Recent Advances in The Synthesis of Pipe Rid Ones and Piperidines PM Weintraub JS Sabol JM Kane DR Borcherding Tetrahedron 59 2953 2989 2003

Tetrahedron 59 (2003) 29532989
Tetrahedron report number 638
Recent advances in the synthesis of piperidones and piperidines

Philip M. Weintraub, Jeffrey S. Sabol,* John M. Kane and David R. Borcherding
Aventis Inc., P.O. Box 6800, Routes 202-206, Bridgewater, NJ 08807-0800, USA
Received 13 December 2002
Contents 1. 2. Introduction Synthesis of 2-piperidones 2.1. Intramolecular N C processes 2.1.1. Lactam formation from acyclic d-amino carboxylates 2.1.2. Ring rearrangements 2.1.3. Amide alkylations 2.1.4. Acylnitroso Diels Alder reactions 2.2. Intramolecular C C processes 2.2.1. Acylvinylimidate Diels Alder reaction 2.2.2. Domino Stille coupling/vinylogous imide Diels Alder reaction 2.2.3. Ring closing metatheses 2.3. Intermolecular processes 2.3.1. Chiral bicyclic lactams 2.3.2. [33] Annulations 2.3.3. 2-Azadiene Diels Alder reaction 2.3.4. Metal catalyzed cyclocarbonylations Synthesis of 3-piperidones 3.1. Oxidative cyclization (aza-Achmatowicz reaction) 3.2. From amino acids 3.3. Ring expansion Synthesis of 4-piperidones 4.1. Intermolecular processes 4.1.1. From 1-acylpyridinium salts 4.1.2. Imino Diels Alder reactions 4.2. Intramolecular processes 4.2.1. Mannich reactions 4.2.2. Cycloadditions 4.2.3. From b-amino carboxylates Synthesis of piperidines 5.1. From 2-piperidones 5.1.1. From N-alkoxycarbonyl enol derivatives 5.1.2. From cyclic N-acyliminium intermediates 5.1.3. From ring opening of N-alkoxycarbonyl-d-lactams 5.2. From 4-piperidones 5.2.1. From N-alkoxycarbonyl vinyl triates 5.2.2. From Wittig olenations 5.3. Intramolecular N C processes 5.3.1. Nucleophilic substitutions 5.3.2. Reductive aminations and imine reductions 5.3.3. Cyclization dehydration to imino glucals
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3.
4.
5.
Keywords: piperidone; piperidinone; piperidine. * Corresponding author. Tel.: 1-908-231-3092; fax: 1-908-231-3577; e-mail: jeff.sabol@aventis.com 00404020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4020(03)00295-3
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6.
5.3.4. Michael additions 5.3.5. Hydroamination/cyclization 5.3.6. Ring expansions 5.3.7. 6p-Azaelectrocyclizations 5.3.8. Schmidt reaction 5.4. Intramolecular C C processes 5.4.1. Ring closing metatheses 5.4.2. Iminium ion cyclizations 5.4.3. Radical cyclizations 5.4.4. 1,3-Dipolar cycloadditions 5.4.5. Palladium mediated couplings 5.4.6. Ene cyclizations 5.4.7. Anion polycyclization 5.5. Intermolecular processes 5.5.1. Formal [33] annulations 5.5.2. Aza Diels Alder reactions 5.5.3. CN(R,S) Methodology 5.5.4. From pyridine reductions Conclusion
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1. Introduction The piperidine ring is an ubiquitous structural feature of many alkaloid natural products and drug candidates. Watson et al. asserted that during a recent 10-year period there were thousands of piperidine compounds mentioned in clinical and preclinical studies.1 Piperidones are somewhat less prominent, but often they serve a role as advanced intermediates prior to their conversion to piperidines. Reviews updating progress in the stereoselective syntheses of substituted piperidines have appeared recently.2 The purpose of this review is to compile stereocontrolled approaches to piperidone and piperidine heterocycles, focusing on the published literature from 1999 to present. The review is organized by bond formation or process leading to the heterocyclic ring. Piperidone syntheses are reviewed rst and are categorized by the position of the carbonyl group. Next, follow methodologies used to convert piperidones to piperidines. Lastly, piperidine syntheses are discussed. The large volume of published literature over the past three years precludes a comprehensive review. Methodologies were selected on the basis of diversity and stereocontrol, with the intent of providing the reader with a variety of options for the synthesis of these useful heterocycles.
benzylidene-p-toluenesulnamide3 with excess sodium enolate of methyl acetate. Deprotection and cyclization provided keto lactam 2 which was deoxygenated to 6-phenyl-2-piperidone (3) en route to a synthesis of (R)()-2-phenylpiperidine.4 Hydride reduction of 1 was syn selective and deprotection/cyclization gave trans-()-4. The synthesis of cis-()-4 was achieved by hydride reduction of 2. Piperidones 4 were advanced intermediates in the asymmetric synthesis of 4-hydroxypipecolic acid stereoisomers5 where the phenyl group served as a CO2H surrogate. The utility of N-sulnyl-d-amino-b-ketoesters in the stereoselective synthesis of the quinolizidine alkaloid (2)-lasubine II was reported,6 and another application will be highlighted in Section 4.2.1. This methodology provides convenient access to polysubstituted nitrogen heterocycles with minimal protecting group chemistry. Methodology from the Beak laboratories7 provides a route to enantiopure, substituted d-lactams and piperidines (Scheme 2). Enecarbamate 7 was prepared by the enantioand diastereoselective conjugate addition of lithiated N-Boc-allylamine 5 to nitroalkene 6, easily allowing the introduction of aliphatic, aromatic and heterocyclic
2. Synthesis of 2-piperidones 2.1. Intramolecular N C processes 2.1.1. Lactam formation from acyclic d-amino carboxylates. Recent reports from the Davis laboratories highlight the versatility of N-sulnyl-d-amino-b-ketoesters as designed polyfunctional chiral building blocks (Scheme 1). Enantiopure sulnimines are prepared readily by the condensation of commercially available (R)- or (S)-ptoluenesulnimides with aromatic and aliphatic aldehydes and serve as versatile intermediates in the asymmetric synthesis of amine derivatives. For example, b-keto ester ()-1 was prepared in one pot by treatment of (S)-()-N-
Scheme 1. (a) TFA, MeOH; (b) NaHCO3 [9092%]; (c) (CH2SH)2, BF3OEt2, room temperature [85%]; (d) W2 Raney Ni [75%]; (e) Zn(BH4)2, THF, 2788C.
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N-protected 9 provided trisubstituted d-lactams that could be reduced to 3,4,5-trisubstituted piperidines. A recently reported chiral acyclic building block was useful for syntheses of glycosidase inhibitors such as polyhydroxylated piperidine and indolizidine alkaloids (Scheme 3).9a Allylic alcohol 1010 underwent selective Mitsunobu inversion to azide 11. Catalytic hydrogenation and cyclization of 11 gave 2-piperidone 12 while Staudinger reduction/cyclization retained the double bond affording 13. This chemistry enabled the chemoselective manipulation of the hydroxyl groups and provided a route to highly functionalized 2-piperidones. Additional strategies to glycosidase inhibitors utilizing d-lactams as advanced intermediates were reported.9b e A diastereoselective Michael addition was the key step of a large-scale asymmetric synthesis of the functionalized d-lactam found in the core fragment of the potent dual NK1/NK2 antagonist 20 (Scheme 4).11 Conjugate addition of the enolate of acyl oxazolidinone 14 to acrylonitrile afforded nitrile 15 (de .99%). Hydrogenation of 15 to amine hydrochloride 16 was followed by reductive amination to secondary amine 17. Thermal cyclization of 17 with extrusion of the oxazolidinone chiral auxiliary
Scheme 2. (a) BuLi, (2)-sparteine, PhMe, 2788C, then 6 [7390%]; (b) HCl, CHCl3; (c) NaClO2, NaH2PO2; (d) HCl, MeOH; (e) H2, Raney Ni [5871%].
substituents. Hydrolysis of enecarbamate 7 to the aldehyde was followed by oxidation and esterication to nitroester 8. Reduction and cyclization to lactam 9 afforded single diastereomers in .94% ee. Additionally, reduction of lactam 9 gave 3,4-disubstituted piperidines that could be functionalized at positions adjacent to the nitrogen atom by lithiation/substitution methodology.8 Enolate alkylation of
Scheme 3. (a) HN3, TPP, DEAD, THF [77%]; (b) H2, 10% Pd/C [62%]; (c) TPP, THF, H2O, reux [62%].
Scheme 4. (a) Ti(OiPr)Cl3, iPr2NEt, 08C, then acrylonitrile, 08C [60%]; (b) H2, Pt/C, TsOH; (c) N-Boc-4-piperidone, NaB(OAc)3H, THF; (d) PhMe, 1108C; (e) NaOH, PhMe, room temperature [5167% from 16].
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provided the d-amino-g-lactone that underwent ring rearrangement to d-lactam 25 upon treatment with DBU at 808C. Additional functionality was introduced at C-3 by alkylation of the corresponding lactam enolate. A similar rearrangement was used in a short, stereocontrolled approach to D-ring analogs of avopiridol,17 a cyclin-dependent kinase inhibitor in phase II clinical trials (Scheme 6). The iodocyclization18 of unsaturated carboxylic acid 26 was completely stereoselective. Subsequent treatment with sodium azide afforded multigram quantities of g-lactones 27. The enolate of 27 (RH) was stereoselectively alkylated to a trans,trans lactone that was converted to 28 by azide reduction and cyclization with base. Direct conversion of 27 (RMe) to 29 was carried out in a similar manner. This approach provided exible access to 2-piperidones with contiguous arrays of stereocenters.
Scheme 5. (a) TBSOTf, CH2Cl2, 2808C [83%, dr9:1]; (b) H2, Pd/C, THF; (c) DBU, 808C [62%].
Scheme 6. (a) I2, MeCN, 08C [7580%]; (b) NaN3 DMF, 1008C [8895%]; (c) LiHMDS, THF, 2708C, then MeI [60%]; (d) H2 (60 psi), EtOH, 10% Pd/C [100%]; (e) MeONa, MeOH, 658C [5775%].
afforded carboxylate 18, which was saponied to enantiopure carboxylic acid 19 (.99% ee). This process was used to prepare multikilogram quantities of 19 with minimal chromatographic purication. 2.1.2. Ring rearrangements. The rearrangement of d-amino-g-lactones to d-lactams is well precedented,12 and recent applications of this procedure were used to prepare glycosidase inhibitors,13,14 that were designed as aza-analogs of natural glycosides. In an approach to the synthesis of cyclic inhibitors of HIV protease,15 a vinylogous Mannich reaction16 was used to construct a d-amino-g-butenolide scaffold with high diastereoselectivity (Scheme 5). The addition of 2-(tert-butyldimethylsilyloxy)furan 21 to N-benzylimine 22 was carried out in the presence of a Lewis acid catalyst producing butenolide 24. Felkin model 23 accounted for the observed diastereoselectivity by addition of the nucleophile to the more accessible Si face. Hydrogenation of 24 with concomitant removal of the benzyl group
An analogous intramolecular transamidation was used in a stereoselective, formal synthesis of the piperidine alkaloid pseudodistomin C (Scheme 7).19a Thus, mesylate 30 was prepared from (S)-pyroglutaminol and converted via azide 31 into amine 32. Translactamization occurred quantitatively to d-lactam 33. An alternate synthesis of 33, using an intramolecular Mitsunobu reaction was reported.19b
Scheme 7. (a) NaN3, DMF [90%]; (b) H2, MeOH, 10% Pd/C [100%]; (c) MeOH, 658C [100%].
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by an established procedure,21 and the stereochemistry at the quaternary center was introduced by copper-promoted Michael addition of pentylmagnesium bromide to the less hindered face of 34. Further manipulation to pyrrolidine 35 was followed by samarium iodide induced22 reductive carbon nitrogen bond cleavage and simultaneous cyclization to furnish d-lactam 36. Removal of the silyl protecting group and oxidation of the corresponding secondary alcohol completed the total synthesis of (2)-adalinine. 2.1.3. Amide alkylations. A convenient asymmetric synthesis of 4-substituted and trans-3,4-disubstituted 2-piperidones and piperidines commenced with the desymmetrization23 of meso-3-substituted glutaric anhydrides 37a c with (S)-methylbenzylamine (Scheme 9).24 The amido acids 38a c were formed in good yields with excellent diastereoselectivities after single recrystallizations. Facile conversion of 38a to 39 was followed by an intramolecular amide alkylation producing 2-piperidone 40 in .99% diastereomeric purity. Lactam enolate alkylation of 40 afforded chiral trans-3,4-disubstituted 2-piperidones. This methodology was applied successfully to the synthesis of paroxetine, a clinically used antidepressant agent. An asymmetric synthesis of (2)-paroxetine using a porcine liver esterase mediated asymmetric desymmetrization as the key step was reported.25 2.1.4. Acylnitroso Diels Alder reactions. The acylnitroso Diels Alder reaction is a powerful tool for the stereoselective synthesis of piperidine, indolizidine, and decahydroquinoline alkaloids.26 This methodology was used as a key step in the enantioselective syntheses of the decahydroquinoline alkaloids (2)-lepadin A, B and C (Scheme 10).27 Ester 41 was prepared from (S)-malic acid and converted to hydroxamic acid 42, whereupon oxidation with tetrapropylammonium periodate generated acyl nitroso intermediate 43 that underwent intramolecular [42] cycloaddition to oxazino lactam 44. The endo boat-like transition state 43 was proposed as most favored and use of aqueous media effected optimum trans selectivity (with respect to C-4a and C-5) in the cycloaddition as a result of secondary orbital interactions and hydrophobic packing of reactants.28 Oxazino lactam 44 was a useful scaffold for the
Scheme 8. (a) nC5H11MgBr, CuBrSMe2, BF3OEt2, THF, 2788C [100%]; (c) TFA, CH2Cl2 [95%]; (d) TBDMS Cl, DMAP, CH2Cl2 [91%]; (c) SmI2, t BuCO2H, THF, HMPA, 08C!room temperature [70%].
Scheme 9. (a) (S)-Methylbenzylamine, Et3N, PhMe, 2788C!room temperature [38a, 70, 95% de; 38b, 67, 94% dec; 38c, 76, 99% de]; (b) Et3N, iBuO2CCI, THF, 278!08C, then NaBH4, H2O, 08C!room temperature [86%]; (c) PBr3, conc HBr [70%]; (d) NaH, THF, reux [85%].
An enantiospecic synthesis of (2)-adalinine, a piperidine alkaloid containing a chiral quaternary center, utilized a ring expansion promoted by samarium iodide regioselective carbon nitrogen bond cleavage. 20 Enaminone 34 (Scheme 8) was prepared from ethyl (S)-(2)-pyroglutamate
Scheme 10. (a) NH2OHHCl, KOH, MeOH, 08C [80%]; (b) Pr4NIO4, H2ODMF, 08C [90%, 6.6:1].
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stereocontrolled introduction of additional substituents. Enolate hydroxylation29 was used to oxidize the C-7 position diastereoselectively, and a tandem process of Grignard addition followed by stereoselective hydride reduction converted the lactam carbonyl group of 44 to an (8S)-methyl group.30 Reductive cleavage of the N O bond was followed by annulation of the side chain and elaboration to cis-fused decahydroquinoline 45. Application of this methodology to the synthesis of (^)-fasicularin and (^)-lepadiformine was reported recently.31 The elegance of this methodology is highlighted by the efcient construction of a substituted bicyclic oxazino lactam and its utility for stereocontrolled functionalization. 2.2. Intramolecular C C processes 2.2.1. Acylvinylimidate Diels Alder reaction. An application of the intramolecular N-acylvinylimidate Diels Alder32 reaction provided an efcient route to the yohimbine alkaloid cis-fused decahydroisoquinoline ring system (Scheme 11). Diels Alder precursor 48 was assembled by coupling carboxylic acid 46 with 2-ethoxy1-aza-1,3-butadiene 47.33 Intramolecular cycloaddition proceeded through an endo transition state affording cycloadducts 49 and 50, with the major cycloadduct 49 possessing three of the ve stereocenters required for the synthesis of decahydroisoquinoline 51. After reduction of the acylimidate and N-protection, the remaining two stereocenters were introduced by olen hydroboration. Installation of the C-6 methyl ether and transposition of the benzyl groups for acetates completed the synthesis of 51, an intermediate previously reported in a total synthesis of reserpine.34 This methodology provided a facile stereocontrolled approach to cis-fused hexahydroisoquinolines, with potential for elaboration to complex isoquinoline ring systems.
