Enantioselective organocatalytic cyclopropanations. The identification of a new class of iminium catalyst based upon directed electrostatic activation

Article abstract of DOI:10.1021/ja042774b

A new method for enantioselective organocatalytic cyclopropanation is described. This study outlines the identification of a new class of iminium catalyst based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide and enal substrates through a proposed electrostatic activation and stereodirected protocol. Formation of trisubstituted cyclopropanes with high levels of enantio- and diastereoinduction is accomplished for a variety of α,β-unsaturated aldehydes and sulfonium ylides. In addition, mechanistic studies have found that this cyclopropanation reaction exhibits enantioselectivity and reactivity profiles that are in accord with the proposed DEA step. Copyright

Full text of DOI:10.1021/ja042774b

Published on Web 02/18/2005
Enantioselective Organocatalytic Cyclopropanations. The Identification of a
New Class of Iminium Catalyst Based upon Directed Electrostatic Activation
Roxanne K. Kunz and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received December 1, 2004; E-mail: dmacmill@caltech.edu
8
With representation in more than 4000 natural isolates and 100
therapeutic agents, the cyclopropane motif has long been established
as a valuable platform for the development of new asymmetric
reactivity patterns, we developed a mechanistic postulate based
upon the concept of directed electrostatic activation (DEA).
Specifically, we rationalized that the proline-derived iminium 5 and
the ylide 1 might readily engage in electrostatic association via
their pendant carboxylate and thionium substituents. In doing so,
the ylide carbanion and the iminium â-carbon would be transiently
activated while in close proximity, thereby facilitating carbon-
carbon bond formation. Furthermore, we assume that the zwitterion
5 can readily populate both E and Z iminium isomers, a configu-
1
technologies. Within the realm of metal catalysis, cyclopropane
formation has been accomplished using a vast array of organo-
1,2
metallic carbenoids, while asymmetric organocatalytic cyclopro-
panations using catalyst-bound ylides have been pioneered by
Aggarwal3 and Gaunt.4 Surprisingly, however, enantioselective
cyclopropanation based upon the activation of olefin substrates has
5
6a,d
yet to be accomplished with either metal or organic catalysts.
rational equilibrium that typically leads to diminished enantio-
Having established the capacity of chiral amines to catalyze a wide
variety of asymmetric transformations using unsaturated aldehydes,6
we recently sought to extend this olefin-activation platform to the
production of three-membered carbocyclic rings. In this context,
we outline a highly efficient protocol for the construction of
enantioenriched cyclopropanes using stabilized ylides with dihy-
droindole catalysts. As part of these studies we also propose a new
stereoinduction concept for organocatalysis that we term directed
electrostatic activation.
control (eq 2). Consistent with our observations, iminium systems
derived from imidazolidinones 2 and 3 are electronically averse to
thionium association and as such are unable to participate in this
electrostatic activation.
Within this mechanistic framework, we rationalized that 2-car-
boxylic acid dihydroindole 6 might function as a useful DEA
cyclopropanation catalyst. Specifically, we anticipated that the
catalyst-derived zwitterion 7 would predominately populate the (Z)-
iminium isomer to minimize van der Waals interactions between
the substrate olefin and the aryl hydrogen. As a result, the
carboxylate group on the catalyst framework would direct ylide
addition selectively to the Re face of the activated olefin, thereby
ensuring enantiocontrol (eq 3). As revealed in eq 4, this catalyst
design plan was successful to furnish the accordant cyclopropane
with excellent levels of induction (94% ee) and reaction efficiency
(78% conversion).
In 1965, E. J. Corey described the propensity of stabilized ylides
to participate in cyclopropanation in lieu of epoxidation with
ambiphilic electrophiles such as R,â-unsaturated aldehydes and
7
ketones. With this chemoselectivity profile in mind, we initiated
our enal-cyclopropanation studies with dimethylphenylacyl sul-
fonium ylide 1 and a variety of chiral amine catalysts (eq 1). Given
the capacity of imidazolidinones to catalyze a diverse range of
