The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine

Article abstract of DOI:10.1021/ol0615228

A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.

Full text of DOI:10.1021/ol0615228

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4007-4010
The Enantioselective Birch−Cope
Sequence for the Synthesis of
Carbocyclic Quaternary Stereocenters.
Application to the Synthesis of
(+)-Mesembrine
Tapas Paul, William P. Malachowski,* and Jisun Lee
Department of Chemistry, Bryn Mawr College, Bryn Mawr, PennsylVania 19010-2899
wmalacho@brynmawr.edu
Received June 21, 2006
ABSTRACT
A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A
sequence of three reactions, enantioselective Birch reduction allylation, enol ether hydrolysis, and Cope rearrangement, is used to
−
stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-
carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the
sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.
One significant challenge in modern synthetic organic
chemistry is the enantioselective synthesis of carbocyclic
quaternary stereogenic centers.1 Recently, we communicated
a sequence of reactions that efficiently generates quaternary
stereogenic centers.2 The three-step sequence involves a
Birch reduction-allylation, enol ether hydrolysis, and Cope
rearrangement (Birch-Cope sequence, Scheme 1). Use of
the elegant asymmetric Birch reduction-alkylation method
of Schultz would make this process enantioselective.3 Herein
we describe our application of the asymmetric Birch reduc-
tion-alkylation method to the Birch-Cope sequence.
(1) (a) Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581-
1587. (b) Lee, K.-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am.
Chem. Soc. 2006, 128, 7182-7184. (c) Fillion, E.; Wilsily, A. J. Am. Chem.
Soc. 2006, 128, 2774-2775. For reviews see: (d) Quaternary Stereocenters;
Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Federal Republic
of Germany, 2005. (e) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367. (f) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105-10146. (g) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591-4597. (h) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388-401. (i) Fuji, K. Chem. ReV. 1993,
93, 2037-2066.
Scheme 1. Birch-Cope Sequence
(2) (a) Malachowski, W. P.; Banerji, M. Tetrahedron Lett. 2004, 45,
8183-8185. (b) Malachowski, W. P.; Banerji, M. Cope Rearrangement of
Birch Reduction-Allylation Products. In Abstract of Papers; 228th National
Meeting of the American Chemical Society, Philadelphia, August 22-26,
2004; American Chemical Society: Washington, DC, 2004.
10.1021/ol0615228 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/08/2006

