Published on Web 06/24/2010
Dynamic Kinetic Asymmetric Synthesis of Substituted
Pyrrolidines from Racemic Cyclopropanes and Aldimines:
Reaction Development and Mechanistic Insights
Andrew T. Parsons, Austin G. Smith, Andrew J. Neel, and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290
Received February 5, 2010; E-mail: jsj@unc.edu
Abstract: An enantioselective preparation of 2,5-cis-disubstituted pyrrolidines has been achieved via a
dynamic kinetic asymmetric transformation (DyKAT) of racemic donor-acceptor cyclopropanes and (E)-
aldimines. Mechanistic studies suggest that isomerization of the aldimine or resultant iminium to the Z
geometry is not a pathway that furnishes the observed 2,5-cis-disubstituted products.
Introduction
(3 + 2) annulations with D-A cyclopropanes 1, yielding
pyrrolidines of type 3.6 A range of diastereoselectivities was
Nitrogen-containing heterocycles are abundant in naturally
occurring and pharmaceutically relevant molecules.1 In
particular, substituted pyrrolidine derivatives are ubiquitous,
and their value is reflected by continued interest in the
development of methods for their preparation.2,3 Efforts in
our lab4 and others5-7 have focused on the asymmetric
synthesis of hetero- and carbocycles via ring-opening reac-
tions of strained donor-acceptor (D-A) cycloalkanes. We
recently reported a dynamic kinetic asymmetric transforma-
tion (DyKAT) of racemic 1,1-cyclopropanediesters (1) via
(pybox)MgI2-catalyzed (3 + 2) annulation with aldehydes
to afford 2,5-cis-disubstituted tetrahydrofurans in a highly
enantioselective manner.4f This article describes the asym-
metric synthesis of pyrrolidines from racemic cyclopropanes
and (E)-aldimines (eq 1) and experiments that reveal a
surprising mechanistic dichotomy with the extant cyclopro-
pane/aldehyde annulations.
observed, depending on the aldimine protecting group (PG), with
an N-benzyl group providing the greatest levels of 2,5-cis
diastereoselectivity. These observations led us to focus our early
efforts on enantioselective annulation of 1a with (E)-N-
benzylidene-1-phenylmethanamine (2a) catalyzed by L1·MgI2
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Results and Discussion
Independent reports by Kerr and Tang demonstrated that (E)-
aldimines are competent dipolarophiles in Lewis acid-catalyzed
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9688 J. AM. CHEM. SOC. 2010, 132, 9688–9692
10.1021/ja1032277 2010 American Chemical Society