Communications
DOI: 10.1002/anie.200903635
Asymmetric Catalysis
Asymmetric Mannich Reaction of Fluorinated Ketoesters with a
Tryptophan-Derived Bifunctional Thiourea Catalyst**
Xiao Han, Jacek Kwiatkowski, Feng Xue, Kuo-Wei Huang,* and Yixin Lu*
In memory of George Just
Small organic molecules capable of hydrogen-bonding inter-
actions with substrates have found widespread application in
asymmetric catalysis.[1] In particular, thiourea-based organic
molecules have become the most prominent hydrogen-bond-
donor catalysts in a wide variety of organic reactions. In this
context, bifunctional[2] organic molecules containing a tertiary
amino functionality and a thiourea moiety are remarkably
useful organic catalysts.[3] Despite their tremendous utility,
Scheme 1. Thiourea catalyst based on a primary amino acid (trypto-
phan).
these bifunctional catalysts are derived from a very limited
range of chiral structural scaffolds, including cyclohexane-1,2-
diamine, 1,1’-binaphthyl-2,2’-diamine, and cinchona alkaloids.
The development of readily accessible novel bifunctional
catalysts of this nature would be highly desirable. As part of
our research program towards the development of practical
organocatalysts based on primary amino acids,[4] we were
intrigued by the possibility of designing novel tertiary amine–
thiourea catalysts on the basis of simple amino acids. The
facile conversion of natural amino acids into 1,2-diamines and
the availability of structurally diverse side chains make this
method very attractive. To investigate the validity of this
approach, we selected l-tryptophan as the chiral precursor.
We reasoned that the indole moiety would be capable of
engaging in aromatic and hydrogen-bonding interactions with
substrates, and these effects may result in efficient chiral
induction (Scheme 1).
metal catalysis have been reported;[6] however, organocata-
lytic approaches for the creation of fluorinated quaternary
centers are rather limited.[7] Recently, organocatalytic syn-
thetic methods with fluorinated substrates have become an
alternative and viable option for accessing chiral fluorinated
molecules. In such approaches, racemic fluorinated nucleo-
À
philes are used as substrates. A C C bond is formed rather
À
than a C F bond, and full advantage is taken of the high
electronegativity and small molecular radius of the fluorine
atom. We and others[8] have used fluorinated substrates in this
way in organocatalytic Michael and alkylation reactions for
the construction of fluorinated chiral molecules.
To assess the utility of tryptophan-based bifunctional
catalysts, we chose to focus on the direct asymmetric Mannich
reaction of a-fluorinated b-ketoesters, as such reactions yield
structurally demanding and biologically important a-fluoro-
b-amino acids. Organocatalytic asymmetric Mannich reac-
tions of b-ketoesters and malonates were reported recently by
the research groups of Schaus, Deng, and Dixon, all of whom
employed organic catalysts derived from cinchona alkaloids.[9]
Herein, we report that tryptophan-based bifunctional thio-
urea derivatives promote the asymmetric Mannich reaction of
fluorinated substrates to afford highly optically enriched
fluorine-containing molecules containing adjacent quaternary
and tertiary stereocenters.
Fluorinated molecules are of high importance in the
pharmaceutical industry, and their asymmetric preparation
has drawn great attention.[5] The catalytic construction of
fluorinated quaternary carbon stereocenters is a formidable
synthetic challenge. A number of excellent methods based on
[*] X. Han, J. Kwiatkowski, Prof. Dr. F. Xue, Prof. Dr. K.-W. Huang,
Prof. Dr. Y. Lu
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: (+65)6779-1691
E-mail: hkw@nus.edu.sg
We selected the Mannich reaction of a-fluoro-b-ketoester
1a with N-Boc imine 2a[10] as a model reaction and examined
the catalytic effects of various bifunctional catalysts (Table 1).
Quinidine-derived thioureas and a quinidine-derived sulfo-
namide[11] gave disappointing results (Table 1, entries 1–3).
On the other hand, the tryptophan-based thiourea derivatives
Trp-1–Trp-3 were found to be good catalysts. They afforded
the Mannich product 3a in quantitative yield and with good
diastereoselectivity and enantioselectivity (Table 1, entries 4–
6). Under optimized reaction conditions, the fluorinated
product containing adjacent quaternary and tertiary stereo-
Prof. Dr. Y. Lu
Medicinal Chemistry Program, Life Sciences Institute
National University of Singapore (Singapore)
J. Kwiatkowski, Prof. Dr. Y. Lu
NUS Graduate School for Integrative Sciences and
Engineering (Singapore)
[**] We thank the National University of Singapore and the Ministry of
Education (MOE) of Singapore (R-143-000-362-112) for generous
financial support.
Supporting information for this article is available on the WWW
7604
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7604 –7607