Furthermore, to illustrate the potential of this tool to
address challenges in the asymmetric synthesis of carbocyclic
quaternary stereogenic centers, the Birch-Cope sequence is
applied to the enantioselective synthesis of (+)-mesembrine
(Figure 1), the unnatural isomer of the bioactive alkaloid.4,5
was subjected to Birch reduction-allylation to afford cyclo-
hexadiene 4 (Scheme 3). Compound 4 was obtained in 72%
Scheme 3. Enantioselective Birch-Cope Sequence
Figure 1. (+)-Mesembrine.
Mesembrine is a member of the Sceletium alkaloids and has
demonstrated interesting bioactivity.6 Most notably, a recent
report7 describes potent serotonin re-uptake inhibitor activity
for the natural isomer, (-)-mesembrine.
The o-anisic acid derivatives, which were used as starting
materials in the Birch-Cope sequence, were synthesized
from commercially available precursors (Scheme 2).3a
isolated yield and shown to be a 110:1 mixture of dia-
stereomers by GC analysis and comparison with an inde-
pendently synthesized 1:1 diastereomeric mixture.8 The other
major product (∼15%) was the result of γ-allylation at the
C-3 position.9 The absolute sense of the new quaternary
center in 4 and all subsequent Birch products is based on
the preferences reported by Schultz.3 Hydrolysis of the
methyl enol ether afforded the 1,5-diene Cope substrate 5,
which was heated at reflux in 1,2-dichlorobenzene (1,2-DCB)
for 10 h to effect the stereospecific Cope rearrangement,10
leading to the thermodynamically more stable isomer 6. The
entire process can be conducted on gram scale in ∼60%
overall yield.
Scheme 2. Birch Reduction-Allylation Substrate Preparation
Variation of the C-5 group of the o-anisic acid derivatives
was pursued through a divergent strategy that utilized 3b as
a substrate in cross-coupling reactions (Scheme 4). Previous
reports have described biaryl Birch substrate synthesis via
(5) For leading references to previous enantioselective syntheses of (-)-
mesembrine, see: (a) Taber, D. F.; He, Y. J. Org. Chem. 2005, 70, 7711-
7714. (b) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143-147.
(c) Ogasawara, K.; Yamada, O. Tetrahedron Lett. 1998, 39, 7747-7750.
(d) Langlois, Y.; Dalko, P. I.; Brun, V. Tetrahedron Lett. 1998, 39, 8979-
8982. (e) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1997, 62, 1675-
1686. (f) Mori, M.; Kuroda, S.; Zhang, C.; Sato, Y. J. Org. Chem. 1997,
62, 3263-3270. (g) Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996, 42,
135-139. (h) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org. Chem. 1995,
60, 6785-6790. (i) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett.
1990, 1239-1242. (j) Takano, S.; Imamura, Y.; Ogasawara, K. Tetrahedron
Lett. 1981, 22, 4479-4482. For leading references to previous enantio-
selective syntheses of (+)-mesembrine, see: (k) Kosugi, H.; Miura, Y.;
Kanna, H.; Uda, H. Tetrahedron: Asymmetry 1993, 4, 1409-1412. (l)
Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. Soc. 1985, 107,
7776-7778.
Methylation of both the phenol and the carboxylic acid was
accomplished with dimethyl sulfate (DMS). After saponifica-
tion, the acid was converted to the acid chloride and coupled
with (L)-prolinol, the chiral auxiliary. Methylation of the
alcohol of (L)-prolinol afforded the o-anisic acid derivatives
3. The entire sequence affords 3 in roughly 75% yield for
the five steps, with chromatographic purification only
necessary for 3.
(6) Smith, M. T.; Crouch, N.; Gericke, N.; Hirst, M. J. Ethnopharmacol.
1996, 50, 119-130.
The 5-methyl derivative 3a was chosen as the first test of
the enantioselective Birch-Cope sequence. o-Anisic acid 3a
(7) Gericke, N. P.; VanWyk, B.-E. PCT Int. Appl., WO 9746234 CAN
128:80030, 1997.
(8) A diastereomeric mixture of 4 was synthesized as described in ref
3a. A diastereomeric mixture of 8 was generated by modifying the Birch
reduction conditions, i.e., removal of NH3, as described in ref 3a.
(9) γ-Alkylation of amide enolates derived from Birch reduction has
previously been reported, see ref 3a and references therein.
(10) (a) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441-
444. For reviews of the Cope rearrangement, see: (b) Nubbemeyer, U.
Synthesis 2003, 7, 961-1008. (c) Hill, R. K. Cope, Oxy-Cope and Anionic
Oxy-Cope Rearrangements. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds., Pergamon Press: Oxford, UK, 1991; Vol. 5,
Chapter 7.1. (d) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1-252.
(3) (a) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.;
Welch, M. J. Am. Chem. Soc. 1988, 110, 7828-7841. For reviews of the
asymmetric Birch reduction-alkylation, see: (b) Schultz, A. G. Chem.
Commun. 1999, 1263-1271. (c) Schultz, A. G. Acc. Chem. Res. 1990, 23,
207-213.
(4) For the isolation and structural determination of the natural isomer
(-)-mesembrine, see: (a) Popelak, A.; Haack, E.; Lettenbauer, G.; Spingler,
H. Naturwissenschaften 1960, 47, 156. (b) Smith, E.; Hosansky, N.;
Shamma, M.; Moss, J. B. Chem. Ind. 1961, 402-403.
4008
Org. Lett., Vol. 8, No. 18, 2006

