The Mannich reaction of malonates with simple imines catalyzed by bifunctional cinchona alkaloids: Enantioselective synthesis of β-amino acids

Article abstract of DOI:10.1021/ja060716f

We describe the first efficient, direct asymmetric Mannich reactions with malonates and N-Boc aryl and alkyl imines by cooperative hydrogen-bonding catalysis with a cinchona alkaloid bearing a thiourea functionality. We have also extended the scope of thi

Full text of DOI:10.1021/ja060716f

Published on Web 04/18/2006
The Mannich Reaction of Malonates with Simple Imines Catalyzed by
Bifunctional Cinchona Alkaloids: Enantioselective Synthesis of
â-Amino Acids
Jun Song, Yi Wang, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received January 30, 2006; E-mail: Deng@brandeis.edu
Enantioselective Mannich reactions1 are of fundamental impor-
tance to the synthesis of optically active chiral amines. Significant
progress has been made in the development of efficient chiral metal
and organic catalysts for enantioselective Mannich reactions with
preactivated enolate nucleophiles such as enolsilane2 and enolizable
carbonyl nucleophiles such as â-keotesters3a-c and 1,3-diketones.3d
Highly enantioselective, direct Mannich reactions with aldehydes
and ketones have also been accomplished with chiral secondary
amines and chiral metal complexes.4 However, a highly enantio-
Figure 1. C6′ or C9 thiourea cinchona alkaloid derivatives.
selective Mannich reaction of malonates with simple imines5
Table 1. Cinchona Alkaloid-Catalyzed Addition of Dimethyl
remains elusive; although, if successfully promoted with a practi-
cally accessible chiral catalyst under air- and moisture-tolerant
conditions, it could provide a highly attractive, convergent approach
toward optically active â-amino acids suitably protected for further
synthetic elaborations.6,7 The realization of such a direct Mannich
reaction is particularly challenging as it involves the combination
of a weakly reactive imine and a carbonyl nucleophile that is,
relative to 1,3-diketones and â-ketoesters, harder to enolize and
unsuitable for chiral enamine catalysis.5 Herein, we wish to describe
the application of cooperative hydrogen-bonding catalysis to
develop a cinchona alkaloid-catalyzed, highly enantioselective
Mannich reaction with malonates and N-Boc imines.
Malonate (5a) to N-Boc-imine (4D)a
Chiral hydrogen-bond donors such as chiral thioureas and
phosphoric acid have been identified as effective catalysts for the
activation of simple imines toward various enantioselective nu-
cleophilic additions8 including Mannich reactions with enolsilane2e,f
and 1,3-diketones.3d On the other hand, chiral hydrogen-bond
acceptors such as cinchona alkaloids were shown to be effective
for the activation of malonates for enantioselective conjugate
additions.9 These observations led us to envision that cinchona
alkaloid derivatives bearing a thiourea functionality8j,10 might act
as efficient bifunctional catalysts for a Mannich reaction of
malonates with simple imines.
a Unless noted, reactions were run with 0.05 mmol of 4D, 0.15 mmol of
5a in 0.10 mL of solvent with 10 mol% catalyst for 16 h. b Cinchona
alkaloids bearing no thiourea functionality afforded moderate ee, see
Supporting Information for detail. c Determined by 1H NMR analysis.
d Determined by HPLC analysis. e Reaction was run with Q-1d (20 mol%)
at -60 °C for 24 h.
Accordingly, we initiated a study of cinchona alkaloid derivatives
bearing either a 6′- or 9-thiourea functionality (Figure 1) as catalysts
for the addition of dimethyl malonate 5a to the N-Boc-protected
imine 4D in dichloromethane. As summarized in Table 1, 6′- or
9-thiourea cinchona alkaloids bearing an electron-withdrawing aryl
substituent emerged as the most effective catalysts. The Mannich
reaction with catalysts Q-1d and 3 took place in 77% and 72% ee,
respectively (entries 4 and 7). A study of the reaction with the
synthetically more accessible Q-1d in various solvents identified
acetonitrile and acetone as suitable alternatives to dichloromethane
(entries 8 and 9). Interestingly, reactions in these solvents responded
differently to temperature change. For reactions at -20 °C vs those
at room temperature, the enantioselectivity was slightly increased
in dichloromethane but decreased noticeably in acetonitrile. A more
pronounced positive temperature effect on the enantioselectivity
was observed in acetone, which led us to a highly enantioselective,
completed reaction of 4D with 5a at -60 °C (entry 13).
The scope of the enantioselective Mannich reaction catalyzed
by both Q-1d and QD-1d was investigated under the optimized
condition identified above (Table 2). The enantioselectivity of
catalyst 1d was found to be nearly independent of the steric
properties of the aryl imines. Reactions with o-, m-, and p-tolyl
imines (4B-D) in the presence of QD-1d took place in 97-99%
ee. Exceedingly high enantioselectivity could also be obtained for
a variety of heteroaryl and aryl imines of varying electronic
properties (4E-L), including electron-rich aryl imines.2f It is
noteworthy that very good enantioselectivity could be attained for
N-Boc alkyl imines, including even R-unbranched alkyl imines
(4M-O).4a Although high loading of QD-1d (100 mol%) was
required to sustain a useful level of enantioselectivity, QD-1d could
be readily recycled in greater than 95% yield. To our knowledge,
the results with 4M-N represent the first highly enantioselective
Mannich reactions with N-Boc R-unbranched alkyl imines (entries
9
6048
J. AM. CHEM. SOC. 2006, 128, 6048-6049
10.1021/ja060716f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Mannich Reaction of Malonate 5 to
N-Boc-imine 4 Catalyzed by QD-1d and Q-1d (in parentheses)a
Acknowledgment. We are grateful for the generous financial
support from National Institutes of Health (GM-61591). We are
grateful to Dr. Jeffrey Agar, and Ms. Qi Wang and Mr. Murat
Karabacak for HRMS analysis
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a Unless noted, reactions were run with 4 (0.20 mmol) and 5 (0.30 mmol)
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13-14). Catalyst 1d also tolerated malonates of different bulk. This
allows the conversion of amine 6 to â-amino acid 7 without using
strongly acidic or basic conditions (Scheme 1).
The 1d-catalyzed Mannich reaction is also applicable to â-keto-
esters (Table 3).3a-c Importantly, steric variations of the keto
substituent are readily accepted by catalyst 1d, thereby allowing
the Mannich reaction to provide access to a wide variety of optically
active â-amino ketones.
In conclusion, by exploring cooperative hydrogen-bonding
catalysis with a readily accessible bifunctional cinchona alkaloid
catalyst,9-11 we have developed a highly enantioselective direct
Mannich reactions of N-Boc aryl and alkyl imines with malonates
and â-ketoesters.12 This leads to the establishment of a convergent
enantioselective synthesis of N-Boc â-amino acids from readily
available starting materials under mild, moisture- and air-compatible
conditions.
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J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006 6049