A general efficient strategy for cis-3a-aryloctahydroindole alkaloids via stereocontrolled ZnBr2-catalyzed rearrangement of 2,3-aziridino alcohols

Article abstract of DOI:10.1021/ol0346685

(Matrix presented) A short and general approach to the cis-3a-aryloctahydroindole alkaloids has been developed on the basis of a key stereocontrolled ZnBr₂-catalyzed rearrangement of 2,3-aziridino alcohols. Two representative members, (±)-crina

Full text of DOI:10.1021/ol0346685

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2319-2321
A General Efficient Strategy for
cis-3a-Aryloctahydroindole Alkaloids via
Stereocontrolled ZnBr2-Catalyzed
Rearrangement of 2,3-Aziridino Alcohols
Zhen Lei Song, Bao Min Wang, Yong Qiang Tu,* Chun An Fan, and
Shu Yu Zhang
Department of Chemistry and State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received April 21, 2003
ABSTRACT
A short and general approach to the cis-3a-aryloctahydroindole alkaloids has been developed on the basis of a key stereocontrolled ZnBr2-
catalyzed rearrangement of 2,3-aziridino alcohols. Two representative members, (±)-crinane and (±)-mesembrine, have been synthesized in
15% and 11% overall yields, respectively.
The cis-3a-aryloctahydroindole alkaloids constitute a large
class of structurally diverse natural products existing widely
in the Sceletium1 and Amaryllidaceae2 alkaloids, such as
mesembrine (2)3 and pretazettine (3),4 as well as some
nonnatural products, such as crinane (1)5 (Figure 1). As a
result of their many biologically significant activities involv-
ing antiviral, antitumor, anticholinergic, even anti-HIV
effects6 and their intriguing structures, these alkaloids have
been attracting considerable attention of organic chemists
(1) Jeffs, P. M. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic
Press: New York, 1981; Vol. 19, pp 1-80.
(2) (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, pp 251-376. (b) Jeffs, P. M. In MTP
International ReView of Science, Alkaloids, Organic Chemistry, Series One;
Hey, D. H., Wiesner, K. F., Eds.; Butterworth: London, 1973; Vol. 9, pp
273-318.
(3) For some previous syntheses of mesembrine, see: (a) Taber, D. F.;
Neubert, T. D. J. Org. Chem. 2001, 66, 143-147. (b) Rigby, J. H.; Dong,
W. Org. Lett. 2000, 2, 1673. (c) Ogasawara, K.; Tamada, O. Tetrahedron
Lett. 1998, 39, 7747. (d) Mori, M.; Kuroda, S.; Zhang, C.; Sato, Y. J. Org.
Chem. 1997, 62, 3263. (e) Denmark, S. E.; Marcin, L. R. J. Org. Chem.
1997, 62, 1675.
(4) For some previous syntheses of pretazettine, see: (a) Baldwin, S.
W.; Debenham, J. S. Org. Lett. 2000, 2, 99. (b) Rigby, J. H.; Cavezza, A.;
Heeg, M. J. J. Am. Chem. Soc. 1998, 120, 3664. (c) Overman, L. E.; Wild,
H. Tetrahedron Lett. 1989, 30, 647.
(5) For some previous syntheses of crinane, see: (a) Padwa, A.; Brodney,
M. A.; Dimitroff, M.; Liu, B.; Wu, T. H. J. Org. Chem. 2001, 66, 3119.
(b) Schkeryantz, J. M.; Pearson, W. H. Tetrahedron 1996, 52, 3107. (c)
Keck, G. E.; Webb, R. R. J. Am. Chem. Soc. 1981, 103, 3173.
Figure 1. Representative members of cis-3a-aryloctahydroindole
alkaloids.
10.1021/ol0346685 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/03/2003

