solution of 0.29g (1.74mmol) of 34 (R4=Rs=8) in dry pyridine (7mL), chilled to 0°C in an ice-water bath, was reacted with p-toluenesulfonyl chloride (0.393g, 2.06mmol). The mixture was stirred for 1h at 000 and overnight at room 40 temperature and was worked up according to the general procedure for the tosylation of pyrrole-diols. Flash chromatography on a column of silica gel yielded 0.462g, 833,» of 34 (R4=st, R6=R) as a yellow viscous liquid. 18- NMR (250MHz, Cst): 5 = 7.75 (d, J=882, 2), 6.72 (d, J=882, 2), 6.43 (t, J=282, 2), 6.30 (t, J=2Rz, 2), 4.02 (brs, 1), 3.81 (m, 2), 3.54 (m, 1), 3.31 (t, J=7Rz, 2), 1.84 (s, 3), 1.60 (m, l), 1.40 (m, 1), 1.02 (m, 2); IR (neat): 3100, 3050, 2930, 2885, 1500, 1280, 1090, 1070, 730 cm’1; RI-MS (70eV): 152 (M’l, 20.4), 151 (M’, 64.9), 134 (38.4), 120 (44.1), 106 (12.6), 93 (19.0), 81 (48.9), 80 (base), 68 (32.5), 53 (14.3). Anal. 0, H, N. General Procedure for Cyclizatiog of Pzrrole Bpoxides with ggg-ogta and Btgfl. ' Preparation of 8-deroxymethy148-Methzl-5,6,7,8-Tetrah1dro- indolizidine (18). To a solution of 11 (0.1g, 0.6mmol) in dry TRF (15mL), cooled to -42°C in a dry ice-08308 bath, was added BtaN (0.083mL, 0.6mmol) followed by freshly distilled RFa-OBta (0.074mL, 0.6mmol). The reaction was allowed to slowly wars to room temperature overnight and then was quenched with saturated aqueous Na8003 (lOmL). The mixture was cast into ether (75mL) and saturated aqueous NaRCOa (50mL). The organic layer was separated, washed with 1" aqueous 801 (50mL), water (50mL), brine (50mL), dried (Na2804), and 41 concentrated in vacuo to provide a yellow viscous liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 25g, 30mm o.d., BtzO-petroleum ether 30:70, l5mL fractions) using the flash technique. Fractions 15-20 provided 0.073g, 738, of 18 as a pale yellow, viscous liquid which solidified upon cooling. 18- NMR (250MHz, 0606): 5 = 6.35 (m, 1), 6.31 (t, J=282, l), 6.05 (m, l), 3.55 (d, J=1182, 1), 3.42 (d, J=1182, 1), 3.31 (t, J=682, 2), 2.62 (brs, l), 1.75 (m, 1), 1.48 (m, 2), 1.27 (m, l), 1.20 (s, 3); IR (neat): 3280, 2940, 1450, 1350, 1050, 720 cm‘l; BI-MS (70eV): 165 (M’, 12.7), 147 (6.56), 134 (base), 118 (9.97), 80 (8.30), 44 (54.4), 40 (88.2). Anal. C, H, N. General Procedure for Cyclization of Pyrrole-Bpoxides with BtAlCla. To a solution of 11 (0.1g, 0.606mmol) in dry 082012 (5 IL), chilled in a dry ice-0014 bath, was added EtA101z (0.82 mL, 1.21mmol, 1.47M in hexane) over 2 min. The reaction mixture was stirred for 25 minutes at -24°C then quenched with saturated aqueous 88401 (5mL). The mixture was cast into BtaO (50mL) and 18 aqueous 801 (50mL). The organic layer was separated, washed with brine (50mL), dried (NazSO4), and concentrated in vacuo to yield a pale yellow, viscous liquid. The crude product was purified by chromatography on a column of silica gel using the flash technique to provide 0.081g, 813, of 18. 42 General Procedpre for Cyclization of Pzrrole-Bpoxides with Bt3A101. Preparation of 18. To a solution of 11 (0.104g, 0.63mmol) in dry 082012, cooled to -40°C in a dry ice-08308 bath, was added BtaAlCl (0.86mL, 1.26mmol, 1.47M in hexane). The mixture was stirred at -40°C for 10 min then quenched by cautiously adding 18 aqueous 801 (10.1). The mixture was cast into Rt20 (50mL) and 18 aqueous 801 (50mL). The organic layer was separated, washed with brine (50nL), dried (Na2804), and concentrated In vacuo to yield a yellow viscous liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, '253, 30.. o.d., BtOAc-petroleun ether 40:60, 15nL fractions) using the flash technique. Fractions 5-10 provided 0.084g, 813, of 18. General Procedure for Cyclization of Pzrrole-Bpoxides with Ti(O-iPr)301. Preparation of 18. To a solution of 11 (0.142g, 0.861mmol) in dry 082012 (20nL), chilled in an ice-water bath, was added Ti(0- iPr)301‘° (3.44mL, 2.58nnol), 0.75M in 082012). The mixture was stirred for 15 min and then quenched with saturated aqueous 88401 (15mL). The solution was cast into 8t20 (75mL) and saturated aqueous 88401 (75mL). The organic layer was separated, washed with 18 aqueous 801 (75mL), 43 water (75mL), brine (75mL), dried (8a2804), and concentrated in vacuo to give an orange viscous liquid. The crude product was purified by chromatography on a column of silica gel using the flash technique to give 0.115g, 808, of 18. Geperal Proceduge for Cyclization of Pzrrole-Bpoxides with 2913-03t3. Prepppation of 18. To a solution of 11 (0.1g, 0.6mmol) in dry benzene (l5mL) at roon temperature was added freshly prepared anz-OBta‘1 (0.472g, 1.2mmol) in one portion. Within 5 min, the colorless suspension became orange in color and the reaction was .complete. The mixture was quenched with saturated aqueous 88401 (lOnL) and was cast into Bt20 (50nL) and saturated 88401 (50mL). The organic layer was separated, washed with 10* aqueous 8a28203 (50nL), water (50mL), saturated aqueous 8a8003 (50mL), brine (50mL), dried (8a2804) and concentrated In new to provide a pale orange viscous liquid. ‘ The crude product was purified by chromatography on a column of silica gel using the flash technique to give 0.072g, 72%, of 18. Cyclization of 8‘with BtgAlCl. Pre a ation of 7-8 drox -5 6 7 8-Tetrah droindolizidine 14 . To a solution of 8 (0.1g, 0.73mmol) in dry 082012 (5.2), chilled to -23°C in a dry ice-0014 bath, was added 8t2A101 (1.0mL, 1.47mmol, 1.478 in hexane). The mixture was 44 stirred