Scheme 12. (a) CH2vCHSnBu3, Pd(PPh3)4, PhMe, reux [68%].
imide furnishing tricycle 54, the ABC ring core of ircinal A. Most noteworthy was the fact that the lone stereocenter in 53 was used to establish the relative stereochemistry and absolute conguration of the three new chiral centers of 54. The intramolecular Diels Alder strategies outlined in Schemes 10 12 provide efcient approaches to polycyclic d-lactams, and serve to highlight their utility in complex alkaloid synthesis. 2.2.3. Ring closing metatheses. Ring closing metathesis (RCM) is one of the most powerful and useful procedures for producing medium to large rings.38 RCM reactions are reversible and driven primarily by favorable entropic factors (DS.0) that are related to the extrusion of a volatile group usually ethylene. Furthermore, RCM reaction rates also depend on both steric and electronic factors. RCM reactions are believed to proceed via a metallacyclobutane-forming mechanism through the catalytic cycle.39 The rst carbene olen [22] cycloaddition is assumed to be the ratedetermining step and takes place on the electronically least deactivated and/or least sterically substituted CvC bond. The faster second cycloaddition is less sensitive to steric hindrance. Simple a,b-unsaturated lactams 56 (Scheme 13) were prepared starting from unsaturated amides 55 using Grubbs catalyst.40 The authors also synthesized trisubstituted 2-piperidones using methacryloylamides. These compounds were prepared in good yield provided Ti(OiPr)4 was added to the reaction. However, if substituents were on the homoallylic double bond no reaction was observed, even when second generation catalysts were employed.
Scheme 11. (a) 2-Chloro-1-methylpyridinium iodide, Et3N, CH2Cl2, 08C (85%); (b) CHCl3, 608C [95%, 49/506:1].
2.2.2. Domino Stille coupling/vinylogous imide Diels Alder reaction. A domino Stille coupling/Diels Alder reaction provided the foundation of a clever strategy culminating in the total syntheses of ircinal A35,36a and manzamine A (Scheme 12).36b The key intermediate 52 was assembled by coupling an unsaturated amino ester with a chiral dienophile derived from D -pyroglutamic acid. Stille coupling37 produced diene 53 that underwent a spontaneous intramolecular Diels Alder reaction with the vinylogous
Scheme 13. (a) PhCHvRh(PCy3)2Cl2, Ti(OiPr)4, CH2Cl2.
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Scheme 14. (a) PhChvRuCy3Cl2(Im), CH2CI2, room temperature, 3 h [74%].
cis-60 and trans-60 (Scheme 15).45 Treatment of cis-60 with TFA afforded multigram quantities of a chromatographically separable mixture favoring trans-60. After lactam cis60 was converted into an activated Michael acceptor, diastereofacial cuprate addition afforded 61 with excellent facial selectivity (97:3 at the b-dicarbonyl center). The same sequence was used to transform trans-60 to 62 with similar yield and facial selectivity. It is important to note that the conguration of H-8a is responsible for the facial selectivity in the conjugate addition. Diastereomers 61 and 62 were converted into the (2)- and ()-enantiomers of the antidepressant agent paroxetine (see Section 2.1.3 for an alternate synthesis). Recent publications reported the functionalizations of g-substituted-a,b-unsaturated bicyclic lactams by stereocontrolled conjugate additions.46
Scheme 15. (a) Ph Me, OHC(CH2)3CO2Me, reux, [86%, cis-60/trans-6085:15]; (b) TFA, CH2Cl2, room temperature [100%, cis-60/trans-6014:86]; (c) LHMDS, ClCO2Me, PhSeBr, THF, 2788C; (d) O3, CH2Cl2, 2788C, then O2, room temperature; (e) 4-FC6H4Cu(CN)Li, THF, 2788C [cis-60!61, 54%; cis-60!62, 77%].
A formal synthesis of the indolizidine alkaloid (2)-dconiceine was reported recently (Scheme 14).41 (2S)-2-(2Propenyl)pyrrolidine was prepared in 3-steps from L -proline methyl ester hydrochloride and reacted with acryloyl chloride to give bisolen 57. The resulting diolen underwent RCM reaction using PhCHvRu(PCy3)Cl2(Im) to afford indolizidin-5-one 58 that can be converted to (2)d-coniciene by known methods.42 Similarly, the RCM with Grubbs catalyst was used in a diastereoselective synthesis of 3-substituted octahydroquinolizin-4-ones 59.43 2.3. Intermolecular processes 2.3.1. Chiral bicyclic lactams. The use of chiral bicyclic lactams for the asymmetric synthesis of functionalized carbocycles and nitrogen heterocycles has proven to be a highly useful and practical strategy.44 Bicyclic lactams can be prepared through the cyclodehydration of amino acid derived (R)- or (S)-b-amino alcohols with g- or d-oxoacid derivatives. An enantiodivergent synthesis of ()- and (2)paroxetine commenced with the cyclodehydration of (R)phenylglycinol and methyl 5-oxopentanoate affording a chromatographically separable mixture of bicyclic lactams
Scheme 16. (a) PhMe, reux.
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The introduction of substituents during cyclodehydration focused on the reaction of (R)-phenylglycinol with racemic substituted d-oxoacid derivatives and examined the diastereoselectivity in bicyclic lactam formation through the processes of dynamic kinetic resolution (DKR) and desymmetrization.47 A series of racemic d-oxoacid derivatives 63 having an epimerizable a-stereocenter afforded either bicyclic lactams 65A or 65B as major products (Scheme 16). The stereoselectivity was attributed to lactamization through chair-like transition states 64A and 64B in which the R1-substituent occupied an equatorial position, with approach of the carboxylate group to the more accessible face of the oxazolidine nitrogen atom. The diastereoselectivities for 65A or 65B were 4:1 indicating that a DKR had occurred. The stereocontrolled reduction of the C-8a bond of 65A (RMe) provided a route to cis- or trans-2,3-disubstituted piperidines.47d Prochiral d-oxodiesters 66 were used in cyclodehydrations with (R)-phenylglycinol to study enantioselective desymmetrization for R1H and tandem desymmetrization-DKR processes for R1alkyl (Scheme 17). Transition states 67A or 67B place R1 and an acetyl chain in equatorial positions with the stereochemical outcome of the cyclodehydration favoring bicyclic lactam 68A for Ralkyl or 68B for RH (drs4 5:1) in examples studied with RH or Me. The desymmetrization of prochiral 4-formylpimelic diesters 69 by cyclodehydration with (R)-phenylglycinol also was studied (Scheme 18). Preferential formation of bicyclic lactam 71B (dr9:1) was a consequence of lactamization through cis-oxazolidine transition state 70B. The oxidation of a phenylglycinol derived 2-pyridone 72 with m-CPBA provided a one-step synthesis of a chiral bicyclic lactam (Scheme 19).48 The interactions between the phenyl ring and the carbonyl group of pyridone 7249 favor the hydroxyl assisted epoxidation taking place through conformation 73. Ring cleavage of epoxide 74 by the nitrogen lone pair and intramolecular hydroxyl group attack produced unsaturated hydroxylactam 76 as a single stereo-
isomer. Lactam 76 is potentially useful for the synthesis of azasugars. The methodologies highlighted in this section expand the utility of chiral bicyclic lactams. A diverse array of polysubstituted chiral bicyclic lactams are available by taking advantage of diastereotopic differentiation during the cyclodehydration of racemic d-oxoacid derivatives with a chiral inductor. These substituted chiral bicyclic lactams are useful substrates for additional stereocontrolled functionalization en route to enantiopure d-lactams and piperidines. 2.3.2. [313] Annulations. Recent reports describe the syntheses of functionalized d-lactams using [33] annulation procedures that combine [C C C] and [N C C] moieties.50,51 An efcient synthesis of N-benzyl-3-sulfonyl glutarimides 79 was accomplished by reaction of the dianion of a-toluenesulfonyl acetamide 77 with a,bunsaturated esters 78 (Scheme 20).50a A useful feature of this approach is the utility of a sulfonyl group to control subsequent regioselective functionalizations that led to a variety of d-lactams with diverse substitution patterns (Scheme 21). A dianion alkylation of 80 was used to produce the quaternary center in glutarimide 81.
Scheme 19. (a) m-CPBA, CH2Cl2, room temperature (3540%).
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both the a-sulfonyl and C-2 carbonyl.50d The intermediate hydroxy piperidone was dehydrated to unsaturated lactam 83 and then converted to piperidone 84 by olen hydrogenation and reductive desulfonylation with sodium amalgam. A slight modication of this glutarimide-based strategy yielded g-substituted-a,b-unsaturated d-lactams 88 from a-sulnyl acetamides 85 (Scheme 22).50b This efcient three-step preparation of 88 provides access to cis- and trans3,4-disubstituted piperidines through the conjugate addition of stabilized anions and organocuprates. A formal synthesis of racemic protoemetinol was also reported. The [33] aza-annulation of chiral non-racemic b-enamino esters with acryloyl chloride provided oxazolo-d-lactams that were used in a synthesis of enantiopure cis- and trans2,3-disubstituted piperidines.52 2.3.3. 2-Azadiene Diels Alder reaction. The aza Diels Alder reaction is an established procedure for the synthesis of nitrogen-containing six-membered rings. The Diels
Scheme 20. (a) NaH, THF, room temperature.
Scheme 21. (a) NaH, THF, EtBr, reux (92%); (b) NaH, THF, room temperature; (c) LAH, THF, room temperature; (d) BF3Et2O, CH2Cl2, room temperature [80%, for 3 steps; (e) NaBH4, MeOH, THF, 478C; (f) BF3Et2O, CH2Cl2, room temperature [80%, for 2 steps]; (g) H2, Pd(OH)2, AcOH, room temperature; (h) Na(Hg), MeOH, room temperature [80%, for 2 steps].
Regioselective reduction of the C-6 carbonyl of glutarimide 80 was accomplished by protection of the C-2 carbonyl as an enolate. The resultant hydroxy piperidone, an N-acyliminium ion precursor, was then dehydrated to unsaturated lactam 82.50c,f Regioselective reduction of the C-2 carbonyl of 80, was best accomplished with NaBH4. This was attributed to chelation of the reducing agent with
Alder reaction of electron rich 2-azadienes53 89 with acyl oxazolidinones 90 catalyzed by C2-symmetric chiral bis(oxazoline)-metal complexes54 was used to synthesize enantiopure polysubstituted d-lactams (Scheme 23).55 The reaction was run at either 2458C or room temperature and yields, diastereoselectivities and enantioselectivities were excellent, the lone exception being a 4-unsubstituted azadiene. An Evans transition state model, proposed for related Diels Alder reactions catalyzed by C2-bis(oxazoline) metal complexes, predicted the stereochemical outcome (Scheme 24).56 The relative stereochemistry and absolute conguration of the stereocenters of 91 were attributed to exo-approach of the diene to the less hindered face of the square planar dienophile chiral catalyst complex. In addition, functional group transformations of 91 are possible without loss of enantiomeric purity. 2.3.4. Metal catalyzed cyclocarbonylations. Pd-catalyzed decarboxylative-carbonylation of vinyloxazolidinones (Scheme 25) provided a useful approach to the enantioselective synthesis of unsaturated d-lactams.57 Treatment of amino acid derived aldehydes and ketones 93 with vinyl Grignard reagents gave alcohols 94 having low diastereoselectivities (dr1 5:1). Cyclization to 5-vinyloxazolidin2-ones 95 was followed by Pd-catalyzed decarboxylative
Scheme 22. (a) NaH, THF, room temperature; (b) LAH, THF, reux; (c) PhMe, reux [4046%, for 3 steps].
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Scheme 23. (a) Catalyst, CH2Cl2, 4 A, MS, 2458C or room temperature; (b) MeOH.
elaboration to more complex nitrogen heterocycles. This procedure also was used to prepare 3,6-disubstituted-3,6dihydro-1H-pyridin-2-ones.57b
3. Synthesis of 3-piperidones 3.1. Oxidative cyclization (aza-Achmatowicz reaction) Two excellent reviews59 provide good background information for this section. The aza-Achmatowicz reaction (Scheme 26) is exemplied by the oxidative rearrangement of furylamides 100 to 1,6-dihydro-2H-pyridin-3-ones 102. Chiral, non-racemic furylamides 100 were obtained by the Sharpless catalytic, asymmetric aminohydroxylation (AA) of 2-vinylfuran 9960 or by transformation of D -glucal 101.61 3-Piperidone 102 was used in the synthesis of azasugars,60a and in the stereoselective preparation of aldehyde 103, an intermediate for the synthesis of 2,3,6-trisubstituted piperidine alkaloids.62 The aza-Achmatowicz reaction also was used in the stereoselective synthesis of 2,5,6-trisubstituted 3-piperidones.63 Additional applications of this oxidative cyclization were used in the asymmetric synthesis of 3-hydroxypipecolic acid d-lactams64 and polyhydroxylated 6-oxa-nor-tropanes.65
Scheme 24.
Scheme 25. (a) BrMg(R2)CvCH2, THF, 2788C!room temperature; (b) NaH, THF, 2788C!room temperature; (c) Pd(PPh3)2(OAc)2, EtOH, CO (65 atm), 65708C [57 87% for step c].
carbonylation to enantio-enriched d-lactams 98. The authors proposed transition states 96 and 97 for the decarboxylation and carbonylation steps, respectively. Citing the similar Pd-catalyzed decarboxylation of N-tosyl vinyloxazolidinones to N-tosyl vinylaziridines, the authors treated 95 (RiPr, R1, R2H) under similar conditions and recovered 95 as a single trans diastereomer.58 It was proposed that ring opening of 95 to form the p-allyl palladium species was reversible, and was not accompanied by fast decarboxylation. This enantioselective process provides access to substituted, unsaturated d-lactones with the potential for
Scheme 26.
3.2. From amino acids An intramolecular nucleophilic acyl substitution (INAS)66 and ring expansion were used to prepare 3-piperidone 106, a
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Scheme 27. (a) Ti(OiPr)4, iPrMgCl, Et2O [86%]; (b) FeCl3, Et2O; (c) NaOAc, MeOH [94%, 2 steps].
Scheme 28. (a) iBuOCOCl, TEA, THF, 2108C, then CH2N2, Et2O [2756%]; (b) TFA, CH2Cl2, 2788C [6288%].
