Dynamic kinetic asymmetric synthesis of substituted pyrrolidines from racemic cyclopropanes and aldimines: Reaction development and mechanistic insights

Article abstract of DOI:10.1021/ja1032277

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.

Full text of DOI:10.1021/ja1032277

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
(4) (a) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057. (b)
Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014.
(c) Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573. (d) Parsons,
A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541. (e)
Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 8642. (f) Parsons, A. T.; Johnson, J. S.
J. Am. Chem. Soc. 2009, 131, 3122. (g) Sanders, S. D.; Ruiz-Olalla,
A.; Johnson, J. S. Chem. Commun. 2009, 5135. (h) Campbell, M. J.;
Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 10370. (i) Parsons, A. T.;
Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 14202.
(5) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Sugita, Y.; Kawai,
K.; Yokoe, I. Heterocycles 2000, 53, 657. (c) Sugita, Y.; Kawai, K.;
Yokoe, I. Heterocycles 2001, 55, 135. (d) England, D. B.; Kuss,
T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704.
(e) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312. (f)
Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023. (g)
Cardona, F.; Goti, A. Angew. Chem., Int. Ed. 2005, 44, 7832. (h)
Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de
Meijere, A. J. Org. Chem. 2007, 72, 7504. (i) Bajtos, B.; Yu, M.;
Zhao, H. D.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631. (j)
Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org.
Lett. 2008, 10, 689. (k) Ivanova, O. A.; Budynina, E. M.; Grishin,
Y. K.; Trushkov, I. G.; Vereletskii, P. V. Angew. Chem., Int. Ed. 2008,
47, 1107. (l) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr,
M. A. J. Am. Chem. Soc. 2008, 130, 4196. (m) Ivanova, O. A.;
Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V.
Eur. J. Org. Chem. 2008, 5329. (n) Sapeta, K.; Kerr, M. A. Org. Lett.
2009, 11, 2081. (o) Lebold, T. P.; Kerr, M. A. Org. Lett. 2009, 11,
4354. (p) Lebold, T. P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009,
11, 3770. (q) Qu, J.-P.; Deng, C.; Zhou, J.; Sun, X.-L.; Tang, Y. J.
Org. Chem. 2009, 74, 7684. (r) Chagarovskiy, A. O.; Budynina, E. M.;
Ivanova, O. A.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V.
Tetrahedron 2009, 65, 5385. (s) Yadav, J. S.; Reddy, B. V. S.;
Narasimhulu, G.; Chandrakanth, D.; Satheesh, G. Synthesis 2009, 3443.
(t) Leduc, A. B.; Lebold, T. P.; Kerr, M. A. J. Org. Chem. 2009, 74,
8414. (u) Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2010,
49, 1133. (v) Wu, L.; Shi, M. Chem.sEur. J. 2010, 16, 1149. (w)
Xing, S. Y.; Pan, W. Y.; Liu, C.; Ren, J.; Wang, Z. W. Angew. Chem.,
Int. Ed. 2010, 49, 3215.
Results and Discussion
Independent reports by Kerr and Tang demonstrated that (E)-
aldimines are competent dipolarophiles in Lewis acid-catalyzed
(1) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(2) For a recent review of the stereoselective preparation of substituted
pyrrolidines, see: Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV.
2006, 106, 4484.
(3) For selected examples, see: (a) Pichon, M.; Figade`re, B. Tetrahedron:
Asymmetry 1996, 7, 927. (b) Cabrera, S.; Arrayas, R. G.; Carretero,
J. C. J. Am. Chem. Soc. 2005, 127, 16394. (c) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213. (d) Wolfe, J. P. Eur. J. Org. Chem. 2007,
571. (e) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem.
Soc. 2008, 130, 17250.
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9688 J. AM. CHEM. SOC. 2010, 132, 9688–9692
10.1021/ja1032277  2010 American Chemical Society

Dynamic Kinetic Asymmetric Synthesis of Substituted Pyrrolidines
A R T I C L E S
a
t
Table 1. Evaluation of Substituted N-Benzyl Aldimine Protecting
Table 2. Evaluation of 4-Substituted Bu-pybox Ligands
Groupsa
a Conditions: 1a (1.0 equiv), 2i (1.1 equiv), MgI2 (0.10 equiv), L
(0.12 equiv), [1a]0 ) 0.05 M in CCl4, rt, 24 h. b Determined by 1H
NMR spectroscopy using a mesitylene internal standard. c Determined
by 1H NMR spectroscopy. d Determined by chiral SFC analysis.
e Average isolated yield of two independent trials. f The value in
parentheses refers to conversion of 1a.