at -23°0 for 30 min and then quenched by cautiously adding 18 aqueous 801. (5mL). The reaction mixture was worked up according to the general procedure for the cyclization of pyrrole epoxides with BtzAlCl. The crude product was purified by chromatography on a column of silica gel (60-230 mesh, 30g, 30m. o.d., BtOAc-petroleun ether 1:1, 20mL fractions) using the flash technique. Fractions 6-12 provided 0.032g, 323, of 14 as a pale yellow, viscous liquid. Ia—Nnn (250882): a = 6.54 (hrs, 1), 6.14 (m, 1), 5.84 (brs, 1), 4.15 (m, l), 3.96 (m, 2), 3.13 (dd, J=16.6,4.28z, 1), 2.77 (dd, J=16.6,8.382, 1), 2.03 (m, 2); IR (0014): 3380, 3100, 2940, 1490, 1430, 1320, 1200, 1070, 980, 700 cm'l; 81- MS (70eV): 137 (8*, 2.31), 118 (0.31), 108 (1.51), 93 (2.79), 44 (16.8), 40 (base). Anal. 0, 8, 8. Cyclization of 9*with Bt3A101. Preparation of 7-fizdroxz-7-nethyl-5,6,7,8-Tetrahxdroindol- izidine (l ). To a solution of 9 (0.085g, 0.566mmol) in dry 082012 (5mL), cooled to -78°0 in a dry ice-i-PrOR bath, was added 8t2A101 (0.76mL, 1.13mmol, 1.478 in hexane). The mixture was stirred at -78°C for 2h and then quenched by cautiously adding 18 aqueous 801 (5mL). The reaction mixture was worked up according to the general procedure for the cyclization of pyrrole-epoxides with Bt2A101. The crude 45 product was purified by chromatography on a column of silica gel (230-400 mesh, 30g, 30mm o.d., BtOAc-petroleum ether 30:70, 15ml fractions) using the flash technique. Fractions 8-13 provided 0.038g, 44x, of 16 as a pale yellow, viscous liquid. l8-88R (250882, 0406): 5 = 6.42 (m, 1), 6.37 (t, J=282, 1), 6.01 (hrs, 1), 3.65 (m, 1), 3.32 (m, 1), 2.50 (s, 2), 1.34 (m, 3), 0.97 (s, 3); IR (neat): 3420, 2900, 1450, 1380, 1330, 1120, 700 cm'l; RI-MS (70eV): 151 (8‘, 61.9), 136 (6.72), 120 (8.70), 108 (23.2), 93 (base), 80 (52.5), 66 (18.0), 43 (31.6). Anal. 0, 8, 8. Cyclization of’lfl with BtaAlcl. Preparation of 7-81droxy-8,8-dimeth11-5,6,7,8-Tetrahydro- indolizidine (1 ). To a solution of 10 (0.023g, 0.139mmo1) in dry 082012 (1.0mL), cooled to -78°C in a dry ice-irPrOH bath, was added BtaAlCl (0.19mL, 0.279mmo1, 1.478 in hexane). The mixture was stirred at -78°C for 20 min and then quenched by the addition of saturated aqueous 88401 (3 mL). The reaction mixture was worked up according to the general procedure for the cyclization of pyrrole-epoxides with BtzAlCl. The crude product was purified by chrosatography on a colunn of silica gel (230-400 mesh, 15g, 20ml o.d., BtOAc-petroleum ether 30:70, l5mL fractions) using the flash technique. Fractions 46 7-12 provided 0.014g, 618, of 17 as a pale yellow, viscous liquid which solidified on cooling. mp = 79-81°0; 18-888 (250882, 0604): 5 = 6.34 (m, 1), 6.30 (n, l), 6.07 (m, 1), 3.55 (m, l), 3.30 (m, 2), 1.56 (m, 2), 1.45 (hrs, 1), 1.20 (s, 3), 1.18 (s, 3); IR (0014): 3460, 2920, 1450, 1370, 1190, 1180, 1080, 1050, 850, 700 cm’l; 81-88 (70eV): 165 (M+, 48.9),1 150 (base), 132 (9.12), 121 (47.0), 106 (38.1), 80 (13.7). Anal. 0, 8, 8. Cyclization of 12 with Ti(0-iPr)301. Preparation of 8-81droxymethyl-5,6,7,8-Tetrahzdroindoli- ’zidine (19). I To a solution of 12 (0.050g, 0.33nmol) in dry 082012 (5mL), chilled in an ice-water bath, was added Ti(O-iPr)201 (0.50mL, 1.0mmol, 2.08 in 082012. The mixture was stirred at 0°C for 1h, warmed to room temperature and allowed to stir for an additional 45 min. The reaction mixture was worked up according to the general procedure for the cyclization of pyrrole-epoxides with Ti(0-iPr)201. The crude product was purified by chromatography on a column of silica gel (230-400 nesh, 20g, 200ml o.d., BtOAc-petroleum ether 30:70, 10mL fractions) using the flash technique. Fractions 10-14 provided 0.032g, 648, of 19 as a pale yellow, viscous liquid. 47 Cyclization of 12 with 8t2A101. Pre aretio of 19 and 6-8 drox -6 7 8 9-Tetrah dro 58 - rrolo 58 r olo 1 2a aze ine 20 . A solution of 12 (0.055g, 0.36mmol) in dry 082012 (?mL) was reacted with 8t2A101 (0.49mL, 0.72mno1, 1.478 in hexane) according to the general procedure for cyclization of pyrrole-epoxides with 8t2A101. The crude product was purified by chromatography on a column of silica gel (230- 400 nesh, 20g, 20mm o.d., EtOAc-petroleum ether 40:60, 15nL fractions) using the flash technique. Fractions 6-8 provided 0.020g, 378, of 19, and fractions 10-13 yielded 0.026g, 488, of 20 as a water-white liquid. l8-888 (250882, 0400): 5 = 6.31 (brs, 1), 6.18 (t, J=1.582, 1), 6.10 (hrs, 1), 3.32 (brs, 1), 3.20 (t, J=6.08z, 2), 3.16 (m, 1), 2.69 (brd, J=15.482, l), 2.63 (dd, J=l5.4,9.482, 1), 1.41 (m, 2), 1.09 (n, 2); IR (0014): 3460, 2920, 1430, 1350, 1280, 1020, 700 cm’l; RI-MS (70eV): 151 (8*, base), 150 (49.3), 134 (6.55), 122 (18.7), 106 (20.6), 94 (75.3), 80 (36.5), 53 (9.77), 41 (10.4). Anal. 0, 8, 8. Cyclization of 13 with Ti(0-iPr) 01. Pre aretion of 5-8 drox meth 1-5 7 8 9-Tetrah dro 58 rrolo- |1,2a|azepine (2 ). To a solution of 13 (0.104g, 0.630mmol) in dry 082012 (15mL), chilled in an ice-water bath, was added Ti(0-iPr)201 (0.945mL, 1.89mmol, 2.08 in 082012). The nixture was 48 stirred at 0°C for 1h, then warmed to room temperature and stirred for an additional 3h. The reaction mixture was worked up according to the general procedure for the cyclization of pyrrole-epoxides with Ti(0-iPr)301. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 30g, 30m. o.d., EtOAc-petroleun ether 30:70, 25mL fractions) using the flash technique. Fractions 8-13 yielded 0.088g, 858, of 21 as a pale yellow, viscous liquid. 