(Scheme 28).69 N-Boc-g-amino acid 107 was prepared efciently from commercially available N-Boc-a-amino acids and its conversion to N-Boc-g0 -amino-a-diazoketone 108 was accomplished through mixed anhydride formation and diazomethane coupling. The TFA-mediated intramolecular N H insertion process then afforded 3-piperidone 109 with concomitant removal of the Boc group. A nitronium species might be involved in this transformation. The reaction was fast (,5 min) and clean provided low substrate concentrations (0.5 mM) were used. Enantiopure 3-piperidones and azabicycles were accessible from D - or L -amino acids with retention of chirality. The synthesis of annulated dihydropyridin-3-ones was the cornerstone of a novel strategy for the enantioselective synthesis of polyhydroxypiperidines (Scheme 29).70 Alkylation of N-benzenesulfonyl amino ester 111 with 5-bromo4-(bromomethyl)-2-phenyloxazole (110, XO), followed by low temperature bromine lithium exchange and intramolecular Barbier-type cyclization provided access to oxazolopyridin-3-one 112. In this efcient approach, the azole ring contributed three carbon ring atoms and two heteroatoms which were liberated late in the synthesis. Other salient features of this strategy were the stereocontrolled introduction of three additional stereocenters and the inclusion of a Mitsunobu step for inversion of conguration or the introduction of additional heterosubstituents. A further extension of this azasugar strategy started with thiazoles as starting materials enabling the preparation of 5-amino-4-thiohydroxypiperidines. 3.3. Ring expansion The rst example of a stereoselective silyl-directed Stevens rearrangement of ammonium ylides was the key step in a short, enantioselective route to hydroxylated quinolizidines (Scheme 30).71 Asymmetric lithiation and silylation were used to prepare (S)-N-Boc-2-phenyldimethylsilylpyrrolidine 114 in 92% yield and 85% ee. Removal of the
Scheme 29. (a) K2CO3, MeCN, reux [90%]; (b) BuLi, THF, 21008C [74%].
versatile chiral building block for the preparation of 1-deoxyazasugars (Scheme 27).67 Thus, D -serine was converted to N-allylated ester 104, and Ti(II)-mediated INAS produced bicyclic cyclopropanol 105. A FeCl3mediated ring expansion of bicyclic cyclopropanols to conjugated cycloalkenones68 was used to convert 105 into enantiopure 106. An efcient route to optically active 3-piperidones utilized a triuoroacetic acid (TFA)-promoted intramolecular N H insertion as the key C N bond forming process
Scheme 30. (a) AcCl, EtOH, EtOAc; (b) K2CO3, Et3N, MeCN, Br(CH2)3C(O)CHN2, (47%); (c) Cu(acac)2, PhMe, 858C (58%).
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protecting group and alkylation furnished diazoketone 115. Copper-catalyzed rearrangement afforded quinolizidine 116 in 58% yield and 77% ee as a single diastereomer, a result attributed to the conformational rigidity of the pyrrolidine ring due to the steric bulk of the phenyldimethylsilyl group. A stereoselective ketone reduction and a Fleming Tamao oxidation provided diol 117.
4. Synthesis of 4-piperidones 4.1. Intermolecular processes 4.1.1. From 1-acylpyridinium salts. 2,3-Dihydro-4-pyridones are utilized in the syntheses of numerous alkaloids due to the variety of stereocontrolled functionalizations that are possible (Scheme 31).72 2-Substituted-N-acyl-2,3-dihydro-4-pyridones were prepared enantiomerically pure by the stereoselective addition of organometallic reagents and metalloenolates to chiral 1-acylpyridinium salts.73 Also, a resin activation/capture approach (RECAP technology) was used for the synthesis and elaboration of 2,3-dihydro-4pyridones on solid support.74 A1,3 strain75 causes the C-2 substituent to occupy an axial position thereby inuencing the stereochemical outcome of subsequent transformations. Iodocyclocarbamation of N-acyl-2-alkenyl-4-piperidones produced bicyclic carbamates in a highly stereoselective manner.76 Enolate alkylations were used to functionalize C-3,72 and C-3 a-acetoxylations afforded trans-2,3-disubstituted products.77 Organocerium reagents added to C-4 from the face opposite the axial C-2 substituent, while reduction with sodium borohydride/cerium chloride provided C-4 equatorial alcohols.72 Substitution at C-5 was achieved via the corresponding vinyl iodide (prepared using iodine monochloride).78 Functionalizations at C-6 were achieved by Mukaiyama Michael73c and copper catalyzed Grignard conjugate additions,78b intramolecular Heck reactions72 and conjugate reduction.79 The intramolecular [22] photocycloaddition of a nitrogen tethered terminal olen was a key reaction in the total synthesis of plumerinine.80
Scheme 32. (a) Zr(OtBu)4, (R)-6,60 -dibromo-1,10 -binaphthol; N-methylimidazole (NMI), Ph Me, 458C [83%, ee82%]; (b) Zr(OtBu)4, (R)-6,60 dibromo-3,30 -diphenyl-1,10 -binaphthol, NMI, Ph H, 3 A, MS, 238C [93%, ee91%].
Danishefskys diene with ortho-hydroxyphenyl imine 118 that produced 2,3-dihydro-4-pyridone (S)-119.86 Use of a similar chiral catalyst 121 with substituents on the 3,30 positions, caused a reversal in the absolute conguration of the product yielding (R)-119. The observed enantioselectivity was rationalized by approach of the diene to the Re-face of complex 122, with shielding provided by one of the phenyl groups and possibly one of the axial tertbutoxy groups. Kobayashi also used polymer-supported (R)1,10 -binaphthols as chiral catalysts in aza Diels Alder reactions of aldimines with Danishefskys diene. High yields, high enantioselectivities and low catalyst loadings were achieved.85b The HDA reaction of Danishefskys diene with the benzylimine derived from Garners aldehyde was used as the key step in an efcient approach to the asymmetric synthesis of carbacepham 127 (Scheme 33).87 Imine 124 was prepared under non-epimerizable conditions,88 and HDA reaction with Danishefskys diene catalyzed by
Scheme 31.
4.1.2. Imino Diels Alder reactions. The hetero Diels Alder (HDA) reaction of imines with Danishefskys diene (1-methoxy-3-trimethylsiloxy-1,3-butadiene) is an efcient method for construction of functionalized 2,3-dihydro-4pyridones with control of regio-, diastereo- and enantioselectivity.81 Recently, Naon-H,82 bismuth(III) chloride and triate,83 and samarium diiodide84 were used as achiral catalysts in these reactions. Kobayashi et al. reported a switch of enantiofacial selectivity when using either (R)-6,60 -dibromo-1,10 -binaphthol or (R)-6,60 -dibromo3,30 diphenyl-1,10 -binaphthol as the ligand in chiral zirconium catalyst systems (Scheme 32).85a Initial studies from the Kobayashi laboratories reported the use of catalyst system 120 in the enantioselective HDA reaction of
Scheme 33. (a) BnNH2 , CH2Cl 2 MgSO4 , room temperature; (b) Danishefskys diene, Et2AlCl, CH2Cl2, 2408C; (c) 1N HCl, then chromatography [65%, S,S/S,R1:4].
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Scheme 34. (a) TFA, MeOH; (b) RCHO, CH2CI2, room temperature, then aq. NaHCO3 [70 84%, 2 steps]; (c) 48% HBr [6266%] (d) LiOH, MeOH, reux [70%].
diethylaluminum chloride gave the best diastereoselectivity for dihydro-4-pyridone 125. Subsequent transformations provided 127 via b-amino acid 126.89 Use of Danishefskys diene in the HDA reaction was central in the asymmetric synthesis of functionalized indolizidines,90 indolo[2,3a]quinolizidine,91 tetracyclic alkaloid phyllanthine92 and enantiopure pipecolic acids.93 Similarly, the HDA reaction of E-1-dimethylamino-3-tertbutyldimethylsiloxy-1,3-butadiene94 with activated imines proceeded at room temperature in the absence of Lewis acid catalysts providing a simple, one-pot synthesis of dihydro4-pyridone derivatives.95 A convenient, large-scale synthesis of chiral 4-oxopipecolates was achieved by HDA reaction of 2-trimethylsilyloxy-1,3-butadiene with activated imines derived from condensation of ethyl glyoxalate with (R)- or (S)-amethylbenzylamine.96 Diastereomerically pure 4-oxopiperidine-2-carboxylates were obtained by crystallization and were converted to a variety of protected 2-substituted 4-oxo-piperidine derivatives. A one-pot, three-component synthesis of 2-substituted 2,3dihydro-4-pyridones was accomplished by a highly efcient aza Diels Alder reaction.97 The reaction was carried out in methanol in the absence of acid and likely proceeded through a Mannich-type pathway. The solid-phase HDA
reaction of 2-amino-1,3-butadienes with nitrogen-bound imines (BOBA resin) and carbon- bound imines (Wang resin) furnished 4-piperidones with 4 points of diversity.98 4.2. Intramolecular processes 4.2.1. Mannich reactions. The intramolecular Mannich reaction is a powerful tool for the rapid, efcient, highly stereoselective assembly of polysubstituted piperidones. Sulnyl amines 128 served as asymmetric precursors to d-amino-b-ketoesters (Scheme 34).99 Treatment with excess triuoroacetic acid removed the sulnyl group and the released chiral amine salt 129 was then reacted with an aldehyde or ketone giving polysubstituted piperidone 131. The major isomer was shown to have the C-2 and C-6 substituents in a cis-orientation with the C-2- and C-3substituents trans. For aldehydes, the nearly exclusive formation of the 2,6-cis-disubstituted piperidone 131 was consistent with transition state 130. Decarboxylation to 132 was best effected with 48% HBr in methanol. Some erosion of chirality was noted and was attributed to a retro-Mannich reaction. The authors demonstrated a base-induced retroMannich reaction of 133 giving 6-phenylpiperidine-2,4dione (134). 2,6-Disubstituted-4-piperidones serve as important building blocks for piperidine alkaloid synthesis. Another approach to 4-piperidones using an intramolecular Mannich-type reaction was described by Troin and
Scheme 35. (a) MgSO4, CH2CI2, relfux, [100%]; (b) TsOH, Ph Me, 708C [90%]; (c) 6% HCl, Me2CO, 208C [92%].
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Scheme 36. (a) CHCl3, reux, [98%]; (b) MsCl, pyridine, 08C; (c) DABCO, MeCN, reux [44%, 2 steps]; (d) SiO2 chromatography (e) H2, Pd(OH)2/C [94%].
co-workers in a series of papers utilizing chiral b-amino ketals as starting materials (Scheme 35).100 Enantiopure amine 135 was condensed with decylaldehyde to form imine 136. Subsequent treatment with p-toluenesulfonic acid afforded 138 with the diastereoselectivity of .95% accounted for by transition state 137. Removal of the ketal protecting group afforded piperidone 139.100b Using this intramolecular Mannich-type reaction, Troin and co-workers rapidly assembled 2,20 -spiro-4-piperidone skeletons101 that are present in a variety of natural products. 4.2.2. Cycloadditions. A short, practical, multigram synthesis of both isomers of ethyl 4-oxopipecolate (145) was achieved utilizing a 1,3-dipolar cycloaddition as the key step (Scheme 36).102 Reaction of nitrone 141 with 3-butenol (140) gave isoxazoline 142 as an equimolar mixture of four diastereomers. Reaction of the mixture with mesyl chloride and treatment of the resulting mesylates 143 with DABCO in reuxing acetonitrile gave a 1:1 mixture of 144 epimeric at C-2. Deprotection of the separated epimers led to (R)- and (S)-4-oxopipecolic acid. 4.2.3. From b-amino carboxylates. Enantiopure b-amino esters are readily available103 and served as starting points
for a simple, efcient synthesis of enantiopure 4-oxo- and 4-hydroxy-2,6-disubstituted-piperidines.104 Their utility in the syntheses of dendrobate alkaloid ()-241D and (2)indolizidine 167B are highlighted in a formal synthesis of the latter (Scheme 37). N-Deprotection of 146 gave a b-amino ester that was transformed to 2,3-dihydropyridone 147. After conversion to diol 148 and selective protection of the amine and primary alcohol with benzyl chloroformate, the secondary alcohol was oxidized. Removal of the protecting groups from the resulting ketone gave 149 which could be converted to 150 by a known procedure.105 3-Triuoroacetylamino-3-arylpropionyl chloride 152 was prepared in two steps from the corresponding b-aryl-bamino acid 151 and condensed with Meldrums acid to afford the chain homologated intermediate 153 (Scheme 38). Ring opening hydrolysis of 153 with reuxing tert-butanol gave the d-aryl-d-triuoroacetylamino-b-ketoester 154 that was cyclized with aqueous NaOH in tetrahydrofuran to 155. This represents an easy, versatile preparation of 6-arylpiperidine-2,4-diones.106 See Scheme 1 for an alternate preparation.
Scheme 37. (a) H2, Pd/C, room temperature; (b) AcOH, then PrCOCH2CO2Et; (c) Na, EtOH [79%, 3 steps]; (d) aq NaOH, EtOH; (e) H2, Pd/C; (f) Cbz-Cl; (g) DessMartin oxidation; (h) H2, Pd/C [82%, 5 steps].
Scheme 38. (a) TFAA, TFA; (b) (COCl)2 , CH2 Cl2 , [74 91%]; (c) Meldrums acid, pyridine, CH2CI2; (d) tBuOH [7179%]; (e) aq NaOH, THF [79 88%].
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5. Synthesis of piperidines 5.1. From 2-piperidones 5.1.1. From N-alkoxycarbonyl enol derivatives. There is a growing interest in the utility of lactam-derived vinyl triates in Pd(0)-catalyzed C C bond forming processes. Palladium-mediated displacement of the triate group with nucleophiles such as cuprates, organotin and organozinc derivatives and methoxycarbonylations were reported.107 Sonogashira cross-coupling reactions with monosubstituted acetylenes were done also.108 A recent paper highlighted methodology for the efcient introduction of aryl, alkenyl, allyl and alkyl groups onto piperidine rings by Suzuki couplings109 with lactam-derived vinyl triate 156 (Scheme 39).110a Substituents were introduced under mild conditions in THF water, whereas coupling with an alkylboronic acid (entry b) required anhydrous conditions and Pd(dppf)Cl2 as a catalyst in the presence of Ag2O to facilitate transmetalation. Suzuki couplings of N-CO2Ph d-lactam-derived vinyl phosphates with aryl and heteroaryl boronic acids have been reported.111 The vinyl phosphates were used as stable, cost effective alternatives to vinyl triates, and couplings proceeded under mild conditions providing C-2 substituted enecarbamates in good yields.
Scheme 40. (a) Bu3(vinyl)Sn, Pd(PPh3)4, LiCl, THF, reux, then ethyl acrylate [68%]; (b) H2, Pd(OH)2 [80%].
of hydrochloric acid and a recent review by Speckamp highlighted their utility in C C bond forming reactions.114 A total synthesis of securinine used a stereoselective addition of a siloxyfuran to an N-acyliminium ion as the key step (Scheme 41).115 The vinylogous Mannich reaction16a of 2-ethoxypiperidine 163 and siloxy furan 164116 provided adduct 165, which possessed the requisite stereochemical relationship of the piperidine and butenolide moieties found in securinine. Conjugate addition of the anion of allyl phenyl sulfoxide afforded a single diastereomer and utilization of a full equivalent of Grubbs reagent was necessary to effect a novel, ring closing metathesis to 166. Similar applications of the vinylogous Mannich reaction were reported.117
Scheme 39. (a) Aq Na2CO3, THF, Pd(PPh3)2Cl2, 40808C; (b) for b, Ag2O, K2CO3, Pd(dppf)Cl2, PhMe, 808C.
Enol triates and phosphates derived from chiral bicyclic lactams were used in the asymmetric synthesis of triuoromethyl-substituted piperidines and decahydroquinolines (Scheme 40).112 Enamine phosphate 158 was converted to diene 159 and trapped as the endo a-face Diels Alder adduct 160 that isomerized to 161 during workup and silica gel chromatography. Hydrogenation of the double bond of 161 occurred with concomitant cleavage of the oxazolidine ring and nitrogen deprotection to produce enantiopure decahydroquinoline 162. An N-p-toluenesulfonyl d-lactam enol triate was converted to a vinylstannane by Pd(0)catalyzed cross-coupling with hexamethyldistannane. Tin lithium exchange followed by addition of cyclobutanone afforded cyclobutanols that were used in a study on the utility of semipinacol type rearrangements for the construction of azaspirocyclic ketones.113 5.1.2. From cyclic N-acyliminium intermediates. N-Acyld-lactams are readily converted to N-acyl-2-alkoxypiperidines by treatment with sodium borohydride in the presence
