Communications
DOI: 10.1002/anie.200805628
Organocatalysis
A Designer Axially Chiral Amino Sulfonamide as an Efficient
Organocatalyst for Direct Asymmetric Mannich Reactions of
N-Boc-Protected Imines**
Taichi Kano, Yukako Yamaguchi, and Keiji Maruoka*
Asymmetric Mannich reactions are the most powerful and
versatile tools for synthesizing optically active b-amino
carbonyl compounds, which are highly attractive chiral
building blocks for biologically and pharmaceutically impor-
tant compounds.[1] Recently, a large number of small organic
molecules, such as proline and its derivatives, were found to
successfully catalyze direct asymmetric Mannich reactions
between aldehydes and N-p-methoxyphenyl-protected
imines.[2,3] However, strong oxidizing agents such as ceric
ammonium nitrate are required to remove the p-methoxy-
phenyl (PMP) group on the nitrogen atom of the Mannich
products, and a method that would allow for the easy removal
of the N-protecting group under mild conditions would offer a
significant synthetic advantage. Recently, the research groups
of List[4] and Cꢀrdova[5] independently reported the proline-
catalyzed syn-selective direct asymmetric Mannich reaction
between aldehydes and imines protected with a readily
cleavable tert-butoxycarbonyl (Boc) group. Furthermore, in
2008, List and co-workers demonstrated that proline can also
catalyze the direct asymmetric Mannich reaction between
acetaldehyde and N-Boc-protected imines to provide the
simplest Mannich products as versatile chiral building blocks,
albeit in low to moderate yields.[6] Since the enamine
intermediate generated from the pyrrolidine-type secondary
amine catalyst is highly nucleophilic, it is difficult to suppress
undesired side reactions, including aldol reactions and further
reactions of the Mannich product
Scheme 1. Strategy to suppress undesired side reactions. Tf=trifluoro-
methanesulfonyl.
which successfully catalyzed the anti-selective direct asym-
metric Mannich reactions of N-PMP-protected a-imino
esters[8] and syn-selective asymmetric cross-aldol reactions.[9]
This catalyst has a highly acidic triflamide group to activate
electrophiles and a less nucleophilic dibenzylic secondary
amine moiety compared to pyrrolidine-type catalysts. These
characteristic features of (S)-1 should suppress the side
reactions, and the hitherto difficult direct Mannich reaction
between acetaldehyde and N-Boc-protected imines could be
achieved. Here we report the direct asymmetric Mannich
reaction between acetaldehyde and N-Boc-protected imines
catalyzed by the axially chiral bifunctional amino sulfonamide
(S)-1. In addition, we also describe the highly anti- and
enantioselective Mannich reaction of N-Boc-protected imines
with other aldehydes—which has previously only been
reported in a few cases.[3e,10]
(Scheme 1). Very recently Hayashi et al.
reported the efficient direct asymmetric
Mannich reaction of acetaldehyde,
although the N-Boc group on most imines
We first examined the reaction between acetaldehyde and
the benzaldehyde-derived N-Boc-protected imine 2 in the
presence of (S)-1 at 08C, and the results are summarized in
Table 1. The reaction with five equivalents of acetaldehyde in
CHCl3 gave the corresponding product 3 in low yield but
excellent enantioselectivity (Table 1, entry 1). It is important
to note that the side product 4 arising from the Mannich
reaction between 2 and 3 was also obtained in 15% yield
during the reaction. Therefore, an increased amount of
acetaldehyde was used, which consequently improved the
yields of 3 (Table 1, entries 2 and 3). The reaction using
CH2Cl2 and THF as solvents provided similar results (Table 1,
entries 4 and 5), while the reaction in toluene was less
satisfactory in terms of the yield (Table 1, entry 6). Under
solvent-free conditions, the desired product was obtained in
higher yield and excellent enantioselectivity (Table 1,
entry 7). Accordingly, the solvent-free conditions were
selected for further studies.
was replaced with an N-benzoyl group.[7]
We previously designed and synthe-
sized the axially chiral bifunctional amino
sulfonamide (S)-1 as an organocatalyst,
[*] Dr. T. Kano, Y. Yamaguchi, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformation of
Carbon Resources” from the Ministry of Education, Culture, Sports,
Science, and Technology (Japan). Y.Y. is grateful to the Japan Society
for the Promotion of Science for Young Scientists for a research
fellowship.
Supporting information for this article is available on the WWW
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1838 –1840