18-888 (250882, 0200): 5 = 6.35 (m, 1), 6.18 (t, J=28z, l), 5.99 (brs, 1), 3.85 (dd, J=10.8,6.782, 1), 3.58 (dd, J=10.8,7.582,I 1), 3.31 (brq, J=7.782, 2), 2.61 (m, 1), 1.74 (n, 1), 1.60 (m, 1), 1.32 (m, 2), 1.15 (m, 2); in (001.): 3580, 2920, 2860, 1480, 1290, 1110, 1080, 1030, 700 cn'l; 81-88 (70eV): 165 (8*, 19.4), 134 (base), 118 (5.85), 106 (7.02), 93 (3.00), 80 (17.8). Anal. C, 8, N. Cyclization of 13 with ZnIz-OEta. Pre aretion of 21 and l-Iodo-2-h drox -6- 8- rrol l exane. A solution of 13 (0.105g, 0.636mmo1) in anhydrous ether (lOmL) was reacted with freshly prepared ZnIa-OBta (0.477g, 1.212mmol) for 3h at room temperature according to the general procedure for cyclization of pyrrole-epoxides with Zn12-08t2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 30g, 30ml o.d., BtOAc-petroleum ether 30:70, 20mL fractions) using the flash 49 technique. Fractions 5 and 6 gave 0.091g, 498, of 1-iodo-2- hydroxy-6-(8-pyrroly1)hexane as a pale yellow, viscous liquid. Fractions 9-13 provided 0.273g, 268, of 21 as a pale yellow, viscous liquid. 18-888 (250882, 0000): 5 = 6.46 (t, J=182, 2),. 6.34 (t, J=182, 2), 3.27 (t, J=68z, 2), 2.92 (m, l), 2.75 (t, J=482, 1), 2.64 (t, 3:682, 1), 1.45 (brs, 1), 1.24 (m, 2), 1.00 (n, 4); IR (neat): 3440, 2920, 1290, 1100, 730 cm'l; 81-88 (70eV): 166 (8-1, 8.07), 151 (5.80), 134 (4.54), 81 (8.11), 61 (13.8), 43 (base). LIST 0? REFERENCES PYRROLES AS TERMINATORS IN CATIONIC CYCLIZATIONS. THE PREPARATION OF 5,6,7,8-TETRA8YDRO-INDOLIZIDINES AND 6,7,8,9-TETRA8YDRO-[58]-PYRROLO[l,2A]-AZEPINES. For discussions and reviews of various aspects of alkaloid chenistry, see for example, the review series: ”The Alkaloids”, Specialist Periodical Reports; The Royal Society of Chemistry; London, Volumes 1-13, superceded by Natural Products Reports. 8einwa1d, J.; 8einwa1d, 7.0. J. 1.. Chen. Soc. m, m, 1305. ' For an elegant synthesis of (+)-he1iotridine 2, see: Che-berlin, A. 8.; Chung, J. Y. 1.. J. Am. 05a. Soc. 193, .106, 3653. For a recent synthesis of related (+)-Dehydroheliotridine, see: Chamberlin, A. 8.; Chung, J. Y. L. J. m. an. 105, 50, 4425. For a synthesis of 3, see: Overman, L. 8.; Bell, 8. I..; Ito, F. J. As. Chen. Soc. 1201, 1m, 4192. For several recent syntheses of 4, see: Fleet, G. 8. J.; Gough, 8. J.; Smith, P. 8. 18¢:er htt. 1’4, 25, 1853. 8esher, 8. A.; Rough, L.; Richardson, A. 0. J. was. Soc. 62.. 0m. 1004, 447. Suami, T.; Tedano, 8.; Iinura, 7. 05a. lett. I”, 513. G5ts, 8; 85gri, T.; Gray, A. 8. htrahedran Lett. 181, 3, 707. Shingu, T.; Tsuda, T.; Uyeo, 8.; Yanamoto, T.; 8arada, 8. 65-. Ind. m, 1191. a) Tenis, S. P.; Rerrinton, P. 8. J. Org. Class. 183, 48, 4572. ' b) Tanis, 8. P.; Rerrinton, P. 8. J. Org. as. m, 50, 3988. See A. Albert in ”8eterocyclic 0hem.”, Athlone Press, London, m, 0hs. 3 and 5. a) For reviews of polyene cyclization, see: Johnson, 8. 8. Acc. Chem. flu. 10m, .1, 1. van Tamelen, 8. 8. (bid. 1975, 8, 152. Johnson, 8. 8. 815511. 62-. 1976, 5, 51. Johnson, 8. S. Angew. 62am. Int. Ed. Eng). 1978, 15’, 9. b) van Tamelen, 8. 8.; 8arson, S. A. J. h. Chas. Soc. 1975, 97, 5614. 50 e) d) e) f) t) h) i) J) k) 1) I) n) 51 Groen, 8. 8.; Zeelen, F. J. Real. Dav. Chin. Pays-Bu. 1978, 97, 301. , Groen, 8. 8.; Zeelen, F. J. J. Org. Chem. 1978, 43, 1961. Peters, J. A. 8.; Posthumus, T. A. P.; van Vliet, 8. P.; Zeelen, F. J.; Johnson, 8. S. 151d. 1m, 46, 2208. _ Johnson, 8. S.; 8c0arry, 8. 8.; Markezich, R.; Roots, S. G. J. Al. Chem. Soc. 1”, 102, 352. Gravestock, 8. 8.; 8orton, 0. R.; Boots, 8. 0.; Johnson, 8. S. 151d. 1a, 102, 800. Johnson, 8. S.; 8c0arry, 8. 8.; Okorie, D. A.; Perry, 8. J. 151d. 1m, 103, 88. Johnson, 8. S.; Berner, 0.; Dumas, 0. J.; 8eder1of, P. J. R.; Relch, J. Ibid. 1m, 104, 3508. Johnson, 8. S.; Dumas, D. J.; Berner, 1). [bid m, 104, 3510. van Tamelen, 8. 8.; Loughhead, I). G. 151d. 1a», 103, 869. van Tanelen, 8. 8.; Zawacky, S. 8.; Russell, R. 8.; Carlson, J. G. 151d. 1a, 105, 142. van Tamelen, 8. 8.; 8wu, J. R. Ibid. 1”, 1M, 2490. 8ishizawa, 8.; Tanaka, 8.; Rayashi, Y. 151d. 195, 107, 522 and references therein. - Stereoselective iminium ion cyclizations: 0) p) q) Johansen, J. 8.; Christie, 8. 1).; Rapoport, 8. J. 011. 05.. 191, 48, 4914. Dean, R. T.; Rapoport, 8. 151d. 1978, 43, 4183. Vlaeminck, F.; Van Rinst, G. Hetetvcycles 1979, 12, 329. Stereoselective g-acyliminiun ion cyclizations: r) 4) t) n) V) W) X) y) 2) aa) bb) For a review, see: Speckamp, 8. 8.; Riemstra, 8. htrabedron 10a), 41, 4367. Rienstra, 8.; Sno, 8. A. 8.; ViJn, R. J.; Speckamp, 8. 8. J. Org. 05a. m, 50, 4014. 8aryanoff, B. 8.; 8c0omsey, D. F.; Duhl-8mswiler, B. A. 151d. 13:, 48, 5062. Hart, 1). J.; Tsai, Y. 8. Tetrahedron Lett. 131, 22, 1567. 8art, l). J.; Yang, T.-K. 151d. 1m, 23, 2761. 8art, D. J.; lanai, 8. J. Al. 011.. Soc. 1”, 105, 1255. Chamberlin, A.‘R.; Chung, J. Y. 1.. ijd. 1003, 105, 3653. Che-berlin, A. R.; Chung, J. Y. 1.. J. Org. Chen. 1m, 50, 4425 and references therein. 8art, D. J.; Yang, T.-8. Tetrahedron Lett. m, 23, 2761. 8ossin, P. 8. 8.; Speckamp, 8. 8. ijd. 1979, 20, 4411. Nossin, P. 8. 8.; 8amersna, J. A. 8.; Speckamp, 8. 8. Had. 1m, 23, 3207. 10. ll. 12. l3. 14. 15. 16. 52 cc) Hidinberg, 8. P.; Speckanps, 8. 8. Tetrabecb'an m, M, 209. dd) Yeenstra, S. J.; Specks-p, 8. 8. J. Al. Chem. Soc. 1m, 103, 4645. as) RiJinberg, B. P.; Speckanp, 8. 