An asymmetric synthesis to the dendrobatid alkaloid (−)-epibatidine has been described, featuring chiral resolution of both optically pure 7-azabicyclo[2.2.1]heptanecarboxylic acid, and subsequent transformations to (−)-epibatidine.</p

Chiang, Yu-Min

Chiou, Wen-Hua

RSC Advances

National Chung Hsing University Institutional Repository

RSC AdvancesCOMMUNICATIONDepartment of Chemistry, National Chung HRepublic of China. E-mail: wchiou@dragTel: +886-4-22840411-420† Electronic supplementary information (all 1H, 13C NMR spectra and assignmchromatograms of 1, 3, 5, 9, 11, 12 andCCDC reference number 954104. For ESother electronic format see DOI: 10.1039/Cite this: RSC Adv., 2014, 4, 11444Received 26th January 2014Accepted 9th February 2014DOI: 10.1039/c4ra00770kwww.rsc.org/advances11444 | RSC Adv., 2014, 4, 11444–1144Synthesis of ()-epibatidine†Wen-Hua Chiou* and Yu-Min ChiangAn asymmetric synthesis to the dendrobatid alkaloid ()-epibatidinehas been described, featuring chiral resolution of both optically pure7-azabicyclo[2.2.1]heptanecarboxylic acid, and subsequent trans-formations to ()-epibatidine. The methodology provides a ﬂexibleaccess to various substituted chiral epibatidine analogues.In 1992, Daly and coworkers reported a dendrobatid alkaloid,epibatidine (1), isolated in trace amounts from the skin of theEcuadoran poison frog Epipedobates tricolor.1,2 Epibatidine (1)has been found to be 200–400 times more potent thanmorphineas an analgesic, and appeared to act via a non-opioid mecha-nism since its eﬀects are not blocked by the opiate receptorantagonist naloxone. In addition, epibatidine (1) is an extremelypotent agonist of the nicotinic acetylcholine receptor.3 Due to itspharmacological activity, epibatidine (1) has attracted muchattention from synthetic chemists, resulting in abundantapproaches. However, its high toxicity also prevents therapeuticapplications, and has prompted a search for safer analoguessuch as epiboxidine (2) (Fig. 1).4Various strategies have been developed for eﬃcientsyntheses of the molecule, which have been reviewed by Tru-dell5 and Olivo.6 One of these approaches to synthesize theunique 7-azabicyclo[2.2.1]heptane framework in epibatidine isthe cycloaddition reaction. N-Protected pyrroles could undergoDiels–Alder reactions with substituted acetylene or ethylenederivatives. Transannular SN2 displacement also provides apractical route to synthesize epibatidine.7 A well-establishedarrangement in a 1,4-disubstituted cyclohexyl ring system couldtrigger an SN2 reaction to give the 7-azabicyclo[2.2.1]heptanesing University, Taichung, Taiwan, 402,on.nchu.edu.tw; Fax: +886-4-22862547;ESI) available: Experimental procedure,ent for all compounds, and HPLC14, and crystallographic data of 4a.I and crystallographic data in CIF orc4ra00770k6structure. Direct coupling of the 7-azabicyclo[2.2.1]heptan-2-one or its derivatives with the aromatic ring is an eﬀectivestrategy for syntheses of epibatidine and analogues. Due to thediversity of the approach, many elegant approaches to synthe-size 7-azabicyclo[2.2.1]heptane derivatives have been reported,8including Aza-Prins-Pinacol rearrangement8e and Favorskiirearrangement of tropinone.9a,b As a part of the project devotedto asymmetric syntheses of alkaloids and derivatives for phar-maceutical purposes, here we describe a diﬀerent approach