We proceeded to examine the effect of the benzyl PG on the
enantioselectivity. Alkoxy-substituted benzyl groups were evalu-
ated, with 2-methoxybenzyl- and 2-isopropoxybenzyl-protected
aldimines (2c and 2h, respectively) providing the highest yield
and stereoselectivity (Table 1, entries 4 and 9). Since the parent
2-methoxybenzylamine is commercially available, we chose to
proceed with 2-methoxybenzyl-protected aldimine dipolaro-
philes. It is noteworthy that the free pyrrolidine can be revealed
by removal of the 2-methoxybenzyl group under hydrogenolytic
conditions (eq 2).10
a Conditions: 1a (1.0 equiv), aldimine (1.1 equiv), MgI2 (0.10 equiv),
4-Cl-tBu-pybox (L1, 0.12 equiv), [1a]0 ) 0.05 M in CCl4, rt, 24 h.
b Determined by 1H NMR spectroscopy using a mesitylene internal
standard. c Determined by 1H NMR spectroscopy. d Determined by
chiral supercritical fluid chromatography (SFC) analysis. e Using 2.0
equiv of the aldimine.
(L1 ) 4-Cl-tBu-pybox).8,9 Under our previously reported
reaction conditions, pyrrolidine 3aa was obtained in 83% yield
and 85.5:14:5 er (Table 1, entry 1). An increase in er to 91:9
was achieved by decreasing the amount of aldimine from 2.0
to 1.1 equiv, although a notable decrease in yield occurred.
(6) (a) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242. (b)
Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4, 299.
(7) For enantioselective transformations of racemic D-A cyclopropanes,
see: (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005,
127, 5764. (b) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem., Int.
Ed. 2007, 46, 3918.
(8) For examples of 4-substituted pybox ligands used in asymmetric
transformations, see: (a) Nishiyama, H.; Yamaguchi, S.; Kondo, M.;
Itoh, K. J. Org. Chem. 1992, 57, 4306. (b) Park, S.-B.; Murata, K.;
Matsumoto, H.; Nishiyama, H. Tetrahedron: Asymmetry 1995, 6, 2487.
(c) Clark, J. S.; Clarke, M.-R.; Clough, J.; Blake, A. J.; Wilson, C.
Tetrahedron Lett. 2004, 45, 9447. (d) Wang, H.; Wang, H.; Liu, P.;
Yang, H.; Xiao, J.; Li, C. J. Mol. Catal. A: Chem. 2008, 285, 128. (e)
Reference 4f. (f) Karimi, B.; Maleki, A. Chem. Commun. 2009, 5180.
We have found that the tert-butyl substituent is optimal for chiral
recognition of malonyl cyclopropanes. See: (g) Parsons, A. T. Ph.D.
Thesis, University of North Carolina, 2010.
(9) For MgI2-catalyzed annulations of aldimines and cyclopropanes, see:
(a) Reference 5a. (b) Fischer, C.; Meyers, C.; Carreira, E. M. HelV.
Chim. Acta 2000, 83, 1175. (c) Lerchner, A.; Carreira, E. M. J. Am.
Chem. Soc. 2002, 124, 14826. (d) Meyers, C.; Carreira, E. M.
Angew. Chem., Int. Ed. 2003, 42, 694.
Having determined a suitable protecting group, we continued
the reaction optimization by examining various 4-X-tBu-pybox
ligands. In our previous studies with aldehydes, highly electron-
rich dipolarophiles proved to be challenging substrates because
of a decrease in enantioselectivity of the transformation. Thus,
electron-rich aldimine 2i was chosen as the dipolarophile in a
screen of 4-X-tBu-pybox ligands. 4-Br-tBu-pybox (L2) provided
the highest yield and er of pyrrolidine 3ai (Table 2, entry 2),
which is in contrast to the aldehyde system, where L1 (X )
(10) Onomura, O.; Kirira, P. G.; Tanaka, T.; Tsukaka, S.; Matsumara, Y.;
Demizu, Y. Tetrahedron 2008, 64, 7498.
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A R T I C L E S
Table 3. Aldimine and Cyclopropane Substrate Scopea b
Parsons et al.
,
Scheme 1. Previously Proposed Stereochemical Models for
Aldehyde/Cyclopropane and Aldimine/Cyclopropane Annulation
doequatorial) in an envelope-type transition state (5 in Scheme
1).6 Such an arrangement would be analogous to the all-
equatorial transition structure 6 that has been invoked for THF-
forming cyclopropane/aldehyde annulations.4 For the all-
equatorial transition structure 5 to be viable in the present case,
the aldimine must exhibit fluxional geometric behavior (E/Z
isomerization) at some point during the reaction.