8. Tetrahedron Lett. 1m, 22, 5079. ff) 8art, D. J.; lanai, 8. J. Org. Chem. 1-, 47, 1555. gg) Hart, 1). J. Mid. 1001, 46, 3576. hh) 8art, 1). J. 151d. 1m, 46', 367 and references therein. A number of steroid syntheses have been completed by Johnson’s group: Johnson, 8. S.; Gravestock, 8. 8.; 8c0arry, 8. 8. J. Amer. was. Soc. 1971, 9.9, 4332; 8orton, 1). R.; Johnson, 8. S. 151d. 1973, Q, 4419; Johnson, 8. S.; Brinkmeyer, R. S.; Kapoor, 7. 8.; Voninel, 8. T. 151d. 1977, Q, 8341. a) Volkmann, R. A.; Andrews, 0. 0.; Johnson, 8. S. J. Am. was. Soc. 1815, 97, 4777. b) Grandall, 0.; Lawton, R. G. 151d. m, 91, 2127. c) 8arshall, J. A.; Cohen, 8.; Ruchstettler, A. R. 151d. 1”, w, 3408. - d) Ireland, R. 8.; Welch, S. 0. 151d. 1816, Q, 7232. e) Tansbury, P. T.; Raddon, V. R.; Stewart, 8. 0. 151‘ d. 1974‘, x, 896 . f) van Tamelen, 8. 8.; Seiler, 8. P.; Nierenga, 8. 151d. 1972, 94, 8229. a) Snider, 8. 8.; Rodini, D. J.; van Struten, J. J. An. Chem. Soc. 190, 102, 5872. b) 8aegeli, P. Tetrahedron Lett. 1978, 19, 2130. c) Johnson, 8. S.; 8arbert, 0. A.; Peatcliffe, 8. 8.; Stipanevie, R. D. J. 4.. 05¢. Soc. 1976, m, 6188. a) Goldsmith, D. J. J. Al. Chem. Soc. 1”, 84, 3913. b) Goldsmith, I). J.; Phillips, 0. F. 151d. 11m, 91, 5862. Lansbury, P. T.; Serelis, A. 8. Tetrahedron Lett. 1818, 19, 1909. a) Schmid, R.; 8uesnann, P. 1..; Johnson, 8. S. J. Al. Chen. Soc. 190, 102, 5122. b) Johnson, 8. S.; Chen, Y.-Q.; Kellogg, 8. S. 151d. 133, 106, 6653. c) Johnson, 8. S.; 811iot, J. 1).; Hanson, G. J. Ibid. 1004, 106, 1138. Boeckman, R. 8., Jr.; Bruza, 8. J.; Heinrich, G. R. J. Al. Chem. Soc. 1818, 100, 7101. 17. 18.. 19. 20. 21. 22. 23. 24. 25. 26. 27. 53 For examples of thiophenes used as cyclization terminators, see: Reference 9t and: s) Reathcock, 0. 8.; Jennings, R. A.; von Geldern, T. 8. J. 0:". 05a. 1m, 48, 3428. b) Janssen, 0. G. 8.; 8acco, A. A.; Buck, 8. 8.; Godefroi, 8. F. Rec]. my. 621m. Pays-Baa. 1819, m, 448. c) 8acco, A. A.; de Brouwer, R. J.; 8ossin, P. 8. 8.; Godefroi, 8. F.; Duck, 8. 8. J. Org. Chem. 1978, 43, 1591. d) Corvers, A.; Scheers, P. 0. 8.; de8aan, J. 8.; Buck, 8. 8. Rec]. Trev. 051m. Pays-8am. 1977, my 279. e) Gourler, J.; Cannone, P. Can. J. 620-. 1810, 48, 2587. f) Hartman, G. 1).; Ralczentzo, 8.; Phillips, 8. T. J. Org. 05a. 1913, 51, 142 and references therein. Trost, 8. 8.; Reiffen, 8.; Climmin, 8. J. Am. Chem. Soc. 1979, 101, 257. See: Jackson, A. 8. in "Comprehensive Organic Chemistry", Sammes, P. 8., 8d., Pergamon Press, Oxford, 1819, Vol. 4, pp 275-320. Nishizawa, 8.; Takenaka, 8.; 8ayashi, Y. J. Am. Chem. Soc. 195, 107, 522 and references therein. 8organs, D. J., Jr.; Sharpless, 8. 8. J. Am. 054-. Soc. m, 103, 462. - Johnson, 8. S.; 8arbert, 0. A.; Peatcliffe, B. 8.; Stipanevic, R. 0. J. Am. Chem. Soc. 1816, 98, 6188. Baldwin, J. 8.; Thomas, R. 0.; Bruse, L. 1.; Silberman, 1.. X. J. Org. Chem. 1977, 42, 3846. Available from the Aldrich Chemical Company, Milwaukee, Wisconsin. Prepared from 4-methy1-4-penten-1-ol which is available by the procedure of 8ori, 8.; Kobayashi, S.; 8atsui, 8. Mia. 3.101. Chem. 1975, 39, 1889. Iodoacetonide 24 was prepared from the corresponding (1) e-hydroxy diolacetonide which has previously been synthesized in the enantiomerically pure R-form, see: Mori, 8.; Takigawa, T.; 8atsui, R. ktrabedran 1979, 35, 933. Miyashita, 8.; Yoshikoshi, A.; Grieco, P. A. J. Org. 05a. 1817, 42, 3772. 29. 31. 34. 35. 36. 37. 38. 40. 41. 54 Compound I was prepared from 5-methy1-3-penten-l-ol by 8oppett, 0. 8.; Sutherland, J. 8. J. 62-. Soc. 188, 3040. ' . Compound 28 was prepared from 1,2,5-pentanetriol: Cervinks, 0.; Rub, L. 0011. Cred. 05a. Om. m, .3, 2927. Compound Q was prepared from commercially available 1,2,6-hexane trial. The diolacetonide of 1,2,8- hexanetriol has been previously prepared; Landini, D.; 8ontanari, F.; Rolls, F. Syntbais 1819, 134. a) Snider, R. R.; Rodini, n. J.; Karras, 8.; van Straten, J. 18¢th 1m, 37, 3927. b) Snider, I. 8.; Rodini, 0. J.; van Straten, J. J. Am. 62.. Sec. 1m, 102, 5872. Feld, R.; Cowe, D. L., ”The Organic Chemistry of Titanium”, Rutterworth, Inc., Washington, 1). 0., 1” and references therein. Stork, G.; Shiner, C. S.; Winkler, J. 1). J. b. a... Soc. 1‘, 104, 310. a) 8arshsll, J. A.; Nuts, P. G. 8. J. Org. M.’ 1817, 42, 1794. b) Reetz, 8. T.; Ruttenhain, S.; 8ubner, F. Syn. Om. 1m, 11, 217. a) Stork, 0.; Cohen, J. F. J. Am. 02-. Soc. 1814, x, 5270. b) van Tamelen, 8. 8.; Leiden, T. 8. 151d. 1m, 104, 2061. See: Bis, 8. J.; lrobel, J. 8.; Gsnem, 8. J. Am. 05a. Soc. 1“, I“, 3693 and references therein. Still, 8. 0.; Mitre, A.; Khan," 8. J. 011. as. 1978, 41, 2923. - 8oppett, C. 8.; Sutherland, J. 8. J. as. Soc. 0 1m, 3040. Van Rheenan, 7.; Kelley, R. 0.; Cha, P. Y. htrabedran Lett. 1976, 1973. See Reference 8a and: Feld, R; Cowe, D. L. in "The Organic Chemistry of Titanium", Rutterworths, Iashington, l). 0., 1”. See Reference 8a and: 8arsha11, J. A.; Huts, P. G. 8. J. Org. 05-. 1977, 42, 1794; Reetz, 8. T.; Ruttenhain, S.; 8ubner, F. Syntb. 0.111. m, 11, 217. INTRODUCTION STUDIES DIRECTED TOWARDS THE SYNTHESIS OF SIMPLE INDOLIZIDINE AND QUINOLIZIDINE ALEALOIDS. INTRODUCTION 8-acy1iminiun ions (1) have been recognized as valuable intermediates in the synthesis of alkaloids and related nitrogen-containing compounds.1 Many examples ‘of intramolecular cyclizations involving 1 as a cyclization initiator reacting with an appropriately nucleophilic terminator function are known. Notable among these are the syntheses of alkaloids, .such as perhydrohistrionicotoxin (812-8TX)3, vertalinea, gephyrotoxin‘, and the necine bases.5 '3 e/R' >-N I" 2’ Y 1' 0 R'. R2. R3 - sryl. alkyl. or H R,“ - C or hater-onto") Hmrel The relatively high reactivity of the N-acyliminium ions (See Figure 1) has been appreciated since the beginning of this century when the Tscherniac-Rinhorn reaction (8q. 1) ' was discovered.