3512
S. G. Davies et al. / Tetrahedron Letters 50 (2009) 3509–3512
Tetrahedron: Asymmetry 1995, 6, 1657; (d) Braun, M.; Buhne, C.; Cougali, D.;
References and notes
Schaper, K.; Frank, W. Synthesis 2004, 2905.
13. For additional references related to the syntheses of various analogues, see: (a)
Gonzalez, F. B.; Baz, J. P.; Espina, M. I. R. Tetrahedron Lett. 1989, 30, 2145; (b)
Sauerberg, P.; Chen, J.; WoldeMussie, E.; Rapoport, H. J. Med. Chem. 1989, 32,
1322; (c) Bermejo Gonzalez, F.; Perez Baz, J.; Ruano Espina, M. I. Tetrahedron
Lett. 1989, 30, 2145; (d) Holden, K. G.; Mattson, M. N.; Cha, K. H.; Rapoport, H. J.
Org. Chem. 2002, 67, 5913.
14. (a) Jones, R. G. J. Am. Chem. Soc. 1949, 71, 644; (b) Jones, R. G.; McLaughlin, K. C.
J. Am. Chem. Soc. 1949, 71, 2444.
15. Bransma, L. Preparative Acetylenic Chemistry, 2nd ed.; Elsevier: Amsterdam,
1988; p 231.
16. Pflieger, D.; Muckensturm, B. Tetrahedron 1989, 45, 2031.
17. Eglinton, G.; Jones, E. R. H.; Whiting, M. C. J. Chem. Soc. 1952, 2873.
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Bandurco, V.; Rigby, R. D. G. J. Org. Chem. 1972, 37, 581.
22. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
23. Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S. M.
Tetrahedron Lett. 1979, 20, 3981.
1. Hardy, E. Bull. Soc. Chim. Fr. 1875, 24, 497.
2. Gerrard, A. W. Pharm. J. 1875, 5, 86.
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1900, 78, 851; (c) Pinner, A.; Kohlhammer, E. Ber. Dtsch. Chem. Ges. 1900, 33,
2357; (d) Pinner, A.; Kohlhammer, E. Ber. Dtsch. Chem. Ges. 1900, 33, 1424; (e)
Jowett, H. A. D. J. Chem. Soc. 1901, 79, 580; (f) Jowett, H. A. D. J. Chem. Soc. 1901,
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Pinner, A.; Schwarz, R. Ber. Dtsch. Chem. Ges. 1902, 35, 192; (i) Pinner, A.;
Schwarz, R. Ber. Dtsch. Chem. Ges. 1902, 35, 2441. The absolute (3S,4R)-
configuration of (+)-pilocarpine 1 was established in 1966, see: Hill, R. K.;
Barcza, S. Tetrahedron 1966, 22, 2889.
4. (a) Battersby, A.R.; Openshaw, H.T. The Alkaloids, Manske, R.H.F.; Holmes, H.L.;
(Eds.), Academic Press: New York, 1953; Vol. 3, p 201.; (b) Maat, L.; Beyerman,
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24. Treatment of 9 under these conditions resulted in a change of colour of the
solution from deep red to yellow, followed by the formation of a light brown
precipitate.
25. The formation of (E)-a-ethylidene lactone
5
presumably arises from the
isomerisation of the initially formed
the basic imidazole ring.
a-vinyl lactone 8, under the influence of
9. Aboul-Enein, H. Y.; Al-Badr, A. A. Methods Find. Exp. Clin. Pharmacol. 1982, 4,
321.
26. Since hydrogenation of exclusively (E)-5 gave a 72:28 mixture of pilocarpine 1
and isopilocarpine 2 in quantitative yield, and hydrogenation of an 88:12
10. (a) Preobrashenski, N. A.; Poljakowa, A. M.; Preobrashenski, W. A. Ber. Dtsch.
Chem. Ges. 1936, 69, 1835; (b) Dey, A. N. J. Chem. Soc. 1937, 1057; (c)
Chumachenko, A. V.; Zvonkova, E. N.; Evstigneeva, R. P. J. Org. Chem. USSR (Engl.
Trans.) 1972, 8, 1112; (d) DeGraw, J. I. Tetrahedron 1972, 28, 967; (e) Link, H.;
Bernauer, K. Helv. Chim. Acta 1972, 55, 1053; (f) Noordam, A.; Maat, L.;
Beyerman, H. C. Rec. J. R. Neth. Chem. Soc. 1981, 100, 441; (g) Compagnone, R. S.;
Rapoport, H. J. Org. Chem. 1986, 51, 1713; (h) Belletire, J. L.; Mahmoodi, N. O. J.
Nat. Prod. 1992, 55, 194; (i) Horne, D. A.; Fugmann, B.; Yakushijin, K.; Büchi, G. J.
Org. Chem. 1993, 58, 62; (j) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem.
1993, 58, 1159.
11. (a) Shapiro, G.; Chengzhi, C. Tetrahedron Lett. 1992, 33, 2447; (b) Wang, Z.; Lu,
X. Tetrahedron Lett. 1997, 38, 5213; (c) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 8198.
12. For additional references related to the synthesis of isopilocarpine 2, see: (a)
Preobrashenski, N. A.; Wompe, A. F.; Preobrashenski, W. A. Ber. Dtsch. Chem.
Ges. 1933, 66, 1187; (b) Poljakowa, A. M.; Preobrashenski, W. A.;
Preobrashenski, N. A. Ber. Dtsch. Chem. Ges. 1936, 69, 1314; (c) Zhu, G.; Lu, X.
mixture of (E)- and (Z)-
generation synthesis) produced
isopilocarpine 2 in quantitative yield, this indicates that the double bond
geometry within 5 does not have a major impact on the product distributions
obtained.
a
-ethylidene lactones
5
(obtained from our first
and
a
70:30 mixture of pilocarpine
1
27. Pilocarpine 1: dH (400 MHz, CDCl3) 1.10 (3H, t, J 7.4, CH3CH2), 1.56–1.63 (1H, m,
CH3CHA), 1.87–1.93 (1H, m, CH3CHB), 2.36–2.84 (4H, m, C(3)H, C(4)H, C(50)CH2),
3.56 (3H, s, NCH3), 4.08 (1H, dd, J 9.4, 2.4, C(5)HA), 4.19 (1H, dd, J 9.4, 5.5,
C(5)HB), 6.79 (1H, s, C(40)H), 7.41 (1H, s, C(20)H).
Isopilocarpine 2: dH (400 MHz, CDCl3) 1.04 (3H, t, J 7.4, CH3CH2), 1.71–1.76 (2H,
m, CH3CH2), 2.26–2.31 (1H, m, C(3)H), 2.58–2.88 (3H, m, C(50)CH2, C(4)H), 3.58
(3H, s, NCH3), 3.92 (1H, dd, J 9.3, 7.1, C(5)HA), 4.41 (1H, dd, J 9.3, 6.6, C(5)HB),
6.81 (1H, s, C(40)H), 7.42 (1H, s, C(20)H).
28. An authentic sample of (+)-pilocarpine 1 was kindly supplied by Macfarlan
Smith Ltd, Edinburgh; base-catalysed epimerisation of this sample also
provided a diastereoisomerically pure sample of (+)-isopilocarpine 2.