Scheme 41. (a) TIPSOTf, heptane, 2788C [78%]; (b) allyl phenyl sulfoxide, LiHMDS, THF, 278!2458C (71%); (c) PhCHvRu(PCy3)2Cl2, DCE, 708C [79%].
Strategies for asymmetric C C bond forming reactions at C-2 of the piperidine ring involving additions to N-acyliminium ions derived from 2-alkoxy piperidine were reported. Addition of the titanium(IV) enolate derived from (S)-oxazolidinone 168 to a piperidine-derived N-acyliminium ion was the key step in an approach to the indolizidine core of stelletamide alkaloids (Scheme 42).118 The reaction proceeded through coordinated intermediate 169 with preferential addition of the Si face of a chelated Z-enolate to the Si face of the N-acyliminium ion resulting in a preference for threo-(2R,2R0 )-170. Hydrogenolysis of
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In an asymmetric synthesis of (2)-adaline,122 chiral N,Oacetals were used to stereoselectively functionalize both the C-2 and C-6 positions of the piperidine ring. N,O-Acetal 177 was used for stereoselective introduction of an allyl substituent onto the C-6 position of lactam 178 (Scheme 44). Reduction to primary alcohol 179 and oxidation to the corresponding aldehyde resulted in ring closure to N,O-acetal 180 that was stereospecically functionalized to 2,2,6-trisubstituted piperidine 181. Subsequent transformations afforded (2)-adaline.
Scheme 42. (a) TiCl4, DIPEA, CH2CI2, 2238C [62%, dr5:1]; (b) H2, Pd(OH)2, EtOH, room temperature [73%].
170 was accompanied by intramolecular alkylation to provide indolizidine 171. A similar strategy was used in a synthesis of d-threo-methylphenidate.119 Asymmetric nucleophilic substitution at the 2-position of an N-acyl3,4-didehydro-2-methoxypiperidine with dimethylmalonate was catalyzed by chiral Cu(II) bis-oxazoline ligands, and 2-substituted piperidines were produced with moderate enantioselectivity.120 A stereodivergent approach to substituted 4-hydroxypiperidines was accomplished by the selective formation of regioisomeric N-acyliminium ion precursors from a common intermediate (Scheme 43).121 The most signicant difference between the acyliminium ions is the position of the acyl group. Racemic 4-hydroxy-2-piperidone 172 was prepared in four steps from vinyl acetic acid, whereas enantiopure 172 was obtained from the biocatalytic desymmetrization of 3-benzoyloxypentanedinitrile. Allylation of the exocyclic acyliminium ion generated from 173 showed a preference for cis-174 due to axial attack by the nucleophile, a result attributed to a transition state conformation in which the oxygen substituent is pseudoaxial thereby enabling its lone pair electrons to partially stabilize the acyliminium cation. By contrast, allylation of the endocyclic acyliminium ion from 175 favored trans-176 due to axial attack of the nucleophile on a transition state conformation with the substituent pseudo-equatorial.
Scheme 44. (a) TiCl4, H2CvCHCH2TMS; (b) LiH2NBH3, THF, 408C [88%]; (c) TPAP, NMO, MeCN, 4 A MS, room temperature [80%]; (d) HCuCLiH2NCH2CH2NH2, THF, 408C [88%].
Stereoselective nucleophilic substitution reactions of N-acyl-2-methoxypiperidine with silyl enol ethers and ketene silyl acetals catalyzed by Sc(OTf) 3123 and BF3Et2O124 were carried out. A coupling of a bicyclic N-acyliminium ion with 3-trimethylsilyl-1-decene was used in a synthesis of piclavines A1 and A2.125 5.1.3. From ring opening of N-alkoxycarbonyl-d-lactams. Another feature that d-lactams afford is the option to replace the lactam carbonyl with a substituent. The process involves regioselective ring opening of an activated lactam with a nucleophile followed by recyclization with dehydration and stereoselective reduction. This and related procedures are well-documented with pyroglutamate derivatives,126 and the utility of this sequence in the synthesis of an all cis-2,4,5-trisubstituted piperidine was reported (Scheme 45).19a Treatment of activated d-lactam 182 with (benzenesulfonyl)methyllithium afforded a ring opened product in modest yield. Subsequent hydrogenation resulted in N-deprotection, cyclization and reduction affording the all cis-trisubstituted piperidine 183, an
Scheme 43. (a) Allyltrimethylsilane, BF3Et2O, MeCN, 2508C!room temperature [92%, cis/trans72:28]; (b) allyltrimethylsilane, BF3Et2O, MeCN, 08C!room temperature [100%, cis/trans11:89].
Scheme 45. (a) PhSO2CH2Li, THF, 2788C [41%]; (b) H2, Pd(OH)2, MeOH, room temperature [76%].
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advanced intermediate in a formal synthesis of the alkaloid pseudodistomin C.127 5.2. From 4-piperidones 5.2.1. From N-alkoxycarbonyl vinyl triates. 4-Arylpiperidines are useful therapeutic entities synthesized through palladium-mediated vinyl tin aryl bromide128 and vinyl triate aryl boronate129 cross-couplings. However, the toxicity of the tin compounds and the limited availability of aryl boronates may restrict their utility in synthetic strategies. A versatile synthesis of 4-aryl-tetrahydropyridines was accomplished by the Suzuki coupling of 4-piperidone derived cyclic vinyl boronates with aryl bromides, iodides and triates (Scheme 46).130 Palladiummediated cross-coupling of N-protected vinyl triates 184 with bis(pinacolato)diboron furnished cyclic boronates 185 and cross-coupling with aromatic substrates afforded 4-aryltetrahydropyridines 186 in good to excellent yields. A variety of substituents were tolerated, as well as o-substitution and heteroaromatic coupling partners. N-Deprotection enabled additional functionalization.
yield and excellent diastereoselectivity (cis/trans10 30:1) after N-deprotection. Removal of the control element prior to conjugate reduction reversed the diastereochemical outcome in favor of the trans-2,4-disubstituted piperidines 189 (cis/trans1:4 88). An adaptation of this methodology was used by the authors to synthesize 8-substitutedquinolizin-4-ones. Wittig olenation of N-Boc-4-piperidone afforded N-Boc-4methylene piperidine that was used as a substrate for b-alkyl Suzuki Miyaura couplings131 with aryl halides in a synthesis of 4-arylmethylpiperidines.132 A wide range of functional groups were tolerated. The intramolecular Pauson Khand reaction of N-Cbz-4-methylene-3-prop-2ynylpiperidine was used as a key step to prepare N-Cbz-3oxo-8-aza-tricyclo[5.3.1.01,5]undec-4-ene.133 5.3. Intramolecular N C processes 5.3.1. Nucleophilic substitutions. The intramolecular SN2 displacement of a halide or activated alcohol by a nitrogen nucleophile is a well established method for forming piperidine rings, and this section will highlight several recent novel applications of this process. A double, reductive cyclization was used to form the indolizidine skeleton of (2)-slaframine (Scheme 48).134 The key azido diol 191 was derived from aldehyde 190 using an enantioselective allyltitanation and a Mitsunobu reaction to introduce functionality and control the C-1 and C-8a stereocenters. Mesylation of the alcohols followed by reduction of the azide resulted in bis-cyclization to indolizidine 192, with a separate hydrogenation step needed to remove the benzyl protecting group en route to (2)slaframine. An alternate synthesis of (2)-slaframine using an intramolecular displacement to form the piperidine ring also was reported.135
Scheme 46. (a) Pd(dppf)Cl2, dppf, KOAc, dioxane, 808C [8587%]; (b) ArX (XI, Br, OTf), Pd(dppf)CI2, K2CO3, DMF, 808C [60 92%].
5.2.2. From Wittig olenations. A highly diastereoselective synthesis of 2,4-disubstituted piperidines was developed that provided access to either diastereomer simply by changing the reaction order (Scheme 47).1 2-Substituted 4-piperidones 187 were prepared using Comins methodology (see Section 4.1.1) and Wittig olenation subsequently provided styrenes and a,b-unsaturated esters in good yields. A1,3 strain was used as a control element for the dissolving metal reduction of the 2-substituted N-acyl-a,b-unsaturated esters and styrenes, and cis2,4-disubstituted piperidines 188 were produced in good
Scheme 48. (a) MsCl, DMAP, pyr; (b) H2, Pd/C, Et3N, MeOH, room temperature!reux [67%, for 2 steps].
Scheme 47. (a) tBuOK, PhCH2PPh3Cl, THF, room temperature or Ph3PvCHCO2Et, PhMe, reux, or tBuOK, 4-ZHN-PhCH2PPh3Cl, THF, 2788C!room temperature [8995%]; (b) Li, NH3, THF, 278!2288C; (c) TFA, CH2CI2 [44100%, for 2 steps].
Optically active v-bromocyanohydrins were used as starting materials in a synthesis of enantiopure 2,3-cisdisubstituted piperidines 195 (Scheme 49).136 Protected cyanohydrin 193 (91% ee) was prepared using an enantioselective (R)-oxynitrilase-catalyzed transcyanation. A one-pot procedure consisting of an initial Grignard addition proceeded through an intermediate cyclic imine 194, and sodium borohydride reduction followed by N-protection afforded cis-(R,R)-piperidine 195 as a single diastereomer. Aromatic Grignard reagents gave higher
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Scheme 49. (a) RMgX, THF, reux; (b) NaBH4, MeBH4, MeOH, room temperature; (c) CbzCl, Na2CO3, H2O, CH2Cl2, 08C [2292%, 91% ee].
yields than aliphatic Grignards in this useful, tandem process. Aminosugars, potent inhibitors of glycosidase and glycoprotein-processing enzymes, were prepared conveniently by a one-pot reduction-alkylation of isoxazoline derivatives (Scheme 50).137 Cyclic sulfates138 196 and 197 were derived from the 1,3-dipolar cycloaddition reaction of the nitrile N-oxide prepared from 1-benzyloxy-2-nitroethane with 2,2-dimethyl-4-vinyl-1,3-dioxolane. Reduction of 196 and 197 was accompanied by hydrogenolysis of the N O bond. Cyclization of the resulting amine was completely regioselective affording piperidines 198 and 200. Interestingly, reduction of the isoxazoline delivered hydrogen to the more hindered face. Sulfate group removal afforded piperidine 199. A similar approach to functionalized indolizidines proceeded through an isoxazolidine scaffold.139
Scheme 51. (a) NH2OTBDPS, PPTS, MgSO4, Et2O, reux; (b) MsCl, Et3N, CH2CI2, 08C [96%, for 2 steps]; (c) TBAT, 4 A MS, THF, reux [84%].
(2R,3R)-3-hydroxypipecolic acid.142 Additional examples of piperidine syntheses utilizing intramolecular N-alkylations were reported.143 5.3.2. Reductive aminations and imine reductions. Intramolecular reductive ring closures are employed often in the synthesis of piperidines and substrates are required in which either the carbonyl or amino component is masked to avoid premature interactions. Ozonolysis of protected cyclopentenol 205 followed by double reductive amination gave trans-disubstituted piperidine 206, the piperidine core of the polycyclic indole alkaloid isogeissoschizoid (Scheme 52).144 The N-propargyl substituent was used later as a component of an intramolecular nickel-catalyzed cyclization, and the protected alcohol functionality was used as a handle for stereocontrol at C-12b, and for a latestage Fischer indole synthesis. Additional examples of double145 and triple146 reductive aminations were reported.
Scheme 50. (a) H2, Pd/C, Na2CO3, MeOH, room temperature; (b) H2SO4, H2O, dioxane, room temperature.
The facile synthesis of cyclic nitrone 203 derived from hemiacetal 201 by a uoride mediated intramolecular desilylative oxime N-alkylation was key to the synthesis of tricycle 204 (Scheme 51).140 Hemiacetal 201, prepared from an L -glutamate, was converted to v-mesyloxy-O-tertbutyldiphenylsilyloxime 202. Treatment with tetrabutylammonium triphenyldiuorosiliconate (TBAT) subsequently afforded cycloadduct 204 via desilylation and intramolecular cycloaddition of the resulting nitrone 203. The authors also presented examples of chiral, cyclic nitrones prepared from sugar hemiacetals that should be useful for the synthesis of polyhydroxylated alkaloids and aza-sugars. A similar nitrone preparation was used for a 1,3dipolar cycloaddition to allyl alcohol in an enantioselective synthesis of the alkaloids ()-febrifugine and ()-isofebrifugine.141 A regioselective, intramolecular nucleophilic substitution of an azido epoxide was the key step in a synthesis of trans-
Scheme 52. (a) O3, MeOH, Me2S; (b) NaBH3CN, HCuCCH2NH2HCl, MeOH [54%, for 2 steps; dr88:12].
A exible asymmetric synthesis of 2-substituted 3-piperidinols 210 used a versatile chiral synthon for the synthesis of a substituted 1,2-amino alcohol prior to a reductive ring closure (Scheme 53).147 The enolate of SAMP hydrazone 207,148 prepared by aldehyde condensation with an (S)-1amino-2-methoxymethylpyrrolidine chiral auxiliary was
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a-alkylated with an acetal protected b-iodopropanal to afford SAMP-hydrazone 208 with excellent stereocontrol. Hydrazine 209 was produced in moderate to excellent yields and excellent diastereoselectivity (de .96%) by treatment of 208 with a variety of alkyllithiums. Cleavage of the N N bond with borane was followed by aqueous HCl release of the aldehyde and spontaneous cyclization to an imine. Sodium borohydride was added to complete the reductive amination. Additional applications of SAMP/RAMP hydrazone methodology149 in the asymmetric synthesis of piperidines were reported.150
Hydrogenation then delivered hydrogen from the less hindered face forming exclusively cis amino acids 214. A brilliant strategy for the stereospecic synthesis of deoxyquinine used a hydride reduction of a tetrahydropyridine as the key step in the rst stereoselective total synthesis of quinine (Scheme 55).152 (S)-4-Vinylbutyrolactone was the starting material for acyclic stereocontrol in the synthesis of keto-azide 215. Intramolecular Staudinger reaction and cyclization afforded tetrahydropyridine 216. Assuming a half-chair conformation with the vinyl group and the protected hydroxyethyl chain in equatorial positions, axial delivery of hydride to the imine produced 2,4,5-trisubstituted piperidine 217 having the correct stereochemistry for further conversion to deoxyquinine and completion of the quinine synthesis.
Scheme 53. (a) LDA, THF, 2788C, then 2-(2-iodoethyl)-1,3-dioxolane, 2788C [42%]; (b) RLi, THF, 2788C [42%]; (b) RLi, THF, 2788C, then aq NaHCO3 [4591%, de .96%]; (c) BH3THF, THF, reux, then 3 M HCl, CH2CI2, room temperature; (d) NaBH4, EtOH, room temperature [5176%, de, ee .96%].
Another application of polyfunctionalized chiral building blocks from the Davis laboratories (see Schemes 1 and 34) led to the synthesis of pipecolic acid derivatives by the intramolecular cyclization/reduction of masked N-sulnyl imines (Scheme 54).151 The masked oxo-aldehyde 211 was converted readily to sulnime 212 and a sulniminemediated asymmetric Strecker synthesis using ethylaluminium cyanoisopropoxide was carried out. The sulnyl group controlled the stereochemistry of cyanide addition and amino nitrile 213 was predicted to have the (Ss-S)conguration. Hydrolysis of the diastereochemically pure amino nitriles removed the N-sulnyl auxiliary and converted the nitrile to an acid, in addition to unmasking the oxo group and promoting cyclization to an iminium ion.
