ORGANIC
LETTERS
2000
Vol. 2, No. 5
675-678
An Efficient Synthesis of Optically
Active Physostigmine from Tryptophan
via Alkylative Cyclization
Michiaki Kawahara, Atsushi Nishida, and Masako Nakagawa*
Faculty of Pharmaceutical Sciences, Chiba UniVersity,
1-33, Yayoi-cho, Inage-ku, Chiba-shi, 263-8522, Japan
Received January 6, 2000
ABSTRACT
A new and efficient synthetic route to physostigmine is described. Corey−Kim reagent reacted with tryptamine or tryptophan carbamates to
give 3a-(methylthiomethyl)hexahydropyrrolo[2,3-b]indole skeletons. Formal total synthesis of racemic and chiral physostigmine was accomplished
in excellent overall yields, in short steps.
Physostigmine1 (1, eserine) is an alkaloid isolated from the
seeds of Physostigma Venenosum (Calabal beans) and has
been shown to be a clinically useful anticholinergic drug.2
More recently, analogues of physostigmine have shown
promise as therapeutic agents for Alzheimer’s disease,2 and
its enantiomer protects against organophosphate poisoning.2
Therefore, several syntheses of 1 have been reported.1e,3
We previously reported various reactions of tryptamine
and tryptophan derivatives with electrophiles which provide
the corresponding tricyclic systems 5 via 4 (Scheme 1), and
we succeeded in developing the chemistry of cyclic tautomers
and the dye-sensitized photooxidation of tryptamines and
tryptophans by this approach.4 Using this method, we first
explored alkylative cyclization reactions of Nb-(methoxy-
carbonyl)tryptamine (6) with alkylating reagents.
(3) For asymmetric syntheses reported since ref 1e, see: (a) Takano, S.;
Sato, T.; Inomata, K.; Ogasawara, K. Heterocycles 1990, 31, 411-414.
(b) Node, M.; Hao, X.; Fuji, K. Chem. Lett. 1991, 57-60. (c) Takano, S.;
Moriya, M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109-112. (d)
Node, M.; Itoh, A.; Masaki, Y.; Fuji, K. Heterocycles 1991, 32, 1705-
1707. (e) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872-875.
(f) Takano, S.; Moriya, M.; Ogasawara, K. J. Org. Chem. 1991, 56. 5982-
5984. (g) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992,
114, 5566-5572. (h) Yu, Q.; Luo, W.; Li, Y.; Brossi, A. Heterocycles 1993,
36, 1279-1285. (i) Ashimori, A.; Matsuura,; T. Overman, L. E.; Poon, D.
J. J. Org. Chem. 1993, 58, 6949-6951. (j) Matsuura, T.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500-6503. (k) Ashimori, A.;
Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J.
Am. Chem. Soc. 1998, 120, 6488-6499. (l) Pallavicini, M.; Valoti, E.; Villa,
L.; Lianza, F. Tetrahedron: Asymmetry 1994, 5, 111-116. (m) Pallavitini,
M.; Valoti, E.; Resta, I. Tetrahedron: Asymmetry 1994, 5, 363-370. (n)
Node, M.; Hao, X.; Nishide, K.; Fuji, K.; Chem. Pharm. Bull. 1996, 44,
715-719. (o) Fuji, K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M.
Heterocycles 1998, 47, 951-964.
In this paper, we report a new concise synthesis of chiral
physostigmine (1) which consists of a one-step construction
of the basic tricyclic framework.
(1) For a review of Calabal alkaloids, see: (a) Marion, L. Alkaloids 1952,
2, 438-450, (b) Coxworth, E. Alkaloids 1965, 8, 27-45. (c) Robinson, B.
Alkaloids 1967, 10, 383-401. (d) Robinson, B. Alkaloids 1971, 13, 213-
226. (e) Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225-251.
(2) For recent reviews of pharmacology, see: Greig, N. H.; Pei. X.-F.;
Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. ReV. 1995, 15, 3-31.
(4) For a review, see: Hino, T.; Nakagawa, M. Alkaloids 1988, 34, 1-75.
10.1021/ol005513p CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/05/2000