° The acid-catalyzed cleavage of 8-(a- 55 56 hydroxyalkyl) amides (See 8q. 1) still remains as one of the nost direct and successful routes to 8-acy1iminium ions. H , ° ° 0 L,Amg .._.. ,Afiw —-""" ,A m run-am .Amg. Scheme I depicts this nethod and several other techniques for the generation of 8-acy1ininium ions. Protonation of ene-anides’, g-acylation of iminesa, and g-alkylation of acylimines’ have been examined but are not generally employed to prepare 8-acyliminium ions in synthetic sequences. .2» R2 V y H 1 “iii MAN/k: o H R'*?J\/‘s 4, “Av/k: 2; Ra (Scheme I 57 I The development of two new and versatile methods for the preparation of carbinolamides and 8-(s-alkoxya1kyl) amides have spurred further examination of the synthetic potential of 8-acyliminium ions (8q. 2 and 3). These two methods, the electrochemical oxidation of amides1° and the p8-controlled 8a884 reduction of cyclic imidesll, are depicted in Equations 2 and 3,. respectively. Recently, a further improvement in the preparation of the carbinolamide precursor of cyclic 8-acy1iminium ions 3 has been reported by Chamberlin (8a884, 8e08, -4°0).5b (3k: C34... _ (31.. " fl 1100'. .1, .1, —"'"' ' .1”, ' 2 R'IIKYIJ'I W N ’ 0 N 6 H 0 8 Cl —-fl——_’ 0 N N (3) i: u: I. § The fate of the 8-acylininium ions produced upon treatment of carbinolamides with acid depends upon the structure of the starting imide (8q. 3) and the nature of the ternination step. The 8-acyliminiun ion can suffer ‘deprotonation to yield an enanidelz, .be captured inter- or intramolecularly by olefinicla, acetylenic13°"314, allylic- 58 1511' and proparglic silanesl‘, allenic17, or aromaticl' terminators, or be quenched by a heteroaromatic nucleophile.1° These terminator moieties are quite useful; however, the spectrum of terminator functions which have been found to be compatible with the conditions required to generate 8-acyliminiua ions is not as broad as those employed in cationic polyene cyclizations.33 Other research in our laboratories has centered upon 2- and 3-substituted furans as cyclization terminators in annulation sequences.30 The majority of these examples have employed epoxides30'131, allylic alcohols3°b-33, and enones3°bt3° as cyclization initiators, thus providing routine access only to terpenoid-type compounds. .Should 8- acyliminium ion precursors containing furan-terminated chains be constructed and should the furyl moiety prove to be sufficiently robust so as to survive intact during 8- acylininium ion formation and subsequent cyclizations, then a variety of biologically active alkaloids could be considered potential targets for total synthesis. For this process to be general, we must be able to prepare a variety of skeletal types including linearly-fused, spirocyclic and bridged. Possible 8-acy1iminium ion precursors to those target structures are depicted in Figure 2. 59 R R ( In ( k. 0 "" '0 m :6 2' 5 )n 0 <2 40 H )1!) IN 9 II ' )0 (£3 _- ~ .5: '~ 7 ~ Figure 2. N-acynmtniun Ion Skeltal types 8-acyliminiun ions 4 and 5 will provide linearly-fused, bicyclic products in which the size of the rings forned can be readily varied. Their cyclization products could be converted to pyrrolizidine, indolizidine, and quinolizidine ‘60 alkaloids (froa 4); or indole- and quinoline-type alkaloids (from 5). Similarly, 8-acy1iminium ions 6 and 7 could lead to a variety of spirocyclic- and bridged-alkaloid precursors. Design and Synthesis of Cycligption Substrates Our initial investigations in this area were directed toward compounds which night result from the cyclization of the readily prepared 8-acy1ininium ion 4. If we assume that 8n = 3- or 2-fury1 (Figure 2, 4), then the resulting products should be readily converted to a variety of indolizidine and quinolizidine alkaloids (Figure 3, 8qs. 4 and 5) with the furyl moiety providing useful residual functionality after standard manipulations. ° 0 ‘ ( u u» 4 <9 .. . " H m ° 0 o o ( ‘ u 4'- " (5) (9 m 0 m 0 n-L2 n-L2 m-j m-I F figure 3 61 Some representative examples of the indolizidine alkaloids are the powerful a-nannosidase inhibitor swainsonine 83“ and the related enzyme inhibitor castanospernine 9.25 The Dedrobates alkaloids, gephyrotoxin 10‘ and perhydrogephyrotoxin 112° together with the 81aeokanine alkaloids A - 0 (12-14)”, which haveno unusual bioactivity, might also be considered members of this class of alkaloids. A few sinple examples of quinolizidines include lupinine l528 and its stereoisomer epilupinine 13.50.29 / Of the structures depicted in Figure 4, we chose the less complex 81aeokanine alkaloids 12-14 and lupinine 15, or its isoaer epilupinine 16, as our initial synthetic targets. Rowever, first we must demonstrate that the 2- and 3-fury1 moieties are sufficiently nucleophilic and stable terminator functions for 8-acylininium ion-initiated cyclizations. Additionally, we hoped to show that the fl-alkyl chain of these cyclization precursors can be readily modified to routinely provide access to six- and seven-menbered linearly-fused carbocyclic ring systems, such as those shown in Equations 6-9. As is illustrated in Equations 6-9, 2- and 3-furyl alcohols 19, 26, 33 and 40 will serve as the source of the furyl moieties. Coupling, utilizing the Mitsunobu protocol3°, so successfully employed by 8art3-‘d-2°°, Chanberlin5, Speckamp14-15’27', and others, with succinimide or glutarimide, should afford inides 20, 23, 27, 30, 34, 37, $3. 