Scheme 55. (a) PPh3, THF, reux [81%]; (b) NaBH4, MeOH, THF [91%].
Additional examples of intramolecular reductive aminations in piperidine syntheses proceeded by catalytic hydrogenation of oxo-azides,153 oxo-Cbz amines,154 oxo-benzylamines155 and amino-lactols,156 and hydride reduction of imines.157 5.3.3. Cyclization dehydration to imino glucals. Imino glucals have been utilized as building blocks for the synthesis of nitrogen containing heterocycles.158 Amino sugars, for example, have gained prominence in their utility as inhibitors of glycosidase enzymes.159 A novel imino glucal building block was developed for the synthesis of highly oxygenated amino sugar C-glycosides (Scheme 56). The acyclic precursor 218 was derived from D -glucal, with the key step being introduction of the amine by a stereocontrolled oxime reduction. Ozonolysis of the double bond and dehydration of the resulting hemiaminal with oxalyl chloride completed the synthesis of imino glucal 219. The latter underwent Lewis acid mediated C C bond formation by allylic displacement of the C-3 acetoxy group. The addition showed a preference for the b-anomer, which is the reverse of the facial selectivity seen in reactions of the same nucleophiles with 3,4,6-tri-O-acetyl-D -glucal under comparable conditions. This result might be attributed to A1,3 strain which biases axial attack of the nucleophile onto
Scheme 54. (a) (1S,2S,5R)-(2)-Methyl (S)-p-toluenesulnate, LHMDS, 2788C or (S)-()-p-toluenesulnamide, Ti(OEt)4, CH2Cl2 [5780%]; (b) Et2AlCN, iPrOH, THF, 2788C [6180%, de9395%]; (c) HCl, reux; (d) H2, Pd/C, MeOH [4895%, ee9597%].
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Scheme 56. (a) O3, CH2Cl2, 2788C, then Me2S; (b) (COCl)2, Et3N, DMF [53%, 2 steps]; (c) BF3Et2O, CH2Cl2, H2CvCHCH(TMS)(CH2)8Me, 260!08C [b/a9:1]; (d) piperidine, CH2Cl2, room temperature [78%, 2 steps]; (e) H2, Pt/C, EtOH; (f) LiOH, THF/H2O [51%, 2 steps].
Scheme 58. (a) Et2Zn, CH2I2, PhMe; (b) morpholine [64%, 2 steps]; (c) H2, Pd/C, HCl, EtOH [100%]; (d) H2, Pd(OH)2/C, EtOH [79%].
a chair-like conformer of 219. Application of this stereocontrolled C-glycoside procedure resulted in a synthesis of ()-deoxoprosophylline. Also, by combining this methodology with dihydroxylation chemistry, the synthesis of more highly oxygenated amino sugar C-glycosides was possible.160 A reported synthesis of the naturally occurring amino sugar ()-fagomine (Scheme 57) was based on imino glucal formation.161 Diastereomerically pure 220 was prepared from tri-O-benzyl- D -glucal. Double bond ozonolysis followed by cyclization dehydration then produced imino glucal 221. Hydrogenation of 221 in the presence of morpholine reduced the double bond and facilitated chromatographic purication. An additional hydrogenation in the presence of hydrochloric acid removed the benzyl protecting groups furnishing ()-fagomine as a hydrochloride salt.
palladium hydroxide on carbon in the absence of acid. Further hydrogenation effected debenzylation affording 226. The versatile strategies highlighted in this section were very useful for preparing novel amino sugars to probe the binding specicity of the glycosidase family of enzymes. A facile synthesis of functionalized imino glucals from v-hydroxycarbamates via tandem oxidative cyclization dehydration was achieved using Dess Martin periodinane in methylene chloride.164 This procedure afforded Bocprotected imino glucals in excellent yields. Interestingly, the reaction did not work for the formation of ve- and sevenmembered ring analogs. 5.3.4. Michael additions. Intramolecular Michael additions are a well-established method for piperidine ring formation and the versatility of this process will be highlighted in this section. An additional application for b-amino carboxylates (see also Section 4.2.3) led to methodology for the synthesis of enantiopure quinolizidinones and indolizidinones (Scheme 59).165 The amino group of enantiopure b-amino ester 228103a was alkylated rst by iodide 227 to form secondary amine 229 that underwent an intramolecular Michael addition generating enolate 230 followed by protonation to 231 or intramolecular condensation to 232. As an added feature, all monocyclic products 231 were
Scheme 57. (a) H2, Pd/C, morpholine, EtOH [70%]; (b) H2, Pd/C, HCl, EtOH [85%].
Novel deoxymannojirimycin analogs were prepared from imino glucals (Scheme 58).162 Olen 222 was prepared from tetra-benzoyl-D -glucopyranose and converted to imino glucal 223 as described in the previous paragraph. Cyclopropanation163 using excess diiodomethane and diethyl zinc was highly stereoselective and removal of the Fmoc group with morpholine provided secondary amine 224 as a single diastereomer. Hydrogenation of 224 in the presence of hydrochloric acid resulted in debenzylation without cyclopropane ring ssion and the conformationally constrained analog 225 was isolated in quantitative yield as a hydrochloride salt. In addition, it was possible to regioselectively cleave the cyclopropane ring without concomitant debenzylation by hydrogenation over
Scheme 59. (a) K2CO3, MeCN, 658C [231/2321.252.27:1]; (b) NaOH, EtOH, room temperature; (c) Ac2O, Et3N, THF [7289%, 2 steps].
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converted to quinolizidinones (n1) or indolizidinones (n0) 232 in high yields by a convenient two-step procedure. This methodology was used for the total synthesis of the quinolizidine alkaloid (2)-lasubine II. Another route to the quinolizidine skeleton used a twodirectional synthesis strategy and a tandem deprotection/ double intramolecular Michael addition as the key step.166 Also, an intramolecular amine conjugate addition was used to form the piperidine A-ring of cylindrospermopsin.167 A synthesis of the azaspiro[5.5]undecane skeleton 235 required two operations from an acyclic symmetrical precursor (Scheme 60).168 Treatment of ketone 233 with hydroxylamine hydrochloride afforded six-membered cyclic nitrone 234 by way of oxime formation and subsequent Michael addition. Intramolecular [32] dipolar cycloaddition produced dinitrile 235 as a single regioisomer. Dinitrile 235 was an advanced intermediate in a recent formal synthesis of histrionicotoxin and histrionicotoxin 235A.169 Additional applications of this strategy for the synthesis of the azaspiro core unit of alkaloids were disclosed recently.170
Scheme 62. (a) Catalyst, PhMe, 758C [7995%].
molecular hydroamination/cyclization of aminoallenes (Scheme 62).173 For a-aryl amines 239, catalyst 241 was optimal in terms of reactivity and regioselectivity, favoring cyclic imines 240 exclusively. This was due to the sterically demanding bis(sulfonamide) ligand that disfavored cycloaddition of the titanium imido species with the internal double bond of the allene. This catalyst system tolerated uoride, chloride (both o- and p-), methoxy, and methyl substituents on the aryl ring, and was used also to form seven-membered cyclic imines. A related strategy from aminoalkynes174 was reported, as well as procedures for the Bronsted acid catalyzed intramolecular hydroamination of protected alkenylamines,175 and the intramolecular radical cyclization of allenic sulfonamides in the presence of AIBN and p-toluenesulfonyl bromide or iodide.176 Progress in the cyclization of amines tethered to 1,2disubstituted alkenes was realized with conjugated aminodienes 242 as substrates and organolanthanide catalysts (Scheme 63).177 Excellent diastereoselectivity was observed in the formation of cis-2,6-disubstituted piperidine (^)pinidine due to a chair-like transition state in which the diene and methyl group occupy equatorial positions. In addition, a catalytic enantioselective cyclization afforded piperidine 243 in 69% ee.
Scheme 60. (a) NH2OHHCl, NaOAc, MeOH, room temperature; (b) PhMe, 1608C [47%, 2 steps].
The synthesis of the azaspiro core of pinnaic acid utilized a stereoselective intramolecular vinylogous (1,6-addition) Michael addition to form the piperidine ring (Scheme 61).171 A chiral bicyclic lactam was used for the synthesis of amine 236. Removal of the Boc protecting group and base-induced cyclization proceeded with excellent diastereoselectivity, generating piperidine 238 exclusively as the E-isomer. Intramolecular 1,6-addition of an amine was used also as a key step for piperidine ring formation in the total synthesis of the erythrina alkaloid cocculolidine.172
Scheme 61. (a) TFA, CH2Cl2, room temperature; (b) DBU, room temperature [81%, 2 steps]. Scheme 63. (a) Chiral catalyst, C6D12, 08C [E/Z95:5, 69% ee]; (b) catalyst, C6D6, room temperature [95%, cis/trans178:1, E/Z94:1.5].
5.3.5. Hydroamination/cyclization. The catalytic intramolecular addition of an N H bond across an unactivated C C multiple bond is a useful, atom-economical transformation and progress in this area will be highlighted. Titanium bissulfonamide catalysts were useful for the efcient intra-
Palladium-catalyzed cyclizations leading to azasugars,178a six-membered heterocycles,178b and a palladium-catalyzed carbonylationcouplingcyclization of allenic sulfonamides
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with aryl iodides and carbon monoxide179 were reported recently. 5.3.6. Ring expansions. An asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine was accomplished using a prolinol ring expansion as the key step (Scheme 64).180 cis-Epoxide 244 was derived from an acetylene precursor by hydrogenation with Lindlars catalyst followed by catalytic enantioselective epoxidation with Jabobsens catalyst.181 Treatment with benzylamine in reuxing acetonitrile afforded prolinol 245, presumably the product of a 5-exo-tet cyclization. After conversion to a mesylate, the reaction proceeded through bicyclic aziridinium intermediate 246, and treatment with tetra-nbutylammonium acetate afforded cis-a-phenyl-b-acetoxypiperidine (247). Chiral pool starting materials were used to prepare prolinols for ring expansions to enantiomerically pure trans-3,4-disubstituted182 and 3,3,5-trisubstituted piperidines.183
Scheme 65. (a) 7-Isopropyl-(1S,2R)-(2)-cis-1-amino-2-indanol, CHCl3, room temperature [96100%, dr (2-position)10.40:1]; (b) LAH, Et2O, [76100%]; (c) MnO2, CH2Cl2, then SiO2 [5569%].
Scheme 64. (a) PhCH2NH2, NaHCO3, NaI, MeCN, reux [65%]; (b) MsCl, Et3N, THF, 2208C; (c) Bu4NOAc, THF, 2208C!room temperature [85, 99% ee].
5.3.7. 6p-Azaelectrocyclizations. Thermal 6p-azaelectrocyclization of 1-azatrienes to 1,2-dihydropiperidines is a well known pericyclic reaction that proceeds in a disrotatory mode.184 Signicant progress in accelerating the azaelectrocyclization was achieved by a combination of C-4 ester and C-6 alkenyl or aryl substituents on the linear 1-azatriene that enhanced HOMO and LUMO orbital interactions. Utilizing 7-alkyl substituted cis-aminoindanols to control diastereoselectivity resulted in the rst highly stereoselective asymmetric 6p-azaelectrocyclization (Scheme 65).185 Optimum conditions for this facile azaelectrocyclization utilized a C-7 isopropyl substituted aminoindanol affording aminoacetal 249. Removal of the chiral auxiliary was initiated with lithium aluminum hydride reduction producing diols 250. Subsequent treatment with manganese dioxide and silica gel chromatography provided piperidine 251. The authors postulated that manganese dioxide affected N-oxide formation with auxiliary removal by an acid catalyzed Polonovski reaction. These authors also reported a formal synthesis of 20-epiuleine. The synthesis of substituted piperidines from the alkylations of vinylogous amides with a,b-unsaturated iminium salts was reported by the Hsung group.186 To illustrate, reaction of vinylogous amide 252 and a,b-unsaturated iminium salt 253 (Scheme 66) afforded the dihydropyridine 256 as a .96:4 mixture of diastereomers.186d The reaction was
Scheme 66. (a) PhH/EtOH, reux [8591%].
suggested to proceed via Knoevenagel-like condensation product 254. b-Elimination afforded 1-azatriene 255 and electrocyclic ring closure produced 256 that was transformed further to (2)-4a,8a-diepi-pumiliotoxin C. 5.3.8. Schmidt reaction. An intramolecular Schmidt reaction187 was the key step in the synthesis of the piperidine ring of dendrobatid alkaloid 251F (Scheme 67).188 The azide 257 was prepared from the corresponding alcohol using an
Scheme 67. (a) TfOH, CH2Cl2, 08C [79%]; (b) LiAlH4, Et2O, 08C [86%].
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azide-modied Mitsunobu reaction.189 Triic acid promoted rearrangement proceeded with migration of C-2 to afford 258 as a single diastereomer. Subsequent reduction completed the asymmetric total synthesis of 251F. The intramolecular Schmidt reaction was used also as the key step in the rst asymmetric, total synthesis of ()-sparteine.190 5.4. Intramolecular C C processes 5.4.1. Ring closing metatheses. The utility of ring closing metathesis (RCM) as a tool for the synthesis of substituted piperidines will be highlighted in this section (see also Section 2.2.3). Progress in catalyst development has greatly expanded the scope of this reaction to the extent that retrosynthetic planning incorporating a RCM reaction has become relatively routine. Recent reviews on olen metathesis reported on the current status of catalyst design, mechanistic understanding and preparative utility.191 The application of this methodology to the synthesis of enantiopure piperidines normally required non-racemic substrates derived from chiral pool sources or available by asymmetric methodologies. Recent advances in olen metathesis led to the development of chiral Mo-based catalysts that promoted asymmetric ring closing metathesis (ARCM) reactions and provided access to optically enriched carbocycles and oxygen heterocycles.192 The rst catalytic ARCM method for the synthesis of non-racemic, small and medium ring, unsaturated N-heterocycles was accomplished by kinetic resolution or desymmetrization of unsaturated amines (Scheme 68).193 Piperidine 260 was prepared efciently and with excellent enantioselectivity by Mo-catalyzed desymmetrization of acyclic aminodiene 259. The reactivity and selectivity of catalytic desymmetrizations were sensitive to the amine substituents. For amines