tosynthesize ()-epibatidine (1). This strategy takes advantage ofreadily available carboxylic acid 3, and features a practicalpreparation of enantiopure acid 3 and construction of the2-chloropyridine moiety from the carboxylic acid end.Our approach commences with the preparation of racemic7-azabicyclo[2.2.1]heptanecarboxylic acid, using Fevig' con-ditions,9c a modication based on Bai's procedure.9a,b We envi-sion both optically active 7-azabicyclo[2.2.1]heptane carboxylicacids 3 are available through covalent bond modication with achiral compound to two separable diastereomers, followed byremoval of the chiral auxiliary. Subsequent functionality trans-formations of the carboxylic acid end eﬀect the formation of the2-chloropyridine moiety in epibatidine. Such an approach doesnot only synthesize the 2-chloropyridine moiety, but also allowdiversity by construction of various bioisosteric rings or othermodication. For example, epiboxidine (2) can be achieved byan acetoxime addition–cyclization protocol.8g With racemic acid3 in hand, transformation of ()-3 to separable diastereomershas been carried out by treating of acid 3 with SOCl2 to theresulting acid chloride, followed by reaction with various chiralauxiliaries.Fig. 1 ()-Epibatidine (1) and epiboxidine (2).This journal is © The Royal Society of Chemistry 2014Fig. 3 ORTEP drawing of oxazolidinone 4a.Communication RSC AdvancesWe have utilized L-menthol and L-borenol as the chiralauxiliary, but both have failed to give separable diastereomericadducts. Fortunately, aer racemic acid 3 has been coupledwith (4S)-benzyl-2-oxazolidinone, readily available fromL-phenylalanine, two diastereomeric adducts were easily sepa-rated by column chromatography, to yield the less polar product4a in 44% yield and the more polar product 4b in 41% yield,respectively (Scheme 1). In addition, recrystallization of oxazo-lidinone 4a within ethyl acetate and hexane provided a crystalfor an X-ray analysis, which conrmed the absolute congura-tion as (1R,2S,4S)-7-azabicyclo[2.2.1]heptane moiety (Fig. 2).10The results also disclosed the absolute conguration of theother diastereomer, amide 4b, as a (1S,2R,4R)-7-azabicyclo[2.2.1]heptane moiety. Subsequent basic hydrolysis conditionsusing H2O2 in THF for the less polar oxazolidinone derivative 4aproceeded successfully to yield optically pure ()-acid 3 in 98%yield, while the more polar one 4b gave optically pure (+)-acid 3in 93% yield (Scheme 1). Chiral HPLC analyses display theoptical purity of ()-acid 3 is more than 99% ee, (tR: 18.4 min for(+)-3, 26.3 min for ()-3, see ESI†) (Fig. 3).The next eﬀorts were involved with the construction of the 5-substituted-2-chloropyridine moiety (Schemes 2 and 3). Withoptically pure acid ()-3 in hand, we converted acid 3 to itshomoaldehyde derivative by one-carbon homologation via an enolether intermediate.11 Thus, reduction of acid ()-3 with BH3$Me2Sin THF produced alcohol ()-5 in 96% yield with 99% ee. Oxida-tion of alcohol ()-5 with Dess–Martin periodinane in CH2Cl2aﬀorded aldehyde (+)-6 in 93% yield. Direct treatment of oxazoli-dinone 4a with BH3$Me2S in THF, followed by Dess–Martinoxidation also aﬀorded aldehyde (+)-6 in 86% yield over two steps.Treatment aldehyde (+)-6 with methoxymethylene yield, preparedby mixing of methoxymethyltriphenylphosphonium chloride withNaHMDS, yielded methyl