[4 + 1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates. Total synthesis of (±)-mesembrine

Article abstract of DOI:10.1021/ol005706c

(matrix presented) The Sceletium alkaloid mesembrine has been synthesized in 13% overall yield by a sequence featuring a [4 + 1] cycloaddition of a bis-(alkylthio)carbene with a functionalized vinyl isocyanate.

Full text of DOI:10.1021/ol005706c

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1673-1675
[4 + 1] Cycloaddition of
Bis(alkylthio)carbenes with Vinyl
Isocyanates. Total Synthesis of
(±)-Mesembrine
James H. Rigby* and Weitong Dong
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received February 22, 2000
ABSTRACT
The Sceletium alkaloid mesembrine has been synthesized in 13% overall yield by a sequence featuring a [4 + 1] cycloaddition of a bis-
(alkylthio)carbene with a functionalized vinyl isocyanate.
The rapid and efficient construction of partially reduced
nitrogen heterocycles continues to present an important
challenge to the synthesis of structurally complex alkaloid
targets. So-called nucleophilic carbenes1,2 have recently
emerged as powerful 1,1-dipole equivalents for the assembly
of functionalized pyrrolidone derivatives via a novel [4 +
1] cycloaddition with vinyl isocyanates (Scheme 1).3
alkaloids and represents a considerable synthetic challenge
as a result of the presence of the highly congested quaternary
center at C3a. Several amaryllis alkaloids of this structural
type, such as tazettine (1a) and pretazettine (1b), exhibit an
oxidized C3 position that renders them ideal targets for
nucleophilic carbene-based synthesis, since these reactive
intermediates deliver a carbon atom at the carbonyl oxidation
level.4
Scheme 1
The cis-3a-aryloctahydroindole nucleus is a prominent
substructural motif in the Amaryllidaceae and Sceletium
(1) (a) Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996,
118, 12848. (b) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org.
Chem. 1998, 63, 5587. (c) Rigby, J. H.; Cavezza, A.; Heeg, M. J.
Tetrahedron Lett. 1999, 40, 2973.
(2) For an excellent overview of nucleophilic carbene chemistry, see:
Warkentin, J. In AdVances in Carbene Chemistry; Brinker, U. H., Ed.;
JAI: Greenwich, 1998; Vol. 2, pp 245-95.
10.1021/ol005706c CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/12/2000