bearing phenyl and p-substituted phenyl groups (entries a c), catalyst 261a proved most efcient. For amines with o-substituted phenyl groups (entries d and e), catalyst 261a proved ineffective. The importance of a modular chiral catalyst for screening resulted in the identication of 261b for efcient ARCM of these substrates. Some practical aspects that highlight the utility of this methodology should be mentioned. The Mo-catalysts were prepared from commercially available materials and used in situ.194 Reactions were carried out in the absence of solvent in an efcient and environmentally friendly manner. Amine 260 (entry a) was prepared in 78% yield and .98% ee under solvent-free conditions (2.5 mol% 261a, 228C, 10 min). This methodology was used also for the enantioselective synthesis of seven and eight-membered ring amines. A stereoselective double RCM was useful for the synthesis of spirocyclic compounds, resulting in the enantioselective synthesis of the selective NK-1 receptor antagonist 265 (Scheme 69).195 The N-tosyl protected tetraene 262 was prepared from commercially available amino acid esters. The key double RCM reaction with Grubbs catalyst proceeded at room temperature affording chromatographically separable spirocycles favoring 5R,6S diastereomers 264. Mechanistic studies determined the predominant pathway involved initial formation of the dihydrofuran ring. A regio- and stereoselective reductive Heck reaction on diene 264 introduced the aryl group in the synthesis of NK-1 receptor antagonist 265. This strategy also was used for the synthesis of functionalized spiropiperidines.196
Scheme 69. (a) PhCHvRu(PCy3)2Cl2, CHCl3, 208C.
Scheme 68. (a) Catalyst, PhH, 228C.
The ruthenium-catalyzed ring rearrangement emerged as a useful complement to RCM. Rapid access to a variety of aza- and oxacycles was achieved using a process in which a carbocycle was transformed into a heterocycle by an intramolecular ring opening ring closing domino metathesis. Starting with enantiomerically pure carbocycles, the
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Scheme 70. (a) PhCHvRu(PCy3)2Cl2, CH2vCH2, CH2Cl2, room temperature [100%]; (b) PhCHvRu(PCy3)2Cl2, CH2Cl2, reux [92%].
metathesis rearrangement transferred chirality into the heterocycle and the formed side chain. Enantiopure piperidines were available from this rearrangement (Scheme 70).197 All reactions were carried out in methylene chloride using Grubbs catalyst. To accelerate the reaction and to avoid formation of side products, the reactions were performed in the presence of ethylene. Piperidines 267 and 269 were produced in excellent yields, with the side chain length being controlled by the size of the carbocyclic ring. This tandem ring rearrangement process was used also to prepare seven-membered heterocycles. Examples of RCM where one of the olens is directly connected to a heteroatom are rare. Recent papers report the RCM reaction of olens containing enamides198 and ynamides199 that were used to prepare N-protected sixmembered cyclic enamides. RCM reactions were used as the key step in the preparation of azasugar analogs and recent reports detail the synthesis of hydroxylated indolizidines200 and oxazolidinyl piperidines.201 The RCM reaction also was used in the synthesis of pipecolic acids,202 pipecolic acid analogs,203 enantiopure bicyclic lactams,204 bridged bicyclic piperidines205 and the hexahydroquinoline DE ring system of the aspidosperma alkaloids.206 The following piperidine alkaloids were synthesized using a RCM reaction as the key step: (S)anabasine and (S)-anatabine,207 (2)-b-conhydrin and analogs,208 (R)-coniine and (2R,6R)-solenopsin A analogs,209 ()-febrifugine,210 fagomine and analogs,211 ()-sedamine210 and (2)-prosophylline.212 In addition, publications have appeared that detail RCM on a soluble poly(ethylene glycol) supported substrate213 and the successful use of polymer supported ruthenium catalysts in RCM reactions.214 5.4.2. Iminium ion cyclizations. Intramolecular cyclizations between iminium ions and allyl or vinyl silanes are an established method for the synthesis of N-heterocycles.215 This intramolecular cyclization, an allylsilane onto an iminium ion, was the key step in a synthesis of enantiopure 6- and 4,6-disubstituted pipecolic acids 275 (Scheme 71).216 Reaction of chiral oxazolidine 270 with {2-[(trimethylsilyl)methyl]prop-2-enyl}lithium afforded functionalized bamino alcohol 272. Addition to oxazoline 270 proceeded through chelated intermediate 271, with internal nucleophilic attack onto the less hindered Si face of the (E)-imine tautomer. Reaction of b-amino alcohol 272 with glyoxal
Scheme 71. (a) TMSCH2C(vCH2)CH2Li, THF, 278!2208C [7380%]; (b) OHCCHO, THF/H2O, room temperature [98%].
generated ene-iminium intermediate 273 that cyclized to bicycle 274 as a single ring-juncture diastereomer. Functional group transformations then were employed to modify the exocyclic methylene group prior to removal of the chiral inductor. Related studies highlighted the intramolecular cyclization of vinylsilane and allylsilane moieties onto iminium ions as the key step in the enantioselective synthesis of pipecolic acid217 and trans-6-alkylpipecolic acid.218 An analogous cyclization was used to synthesize 5-substituted pipecolic acids (Scheme 72).219 A separable 3:1 mixture of allylsilanes 276a and 276b was prepared by alkylation of (R)-cyanomethyloxazolidine with a functionalized allylsilane. Treatment of oxazolidine 276a with TMSOTf generated iminium ion 277, and intramolecular
Scheme 72. (a) TMSOTf, CH2CI2, 2408C [96% for 276a!278a and b, 278a:b9:1; 62% for 276b!278c]; (b) HCl(g)/EtOAc, room temperature, [77% for 278a and b!279a and 279b, 279a:b4:1; 60% for 278c!279c].
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cyclization afforded a 9:1 mixture of diastereomers 278a and b. Similar treatment of 276b led to formation of cyanopiperidine 278c as a single diastereomer. The mixture of diastereomers 278a and b was treated with gaseous hydrochloric acid in ethyl acetate affording a chromatographically separable mixture of lactones that were readily characterized by NMR as piperidines 279a and 279b with the assigned absolute congurations. Diastereomer 278c was converted to 2,5-disubstituted piperidine 279c in similar fashion. The lactones were readily converted to 5-substituted pipecolic acids. An intramolecular iminium ion cyclization hydride migration sequence was the salient feature of an asymmetric synthesis of 1-substituted-trans-5-oxooctahydroisoquinolines (Scheme 73).220 Amine 280 was prepared from 2-iodocyclohexenone using a catalytic asymmetric hydride reduction221 and a Suzuki b-aminoethylation as key steps. An a-ethoxy carbamate was generated from amine 280 following imine formation and treatment with diethyl pyrocarbonate. Reaction of this intermediate with boron triuoride etherate and a proton scavenger led to generation of the acyl iminium ion 281. Cyclization to 282 and subsequent hydride migration produced hydroisoquinoline 283. In this efcient procedure, the lone stereocenter of protected allylic alcohol 280 was used to establish the absolute conguration and relative stereochemistry of the three new chiral centers of 283. Also, the (E)-iminium ion geometry was required to avoid A1,3 strain during the cyclization with approach of the iminium ion electrophile to the cyclohexene face opposite the bulky siloxy group. This procedure enabled the synthesis of enantioenriched transhydroisoquinolones with axial alkyl, aryl or alkenyl substituents at C-1. The ytterbium(III) triate catalyzed electrophilic cyclization of glyoxalate derived unsaturated imines was used to prepare piperidines fused to d-lactones222 that also was adapted to solid-phase synthesis.
Scheme 74. (a) N-Phenylselenophthalimide, PBu3, THF, 08C [75 79%]; (b) NaNH2, NH3 [9193%]; (c) Bu3SnH, AIBN, PhH, reux [4068%].
5-exo-Trig cyclization onto the double bond generated an aziridinylcarbinyl radical that then underwent C N bond cleavage to relieve strain. An acid/base extractive work-up facilitated separation of the product piperidine 286 from tin by-products. A one carbon homolog of 285 failed to yield an azepine. Phenylselenide 287 was synthesized to examine the reactivity of the putative aminyl radical. In this case, cyclization proceeded through radical intermediates 288 and 289 with an additional cyclization producing octahydroindolizine 290 as a single diastereomer. This methodology also was used to prepare a substituted decahydroquinoline. Radical 6-exo-trig cyclizations were used in a synthesis of (2)-indolizidine 223AB224 and the synthesis of enantiopure 3-alkylpiperidines.225 Photoinduced electron transfer catalyzed radical cyclization reactions of unsaturated N-trimethylsilylmethyl amino acid derivatives were used in peptide chemistry for the formation of piperidines.226 A phenylselenide was used as a radical source for an intramolecular 6-endo-trig cyclization in the synthesis of the spirocycle alkaloid (2)-sibirine (Scheme 75).227 Carbamate 291 was prepared from 3-phenylthio-2-bromo-2-cyclohexen-1-one using a catalytic asymmetric hydride reduction
Scheme 73. (a) RCHO, MgSO4, CH2Cl2, room temperature; (b) (EtO2C)2O, EtOH, room temperature; (c) BF3Et2O, 6,6-di-tbutyl-4-methylpyridine, CH2Cl2, 08C [1574%, for 3 steps, 8590% ee].
5.4.3. Radical cyclizations. Intramolecular radical additions to substituted 2-methyleneaziridines provide a novel route to functionalized piperidines (Scheme 74).223 Phenylselenide 285 was chosen as the radical source and was available from alcohol 284. Radical generation was initiated by slow addition of tributyltin hydride and AIBN.
Scheme 75. (a) MCPBA, CH2Cl2, room temperature [98%]; (b) tBuOK, (CH2O)n, tBuOH, room temperature [75%]; (c) PhSeH, TsOH, room temperature, [71%]; (d) Bu3SnH, AIBN, PhMe, reux [60%].
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and a b-alkyl Suzuki coupling reaction (see also Scheme 73). Oxidation of the PhS group of 291 to the corresponding sulfone facilitated the preparation of phenylselenide 292 via its N-hydroxymethyl derivative. Treatment of phenylselenide 292 with tributyltin hydride in the presence of a catalytic amount of AIBN generated an (alkoxycarbonylamino)methyl radical that underwent 6-endo-trig cyclization to spirocycle 293. Cyclization of 292 lacking the phenylsulfonyl group gave a mixture of 6-exo spirocycle and 7-endo bicycle. Functional group transformations completed the synthesis of (2)-sibirine. 5.4.4. 1,3-Dipolar cycloadditions. The utility of intramolecular 1,3-dipolar cycloadditions in the synthesis of N-heterocycles is well documented.228 Synthesis of the functionalized piperidine A-ring of the marine heptatoxin cylindrospermopsin featured an intramolecular oxazinone N-oxide/alkene dipolar cycloaddition (Scheme 76).229 Oxazin-2-one 294 was prepared from an optically active N-Boc-crotylglycine derivative and its oxidation with Davis oxaziridine yielded the conjugated oxazinone-Noxide 295. Sealed tube thermolysis of 295 effected cycloaddition to tricyclic isoxazolidine 297 through chairlike exo-transition state 296. Hydrogenolysis of 297 in methanol produced piperidine 298. N-Oxide 295 may be viewed as a constrained a-alkoxycarbonyl nitrone and highly functionalized cycloadducts such as 297 provide opportunities for further elaboration. Additional reports appeared recently that utilize intramolecular 1,3-dipolar cycloaddition strategies to synthesize polysubstituted piperidines.230
Scheme 77. (a) Pd(PPh3)4, tBuOK, THF, reux [299a55 60%, 299b75%].
This methodology was used also for the synthesis of the 2-azabicyclo[4.3.1]decane ring system and ve-membered nitrogen heterocycles. In another report, the intramolecular Heck reaction of vinyl iodide 301 was used to form the piperidine ring of pentacycle 302 as part of a total synthesis of (2)-strychnine (Scheme 78).233
Scheme 78. (a) Pd(OAc)2, Bu4NCl, K2CO3, DMF, 708C [48%].
Palladium-mediated intramolecular cyclizations were used to functionalize piperidines. Halogenated phenols and unsaturated piperidinols were coupled via Mitsunobu condensation and an intramolecular Heck reaction provided hexahydrobenzofuro[2.3-c]pyridines.234 An intramolecular Heck arylation onto a piperidine enamide was the key reaction used in the synthesis of azaspirocycles prepared as conformationally constrained nicotine analogs.108c An
Scheme 76. (a) 2-Benzenesulfonyl-3-phenyloxaziridine, THF, 08C [75%]; (b) PhMe, 2008C [78%]; (c) H2, Pd/C, MeOH [98%].
5.4.5. Palladium mediated couplings. A recent review on the intramolecular Heck reaction231 highlights applications of this procedure for the synthesis of a variety of heterocyclic systems. The palladium-catalyzed intramolecular coupling of amine tethered vinyl iodides and ketone enolates was useful for the synthesis of the 2-azabicyclo[3.3.1]nonane ring system (Scheme 77).232 Vinyl iodides 299 were available readily by N-alkylation of 4-(benzylamino)cyclohexanone. Intramolecular cyclization of 299 to 300 was accomplished with 0.2 equiv. of Pd(PPh3)4 and potassium tert-butoxide as base in reuxing tetrahydrofuran (RH, Me). The cyclization was achieved also at room temperature in 42% yield (RH). In contrast, the same reaction run at room temperature with the vinyl bromide of 299a returned only unreacted starting material.
Scheme 79. (a) Ti(OiPr)4, iPrMgCl, Et2O, 278!2508C, then Li2Cu(CN)Cl2, H2CvCHCH2Br, 2508C [81%].
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N-alkyl glutarimide ketene aminal was a substrate for a novel application of an intramolecular Heck cyclization that was used to synthesize the tricyclic carbon skeleton of cytisine.235 5.4.6. Ene cyclizations. A titanium(II)-mediated intramolecular cyclization of 2,8-bis-unsaturated carbonates was used as the key step in a stereoselective synthesis of enantiopure substituted piperidines.236 A recent modication of this methodology was used in the synthesis of octahydroquinolines (Scheme 79).237 Cyclization of enyne 303 proceeded through titanocycle 304 followed by elimination of the diethylphosphoryloxy group to vinyltitanium intermediate 305. The titanium carbon bond of 305 was functionalized by a copper-mediated allylation238 producing triene 306. Both cis- and trans-303 provided only trans-octahydroquinolines as products but changing the leaving group to an acetoxy resulted in a lower yield of 306. Intramolecular carbonyl cyclizations were used to synthesize cis- and trans-3,4-disubstituted piperidines. Lewis acid-catalyzed carbonyl ene cyclization of aldehydes 307 produced trans-piperidine 309 with diastereomeric ratios of #93:7 (Scheme 80).239 Studies revealed that ene cyclization at 2788C favored cis-piperidine 308. Raising the temperature of the reaction resulted in preferential formation of trans-309 suggesting the carbonyl ene cyclization was reversible and cis-308 was the kinetic product. By contrast, Prins cyclization of 307 catalyzed by a Bronsted acid at 2788C preferentially afforded cis-piperidine 308, but raising the temperature had little effect on the cisdiastereoselectivity. Thus, both reactions proceeded initially through the kinetic product 308 with signicant conversion to the thermodynamic product trans-309 observed only under Lewis acid catalysis. The switch in diastereoselectivity between Lewis and Bronsted acid catalysis is an intriguing but useful feature of this methodology.
