J. Org. Chem. 1993,58,62-64
62
A Synthesis of Pilocarpine David A. Home,+Burkhard Fugmann, Kenichi Yakushijin, and George Biichi' Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received July 2, 1992
Pilocarpine (1) was synthesized in seven steps starting from 2-acetylbutyrolactone. Chirality was introduced by asymmetric reduction of enone 4 and transferred via a Claisen rearrangement. A mild procedure for the preparation of 1,5-disubstituted imidazoles in the last synthetic operation led to pilocarpine unaccompanied by isopilocarpine. Pilocarpine (l),first isolated in 1875from the leaves of Pilocarpus jaborandi,' is a leading therapeutic agent for the treatment of narrow and wide angle glaucoma.2 The sole source for pilocarpine during the past century has been from the leaves of a tree (P.microphyllus)that grows only in the tropical rainforests of Brazil and Paraguay. Man'scontinued devastationof these forests will inevitably lead to its disappearance as well as the loss of many other medicinally important natural products. At a glance, pilocarpine is a deceptively simple looking molecule. The stereospecific construction of the imidazole moiety cis to the ethyl group on the butyrolactone ring represents a challengethat has attracted seven independent ~yntheses.~ Three of these give optically active none produce the alkaloid without its undesirable C3 epimer, isopilocarpine. In this report, we describe a four-step synthesis of pilocarpine (1) from acetylbutenolide 4. CH3
1
Chemical degradation of pilocarpine through its imidazolering has produced severalderivativesof homopilopic acid4which may hypothetically serve as precursors in the biogeneticpathway. When consideringpossiblesynthetic approaches to this alkaloid, we felt that homopilopic aldehyde7 would be a suitable intermediatefor the delayed
preparation of the imidazole moiety. The first key intermediate of the synthesis, unsaturated acetylbutyrolactone 4, has been described by Hoye6 as unstable, a fiiding which is contraryto a report by Li0tta.G Our efforts revealed that 4 was indeed unstable under the conditions used for its generation. Starting from commercial2-acetylbutyrolactone, selenenylationproceeded in a straightforward manner affording selenolactone 2 in 94% yield. Only the corresponding epoxide could be isolated from the selenoxide elimination under the oxidative conditions utilizing hydrogen peroxide.' When the oxidative elimination was carried out in the presence of excess cyclopentadiene, however, good yields of endo and exo bicyclo ketones 3n and 3x were obtained in a 2.3:l ratio, respectively.5 Flash vacuum thermolysis of ketones 3n and 3x worked beautifully to give prochiral enone 4 as a white solid in 95% yield. While the problem of establishing asymmetry at C3 and C4 has been partially overcome through modifications of optically active starting materials,aa,b our synthetic plan is based on a reagentcontrolled approach where asymmetry would be introduced by an enantioselective reduction of ketone 4 and transferred via a Claisen rearrangement. Among the various asymmetric reducing agents which have been reported for chiral reductions? we found (+)-fl-chlorodiisopinocamphenylboraneO[(+)-IpczBClIto be the reagent of choice. By necessity, reduction occurred under mild conditions with high regio- and enantiospecificity. The desired (R)-alcohol5was produced in 60% chemicalyieldlo
