J. Am. Chem. Soc. 1996, 118, 3299-3300
Vinylogous Mannich Reactions. The Asymmetric
Scheme 1
3299
Total Synthesis of (+)-Croomine
Stephen F. Martin* and Kenneth J. Barr
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, Texas 78712
ReceiVed December 15, 1995
The alkaloid-rich extracts obtained from plants belonging to
the Stemonaceae family (Stemona and Croomia species) have
been used in traditional Chinese folk medicine to prepare herbal
teas for treating numerous disorders, including pertussis,
pulmonary tuberculosis, and bronchitis; several alkaloids also
exhibit insecticidal activity.1 Although this class of alkaloids
is relatively small, there is an increasing interest in representative
members of the family owing to their unique and complex
structures coupled with the rich opportunities for developing
new chemistry for their synthesis.2 As illustrated by the
prototypical examples croomine (1) and stemonine (2), these
novel polycyclic alkaloids incorporate a butyrolactone ring that
is appended or annelated to a 1-azabicyclo[5.3.0]decane nucleus.
We have recently investigated the vinylogous Mannich
reaction as a key construction for the synthesis of alkaloid
natural products.3 The general plan is illustrated by the
nucleophilic addition of the 2-trialkylsilyloxy furan 4 to the
cyclic iminium ion 3 to provide a mixture of the isomeric
adducts threo-5 and erythro-5 in which the threo-5 product
typically dominates (eq 1).3 Since the stereochemistry at the
a,4
reactions might be applied to the design of a highly convergent
strategy for the synthesis of 1 and related alkaloids. In such an
approach to 1, both the A and D rings would be appended by
sequential addition of substituted silyloxy furan subunits to the
pyrrolidine core C, thereby forming bonds a and c. The seven-
membered B ring would be constructed via intramolecular
N-alkylation to make bond b. We now report the successful
implementation of this strategy in an extraordinarily concise,
asymmetric synthesis of (+)-croomine (1).
newly created stereogenic centers in the threo-5 adduct corre-
sponds to the pairwise relationships at C(9)-C(9a) and C(3)-
C(14) of croomine (1), it occurred to us that vinylogous Mannich
The synthesis commenced with the reaction of commercially
available 3-methyl-2-(5H)-furanone (6) (Scheme 1) with triiso-
propylsilyl triflate (TIPS-OTf) in the presence of triethylamine
(
1) For leading references to structural and biological investigations of
the Stemona alkaloids, see: (a) Koyanma, H.; Oda, K. J. Chem. Soc. B
5,6
to give the (trialkylsilyl)oxy furan 7 in 99% yield. The furan
1
970, 268. (b) Lizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. J. Chem.
7
is destined to be incorporated as both the A and D rings of
Soc., Chem. Commun. 1973, 125. (c) Nakanishi, K.; Goto, T.; Ito, S.; Natori,
S.; Nozoe, S. In Natural Products Chemistry; Academic Press: New York,
the target 1. Metallation of 7 followed by alkylation with 1,4-
1
975; Vol. 2, p 292 ff. (d) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakaurai,
A.; Tamura, S.; Mukakoshi, S. Agric. Biol. Chem. 1978, 42, 457. (e) Noro,
T.; Fukushima, S.; Ueno, A.; Litaka, Y.; Saiki, Y. Chem. Pharm. Bull. 1979,
(3) (a) Martin, S. F.; Corbett, J. W. Synthesis 1992, 55. (b) Martin, S.
F.; Liras, S. J. Am. Chem. Soc. 1993, 115, 10450. (c) Martin, S. F.; Clark,
C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236.
2
7, 1495. (f) Xu, R.-S.; Lu, Y.-J.; Chu, J.-H.; Iwashita, T.; Naoki, H.; Naya,
Y.; Nakanishi, K. Tetrahedron 1982, 38, 2667. (g) Tereda, M.; Sano, M.;
Ishii, A. I.; Kino, H.; Fukushima, S.; Noro, T. J. Pharm. Soc. Jpn. 1982,
(4) For a review of the reactions of trialkylsilyloxy furans with
electrophiles, see: (a) Casiraghi, G.; Rassu, G. Synthesis 1995, 607. For
related reactions, see: (b) Harding, K. E.; Coleman, M. T.; Liu, L. T.
Tetrahedron Lett. 1991, 31, 3795. (c) Morimoto, Y.; Nishida, K.; Hayashi,
Y. Tetrahedron Lett. 1993, 34, 5773. (d) Pelter, A.; Ward, R. S.; Sirit, A.
Tetrahedron: Asymm. 1994, 5, 1745. (e) Hanessian, S.; Raghavan, S. Biorg.
Med. Chem. Lett. 1994, 4, 1697.
7
5
9, 93. (h) Cheng, D.; Guo, J.; Chu, T. T.; R o¨ der, E. J. Nat. Prod. 1988,
1, 202. (i) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571. (j)
Ye, Y.; Qin, G.; Xu, R. Phytochem. 1994, 37, 1201, 1205.
(
2) (a) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem.
Soc. 1989, 111, 1923. (b) Chen, C.-y.; Hart, D. J. J. Org. Chem. 1990, 55,
236. (c) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477. (d) Morimoto,
6
(5) The structure assigned to each compound is in full accord with its
1
13
Y.; Nishida, K.; Hayashi, Y. Tetrahedron Lett. 1993, 34, 5773. (e) Chen,
C.-y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840. (f) Williams, D. R.; Reddy,
J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417. (g) Wipf, P.; Kim,
Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (h) Morimoto,
Y.; Iwahashi, M. Synlett 1995, 1221.
spectral ( H and C NMR, IR, mass) characteristics; molecular composition
of new compounds was established by high resolution mass measurements
of purified materials. All yields are based on isolated, purified material
1
judged >95% pure by H NMR spectroscopy; the structures of compounds
10, 11, 15, and 16 were determined by X-ray crystallography.
0
002-7863/96/1518-3299$12.00/0 © 1996 American Chemical Society