over the years. As a structural feature common to all of these
species, the cis-3a-aryloctahydroindole nucleus (Figure 1)
containing a sterically congested quaternary carbon center
located at the hydroindolone bridgehead (C3a) represents a
central synthetic challenge, and a number of synthetic efforts
have emerged to address this problem.
Scheme 2. Retrosynthetic Analysis of (()-Crinane (1) and
(()-Mesembrine (2)
During the course of our investigation on the stereoselec-
tive construction of quaternary carbon centers,7,8 we recently
reported an efficient method to prepare 2-quarternery 1,3-
amino carbonyl compounds by Lewis acid promoted highly
stereoselective rearrangement of 2,3-aziridino alcohols under
fairly mild conditions (Scheme 1).9 The Mannich bases
Scheme 1
ring, as an optimal target to test our methodology. According
to our reported protocol,9 the 2,3-aziridino alcohol 8 (Scheme
3) was obtained from cyclohexenyl chloride 711 in 33%
Scheme 3. Total Synthesis of (()-Crinane (1)
obtained, which are particularly versatile intermediates in
the synthesis of numerous pharmaceuticals and natural
products, are not accessible by the classical Mannich
reaction.10 More importantly, our further studies have
discovered that catalytic amounts (0.1 equiv) of ZnBr2 could
also effect this reaction smoothly. Hence, the great potential
of this method inspired us to apply it as a key step to
accomplish the construction of the cis-3a-aryloctahydroindole
alkaloids. Herein, the total syntheses of (()-crinane (1) and
(()-mesembrine (2) on the basis of this methodology are
reported.
Our retrosynthetic analysis is outlined in Scheme 2. We
envisioned that both of these two target molecules could be
available from the corresponding crucial cis-3a-aryloctahy-
droindole core structures 4 by some facile steps. In turn, 4
might be prepared from 2-aryl 1,3-amino aldehydes 5 through
several transformations involving Wittig reaction and reduc-
tive cyclization. As the key strategy-level step, a ZnBr2-
catalyzed rearrangement of 2,3-aziridino alcohols 6 would
provide the desired precursors 5 with requisite stereoselec-
tivity.
Initially, we selected (()-crinane (1) possessing the basic
structural element of interest, although not naturally occur-
(6) Lin, L. Z.; Hu, S. F.; Chai, H. B.; Pengsuparp, T.; Pezzuto, J. M.;
Cordell, G. A.; Ruangrungsi, N. Phytochemistry 1995, 40, 1295.
(7) For recent reviews on stereoselective construction of a quaternary
carbon center, see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388. (c) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew.
Chem., Int. Ed. 1996, 35, 2708. (d) Fuji, K. Chem. ReV. 1993, 93,
2037.
overall yield via two steps involving nucleophilic addition
and aziridination of the corresponding allylic alcohol by the
procedure of Sharpless.12 With 8 in hand, the key stereose-
lective rearrangement was investigated. As expected, subjec-
(8) (a) Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1999, 64, 629.
(b) Fan, C. A.; Wang, B. M.; Tu, Y. Q.; Song, Z. L. Angew. Chem., Int.
Ed. 2001, 40, 3877.
(9) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Shi, Y. Org. Lett.
2002, 4, 363.
(10) For a general review on Mannich reaction, see: Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
(11) Braude, E. A.; Coles, J. A. J. Chem. Soc. 1950, 2014.
(12) Jeong, J. K.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844.
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Org. Lett., Vol. 5, No. 13, 2003