Aryloctahydroindole alkaloids possessing a fully reduced
carbon at C3 are quite common, and their synthesis by a
similar strategy would require the use of a nucleophilic
carbene partner at the corresponding reduced oxidation level
such as methylene itself or, more reasonably, one that is
readily reduced to the desired oxidation state after cyclo-
addition. A potential solution to this problem has been
introduced recently in the form of bis(alkylthio)carbenes.5
These species have been shown to exhibit a reaction profile
similar in many respects to that of dialkoxycarbenes;
however, they also offer the opportunity to serve as meth-
ylene equivalents via post-cycloaddition reductive desulfu-
rization. We wish to disclose that this notion has been
brought to practice in an efficient synthesis of the Sceletium
alkaloid, (()-mesembrine (2).6 The basic strategy for this
synthesis is outlined in Scheme 2. The key strategy-level
undergo cycloaddition with â-aryl-substituted vinyl iso-
cyanate 4 to afford hydroindolone 5. Desulfurization and
enamide reduction would complete the synthesis of mesem-
brine.
The synthesis commences with commercially available
monoprotected dione 6, which is transformed in four steps
via vinyl triflate 77 to the key â-aryl-R,â-unsaturated acid
87 in 71% overall yield (Scheme 3). Exposure of 8 to DPPA8/
Scheme 3
Scheme 2
transformation is a thermal decomposition of dithiooxadia-
zoline 3, giving the corresponding carbene, which would
(3) For a review of vinyl isocyanate chemistry, see: Rigby, J. H. Synlett.
2000, 1.
(4) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998,
120, 3664.
(5) (a) Rigby, J. H.; Laurent, S. J. Org. Chem. 1999, 64, 1766. (b) Rigby,
J. H.; Danca, M. D. Tetrahedron Lett. 1999, 40, 6891.
TEA followed by attempted purification on silica gel of the
resultant acyl azide gave, surprisingly, the rearranged vinyl
isocyanate 9, which was immediately heated in refluxing
benzene in the presence of excess oxadiazoline 35a to afford
the crucial 2:1 adduct 10.7 This material possesses a fully
intact 3a-aryloctahydroindole structure. The success of this
transformation highlights in dramatic fashion the power of
nucleophilic carbenes for ring construction even at very
sterically hindered locations. In the case at hand, there is
considerable congestion in the vicinity of the newly created
bond between C3 and C3a, and it is presumed that the reaction
proceeds through intermediate 9a in which the crucial bond
formation benefits from intramolecularity.
(6) For previous synthesis of mesembrine, see: (a) Kamikubo, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1998, 783. (b) Yamada,
O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747. (c) Dalko, P. I.; Brun,
V.; Langlois, Y. Tetrahedron Lett. 1998, 39, 8979. (d) Mori, M.; Kuroda,
S.; Zhang, C.-S.; Sato, Y. J. Org. Chem. 1997, 62, 3263. (e) Denmark, S.
E.; Marcin, L. R. J. Org. Chem. 1997, 62, 1675. (f) Rajagopalan, P.
Tetrahedron Lett. 1997, 38, 1893. (g) Takano, S.; Samizu, K.; Ogasawara,
K. Chem. Lett. 1990, 1239. (h) Winkler, J. D.; Muller, C. L.; Scott, R. D.
J. Am. Chem. Soc. 1988, 110, 4831. (i) Hoshino, O.; Sanaki, S.; Shimamura,
N.; Onodera, A.; Umezawa, B. Chem. Pharm. Bull. 1987, 35, 2734. (j)
Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. Soc. 1985, 107,
7776. (k) Kochhar, K. S.; Pinnick, H. W. Tetrahedron Lett. 1983, 24, 4785.
(l) Sanchez, I. H.; Soria, J. J.; Larraza, M. I.; Flores, H. J. Tetrahedron
Lett. 1983, 24, 551. (m) Keck, G. E.; Webb, R. R., II. J. Org. Chem. 1982,
47, 1302. (n) Takano, S.; Imamura, Y.; Ogasawara, K. Tetrahedron Lett.
1981, 22, 4479. (o) Takano, S.; Imamura, Y.; Ogasawara, K. Chem. Lett.
1981, 1385. (p) Strauss, H. F.; Wiechers, A. Tetrahedron Lett. 1979, 4495.
(q) Martin, S. F.; Puckette, T. A.; Colapret, J. A. J. Org. Chem. 1979, 44,
3391. (r) Stevens, R. V.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90,
5580. (s) Keely, S. L., Jr.; Tahk, F. C. J. Am. Chem. Soc. 1968, 90, 5584.
(t) Shamma, M.; Rodriguez, H. R. Tetrahedron 1968, 24, 6583. (u) Curphey,
T. J.; Kim, H. L. Tetrahedron Lett. 1968, 1441.
With hydroindolone 10 in hand, the projected reductive
desulfurization step becomes important. It should be noted
(7) This compound exhibited spectral (1H NMR, 13C NMR, IR) and
analytical (combustion analysis and/or HRMS) data fully consistent with
the assigned structure.
(8) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203.
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Org. Lett., Vol. 2, No. 12, 2000

at this juncture that the [4 + 1] cycloaddition not only
inserted a new carbon atom at C3 amenable to subsequent
reduction but simultaneously installed the carbon atom
required for conversion into the N-methyl group of the target
structure as well. In light of this result, it was anticipated
that both centers could be reduced to their requisite oxidation
levels in one operation. Thus, Ra-Ni-mediated reductive
cleavage of all four carbon-sulfur bonds delivered the
requisite enamide 117 after acetal hydrolysis. The efficiency
of these two steps is noteworthy.
in 13% overall yield from 6. The preparation of mesembrine
1
was confirmed by comparison of the H and 13C NMR
spectra of the synthetic material with those reported for the
natural product.6e
In summary, a novel [4 + 1] cycloaddition between a bis-
(alkylthio)carbene and a functionalized vinyl isocyanate
afforded the Sceletium alkaloid, (()-mesembrine, after
appropriate oxidation level adjustments.
Reduction of the remaining enamide alkene to the cis-
fused aryloctahydroindole system 127 was achieved after
considerable effort by employing an interesting SmI2-based
reduction protocol reported initially by Molander and McKie
several years ago.9 A routine series of operations followed
to afford mesembrine in 75% yield for the three steps and
Acknowledgment. The authors wish to thank the Na-
tional Science Foundation for their generous support of this
research.
(9) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186.
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