0 \_/\/ H = = “\m H 14 62 1.3. 15 ~~ Figure 4. Indoltzidlnes and Ouinolmdines 11 av” 63 11' ("'11 12(0)“) m(n'l,M'l) 21 (11.1.81'1) Ia (n-z) gg (m-z) \ g; (n-2.m-n g3 mm.” (6) .. 21 (ml . 01-2) 29 (ml . m=2) so (n-2.m-2) E1 ("'2.m-2) (7) ”00:" | ( ), n L c-C,H,, . 1. g; (n-l,m-I) g§ (n-Z,m-I) 32 (n-I,m-2) g; (n-2.m-2) ° 0 I I. DEAD M" II a ——-—i—> ll ‘C-V “13 w- 4;.” m (I 6 m 6 0 0 m 11"”) Elm") 34 (081 01-1) 35(n-1 m-I) - 1‘8. (“'2’ 19’ ("1.2) \ ii (“‘2,m'l) §§ ("-2.")31) (8) _ fl (n-l,m-2) 12(n-I,m=2) 11 (na2.m-2) 1:3 (n-2.m=2) (9) C430"): §§ (n-I.m-|) §g(n-2.m-1) _§_(n-I.m-2) fi(n-2.m-2) , 64 41 and 44. Reduction to the carbinolamide and subsequent cyclization could lead to the corresponding cyclized products (See 8qs. 6-9). In the event, treatment of 2-(2- furyl)ethanol 19 (m=1)31 with either succinimide 1? (n=1) or glutarimide 18 (n=2) in the presence of diethyl azodicarboxylate (D8AD) and triphenyl phosphine (PhaP) provided fl-substituted imides 2D (n=1, m=1) and 23 (n=2, m=1) in 318 and 518 yields, respectively, after chromatography. Similarly, the Mitsunobu reaction of 3-(2- furyl)propanol 26 (n=2) with succinimide l7 and glutarimide 18 led to inides 27 (698) and 39 (538). With the complement of imides 20, 23, 27 and 30 designed to examine the effects of preforned (5 or 6) ring and forming ring (6 or 7) size upon the 8-acyliminium ion-initiated furan (2-3 position) terminated cyclization in hand, we next examined the reduction-cyclization sequence. - Sodium borohydride reduction of 20, 23, 27 and 30, according to the procedure of Chaaberlin5b (8a884, ‘ 8e08, -4°C), provided the corresponding carbinolamides 21, 24, 28 and 31 in 888, 958, 948 and 958 yields, respectively. Carbinolanide 211was then subjected to the cyclization conditions we had successfully employed in our sequences with allylic alcohol and enone initiators.3°b Exposure of 21 to a two-phase mixture of anhydrous 80028 and c-06812 for 2-3 minutes gave the desired indolizidine alkaloid precursor 22 in 708 yield. The time before workup (2-3 sin.) was found to be crucial as lengthening of the reaction time (5-10 nin.) caused a 65 substantial reduction in yield and a poor aass balance. The isolation of a good yield of 22 is noteworthy in that it is but our second example of the previously unknown and relatively disfavored 2-substituted-to-3-fury1 cyclization.3°b Sinilarly, carbinolamide 24 afforded quinolizidine precursor 25 in 718 yield after purification by chromatography. The seven-menbered ring precursors 28 and 31 were examined extensively, and we were unable to prepare either the 5,7-membered ring compound 29 or the 6,7- fused 32 under a variety of reaction conditions (e.g., i. 8CO2R, c-C6812; ii. MsCl, EtaN; iii. 8C1, aq. TRF). Based upon our previous experience in furan-terminated cationic cyclization205, we expected not to encounter such forming-ring size problems in the electronically favored 3- to-2-closure (8qs. 8 and 9). Therefore, we prepared the requisite imides 34(1002), 37(1002), 41 (568), and44 (848) from glutarimide or succininide, 2-(3-furyl)ethanol 33 (n=1)32 and 3-(3-furyl)propanol 40 (m-2) and subjected these materials to the standard reduction and cyclization conditions. The yields of product carbinolamides were uniformly high; and, to our delight, all of these substrates provided good yields (668, 718, 508, 678) of cyclized products 35, 39, 43 and 46 after brief treatment with 80028/c05812. 66 Furan Manipulations - The Preparation of Alkaloid Precursors With the desired cyclized substrates (See 8qs. 6-9) in hand, the next important transformation to be exa-ined was the crucial oxidative cleavage of the 2,3-Disubstituted furyl moiety. Of the six possible (a, 25, 36, 39, 43 and 46) cyclized materials to be subjected to various. oxidative methods, we chose as representative examples the indolizidine and quinolizidine precursors 22 and 25, respectively, and the seven-membered, 3- to 2-cyclized substrates 43 and 46. Successful oxidation of substrates 22, 25, 43 and 46 could afford either the corresponding butenolides (47 - 50) or cleaved products, the keto-enals (51 - 54), as a function of the conditions employed for the oxidation (See Figure 5). 67 FIGURE 5: Oxidation of 2.3-0150541110144 Furans smug,” Possible Oxidation Products 30161101166 K610 _ EMI . 0 00 0 ° 0 ( , n H ( and/or ( )n 8 8 0 gen-1 ° ° 250.2 3211-1 5) n.) ‘32 " ' 2 §g n - 2 0 cm 0 ( 8 and/or ( 0 N g§Ir-l o ~~ §sn-2 Numerous nethods for transforming a wide variety of variously substituted furans into their corresponding butenolides or keto-enals have been reported. Of these methods, we initially investigated oxidation with ICPRA in 082012 buffered with 8a800233 or unbuffered33'3‘, the ‘ chrominum VI-based reagents (P0035 and variants, such as 2- CNPCC3°; and the more classical Clauson-Kaas oxidation, Brz 68 in buffered 08208)37, followed by hydrolysis of the intermediate a,s'-dimethoxy-dihydro furan derivative.