Experiments that directly probe the aldimine geometric
stability are illustrated in eqs 3 and 4. We selected (Z)-aldimine
2n as a reaction partner that, through cyclic constraint, would
preclude E/Z isomerization. Strikingly, Lewis acid-catalyzed
annulation of 2n12 and cyclopropane 1a delivered pyrrolidine
(3an) exclusively as the 2,5-trans isomer with negligible
enantioenrichment (diastereoselection >20:1, er 55.5:44.5) (eq
3). Conversely, the minor 2,5-trans adduct obtained from
annulation of (E)-aldimine 2c and 1b was produced with high
enantioselectivity (eq 4).
a Conditions:
1 (1.0 equiv), 2 (1.1 equiv), MgI2 (0.10 equiv),
4-Br-tBu-pybox (L2, 0.11 equiv), [1]0 ) 0.05 M in CCl4, rt. b The dr
1
was determined by H NMR spectroscopy to be >92:8, unless otherwise
noted. c Yield refers to the average isolated yield (of the diastereomeric
mixture) of two independent trials. d Determined by chiral SFC analysis.
e The er of the minor (trans) diastereomer was 98:2. f The er was
determined for the major cis diastereomer.
Cl) was the preferred ligand. Furthermore, the range of yields
and stereoselectivities within this class of ligands was quite
broad, with electron-neutral species producing the poorest results
of those examined.
Previous studies have led us4b,e and others5j,13 to propose that
Lewis acid-catalyzed (3 + n) annulations of cyclopropanes 1
proceed via stereospecific nucleophilic attack by the dipolaro-
phile on the donor-substituted site of the cyclopropane, leading
to inversion at that position. Our experiments with the L1·MgI2
complex revealed preferential reaction with cyclopropane (S)-
1.14 The absolute configurations of the pyrrolidine products in
this study are consistent with both of these findings.15 With
respect to diastereoselectivity, the configuration of the C2′
pyrrolidine stereocenter arising via Mannich cyclization may
After the optimized reaction conditions had been identified,
a range of N-2-methoxybenzyl-protected aryl aldimines and
D-A cyclopropanes were subjected to the L2·MgI2 conditions
(Table 3, footnote a). Previous studies had indicated that
electron-rich cyclopropane donor groups are required to achieve
dynamic behavior; thus, cyclopropanes bearing 4-MeOPh (1a),
(E)-CHdCHPh (1b), and 2-thienyl (1c) donor groups were
competent substrates.11 Electron-rich and -neutral aryl aldimines
of type 2 provided high yields and enantioselectivities (up to
86% yield and 98:2 er; Table 3). Electron-poor aryl, alkenyl,
and aliphatic aldimines were not successful coupling partners,
consistent with Kerr’s observations.6a
(12) Weitzberg, M.; Abu-Shakra, E.; Azeb, A.; Aizenshtat, Z.; Blum, J. J.
Org. Chem. 1987, 52, 529.
(13) (a) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597. (b)
Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72, 10251.
(14) Previous work in our group has shown that dipolarophiles are selective
for nucleophilic attack on the (S)-cyclopropane when (S,S)-4-X-tBu-
pybox·MgI2 is used (see ref 4f.) For cyclopropane 1c, the Cahn-
Ingold-Prelog priorities change because of the thienyl group, so it is
the R enantiomer that is the reactive one. Our allusions to the general
preference of L2·MgI2 for (S)-1 should be understood to mean
selective reaction of (S)-1a, (S)-1b, (R)-1c, and (S)-1d, all of which
possess the same disposition of the C-2 alkyl substituent.
Models that account for the high 2,5-cis-diastereoselectivity
in cyclopropane/aldimine annulations have posited a “meridi-
onal” orientation of the R, Y, and R1 substituents (all pseu-
(11) For annulation results with diisopropyl 2-(4-methoxyphenyl)cyclo-
propane-1,1-dicarboxylate (1d) and dibenzyl 2-(4-methoxyphenyl)cy-
clopropane-1,1-dicarboxylate (1e), see the Supporting Information.
