ORGANIC
LETTERS
2007
Vol. 9, No. 10
1847-1850
Enantioselective Organocatalytic
Intramolecular Ring-Closing
Friedel−Crafts-Type Alkylation of Indoles
Chang-Feng Li, Hiu Liu, Jie Liao, Yi-Ju Cao, Xiao-Peng Liu, and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal UniVersity, 152 Luoyu Road, Wuhan, Hubei,
430079, China
Received February 7, 2007 (Revised Manuscript Received April 3, 2007)
ABSTRACT
An enantioselective organocatalytic intramolecular ring-closing Friedel−Crafts-type alkylation of indolyl
r,
â
-unsaturated aldehydes has been
developed. This powerful new strategy allows enantioselective access to THPIs and THBCs in a straightforward and atom-economical manner.
Catalytic transformations of direct C-H bond functional-
ization involving the indole framework are still a challenging
area of intense interest and would be particularly attractive
to both academic and industrial chemists.1 Over the past few
years, considerable research efforts have been directed toward
the development of new and efficient catalytic routes to
polycyclic indoles through both Lewis acid and transition-
metal-catalyzed intramolecular alkylations of indoles (IMAI),2,3
among which high levels of enantiocontrol are achieved in
some cases.2a,d,3h,i Surprisingly, however, organocatalytic
IMAI has remained largely unexplored. Only chiral thiourea
and phosphoric acid catalyzed Pictet-Spengler reactions
have been reported by Jacobsen4 and List,5 respectively, to
the best of our knowledge. In addition, few catalytic
asymmetric transformations have been developed to prepare
tetrahydropyrano[3,4-b]indoles (THPIs), although this ring
system has become widely identified as a common structural
component of a broad range of naturally occurring and
biologically active molecules.1d,6 These facts have stimulated
us to explore an enantioselective organocatalytic IMAI,
which could be employed as a general approach to enantio-
riched polycyclic indoles.
With the development of MacMillan’s LUMO-lowering
activation of R,â-unsaturated aldehydes, a wide range of
(3) For selected transition-metal-catalyzed procedures, see: (a) Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (b) Liu, C.; Han,
X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700. (c)
Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250. (d) Youn,
S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (e) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199. (f) Zhang, Z.;
Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2006, 128, 9066. (g) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi,
R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424.
(h) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801.
(1) For lead references, see: (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19,
773. (b) Bandini, M.; Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J.
Org. Chem. 2006, 3527. (c) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert,
D. Pharmaceutical Substances, 4th ed.; Thieme: New York, 2001. (d)
Sundberg, R. J. Indoles; Academic Press: San Diego, 1996.
(2) For selected Lewis acid catalyzed procedures, see: (a) Yamada, H.;
Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M.
J. Org. Chem. 1998, 63, 6348. (b) Agnusdei, M.; Bandini, M.; Melloni,
A.; Umani-Ronchi, A. J. Org. Chem. 2003, 68, 7126. (c) Kinderman, S.
S.; Wekking, M. M.; Maarseveen, T. J. H.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519. (d) Evans, D. A.;
Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (e) Angeli,
M.; Bandini, M.; Garelli, A.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi,
A. Org. Biomol. Chem. 2006, 4, 3291.
(4) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
(5) (a) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086. For other typical organocatalytic cyclizations developed by the List
group, please see: (b) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2003, 42, 2785. (c) Fonseca, M. T. H.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 3958. (d) Vignola, N.; List, B. J. Am. Chem. Soc.
2004, 126, 450.
(6) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 187 and references
cited therein.
10.1021/ol0703130 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/12/2007