our knowledge, this represents the first case of a Cope
equilibrium that balances the stabilization of phenyl group
conjugation versus conjugation with a ketone. Amide con-
jugation is expected to be weak based on literature reports
of related structures13 and computational studies14 (Figure
2) that show the amide to be orthogonal to the enone system
due to steric hindrance.
Scheme 4. Biaryl Birch Substrate Preparation
Suzuki-Miyaura reactions prior to the addition of the chiral
auxiliary.11 However, (L)-proline is inexpensive and the
divergent strategy was more efficient to synthesize a selection
of biaryl compounds. For the present study, a cross-coupling
reaction between 3b and 3,4-dimethoxyphenylboronic acid
generated 7.
Application of the Birch-Cope sequence to 7 began with
the asymmetric Birch reduction-allylation to yield 8 (Scheme
5). The Birch reduction demonstrates excellent chemoselec-
Figure 2. Semiempirical minimization of 6.
Scheme 5. Birch-Cope Sequence with Biaryl Substrate
With both 5 and 7, the Cope rearrangement generated a
versatile 4-allyl-2-cyclohexen-1-one system. To demonstrate
the potential of these structures as important intermediates
in complex natural product synthesis, 10 was elaborated into
(+)-mesembrine (Scheme 6). Ozonolysis of the terminal
Scheme 6. (+)-Mesembrine Synthesis
tivity for the more electron deficient aromatic ring.12
Decomposition of 8 under GC conditions necessitated the
use of HPLC analysis to determine the stereoselectivity of
the process. HPLC analysis of 8 revealed maximum stereo-
selectivity with more dilute reactions. Therefore a dia-
stereomeric ratio (dr) of 60:1 was seen when 7 was reduced
at 8 mM, but that stereoselectivity increased to >99:1 when
7 was reduced at a more dilute 4 mM. Completion of the
Birch-Cope sequence entailed hydrolysis of 8 to provide a
3-cyclohexen-2-one 9 that efficiently rearranged to 10.
Despite the presence of phenyl conjugation in 9, the
equilibrium favors 10 to a significant extent, albeit slightly
less than the equilibrium for 5/6. The Cope rearrangement
of 5/6 provides complete conversion to 6. However, under
the same thermal equilibration conditions, 15% of 9 is
recovered after chromatographic purification. To the best of
alkene afforded aldehyde 11. This was unstable, so it was
immediately subjected to reductive amination. The resulting
secondary amine spontaneously underwent conjugate addition
to afford 12. Cleavage of the chiral auxiliary with N-
methylhydroxylamine afforded 13, which was reduced,
hydrolyzed, and decarboxylated in one step to afford (+)-
(11) Khim, S.-K.; Dai, M.; Zhang, X.; Chen, L.; Pettus, L.; Thakkar,
K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7728-7733.
(12) For other examples of chemoselective biaryl Birch reduction-
alkylations, see ref 11 and: (a) Guo, Z.; Schultz, A. G. Tetrahedron Lett.
2004, 45, 919-921. (b) Guo, Z.; Schultz, A. G.; Antoulinakis, E. Org. Lett.
2001, 3, 1177-1180. (c) Schultz, A. G.; Green, N. J. J. Am. Chem. Soc.
1991, 113, 4931-4936. (d) Schultz, A. G.; Macielag, M.; Podhorez, D. E.;
Suhadolnik, J. C.; Kullnig, R. K. J. Org. Chem. 1988, 53, 2456-2464.
(13) Schultz, A. G.; Harrington, R. E. J. Am. Chem. Soc. 1991, 113,
4926-4931.
Org. Lett., Vol. 8, No. 18, 2006
4009

mesembrine, identical with authentic material (see the
Supporting Information). The one-step N-O reduction,
hydrolysis, and concomitant decarboxylation was a fortuitous
event and, to our knowledge, represents the first report of
such a tandem process caused by Mo(CO)6.15
In conclusion, an enantioselective Birch-Cope sequence
has been developed and shown to be effective in the synthesis
of carbocyclic quaternary stereocenters. To demonstrate the
application of this synthetic tool, (+)-mesembrine has been
synthesized in a concise sequence of eight steps from 3b.
Further studies are being undertaken to explore the breadth
of applications possible for this exciting new sequence.
Acknowledgment. We thank the Petroleum Research
Fund (PRF No. 43238-AC1), administered by the American
Chemical Society, and Bryn Mawr College for generous
financial support of this work. We thank the Villanova
University Chemistry Department for use of their ozone
generator and polarimeter. We also thank Prof. Douglass F.
Taber of the University of Delaware for his advice in the
preparation of the manuscript.
(14) Minimization of compound 6 was accomplished with semiempirical
calculations (AM1), using the Gaussian 03 suite of programs. Frisch, M.
J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.05; Gaussian, Inc.: Wallingford, CT, 2004.
Supporting Information Available: General experimen-
1
tal details, copies of H and 13C NMR spectra, and chro-
matographs. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0615228
(15) Molybdenum hexacarbonyl deallylation and decarboxylation of a
â-ketoester has been described: Tsuji, J.; Minami, I.; Shimizu, I. Chem.
Lett. 1984, 10, 1721-1724.
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