J. Am. Chem. Soc. 1997, 119, 3409-3410
3409
the C1-C9a pyrrolidinone bond have a dihedral angle close to
0° (pseudoeclipsed). Assuming free equilibration, epimerization
at C8 has the effect of increasing this dihedral angle to ∼60°
(pseudostaggered), thereby greatly reducing steric interactions.3
This relationship, which is qualitatively apparent with models,
was verified with molecular mechanics calculations (MM2*
strain energy difference for 4 and 5: ∆H4,5 ) 3.9 kcal/mol).4
Once in hand, we expected that cis reduction of 5 from the least
hindered -face would afford the methyl lactone 6, which again
suffers from van der Waal’s repulsion between Me10 and C1.
However, epimerization at C10 would relieve this interaction
and provide (()-stemoamide (1) as the thermodynamically most
stable product (∆H6,1 ) 4.6 kcal/mol).
Total Synthesis of (()-Stemoamide
Peter A. Jacobi* and Kyungae Lee
Department of Chemistry, Wesleyan UniVersity
Middletown, Connecticut 06459-0180
ReceiVed December 12, 1996
Stemoamide (1) is a member of the stemona class of alkaloids
that was isolated in 1992 from the roots of Stemona tuberosa
(Figure 1).1a Alkaloids of this genus typically incorporate a
perhydroazaazulene ring (cf. 3), a structural feature that is
present in nearly all compounds isolated thus far [see also
stenine (2)]. Most members also contain an R-methyl- -
butyrolactone functionality. Extracts of the Stemonaceae species
have been used for many years in Chinese traditional medicine
for treating a variety of respiratory ailments, including bronchitis,
pertussis, and tuberculosis.1b In addition, certain stemona
alkaloids have potent insecticidal activity.
Figure 1.
Recently, members of this class have attracted considerable
synthetic attention, in particular with respect to developing new
ring-forming reactions.2 Noteworthy accomplishments include
the synthesis in 1995 of (-)-stenine (2) by Wipf et al.2a and an
earlier synthesis of (()-2 by Hart and Chen.2c,d In 1994,
Williams et al. described the first total synthesis of (-)-
stemoamide (1), beginning with (R)-(-)-methyl 3-hydroxy-2-
methyl-propionate.2e Very recently, a second synthesis of (-)-1
has appeared which made use of a novel Ru-catalyzed enyne
metathesis reaction.2l In this paper we describe a concise
synthesis of (()-1 which can be utilized for preparing this
important compound on 0.5 g scales and larger. In addition, it
should be readily adaptable to the preparation of naturally
occurring (-)-1.
Figure 2.
The most logical precursor to 5 was the corresponding
methoxyfuran, which we hoped to prepare using the oxazole
Diels-Alder chemistry we have employed in the synthesis of
various furanoterpenes (Figure 3; 7 f 8).5 Transformations of
this type are of considerable synthetic utility, since the appended
groups A, B, and C are transposed in an unequivocal fashion
to the fused-ring furan 8. For the case where A ) OMe, this
approach offered the potential for forming the entire skeleton
of 1 in a single step, since hydrolysis of 8 would in principle
afford the butenolide 9.5
The key intermediate for our synthesis of 1 was the butenolide
derivative 5 (Figure 2), which we expected would be an ideal
precursor for establishing the trans relative stereochemistry at
C8 and C9a under thermodynamic control.2n Thus, with the C9a
configuration set, models clearly indicate that the alternative
cis arrangement found in 4 suffers from severe steric crowding.
This is a consequence of the fact that the C10 methyl group is
forced into close proximity to the C1 methylene hydrogens.
Viewed from a different perspective, the C10 methyl bond and
Figure 3.
In order to test this possibility, we have developed a highly
efficient synthesis of the acetylenic oxazole 16, which was
prepared in multigram quantities beginning with -chlorobutryl
chloride (10) (Scheme 1). First, acid chloride 10 was readily
converted to the methoxyoxazole 12 by initial condensation with
methyl alaninate, followed by cyclodehydration of the resultant
amide 11 with P2O5 (20 g scale; 80%).5 It proved to be
unnecessary to isolate intermediate 11, which was formed in a
high state of purity. Next, N-alkylation of succinimide with
12 proceeded in routine fashion to afford a 97% yield of the
oxazole imide 13. Several possibilities were considered for
converting the oxazole imide 13 to the desired acetylenic oxazole
(1) Isolation: (a) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55,
571. (b) Goetz, M.; Edwards, O. E. In The Alkaloids; Manske, R. H. F.,
Ed.; Academic Press: New York, 1976; Vol. IX, pp 545-551 and references
cited therein. See, also: (c) Nakanishi, K.; Goto, T.; Ito, S.; Natori, S.;
Nozoe, S. In Natural Products Chemistry; Academic Press: New York,
1975; Vol. 2, pp 292-93.
(2) Recent synthetic efforts: (a) Wipf, P.; Kim, Y.; Goldstein, D. M. J.
Am. Chem. Soc., 1995, 117, 11106. (b) Goldstein, D. M.; Wipf, P.
Tetrahedron Lett. 1996, 37, 739. (c) Chen, C.-Y.; Hart, D. J. J. Org. Chem.
1993, 58, 3840. (d) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236.
(e) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994,
35, 6417. (f) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H.
Tetrahedron Lett. 1993, 34, 5773. (g) Martin, S. F.; Corbett, J. W. Synthesis
1992, 55. (h) Beddoes, R. L.; Davies, M. P. H.; Thomas, E. J. J. Chem.
Soc., Chem. Commun. 1992, 538. (i) Wipf, P.; Kim, Y. Tetrahedron Lett.
1992, 33, 5477. (j) Xiang, L. I.; Kozikowski, A. P. Synlett 1990, 2, 279.
(k) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989,
111, 1923. (l) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356. See,
also: (m) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(n) Following the completion of this work, Kinoshita and Mori reported a
synthesis of (-)-1 which also employed butenolide 5, although the mp for
their 5 varies significantly from that reported here (127-29 °C vs 185-86
°C).2l
(3) Epimerization at C9a in 4, while having the same effect, is viewed as
less likely due to the lower pKa of H8.
(4) (a) Calculations were carried out using MacroModel V5.5, employing
the MM2* force field, and using Monte Carlo simulations to locate global
minima (>1000 MC steps).4b (b) Chang, G.; Guida, W. C.; Still, W. C. J.
Am. Chem. Soc. 1989, 111, 4379. See, also: (c) Mohamadi, F.; Richards,
N. G. J.; Guida, W. C.; Liskamp, R.; Caufield, C.; Chang, G.; Hendrickson,
T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
(5) Jacobi, P. A. In AdVances in Heterocyclic Natural Product Synthesis;
Pearson, W. H., Ed.; Jai Press Inc.: Greenwich, CT, 1992; Vol. II, pp 251-
98, and references cited therein.
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