hydrogenation6 and conjugate
e
6c,d
and cycloaddition
6a,b
reactions,
we were disappointed to find that the iminium species derived from
catalysts 2 and 3 were inert to the ylide 1 (0% conversion). To our
further surprise, the use of catalytic proline provided good levels
of reaction efficiency (72% conversion) albeit with moderate
enantiocontrol (46% ee). In an effort to reconcile these atypical
3240
9
J. AM. CHEM. SOC. 2005, 127, 3240-3241
10.1021/ja042774b CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Evidence for Proposed DEA Mechanism
Table 1. Scope of Organocatalytic Ylide-Cyclopropanation
framework, a step that removes the possibility of iminium formation,
leads to a complete loss of catalytic activity (see catalyst 8). We
have also found a trend toward increased rates and enantiocontrol
as the polarity of the solvent is decreased. These results are
consistent with the proposed DEA mechanism wherein substrate
activation and π-facial delivery are accelerated by ionic interactions
between the ylide and catalyst without substrate stabilization by
the reaction medium. Furthermore, O-methylation of the carboxylic
dihydroindole is found to suppress catalyst function (see catalyst
9), again consistent with the need for a zwitterionic iminium. Last,
the sense of asymmetric induction observed in all cases was
anticipated by this electrostatic model.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen and
Merck. R.K.K. is grateful for an NIH postdoctoral fellowship (5
F32 GM 066595-02).
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
1
b
Diastereoselectivity determined by GLC or HNMR analysis. Deter-
c
mined by chiral GLC analysis. Reaction was conducted at 4 °C.
Experiments that probe the scope of this new organocatalytic
ylide cyclopropanation are summarized in Table 1. Significant
latitude in the steric demands of the R,â-unsaturated aldehyde
References
(
1) For a superb review on stereoselective cyclopropanations, see: Lebel,
H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103,
977.
component is possible (entries 1-6, R
>
1
) Me, Pr, i-Bu, Ph; dr
19:1, 89-96% ee). Moreover, high levels of asymmetric
induction are available with enals that do not readily participate in
iminium formation (entry 2, R ) CH OAllyl, 77% yield, 91% ee),
as well as aldehydes that provide stable iminium intermediates
entry 5, R ) Ph, 73% yield, 89% ee). Structural variation in the
(
2) (a) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001,
123, 12168. (b) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong,
N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897. (c) Nishiyama, H.;
Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc. 1994,
116, 2223. (d) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M.
M. J. Am. Chem. Soc. 1991, 113, 726.
9
1
2
(
(
(
(
3) Aggarwal, V. K.; Alsono, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni,
(
1
M. Angew. Chem., Int. Ed. 2001, 40, 1433.
4) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2004, 43, 4641.
ketone ylide component can also be realized (Table 1). The
electronic nature of the aryl ring of phenylacyl ylides has apparently
little influence on the stereochemical outcome (entries 1, 7, and 8,
5) For elegant work on metal-mediated enantioselective cyclopropanations,
see: Mamai, A.; Madalengoita, J. S. Tetrahedron Lett. 2000, 41, 9009.
6) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2000, 122, 9874. (c) Paras, N. A.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2001, 123, 4370. (d) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (e) Ouellet, S. G.; Tuttle,
J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32-33.
7) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. (b)
Payne, G. B. J. Org. Chem. 1967, 32, 3351.
92-96% ee). Moreover, sterically encumbered ylides are readily
tolerated (entry 9, R ) COtBu, 95% ee).
2
We next performed experiments to test the validity of the
proposed DEA mechanism (Scheme 1). The observation that this
cyclopropanation can be conducted with enals but not electron-
deficient olefins, such as unsaturated nitrile, nitro, or alkylidene
malonate systems, lends support for an iminium-mediated pathway
(
(8) Proline is typically a poor catalyst for iminium-activated processes.
(9) Entry 1 has been performed on a 1 mmol scale (88% yield, 95% ee).
(eq 5). Moreover, N-methylation of the carboxylic dihydroindole
JA042774B
J. AM. CHEM. SOC.
9
VOL. 127, NO. 10, 2005 3241