Finally, using the reported Pictet-Spengler cyclization
procedure,5c treatment of 14 with Eschenmoser’s salt at 40
°C in THF for 24 h yielded (()-crinane (1).
Scheme 4. Total Synthesis of (()-Mesembrine (2)
The successful synthesis of (()-crinane encouraged us to
apply the strategy above to another more complex target
molecule, (()-mesembrine (2), which incorporates a different
aryl substituent and oxygenation at C-6. As shown in Scheme
4, the starting point of the synthesis is commercially available
cyclohexane-1,4-diol 15, which was transformed to hydra-
zone 16 via three steps in 60% overall yield. Then, Shapiro
coupling16 of 16 with 3,4-dimethoxybenzaldehyde followed
by aziridination afforded the desired aziridino alcohol 17 as
two isomers (2:1) in 26% overall yield. Following the same
sequence in the synthesis of (()-crinane, both isomers of
17 furnished 1817 in a single diastereoisomeric form, which
then was converted into 19 in 85% overall yield. Treatment
of 19 with Red-Al (8.0 equiv) resulted in the amino alcohol
20, but the extreme condition and moderate yield of 50%
led us to develop an alternative improved method. Subjected
to NaBH3CN and TiCl4 in CH2Cl2 at -78 °C18,19 followed
by removal of the tosyl group using sodium naphthalenide,20
19 was transformed to 20 in 93% overall yield. After
N-methylation21 followed by oxidation using PDC, 20
ultimately was converted into (()-mesembrine (2), which
has spectral characteristics identical to those reported in the
literature.
In summary, we have developed a new and general
strategy for the syntheses of cis-3a-aryloctahydroindole
alkaloids using a ZnBr2-catalyzed highly stereoselective
rearrangment of 2,3-aziridino alcohols as the key step, and
the total syntheses of (()-crinane and (()-mesembrine have
been achieved. Application of this methodology to other
kinds of more complex alkaloids, especially to enantiose-
lective syntheses of some important molecules, is currently
under investigation in our group.
tion of 8 to catalytic amounts of ZnBr2 in dry CH2Cl2 at
room temperature for 1 h gave rise to 11 as a single
diastereoisomer smoothly in 96% yield. The stereochemical
assignment of 11 was confirmed by our previously reported
results.9 Meanwhile, the proposed transition state 9 and 10
interpreted effectively the perfect stereocontrol observed in
this reaction.
At the beginning of constructing the dihydropyrrole
moiety, the Wittig reaction was selected to realize carbonyl
homologation. Exposure of 11 to the ylide (4.0 equiv,
prepared from methyoxymethyltriphenyl phosphonium chlo-
ride13 and n-BuLi in THF) gave a 1:1 E/Z mixture of vinyl
ethers 12. When 12 was stirred in Et2O with several drops
of aqueous HClO4 (70%) for 8 h, the unique cyclizing
product R-hydroxy sulfonamide 13 was formed and none of
the corresponding sulfonamide aldehyde tautomer was
detected.14 When selecting suitable routes for the transforma-
tion of 13 to 14, we first referred to the method reported by
Hoshino.15 To our delight, heating 13 in refluxing o-xylene
in the presence of excessive sodium bis(2-methoxyethoxy)-
aluminum hydride (Red-Al) for 8 h afforded the desired cis-
3a-aryloctahydroindole 14 directly in 70% yield. Its spectral
properties were in agreement with those previously reported.5a
Acknowledgment. This work was supported by NSFC
(29972019, 29925205 and QT program), FUKTME of China,
the Young Teachers’ Fund of Ministry of Education and the
Fund of Ministry of Education (99209).
Supporting Information Available: Experimental pro-
cedure and spectroscopic and analytical data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0346685
(16) Shapiro, R. H.; Health, M. J. J. Am. Chem. Soc. 1967, 89, 5734.
(17) As only one isomer of 18 was obtained, we thought that both isomers
of 17 underwent the migration of the aryl substituent, which has the superior
migrating ability to hydrogen.
(18) (a) Ahman, J.; Somfai, P. Tetrahedron 1992, 48, 9537. (b) Comins,
D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506. (c) Jefford, C. W.;
Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(19) Through the 1H NMR NOE experiments of the product in this step
and the spectral properties of 17-20, the relative configuration of C3a, C7a,
C6 in 17-20 could be confirmed. For the detailed analysis, see Supporting
Information.
(13) Wittig, G.; Schlosser, M. Chem. Ber. 1961, 1373.
(14) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
4.5, p 1049.
(20) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem.
1989, 54, 1548.
(21) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem.
1985, 50, 1927.
(15) Ishizaki, M.; Hoshino, O. J. Org. Chem. 1992, 57, 7285.
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