C O M M U N I C A T I O N S
Scheme 1 . Synthesis of (-)-Esermethole
Table 3. Scope of the Reaction
disubstituted indolenines and indolines. High enantioselectivities
could be achieved using 9-BBN-C6H13 as the promoter of the
reaction, and electron-rich indoles give higher selectivities. The
dependence of the selectivity on the nature of the borane suggests
that, in addition to promoting the ionization of allyl alcohol,14 the
boron is directly involved in the enantiodiscriminating step. Studies
to elucidate the mechanism of this reaction are underway and will
be reported shortly.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM33049) for their generous
support of our programs. J.Q. thanks the Association pour la
Recherche sur le Cancer (France) for a postdoctoral fellowship.
We thank Johnson Matthey for a generous gift of palladium salts.
Supporting Information Available: Synthesis all new indole
substrates, experimental details, and characterization data for all new
compounds (PDF). This material is available free of charge via the
References
(1) (a) Somei, M. S.; Yamada, F. Y. Nat. Prod. Rep. 2005, 22, 73. (b) Rahman,
A. U.; Basha, A. Indole Alkaloids; Hawood Academic Publishers:
Amsterdam, 1997.
(2) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308 and references cited therein. (b) Huang, A. K.; Kodanko, J. J.;
Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043. (c) Adhikari, S.;
Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,
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(3) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.
(4) Other approaches to the formation of a quaternary center at C3 of the
indole core include the following. (a) Asymmetric Heck-iminium ion
cyclization: Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am.
Chem. Soc. 2005, 127, 10186. (b) Enantioselective oxidative cyclization
of tryptophol: Hirose, T.; Sunazuka, T.; Yamamoto, D.; Kojima, N.;
Shirahata, T.; Harigaya, Y.; Kuwajima, I.; Omura, S. Tetrahedron 2005,
61, 6015 and previous work cited therein.
a All reactions were performed on a 0.2 mmol scale for 20 h using 2.5
mol % of Pd2(dba)3CHCl3, 7.5% of (S,S)-A, 1.1 equiv of 9-BBN-(C6H13),
and 3 equiv of allyl alcohol. b Cyclization to the indoline occurred after
addition of ethanolamine to the indolenine in THF (5 min stirring for 18
and 24 h stirring for 20).
(5) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 4592.
(6) (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (b) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921. (c) Trost, B. M. J. Org. Chem. 2004,
69, 5813.
(7) A systematic study of base and solvent effect on the C-3 versus
N-selectivity in the palladium-catalyzed allylation of indoles using allyl
carbonates showed that the formation of a tight indolyl-metal ion favors
the C-3 allylation process. Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Org. Lett. 2004, 6, 3199.
(8) Kol, M.; Bar-Haim, G. Tetrahedron Lett. 1998, 39, 2643.
(9) The relative stereochemistry was confirmed by NOE on 12a and 16.
(10) Unprotected tryptamines failed to give clean reactions and high enanti-
oselectivity.
We were also interested in the oxidation of indolenines which
could allow an easy access to the oxindole family of natural
products. After examining various oxidative conditions, we found
that treatment of 2 with tetrabutylammonium oxone12 and acetic
acid gave oxindole 23 in good yield (Scheme 1). Recrystallization
of 23 provided enantiopure material. Furthermore, after methylation
and oxidative cleavage, aldehyde 24 was converted to (-)-
esermethole by reductive amination-cyclization following Over-
man’s procedure.13 This intermediate has been previously used to
synthesize (-)-phenserine,2b which is a drug candidate for treatment
of Alzheimer’s disease.
(11) Except for 4f, which led to about 5% of allylated phenol, no allylation of
the pendant nucleophile nor of the indole nitrogen was detected.
(12) Trost, B. M.; Braslau, R. J. Org. Chem. 1988, 53, 532.
(13) 23 was used to assign the absolute configuration of 2 and, by extension,
of all indolenines and indolines. Matsuura, T.; Overman, L. E.; Poon, D.
J. J. Am. Chem. Soc. 1998, 120, 6500.
(14) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647-2656.
In summary, we have developed a new enantioselective C-3
allylation of 3-substituted indoles to give the corresponding 3,3-
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