(6)Liotta, D.; Saindane, M.; Barnum, C.; Ensley, H.; Bdakrishnan, P. Tetrahedron Lett. 1981,22,3043. (7)The following epoxide was isolated as a colorlees liquid from the reaction: 1H NMR (CDCld 6 2.36 (8, 3 H), 4.36 (dd, J = 11.8,l.S Hz, 1 * Author to whom correspondence should be addressed. H), 4.45(d, J 1.5 Hz, 1 H), 4.48 (d, J 11.8 Hz, 1 H); '3C NMR (CDCl,) + Present address: Department of Chemistry, Columbia University, 8 26.8 (q),58.8 (a), 62.2 (d), 67.1(t), 167.4 (a), 197.0 ( 8 ) ; IR (CHCla)3005, New York, NY 10027. cm-I; MS, mlz (re1intensity) 142 (M+, (1)Systematic name: (3S-cis)-3-ethyldihydro-4-[(l-methyl-lH-imi- 1800,1720,1400,1360,1090,1070 23.8),43 (100). dazol-5-yl)methyl]-2(3H)-furanone.(a) Gerrard, A. W. Pharm. J. 1875, 5,86. (b) Hardy, E. Bull. Soc. Chim. Fr. 1876,24,497.For pilocarpine reviews, see: (c) Maat, L.; Beyerman, H. C. The Alkaloids; Academic Press: New York, 1983;Vol. 22,p 281. (d) Battersby, A. R.; Openshaw, H. T. The Alkaloib, Academic Press: New York, 1953;Vol. 3, p 201. O%0 0 (2)(a) Watson, P. G. Br. J. Ophthalmol. 1972,56,145. (b) Schwartz, B.N . Engl. J. Med. 1978,290, 182. (c) Leopold, I. H.; Keates, E. Clin. Pharm. "her. 1968,6,262.(d) Worthen,D. M.;Zimmerman,T. J.; Wind, (8)For reviews on asymmetric ketone reduction, see: (a) Morrison, J. C. A. Znuest. Ophthalmol. 1974,13,296. (e) Sanders, H. J. Chem. Eng. D. Asymmetric Synthesis: Academic Press: New York, 1983;Vol. 2, News 1985,63(13),30. Chapters 2-5. (b) Brown, H. C. Modern Synthetic Methods ZE New (3)(a) Compagnone,R. S.; Rapoport, H. J. Org. Chem. 1986,51,1713. York Springer-Verlag, 1986; p 307, For recent developments, see: (c) (b) Noordam, A.; Maat, L.; Beyerman, H. C. R. Rec. J. R. Neth. Chem. Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollman, T.; Kennedy, SOC.1981,100,441. (c) Link, H.; Bernauer, K. Helu. Chim. Acta 1972, R.; Masamune, S. J. Am. Chem. SOC. 1986,108,7402. (d) Corey, E. J.; 55,1053. (d) DeGraw,J.I. Tetrahedron 1972,28,967. (e) Chumachenko, Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. SOC. 1987,109,7925. A. V.; Zvonkova, E. N.; Evstigneeva, R. P. J. Org. Chem. USSR (Engl. Transl.) 1972,8, 1112. (0Preobrashenski, N. A.; Poljakowa, A. M.; (9)Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Org. Preobrashenski, W. A. Ber. Dtsch. Chem. Ges. 1936,69,1835.(g) Dey, Chem. 1986,51,3394. A. N. J. Chem. SOC.1937. 1057. (10)In an alternative synthetic sequence for the preparation of (R)(4)(a)Jowett, H. A. D. 2. Chem. SOC.1901,79,1331.(b) Langenbeck, alcohol 5, asymmetric reduction of endo and ex0 ketones 3n and.3 with W. Ber. 1924,57,2072. (+)-IpcSBClgave a separable mixture of cryetallinediastereomericalcohola (5)Hoye, T. R.; Caruso, A. J.; Magee, A. S. J. Org. Chem. 1982,47, with the (R)-configuration. Although the percent dimtereomeric exceasw 4152. are somewhat lower for these alcohola (7692% ee), they can, in principle,
0022-326319311958-0062$04.00/0 0 1993 American Chemical Society
J. Org. Chem., Vol. 58, No.1, 1993 63
A Synthesis of Pilocarpine
with an optical purity of greater than 92 7% as determined by 300-MHz lH NMR analysis of ita Mosher ester.
3n
2
4
T
C
H
O
7
Experimental Section
3x
5
. b C H O
X
0 6
0
21 cycloaddition-eliminationreaction of @-tolylsulfonyl)methyl isocyanide (TosMIC)with aldimines. The reaction is initiated by a mildly basic solution of potassium carbonate in methanol. We have found that under these conditionsthe formation of pilocarpinethrough the methyl imine of aldehyde 7 proceeded with only limited success (