vinyl ether 7 in 88% yield. About 3 : 2Scheme 1 Separation of racemic acid 3 using (4S)-benzyl-2-oxazolidinone.Fig. 2 Approaches towards epibatidine.This journal is © The Royal Society of Chemistry 2014ratio of the trans isomer to cis isomer was observed in 1H-NMRspectra, i.e. a doublet at 6.27 ppm with coupling constant 12.8 Hzimplied the trans isomer while a doublet at 5.70 ppm withcoupling constant 6.0 Hz implied the cis isomer. Hydrolysis ofvinyl ether 7 in 1 N HCl in THF furnished homoaldehyde ()-8 in92% yield. To conrm the chiral integrity, homoaldehyde ()-8was oxidized by Jones reagent to homoacid ()-9. Chiral HPLCanalysis of homoacid ()-9 conrmed the chiral integrity arrivedintact during the processesmentioned above (>99% ee, Scheme 2).Homoaldehyde ()-8 was treated with pyrrolidine in thepresence of K2CO3 to the corresponding enamine, followed byreaction with ethyl acrylate, and then hydrolysis in an acidicmedia to furnish glutarate semialdehyde 10 in 55% yield. Theyield was improved to 81% yield by Hagiwara's protocol,12 usingTMSNEt2 and ethyl acrylate in reuxing acetonitrile. Glutaratesemialdehyde 10 underwent a double condensation processwith NH4OAc in reuxing benzene to yield dihydropyridone()-11 in 93% yield with 99% ee. Oxidation with 9 equivalents ofMnO2 in reuxing benzene produced 5-substituted 2-pyridone(+)-12 in 90% yield. Slow addition of MnO2 during a long periodwas crucial for the yield in that addition at once brought about ayield decrease in this reaction. Treatment of 2-pyridone (+)-12with POCl3 and in DMF did not only convert the 2-pyridonegroup to the 2-chloropyridine group, but also replaced the Cbzgroup by a formyl group as formamide 13 in 73% isolated yield.Since two sets of peaks with almost equal intensity have beenobserved in 13C-NMR, the product appeared to be a mixture ofE/Z isomers with equal amount due to the restrict rotation ofthe formamide bonding. Exposure of formamide 13 in 5% HClin MeOH aﬀorded nal product epibatidine ()-1 in 92% yieldwith >99% ee. The specic rotation value of ()-1, [a]25D  6.8 (c:1.04 CHCl3) was consistent with the reported value, [a]25D  6.5Scheme 2 Synthesis of chiral aldehyde ()-8.RSC Adv., 2014, 4, 11444–11446 | 11445Scheme 3 Syntheses of ()-epibatidine and (+)-methylepibatidine.RSC Advances Communication(c: 1.00, CHCl3).13 Treatment of formamide 13 with alanecomplex, prepared by mixing LiAlH4 and Et3N$HCl,14 producedN-methyl epibatidine analogue (+)-14 in 76% yield with 99% ee(Scheme 3).In conclusion, we have described an eﬃcient preparation ofboth enantiomers of 7-azabicyclo[2.2.1]heptane carboxylic acid3, and a feasible strategy to synthesize a 5-substituted 2-chlor-opyridine structure from a cycloalkanecarboxylic acid, demon-strated as the synthesis of ()-epibatidine 1. The methodologyprovides exible access to various substituted alkaloids bearinga 7-azabicyclo[2.2.1]heptane moiety, which may benet thedevelopment of more potent and safer analgesics. Subsequentextension of this methodology towards other natural productsof interest is currently underway.AcknowledgementsThe authors thank the National Science Council, Taiwan (NSC101-2113-M-005-009-MY3) and the Nanotechnological Center ofNational Chung Hsing University for support of this research.Notes and references1 T. F. Spande, H. M. Garraﬀo, M. W. Edwards, H. J. C. Yeh,L. Pannell