5.4.7. Anion polycyclization. The efcient use of a novel anionic polycyclization cascade was the key feature of a rapid, stereocontrolled synthesis of functionalized tetracycles (Scheme 81).240 In a one-pot sequence, an indol-3-ylmethylamine was reacted sequentially with acrolein and the anion of a b-ketophosphonate. The resulting enone 310 was treated with a catalytic amount of potassium tert-butoxide and tetracyclic ketone 313 was produced as the transdiastereomer. The cascade sequence was initiated by proton abstraction from indole 310 and an intramolecular Michael addition afforded 311. Enolate isomerization of 311 to 312 and an intramolecular iminoaldol cyclization produced an indolenine anion that was quenched by a proton exchange with 310 thereby propagating the cycle. The reaction tolerated a variety of N-protecting groups with the newly introduced substituent at C-3 oriented toward the most crowded face of the polycycle. These functionalized polycycles are similar to the core of the manzamine family of indole alkaloids (see also Scheme 12).
Scheme 81. (a) tBuOK, THF, room temperature [35 60%].
5.5. Intermolecular processes 5.5.1. Formal [313] annulations. A [33] bis-alkylation was used to form the piperidine ring in (2)-d-coniceine.241 (S)-Pyroglutaminol (314) afforded tosylate 315 and displacement with 4-methylthiophenol followed by oxidation produced bis-nucleophile precursor 316 (Scheme 82).
Scheme 80. (a) MeAlCl2, CHCl3, 618C; (b) conc. HCl, CH2Cl2, 2788C.
Scheme 82. (a) TsCl, Et3N, DMAP, CH2Cl2, room temperature [60%]; (b) MePhSH, NaOH, MeCN, reux; (c) Oxonew, aq MeOH, room temperature [90%, for 2 steps]; (d) NaH, DMF, room temperature, then I(CH2)3I, [60%]; (e) Na/Mg, NaHPO4, MeOH [51%]; (f) LiAlH4, Et2O [85%].
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Deprotonation of both acidic sites with sodium hydride and alkylation with diiodopropane afforded piperidine 317. Reductive cleavage of the tosyl group and amide reduction completed the synthesis of (2)-d-coniceine. The synthesis of enantiomerically pure piperidines was reported via [33] cycloadditions of Pd trimethylenemethane complexes with aziridines and this approach was parlayed to the total synthesis of (2)-pseudoconhydrine (Scheme 83).242 Specically, [33] cycloaddition of the Pd trimethylenemethane complex generated from 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate (318) and enantiomerically pure aziridine 319 (PMBSp-methoxybenzenesulfonyl) afforded piperidine 320. Oxidative cleavage of the double bond followed by reduction with L -selectridew afforded the corresponding carbinol that, following deprotection, gave (2)-pseudoconhydrine.
Scheme 84. (a) PhMe, 808C [47 52%]; (b) H2, Ra Ni, MeOH, 408C [51%]; (c) H2, Pd/C, EtOH, room temperature [72%].
afforded bicyclic piperidine 325a. Alternatively, hydrogenation over Pd/C produced 325b. Syntheses of piperidines derived from the Diels Alder reactions of 2-azadienes also were reported. For example, the Nicolaou group recently described the synthesis of the tetrahydropyridine core of thiostrepton.246 Specically, rupture of the thiazolidine moiety in 326 afforded 2-azadiene 327 that underwent [42] dimerization to tetrahydropyridine 328 (Scheme 85). Tautomerization of the tetrahydropyridine to the corresponding enamine and subsequent aza-Mannich cyclization resulted in a signicant amount of a [3.2.1]bicyclic impurity. Interestingly, addition of a stoichiometric amount of benzylamine to the reaction almost completely suppressed the formation of this bridged impurity and quenching with water afforded the desired primary amine 329. Also, this Diels Alder reaction was regioselective and endo-selective but showed no facial selectivity. The Diels Alder reaction of an in situ derived 2-azadiene was employed in the total synthesis of martinellic acid and martinelline.247 Thus, reaction of two equivalents of Cbzprotected pyrroline 330 and methyl 4-aminobenzoate (331) in the presence of a catalytic amount of Dy(OTf)3 gave 332 (exo/endo15:85) (Scheme 86). Fortunately for the authors, the stereochemistry of this reaction could be reversed by switching catalysts to CSA (exo/endo89:11). exo-Isomer 332 was subsequently transformed to martinellic acid and martinelline. 3-Substituted 2H-1,4-oxazin-2-ones also were used as 2-azadienes. For example, [42] cycloaddition of oxazinones 333 and ethylene afforded bicyclic lactones 334 that were immediately reduced with LiAlH4 in reuxing THF affording piperidines 335 (Scheme 87).248 As mentioned above, the nitrogen atom of the piperidine may be derived from the dienophile. The Davis group recently prepared the rst examples of enantiopure, quaternary piperidine phosphonates using this concept
Scheme 83. (a) Pd(OAc)2, P(OiPr)3, BuLi, PhMe/THF [63%]; (b) O3, DMS; (c) L -Selectridew [77%]; (d) Na-naphthalide [79%].
5.5.2. Aza Diels Alder reactions. The Diels Alder reaction is arguably one of the most important reactions used to prepare six-membered rings. Its popularity is due to a number of factors which include: formation of the sixmembered ring in a single step, toleration of a wide variety of substituents and varying degrees of stereocontrol at as many as four new stereocenters. Given the rather ubiquitous appearance of the piperidine ring in natural products and pharmaceuticals, it is understandable that aza-equivalents of this venerable reaction are utilized as a way to synthesize this heterocycle. In principle, the nitrogen atom of the piperidine may be derived from either the diene (as a 1- or 2-azadiene) or the dienophile (as an imine). Examples of these three motifs are known. The Diels Alder reactions of 1-azadienes were reviewed recently.243 In addition, the mechanism of the reaction of N-acyl-1-aza-1,3-butadiene with N,N-dimethylvinylamine was investigated using density functional theory methods.244 A tandem 1-aza-Diels Alder/allylboration reaction has been used to prepare bicyclic piperidine derivatives with a high degree of stereocontrol (Scheme 84).245 Thus, the three-component reaction of 1-azadiene 321, substituted maleimides 322 and aldehydes 323 in toluene at 808C afforded tetrahydropyridines 324 (Scheme 84). High diastereoselectivity was attained by incorporating a chiral auxiliary as the R1-substituent. Reduction of 324 (R1Me, R2Ph) with Raney nickel
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Scheme 85. (a) Ag2CO3, DBU, PhCH2NH2, pyridine, 2158C [4252%]; (b) H2O [60%].
(Scheme 88).249 More specically, chiral aziridine phospnonate 336 was prepared using their chiral sulfoximine methodology. Swern oxidation of 336 afforded the 2Hazirine 3-phosphonate 337 along with a small amount of the corresponding 2H-azirine 2-phosphonate isomer. Diels Alder cycloaddition of 337 and trans-piperylene gave bicyclic piperidine 338 as a single stereoisomer. Hydrogenation of the double bond and concomitant opening of the aziridine ring gave the quaternary piperidine phosphonate 339. A number of other piperidine syntheses featuring imines as dienophiles were published recently.250
Scheme 86. (a) CSA, THF [74%].
Scheme 87. (a) CH2vCH2, PhMe, 1108C (sealed tube); (b) LiAlH4, THF, reux [6070%, for 2 steps].
Scheme 88. (a) (COCl)2, DMSO, then Et3N, 2788C!room temperature [68%]; (b) trans-piperylene, room temperature [89%]; (c) H2, Pd/C, THF [81%].
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(Scheme 90). Hydrogenation of the three double bonds and hydrogenolysis of the chiral auxiliary afforded (2)-coniine which was isolated as its N-Boc derivative 347. Addition of other Grignard reagents to 345 gave yields between 65 and 89%. The C-2 vs C-4 regioselectivity varied between 75:25 and .95:5 while, in all cases, the C-2 diastereoselectivity was .95:5. Other sequential reductions of pyridine derivatives were used to prepare the piperidine moieties found in the azasugar equivalent of L -idose,257 (^)-dihydropinidine,258 (^)-tashiromine,259 the GABAc antagonist (piperidin-4yl)methylphosphinic acid,260 ()-isofagomine261 and (^)catharanthine.262 The concept also was applied to solidphase synthesis of vesamicol analogs.263
Scheme 89. (a) NaIO4, NaHCO3; (b) DOWEXw H, H2O; (c) (R)-(2)phenylglycinol, KCN, citric acid buffer, H2O; (d) ZnBr2, MeOH [45%, for 4 steps]; (e) H2, Pd/C, HCl, EtOH [90%].
5.5.3. CN(R,S) Methodology. Husson and co-workers developed CN(R,S) methodology to prepare substituted piperidines. Using this methodology they reported an expeditious synthesis of 6-amino analogs of 1-deoxynojirimycin and 1-deoxymannonojirimycin.251 Oxidation and deprotection of D -glucofuranose 340 afforded glutaraldehyde 341 that was immediately condensed with (R)-(2)phenylglycinol in the presence of potassium cyanide and zinc bromide to give piperidine N,O-acetal 342 (Scheme 89). Subsequent hydrogenation gave primary amine 343. A review covering this methodology has also appeared.252 The method also was demonstrated on solid-phase.253 5.5.4. From pyridine reductions. This section focuses on the synthesis of piperidines by either the complete or sequential reduction of pyridines. For example, substituted piperidines were prepared by hydrogenation of pyridines254 and their corresponding N-oxides.255 In contrast, the sequential reduction of pyridines allows for further functionalization of the corresponding dihydro and tetrahydro intermediates prior to reduction to the desired piperidine. An interesting application of the latter concept was used to prepare (2)-coniine.256 Thus, reaction of the triate of chiral amide 344 and pyridine generated pyridinium amidine 345 that was reacted in situ with cis1-propenyl magnesium bromide giving dihydropyridine 346
6. Conclusion A plethora of methodologies are available for the stereocontrolled syntheses of piperidones and piperidines. Piperidones, by alkylations and conjugate additions, provide additional opportunity for introduction of substituents a and b to the carbonyl group. Additionally, the carbonyl group may itself be functionalized. In this regard, chiral bicyclic lactams and N-acylpyridinium salts often were utilized. Tremendous progress was made in the stereocontrolled assemblage of acyclic precursors to piperidones and piperidines. Also, ring closing metathesis has emerged as a useful strategy. The variety of methods presented in this review and their broad applicability will, hopefully, provide an impetus for additional applications.
Acknowledgements We wish to thank our colleague, Dr Paul Cox, for helpful discussions. We also gratefully acknowledge Professor Franklin A. Davis of Temple University and Professors Daniel M. Ketcha and Kenneth Turnbull of Wright State University for reviewing the manuscript.
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244. Domingo, L. R. Tetrahedron 2002, 58, 3765 3774. 245. Tailor, J.; Hall, D. G. Org. Lett. 2000, 2, 3715 3718. 246. Nicolaou, K. C.; Nevalainen, M.; Sana, B. S.; Zak, M.; Bulat, S. Angew. Chem. Int. Ed. 2002, 41, 1941 1945. 247. Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 29132916. 248. Wu, X.; Dubois, K.; Rogiers, J.; Toppet, S.; Compernolle, F.; Hoornaert, G. J. Tetrahedron 2000, 56, 3043 3051. 249. Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org. Lett. 2002, 4, 655 658. 250. (a) Schurer, S. C.; Blechert, S. Tetrahedron Lett. 1999, 40, 1877 1880. (b) Morgan, P. E.; McCague, R.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000, 515 525. (c) Hedberg, C.; Pinho, P.; Roth, P.; Andersson, P. G. J. Org. Chem. 2000, 65, 2810 2812. (d) Ekegren, J. K.; Modin, S. A.; Alonso, D. A.; Andersson, P. G. Tetrahedron: Asymmetry 2002, 13, 447 449. (e) Bailey, P. D.; Smith, P. D.; Pederson, F.; Clegg, W.; Rosair, G. M.; Teat, S. J. Tetrahedron Lett. 2002, 43, 1067 1070. (f) Bailey, P. D.; Smith, P. D.; Morgan, K. M.; Rosair, G. M. Tetrahedron Lett. 2002, 43, 1071 1074. (g) Maison, W.; Adiwidjaja, G. Tetrahedron Lett. 2002, 43, 5957 5960. (h) Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C. Org. Lett. 2002, 4, 1971 1974. 251. Poupon, E.; Luong, B.-X.; Chiaroni, A.; Kunesch, N.; Husson, H. P. J. Org. Chem. 2000, 65, 7208 7210. 252. Review: Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383 394. 253. Blommaert, A.; James, P.; Valleix, F.; Husson, H.-P.; Royer, J. Heterocycles 2001, 55, 2273 2278. 254. (a) Scott, J. D.; Williams, R. M. Tetrahedron Lett. 2000, 41, 8413 8416. (b) Herold, F.; Kleps, J.; Anulewicz-Ostroloska, R.; Szczesna, B. J. Heterocycl. Chem. 2002, 39, 773 782. 255. Zacharie, B.; Moreau, N.; Dockendorff, C. J. Org. Chem. 2001, 66, 5264 5265. 256. Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829 11830. 257. Gil, L.; Compere, D.; Guilloteau-Bertin, B.; Chiaroni, A.; Marazano, C. Synthesis 2000, 2117 2126. 258. Loh, T.-P.; Lye, P.-L.; Wang, R.-B.; Sim, K.-Y. Tetrahedron Lett. 2000, 41, 7779 7783. 259. Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654 656. 260. Hanrahan, J. R.; Mewett, K. N.; Chebib, M.; Burden, P. M.; Johnston, G. A. R. J. Chem. Soc., Perkin Trans. 1 2001, 2389 2392. 261. Zhao, G.; Deo, U. C.; Ganem, B. Org. Lett. 2001, 3, 201 203. 262. Reding, M. T.; Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. Heterocycles 2002, 56, 313 330. 263. Eda, M.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 2063 2068.
P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989 Biographical sketch
2989
Philip M. Weintraub completed his Masters and PhD degrees at The Ohio State University under the direction of Michael P. Cava. After a brief stint at the DuPont experimental station, he moved to Hess & Clark, a vetenary division of Richardson Merrell. In 1970 he was transferred to the Wm S. Merrell Pharmaceutical Co. where he remained through several mergers. In 1998 he was transferred to Aventis in Bridgewater, New Jersey as a member of the medicinal chemistry department. He has been an editor of Annual Reports in Organic Synthesis since 1990.
Jeffrey S. Sabol completed his undergraduate work at Purdue University, and then initiated his graduate studies at Columbia University where he received a Masters degree. He completed his graduate work at Northwestern University and received a PhD degree under the guidance of Professor James. A. Marshall. He joined Dow Chemical Co. in Indianapolis, Ind., and was transferred to Merrel Dow Phamaceuticals in 1987. In 1998 he was transferred to the medicinal chemistry department of Aventis Phamaceuticals in Bridgewater, New Jersey. He has been an editor of Annual Reports in Organic Synthesis since 2001.
John M. Kane (Mike) completed his PhD at Rensselaer Polytechnic Institute under the direction of Kevin T. Potts. After leaving RPI, he moved to the Colorado State University as a postdoctoral associate of Albert I. Meyers working on the total synthesis of maytansine. Finding gainful employment as a medicinal chemist, he moved to the Richardson Merrel Company in Cincinnati, Ohio where he remained through four mergers. Finally losing his grip on the Midwest, he recently transferred to Aventis in Bridgewater, New Jersey where he is a member of the chemical development department.
David R. Borcherding completed his PhD in Medicinal Chemistry at the University of Kansas under the direction of Ronald T. Borchardt. After graduate school he was hired into the Medicinal Chemistry group at Marion Laboratories in 1988. Through a series of mergers and transfers he now works for Aventis Pharmaceuticals in Bridgewater, NJ.

