C O M M U N I C A T I O N S
Scheme 1. Conversion to â,â-Disubstituted Amino Acid
Table 2. Optimization of Catalytic Enantioselective Mannich
Reaction to Aliphatic Ketoimine
thetically appreciable range. Enantioselectivity was consistently
higher when using new DuPHOS 8 rather than 7 (entries 8, 10,
and 12), which suggests that the enantioselectivity of the aliphatic
ketoimines can be improved with future intensive ligand optimiza-
tion.
The Mannich product 5a was successfully converted to a â,â-
disubstituted amino acid 9 in high yield through removal of the
phosphinoyl group under acidic conditions followed by hydrolysis
of the ester with aqueous NaOH (Scheme 1).
In conclusion, we have developed a Cu(I)-catalyzed enantiose-
lective Mannich reaction of simple ketoimines. The reaction is a
platform for the synthesis of optically active â,â-disubstituted amino
acids, which are important building blocks in many fields. Further
studies to improve the reaction efficacy and substrate generality
are in progress.
yielda
eeb
(%)
entry
ligand
additive
(%)
1
2
3
4
6
6
7
8
(EtO)2Si(OAc)2
(EtO)3SiF
(EtO)3SiF
29
58
90
99
87
86
75
81
(EtO)3SiF
a Isolated yield. b Determined by chiral HPLC.
Table 3. Catalytic Enantioselective Mannich Reaction of
Ketoimines
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Specially Promoted Research of MEXT. Y.S. thanks to
JSPS for a research fellowship. We thank Kounosuke Oisaki for
his original contribution in the synthesis of 8.
Supporting Information Available: Results of optimization pro-
cess, proposed catalytic cycle, experimental procedures, and charac-
terization of the products. This material is available free of charge via
References
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101, 2181. (d) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
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(3) To date, two examples of tetrasubstituted carbon-forming catalytic
enantioselective Mannich reactions of special ketoiminoesters have been
reported. See: (a) Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.;
Jørgensen, K. A. Chem.sEur. J. 2003, 9, 6145. (b) Zhuang, W.; Saaby,
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(4) Mapp recently reported a general â,â-disubstituted amino acid synthesis
utilizing diastereoselective nitrile oxide [3 + 2] cycloaddition as a key
step. See: (a) Minter, A. R.; Fuller, A. A.; Mapp, A. K. J. Am. Chem.
Soc. 2003, 125, 6846. (b) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp,
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128, 7164.
(6) For pioneering studies on transmetalation from a silyl enoate to a copper
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(7) The trimethylsilyl enolate derived from methyl acetate produced compa-
rable results; however, in this case, isolation of the product from 1d was
difficult.
t
(8) Slow addition of a protic additive (such as BuOH) did not improve the
a Condition A: 3 ) 2 equiv, ligand ) 6, additive ) (EtO)2Si(OAc)2 (1
equiv). Condition B: 2 ) 4 equiv, ligand ) DuPHOS (7 or 8), additive )
(EtO)3SiF (1.2 equiv). b Isolated yield. c Determined by chiral HPLC. d 4
equiv of 3 were used. e Ligand ) 7. f Ligand ) 8. g Absolute configuration
was determined to be (S).
yield in this case. On the other hand, a protic additive facilitated the catalyst
turnover in Cu-catalyzed enantioselective allylation of ketoimines: Wada,
R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 7687.
(9) August, J. M. J. Org. Chem. 1988, 53, 3364.
(10) (EtO)2Si(OAc)2 can be easily synthesized in a multi-gram scale. See
Supporting Information.
(11) The yield was slightly lower when using 2d rather than 1d as a substrate.
In many substrates shown in Table 3, however, both yield and enanti-
oselectivity were improved using a N-di(3,5-xylyl)phosphinoyl protecting
group rather than a simple N-diphenylphosphinoyl group.
(2h, 2i, and 2j) were used, the enantioselectivity was not completely
satisfactory, even under optimized condition B using CuOAc-
DuPHOS 8 as the catalyst and (EtO)3SiF as the trapping reagent
(entries 9, 11, and 13). Considering the unprecedented features of
this type of reaction, however, the enantioselectivity is in a syn-
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