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Dynamic Kinetic Asymmetric Synthesis of Substituted Pyrrolidines
A R T I C L E S
Scheme 2. Mechanistic Proposal To Account for the Observed
2,5-trans Relationship Obtained from Annulation of 1 with
(Z)-Aldimine 2n
Scheme 3. Summary of Observed Substituent and Geometric
Effects in Enantioselective Cyclopropane/Aldehyde Annulation
Scheme 4. Mechanistic Proposal for the Formation of
2,5-cis-Pyrrolidines via Annulation of 1 with (E)-Aldimines
vary as a result of at least two different factors: (a) ring flip
prior to ring closure and (b) iminium isomerization prior to ring
closure. The application of the nonfluxional (Z)-aldimine 2n
allowed us to separately examine (a) and (b), since iminium
isomerization was precluded. In conjunction with the results
from eq 3, the analysis in Scheme 2 reveals that the “meridional”
transition structure 7 resulting from a ring flip is not competitive,
since cis-3an was not observed. Nonbonded steric compression
apparently favors placing R (the C5′ substituent) in the axial
position (transition state 8).
The low enantioselectivity exhibited in eq 3 could arise from
either poor enantiomer discrimination (as a function of nucleo-
phile identity) or inefficient racemization relative to annulation.
We sought to determine the degree of enantiodifferentiation of
the R and S enantiomers of 1 by (Z)-aldimine 2n (eq 5). Because
of its low rate of enantiomer interconversion, cyclopropane 1f
bearing a phenyl donor group is a substrate for simple kinetic
resolution under the (pybox)MgI2 reaction conditions. Reaction
of rac-1f and 2n was carried to partial conversion to furnish
pyrrolidine 3fn as the trans isomer with a moderate level of
enantioenrichment. The recovered 1f was highly enriched in
the R enantiomer. These results indicate that 2n is selective for
reaction with (S)-1f.
(Z)-aldimine is expected to exhibit greater nucleophilicity than
the E isomer because of steric effects. In the reaction of rac-1a
with 2n, this enhanced nucleophilicity means that both (S)-1a
and (R)-1a undergo annulation faster than the enantiomers can
interconvert [k(S), k(R) > kint, kint′]. The results of eq 5 intimate
that the inherent preference exhibited by L2·MgI2 for the (S)-
malonyl cyclopropanes is preserved regardless of the aldimine
geometry [k(S) > k(R)]; therefore, the poor enantioselectivity in
the formation of 3an is a consequence of noncompetitive
substrate racemization rather than poor enantiomer discrimination.
A unified least-motion model for the stereoselective (3 +
2) annulation of 1 and (E)-aldimines is presented in Scheme
4. An attack trajectory that minimizes steric interactions and
maximizes orbital overlap is analogous to that of the (Z)-
aldimine. In contrast to reactions with aldehydes, the nu-
cleophilic lone pair is oriented syn to the Ar group. Counter
to the annulation of 1 with 2n, a 120° rotation of the C2-C3
bond places both R and Ar in pseudoaxial orientations within
the envelope transition state (9), presumably minimizing
steric penalties associated with structures 10 (R T PG) and
11 (Ar T PG). These structures are in accord with precedent
provided by related cyclizations of N-acyl iminium ions.16
The results of eqs 3 and 5 may be collectively understood in
terms of the relative rate constants illustrated in Scheme 3. A
(15) CCDC 773308 and CCDC 773309 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(16) Hart, D. J. J. Am. Chem. Soc. 1980, 102, 397.
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A R T I C L E S
Parsons et al.
Ring closure provides the major 2,5-cis-disubstituted pyrro-
lidines cis-3. Formation of the minor trans adducts (trans-
3) may arise from several as yet indistinguishable pathways:
aldimine isomerization to (Z)-2 prior to alkylation and ring
flip (path a) or iminium isomerization (path b) after alkylation
but prior to ring closure.
chemical observations suggest that the aldimine dipolarophiles
react through the E geometry via the unusual diaxial transition
state 9. Experiments that probe the structure of the cyclopropane/
Lewis acid complex and extend the scope of this reaction family
are underway.
Acknowledgment. This work was supported by the NSF (CHE-
0749691) and Novartis. We thank Dr. Peter S. White for X-ray
crystallographic analysis.
Conclusion
In summary, we have developed an enantioselective synthesis
of 2,5-cis-disubstituted pyrrolidines through a dynamic kinetic
asymmetric (3 + 2) annulation of racemic cyclopropanes and
(E)-aldimines. Careful selection of the substituted N-benzyl
protecting group of the aldimine allowed for an increase in
enantioselectivity as well as selective deprotection of the
pyrrolidine cycloadduct in the presence of other electron-rich
benzyl substituents. Simple mechanistic studies and stereo-
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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