°3-°'¢'3' In the event, the readily available quinolizidine precursor 25 was subjected to the oxidation methods aentioned above. Thus, treat-ant of’25 with mCPRA under a variety of reaction conditions (2.2 equiv., 082012, 0°C to reflux3'v3‘; 2.2 equiv., 8a8002, 0°C to reflux33; 2.2 equiv., 8aOAc, ROAc) followed by reductive (8a584) workup3’; and finally, 2.2 equiv., 082012, 0°C to 25°C followed by trifluoroacetic acid (TFA) quench33, led only to recovery of the starting material 25 or a number of unidentified products with overall poor mass-balance. .Similarly ineffective in oxidizing the furyl residue of 5 was P00, 082012, 25°C to reflux" and the more reactive 2-08PCC, 082012, 25°C to reflux.3° Clauson-Raas oxidation (Bra. 8a2002, 8e08, -30°C)37 of the indolizidine precursor 25 did provide the corresponding a,a'-dimethoxy-dihydro derivative in 778 yield; however, we were unable; to isolate the presumably formed keto-enal upon acid hydrolysis of the crude reaction mixture using a variety of known aethods (i. 18 aqueous ROAc, 53"; 820, 45°03°¢; ii. 18801, 820, 45°C°"; iii. 28 aqueous 82804, 25°C).3'° Other methods that have been successfully employed in oxidizing lrelated substituted furan systems, but which failed to oxidatively open the furyl residue in 25, were 8882 8aOAo, dioxene-RaO, followed by 8e884 reduction‘0 and 69 Ce"(884)2(803)s, 820-08308, 2500.‘1 We can safely conclude after this extensive examination of chemical oxidants that furan cleavages are non-standard operations which are extremely substrate dependent. Since standard and other esoteric methods for oxidizing the furyl moiety of substrate 25 proved fruitless, efforts were directed towards a photochemical means of achieving this necessary transformation. The use of photochemically generated singlet oxygen to oxidize variously mono- and di- substituted furans has received considerable attention over the years.‘2 Treatment of 45 and or 46 with 102, generated by bubbling oxygen through solution of substrates in 08208 or 082012 and either rose benga1‘3, hematoporphrin‘z, or tetrahydroporphrin‘2’44 as sensitizers at 25°C using either a medium-pressure Hanovia lamp or a 5008 Tungsten filiment source, failed to provide any of the desired products and, in general, resulted in poor mass-recovery. Consequently, the temperature at which the photolyses were performed was lowered to -78°C‘4¢; and the crude photolysis mixtures were quenched with reducing agents, including 8a884 in MeOR or i- Pr0845 and PhaP.43‘-“b In these low-temperature photolyses, only recovered starting material was observed with no traces of oxidatively cleaved photoproducts, such as butenolides or keto-enals detected (See Figure 5). The failure of the standard chemical and 102 oxidations, thus far examined, caused us to consider the alternatives outlined below. 70 Based upon our previous experiences in oxidizing furans“ and the studies of others“°"7, we decided to increase the nucleophilicity of the furyl moiety in cyclized substrate 25 by introducing a TMS group at the unsubstituted-a'-position. Following a procedure by German workers, who successfully silylated analogous pyrrole systems using 8t28 and TMSOTf at 5°C to 2500‘9, we exposed furan 25 to TMSOTf in 8t38. After a number of attempts, we failed to obtain any of the desired C-silylated furan. In fact, it appeared from a cursory examination of the RI-MS and 18-888 (250882) spectra that the lactam moiety had been silylated; a surmise which was substantiated by treating the crude silylated mixtures with 82002 in methanol leading to recovery of 25. Alternatively, the silyl group could be introduced intact on the furyl piece prior to the Mitsunobu coupling reaction as is outlined in Scheme II. ( ° Nll 0540 o I! m 0 "5 FM? (to yield 220mg of crude cyclized material 22. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40g, 30mm o.d., ethyl acetate—petroleum ether 4:1, 30mL fractions) using the flash technique. Fractions 8-13 yielded 0.139mg, 742, of 22 as a viscous water-white liquid. 18-NMR (250882): 6 = 7.27 (m, 1), 6.20 (m, 1), 4.98 (m, 2), 4.42 (m, 1), 2.78 (m, 2), 2.33 (n, 2), 1.94-1.62 (m, 2); IR (08013): 3000, 2860, 1675, 1420, 1310, 1220, 1110, 900 cm‘l; BI-MS (70eV): 178 (M*+l, 20.8), 177 (M’, base), 176 (66.2), 148 (11.1), 134 (10.5), 120 (45.5), 107 (9.88), 91 (27.0), 65 (25.0). 92 Cyclization of 0arbinol Amide (24). According to the general procedure for the cyclization of carbinol amides, a two-phase mixture of 80028 (6.0mL), carbinol amide 24 (326mg, 1.56mmol), and cyclohexane (25mL) was stirred vigorously at 25°C for 3 min. to yield 0.28g of a viscous pale yellow liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 32g, 30mm o.d., ethyl acetate-petroleum ether 4:1, 20mL fractions) using the flash technique. Fractions 13-22 provided 0.211g, 713, of 25 as a viscous water-white liquid. 18-NMR (250882, 0606): 6 = 7.02 (bs, 1), 5.84 (m, 1), 5.12 (dd, J;12.5,5.082, l), 3.78 (m, 2), 2.55 (m, 2); IR (0801:): 3000, 2945, 1625, 1465, 1440, 1415, 1350, 1330, 1310, 1220, 1160, 1140, 1115 cm'1; BI-MS (70eV): 192 (M*+1, 14.6), 191 (8*, base), 163 (11.8), 162 (20.5), 148 (7.75), 135 (41.9), 121 (54.5), 120 (57.7), 104 (26.1), 91 (30.3), 77 (29.3), 55 (73.1). Cyclization of 0arbinol Amide (35). According to the general procedure for the cyclization of carbinol amides, a two-phase mixture of 80028 (1.0mL), carbinol amide 35 (50mg, 0.256mmol), and cyclohexane (4.0mL) was stirred vigorously at 25°C for 3 min. to yield a viscous pale yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 15g, 20mm o.d., ethyl acetate-petroleum ether 4:1, 10mL 93 fractions) using' the flash technique. Fractions 10-22 provided 30mg, 668, of 38 as a white crystalline solid. mp = 84-87°0. 