COMMUNICATION
DOI: 10.1002/chem.200902449
Enantioselective Michael Addition to a,b-Unsaturated Aldehydes:
Combinatorial Catalyst Preparation and Screening, Reaction Optimization,
and Mechanistic Studies
Ivana Fleischer and Andreas Pfaltz*[a]
Organocatalysis is one of the fastest growing fields of cur-
rent research in organic chemistry.[1] Many of the known or-
ganocatalysts are readily prepared and easily modified,
making it possible to synthesize large catalyst libraries with-
out too much effort. Therefore, considerable efforts have
been made to develop efficient screening methods for cata-
lyst development and optimization.[2] We have recently re-
ported a new screening method for chiral catalysts, based on
mass-labeled quasi-enantiomeric substrates and electrospray
mass spectrometry (ESI-MS).[3–5] This method allows the de-
termination of the intrinsic enantioselectivity of a catalyst
by mass spectrometric monitoring of catalytic intermediates.
In contrast to conventional screening methods, which are
based on product analysis, simultaneous screening of cata-
lyst mixtures in homogeneous solution is possible. As we
have shown, our method allows rapid screening of chiral or-
ganocatalysts for Diels–Alder reactions.[4d,5]
Herein, we report the successful application of our meth-
odology to the organocatalyzed Michael reaction of malo-
nates 2 to a,b-unsaturated aldehydes 1 (Scheme 1).[6,7] Based
on the principle of microscopic reversibility, it is possible to
determine the enantioselectivity of a catalyst by screening
the intermediates in the retro-Michael reaction of a pair of
quasienantiomeric Michael adducts 3a and 3b.[8] Because
the transition states of the forward and back reaction are
identical, the ratio of the signal intensities of intermediates
6a and 6b with masses Ma and Mb reflects the enantioselec-
tivity of the catalyst.
ture of Et- and iPr-substituted quasi-enantiomers 3a and 3b
and a catalyst (10 mol%) in a 1:9 CH2Cl2/EtOH mixture
was stirred for 5 min, then diluted with MeCN and analyzed
by ESI-MS. The signals of the iminium derivatives of the
Michael adducts 5a and 5b and the retro-Michael products
6a and 6b were clearly visible in the spectra (Scheme 1).
Because the reaction is reversible, it is important to take
samples after a short time, as longer reaction times will
result in racemization of the quasi-enantiomeric Michael ad-
ducts. Several very selective catalysts were identified, with
the TBDMS derivative 4d being the catalyst of choice. The
results were validated both by screening of the inversely la-
beled quasi-enantiomers and by comparison with the prepa-
rative forward reaction under the same conditions (Table 1,
column A). Preparative reactions were also carried out at
08C (Table 1, column B) and under these conditions, enan-
tiomeric ratios of ꢀ99:1 were obtained with catalysts 4d
and 4e. As a further control, both enantiomers of catalysts
4a and 4d were tested and, as expected, they gave identical
results within the margin of error.[10] No intermediates were
observed in the reaction with catalyst 4 f, possibly due to the
formation of an inactive cyclic species.
Based on the above concept, ESI-MS screening of differ-
ent prolinol-derived organocatalysts 4a–f and 8,[9a,b] and imi-
dazolidinone 7[9c] was conducted (see Table 1). A 1:1 mix-
This procedure was then extended to multi-catalyst
screening.[11] To demonstrate the potential of our method
for combinatorial catalyst development, we synthesized a
small library of six catalysts in three steps without isolation
of the intermediates and purification of the resulting proline
derivatives 4b, 4d, 4h, 4j, and 4g/4h, which were formed as
mixtures of diastereomers (Scheme 2). Grignard reaction
[a] I. Fleischer, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
Supporting information for this article is available on the WWW
Chem. Eur. J. 2010, 16, 95 – 99
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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