and J. W. Daly, J. Am. Chem. Soc., 1992, 114, 3475.2 J. W. Daly, H. M. Garraﬀo, T. F. Spande, M. W. Decker,J. P. Sullivan and M. Williams, Nat. Prod. Rep., 2000, 17,131.3 B. Badio and J. W. Daly, Mol. Pharmacol., 1994, 45, 563.4 B. Badio, H. M. Garraﬀo, C. V. Plummer, W. L. Padgett andJ. W. Daly, Eur. J. Pharmacol., 1997, 321, 189.5 Z. Chen and M. L. Trudell, Chem. Rev., 1996, 96, 1179.11446 | RSC Adv., 2014, 4, 11444–114466 H. F. Olivo and M. S. Hemenway, Org. Prep. Proced. Int., 2002,34, 1.7 For the synthesis published before 2002, please see ref. 5 and6. Published aer 2002, please see: (a) Y. Hoashi, T. Yabutaand Y. Takemoto, Tetrahedron Lett., 2004, 45, 9185; (b)V. K. Aggarwal and B. Olofsson, Angew. Chem., Int. Ed.,2005, 44, 5516–5519; (c) C.-L. K. Lee and T.-P. Loh, Org.Lett., 2005, 7, 2965; (d) Y. Hoashi, T. Yabuta, P. Yuan,H. Miyabe and Y. Takemoto, Tetrahedron, 2006, 62, 365; (e)D. R. Boyd, N. D. Sharma, M. Kaik, P. B. A. McIntyre,P. J. Stevenson and C. C. R. Allen, Org. Biomol. Chem.,2012, 10, 2774; (f) X. Huang, H. Shi, J. Ren, G. Liu, Y. Tangand B. Zeng, Chin. J. Chem., 2012, 30, 1305; (g)K. L. Jensen, C. F. Weise, G. Dickmeiss, F. Morana,R. L. Davis and K. A. Jorgensen, Chem.–Eur. J., 2012, 18,11913.8 For the reports published before 2002, please see ref. 5 and 6.Published aer 2002, please see: (a) T. Tachihara,H. Watanabe and T. Kitahara, Heterocycles, 2002, 57, 781;(b) C. Che, G. Petit, F. Kotzyba-Hibert, S. Bertrand,D. Bertrand, T. Grutter and M. Goeldner, Bioorg. Med.Chem. Lett., 2003, 13, 1001; (c) A. J. Moreno-Vargas andP. Vogel, Tetrahedron: Asymmetry, 2003, 14, 3173; (d)M.-Y. Chang and H.-P. Chen, Heterocycles, 2005, 65, 1705;(e) A. Armstrong and S. E. Shanahan, Org. Lett., 2005, 7,1335; (f) H. Kimura, T. Fujiwara, T. Katoh, K. Nishide,T. Kajimoto and M. Node, Chem. Pharm. Bull., 2006, 54,399; (g) A. Armstrong, Y. Bhonoah and S. E. Shanahan,J. Org. Chem., 2007, 72, 8019; (h) E. Gomez-Sanchez,E. Soriano and J. Marco-Contelles, J. Org. Chem., 2007, 72,8656; (i) E. Gomez-Sanchez, E. Soriano and J. Marco-Contelles, J. Org. Chem., 2008, 73, 6784; (j) A. Armstrong,Y. Bhonoah and A. J. P. White, J. Org. Chem., 2009, 74,5041; (k) J. Bexrud and M. Lautens, Org. Lett., 2010, 12, 3160.9 (a) D. Bai, R. Xu, G. Chu and X. Zhu, J. Org. Chem., 1996, 61,4600; (b) R. Xu, G. Chu and D. Bai, Tetrahedron Lett., 1996, 37,1463; (c) T. E. Fevig, T. E. Anjeh, J. P. Lawson, D. P. Walkerand D. G. Wishka, U. S. Patent 0173063 A1, Pzer Inc., 2006.10 ESI.†11 Although there are many reported valuable homologationmethods, the present route has been taken for the reliableand safety reason.12 H. Hagiwara, N. Komatsubara, H. Ono, T. Okabe, T. Hoshi,T. Suzuki, M. Ando and M. Kato, J. Chem. Soc., PerkinTrans. 1, 2001, 316.13 S. R. Fletcher, R. Baker, M. S. Chambers, R. H. Herbert,S. C. Hobbs, S. R. Thomas, H. M. Verrier, A. P. Watt andR. G. Ball, J. Org. Chem., 1994, 59, 1771.14 W. Chiou, G.-H. Lin, C.-C. Hsu, S. J. Chaterpaul and I. Ojima,Org. Lett., 2009, 11, 2659.This journal is © The Royal Society of Chemistry 2014

Synthesis of (−)-epibatidine

Wen-Hua Chiou

Yu-Min Chiang

Crossref

http://ir.lib.nchu.edu.tw/bitstream/11455/86204/1/2015-3-4-4-15-2.pdf

Synthesis of (−)-epibatidine

Abstract

Similar works

Full text

Available Versions

National Chung Hsing University Institutional Repository

Crossref