ORGANIC
LETTERS
2011
Vol. 13, No. 15
4056–4059
A New Synthesis of Pyrrolidines by Way of
an Enantioselective Mannich/
Diastereoselective Hydroamination
Reaction Sequence
Jenny M. Baxter Vu and James L. Leighton*
Department of Chemistry, Columbia University, New York, New York 10027,
United States
Received June 10, 2011
ABSTRACT
A new two-step synthesis of highly substituted pyrrolidines has been developed. Chiral silane Lewis acid promoted enantioselective Mannich
reactions of silyl ketene imines with acylhydrazones may be used to access bishomoallylic benzoic hydrazides that in turn may be cyclized to
pyrrolidines by way of the thermal hydroamination reaction reported recently by Beauchemin. Importantly, excellent diastereoselectivity may be
realized in the hydroamination reactions.
The development of experimentally simple, efficient,
and highly enantioselective methods to synthesize chiral
pyrrolidines is an important goal for chemical synthesis.
While great strides have recently been made in the devel-
opment of enantioselective azomethine ylide cycloaddition
reactions,1 this approach has significant limitations in
scope, and there is a continuing need for new methods to
access a greater range of pyrrolidine structures, especially
those with a high degree of substitution. Beauchemin and
co-workers recently reported that bishomoallylic benzoic
hydrazides may be converted to pyrrolidines by way of a
thermal hydroamination reaction,2 and because our acyl-
hydrazone-silane Lewis acid platform provides access to a
structurally diverse array of benzoic hydrazides,3 the cou-
pling of these two processes seemed a worthwhile pursuit
(Scheme 1A). Realization of this idea would require (1) an
enantioselective hydrazone addition reaction that would
lend itself to the synthesis of highly substituted bisho-
moallylic benzoic hydrazides and (2) the development of
diastereoselective variants of the hydroamination reaction,
ꢀ
(1) (a) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44,
6272. (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106,
ꢀ
4484. (c) Pellissier, H. Tetrahedron 2007, 63, 3235. (d) Najera, C.;
Sansano, J. M. Chem. Rev. 2007, 107, 4584. (e) Stanley, L. M.; Sibi,
ꢀ
~
M. P. Chem. Rev. 2008, 108, 2887. (f) Alvarez-Corral, M.; Munoz-
Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174. (g) Patil,
N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(4) For early studies on the generation of silyl ketene imines and their
use in reactions with electrophiles, see: (a) Gornowicz, G. A.; West, R. J.
Am. Chem. Soc. 1971, 93, 1714. (b) Watt, D. S. Synth. Commun. 1974, 4,
127. (c) Cazeau, P.; Llonch, J.-P.; Simonin-Dabescat, F.; Frainnet, E.
J. Organomet. Chem. 1976, 105, 145. (d) Cazeau, P.; Llonch, J.-P.;
Simonin-Dabescat, F.; Frainnet, E. J. Organomet. Chem. 1976, 105,
(2) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky, S. I.; Whipp,
C. J.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740.
(3) (a) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004,
126, 5686. (b) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem.
Soc. 2005, 127, 2858. (c) Shirakawa, S.; Lombardi, P. J.; Leighton, J. L.
J. Am. Chem. Soc. 2005, 127, 9974. (d) Notte, G. T.; Leighton, J. L. J.
Am. Chem. Soc. 2008, 130, 6676. (e) Valdez, S. C.; Leighton, J. L. J. Am.
Chem. Soc. 2009, 131, 14638. (f) Lee, S. K.; Tambar, U. K.; Perl, N. R.;
Leighton, J. L. Tetrahedron 2010, 66, 4769. (g) Notte, G. T.; Baxter Vu,
J. M.; Leighton, J. L. Org. Lett. 2011, 13, 816.
€
157. (e) Meier, S.; Wurthwein, E.-U. Chem. Ber 1990, 123, 2339.
(5) For two recent examples of the use of silyl ketene imines in
asymmetric reactions, see: (a) Mermerian, A. H.; Fu, G. C. Angew.
Chem., Int. Ed. 2005, 44, 949. (b) Denmark, S. E.; Wilson, T. W.; Burk,
M. T.; Heemstra, J. R., Jr. J. Am. Chem. Soc. 2007, 129, 14864.
r
10.1021/ol201566u
Published on Web 07/12/2011
2011 American Chemical Society