Recent Advances in The Synthesis of Pipe Rid Ones and Piperidines PM Weintraub JS Sabol JM Kane DR Borcherding Tetrahedron 59 2953 2989 2003

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Tetrahedron 59 (2003) 29532989

Tetrahedron report number 638

Recent advances in the synthesis of piperidones and piperidines

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 12. (a) CH2vCHSnBu3, Pd(PPh3)4, PhMe, reux [68%].

Scheme 13. (a) PhCHvRh(PCy3)2Cl2, Ti(OiPr)4, CH2Cl2.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 14. (a) PhChvRuCy3Cl2(Im), CH2CI2, room temperature, 3 h [74%].

Scheme 16. (a) PhMe, reux.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 17. (a) PhMe, reux.

Scheme 18. (a) PhMe, reux.

Scheme 19. (a) m-CPBA, CH2Cl2, room temperature (3540%).

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 20. (a) NaH, THF, room temperature.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 66. (a) PhH/EtOH, reux [8591%].

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 69. (a) PhCHvRu(PCy3)2Cl2, CHCl3, 208C.

Scheme 68. (a) Catalyst, PhH, 228C.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 78. (a) Pd(OAc)2, Bu4NCl, K2CO3, DMF, 708C [48%].

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 81. (a) tBuOK, THF, room temperature [35 60%].

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

Scheme 86. (a) CSA, THF [74%].

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

14. 15. 16.

17. 18. 19. 20. 21. 22. 23. 24.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

94. 95. 96.

97. 98. 99. 100.

101. 102. 103.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

172. 173. 174. 175. 176. 177.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

204. 205. 206. 207.

209. 210. 211. 212.

213. 214. 215.

216. 217. 218. 219. 220. 221. 222.

P. M. Weintraub et al. / Tetrahedron 59 (2003) 29532989

225. 226. 227. 228.