18-NMR (250882): 6 = 7.28 (m, 1), 6.21 (m, 1), 4.69 (m, 1), 4.35 (dd, J=19,5.88z, 2), 2.87 (m, 2), 2.70-2.35 (m,2), 1.89 (m, 2); IR (08019): 3000, 2860, 1680, 1420, 1310, 1220, 1110, 1040, 900 cm‘l; BI-MS (70eV): 177 (M*+1, 64.8), 176 (8*, base), 149 (11.6), 148 (25.1), 134 (6.48), 120 (38.4), 107 (6.69), 91 (15.8), 65 (19.2), 39 (48.6). \ Cyclization of 0arbinol Amide (38). According to the general procedure for the cyclization of carbinol amides, a two-phase mixture of 80028 (2.4mL), carbinol amide 38 (128mg, 0.612mmol), and cyclohexane (9.5mL) was stirred vigorously at 25°C for 2 min. to afford a viscous white-water liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 30g, 30mm o.d., ethyl acetate—petroleum ether 4:1, 30mL fractions) using the flash technique. Fractions 9-15 provided 83mg, 718, of 39 as a white crystalline solid. mp = 82-8400. 18-NMR (250882): 6 = 7.25 (m, l), 6.21 (m, l), 4.98 (m, 2), 4.50 (m, l), 2.65 (m, 2), 2.39 (m, 2), 1.92-1.55 (m, 4); I8 (0801:): 2965, 2860, 1630, 1440, 1415, 1310, 1220, 1165, 1120, 1035 cm'l; EI-MS (70eV): 192 (M*+l, 13.7), 191 (M’, 'base), 190 (M+~1, 85.1), 163 (16.4), 162 (26.1), 148 (8.78), 135 (29.3), 121 (45.0), 120 (54.0), 91 (19.5), 55 (48.5). 94 Cyclisation of 0arbinol Amide (42). According to the general procedure for the cyclization of carbinol amides, ‘a two-phase mixture of 80028 (3.1mL), carbinol amide 42 (1.66g, 7.94mmol), and cyclohexane (l24mL) was stirred vigorously at 25°C for 3 min. to yield a tan solid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 50g, 40mm o.d., ethyl acetate-petroleum ether 4:1, 50mL fractions) using the flash technique. Fractions 7-14 provided 757mg, 508, of 43 as a viscous pale yellow liquid. 18-888 (25088:): 6 = 7.20 (m, 1), 6.14 (m, 1), 4.75 (m, 1), 4.30 (m, 2), 2.88 (m, 2), 2.56 (m, z), 2.00-1.71 (m, 4); 13 (neat): 3420, 2940, 2860, 1660, 1460, 1405, 1330, 1280, 1210, 920 cm'l; nx—us (70eV): 192 (M++, 23.4), 1191 (8*, base), 190 (M*-1, 98.3), 163 (35.8), 162 (37.6), 148 (12.5), 135 (33.5), 134 (46.4), 120 (28.5), 107 (39.8), 91 (34.0), 77 (38.9), 55 (44.8). Cyclisation of 0arbinol Amide (45). According to the general procedure for the cyclization of carbinol amides, a two-phase mixture of 80028 (3.6mL), carbinol amide 45 (2.09s, 9.0..01), and cyclohexane (144.1) was stirred vigorously for 3 min. to yield 2.08g of a viscous yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 60g, 40mm o.d., ethyl acetate-petroleum ether 4:1, 50mL 95 fractions) using the flash technique. Fractions 6-17 provided 1.23g, 678, of 45 as a white solid. mp = 72-74°0. 18-NMR (250882): a = 7.23 (m, l), 6.19 (m, 1), 4.62 (t, J=5.082, 2), 4.56 (t, J=4.282, 1), 2.72 (m, 2), 2.43 (m, 2), 2.09 (m, 2), 1.91 (m, 2), 1.78 (m, 2); IR (08013): 3380, 2940, 2870, 1620, 1460, 1410, 1330, 1280, 1210, 1130, 920, 880 cm'l; BI-MS (70eV): 206 (M*+l, 14.6), 205 (M’, 92.3), 206 (M*-l, 18.7), 177 (18.9), 176 (12.8), 162 (16.7), 149 (22.1), 135 (base), 134 (31.6), 120 (22.5), 107 (18.9), 91 (21.1), 77 (22.8), 55 (33.8). Clauson-Kaas Oxidation of 46. To a solution of 46 (39mg, 0.19mmol) and Na2009 (40mg, 0.38mmol) in anhydrous methanol (0.25mL), cooled in a dry- 0014 ice bath to -22°C, was added a cooled (-22°0) solution of bromine in methanol (0.20mL, 0.19mmol, 1.08) over five . min. The mixture was stirred at -22°0 for 90 min. then cast into 082012 (15mL) and brine (15mL). The aqueous layer was separated and extracted with 082012 (2 x l5mL). The combined organic layers were washed with 108 aqueous NazSan, brine (15mL each), dried (Mg804) and concentrated in vacuo to provide 39mg, 778, of the s,¢'-dinethoxy-dihydro derivative as a mixture of diastereomers. 18-NMR (250882): 6 = 5.76 (m, 0.5), 5.71 (m, 0.5), 5.66 (m, 0.5), 5.29 (m, 0.5), 4.63 (m, 0.5), 4.55 (m, 0.5), 3.73 (m, 0.5), 3.68 (m, 0.5), 3.49 (s, 1.5), 3.44 (s, 1.5), 3.15 (s, 1.5), 3.03 (s, 1.5), 2.66-1.60 (m, 12); IR (0014): 3380, 96 2960, 2880, 1660, 1620, 1460, 1420, 1250, 1090, 1010, 800 cm'l: BI-Ms (70eV): 268 (10.0), 267 (5.41), 252 (3.06), 236 (18.5), 235 (48.0), 220 (3.78), 207 (18.53), 168 (12.4), 153 (14.3), 137 (17.5), 123 (22.6), 112 (43.0), 84 (35.0), 69 (34.3), 55 (base). Pre aration of N- 2— 5-Trimeth lsil 1-2-fur 1 eth 1 -2 6- piperidinedione (58, n=2). According to the general procedure for the preparation of N-substituted imides, to glutarimide (781mg, 6.90mmol), triphenylphosphine (2.07g, 7.90mmol), and 2-(5- trimethylsilyl-Z-furyl) ethanol 55 (1.27g, 6.9mmol) in THF (5.8mL) was added a solution of diethyl azodicarboxylate- (1.38g, 7.9mmol) in THF (3.1mL) over 20 min. to yield 3.0g of a viscous orange liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 120g, 50mm o.d., ethyl acetate-petroleum ether 1:1, 50-75mL fractions) using the flash technique. Fractions 11-19 provided 1.67g, 878, of 56 as a viscous yellow liquid. 18- 888 (250882): 6 = 6.50 (d, J=4.282, 1), 6.03 (d, J=4.282, 1), 4.07 (t, J=8.382, 2), 2.90 (t, J=8.382, 2), 2.62 (t, J=6.382, 4), 1.90 (m, 2), 0.24 (s, 9); IR (neat): 3320, 2970, 1730, 1675, 1360, 1255, 1135, 1040, 1015, 930, 850 cm‘ 1: sx-as (100V): 280 (n++1. 0.94). 219