LETTER
Asymmetric Aldol Reactions
493
tive of the structure of the catalyst used. The aldol reaction believe that amines 1–4 would serve as useful building
catalyzed by alanine-derived amines (±)-1, (R)-1, and (S)- blocks for further elaboration.
1, afforded 0/0, 32/29, and 23/32% ee values for syn/anti
diastereoisomers, respectively. Whereas the attained ee
values for the syn-stereoisomers were all modest 23–32%,
Acknowledgment
This research was supported by the Ministry of Education, Youth
and Sport of the Czech Republic.
those of the dominant anti-18 ranged from 29 to 62%. By
using (S)-catalysts 1–4, the (2S,1′R) and (2R,1′R) anti/syn
enantiomers were isolated in enantiomeric excess. The
highest ee values (62 and 39%) were achieved within the
aldol reaction catalyzed by valine- and isoleucine-derived
amines (S)-2 and (S)-4. Hence, branching of the R-substit-
uent seems to be crucial.
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References and Notes
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OH
O
O
O
O2N
syn-18
OH
H
O
1–4 (9 mol%)
TFA (4.5 mol%)
O2N
O2N
anti-18
(4) (a) Guo, Q.; Zhao, J. C.-G. Tetrahedron Lett. 2012, 53,
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Scheme 3 Asymmetric aldol reaction with cyclohexanone
Table 3 Aldol Reaction with Cyclohexanone11
Entry Catalyst Yield (%)a syn/antib ee (syn) (%)c ee (anti) (%)c
1
2
3
4
5
6
(±)-1
(R)-1
(S)-1
(S)-2
(S)-3
(S)-4
48
46
49
51
60
64
2:98
3:97
17:83
7:93
4:96
8:92
0
0
32 (2S,1′S) 29 (2R,1′S)
23 (2R,1′R) 32 (2S,1′R)
32 (2R,1′R) 62 (2S,1′R)
23 (2R,1′R) 32 (2S,1′R)
31 (2R,1′R) 39 (2S,1′R)
a Isolated chemical yield after column chromatography (SiO2; EtOAc–
hexane, 1:1).
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b Determined by 1H NMR and chiral phase HPLC analysis (Chiralpak
AD-H).12
b Absolute configurations were determined by comparison of chiral
phase HPLC analysis with reported data.4h
In conclusion, we have demonstrated that 1-methylben-
zo[d]imidazole linked to α-amino acid residues represent
an interesting class of chiral amines that organocatalyze
direct aldol reactions. Their straightforward synthesis in-
volved reaction of activated Boc-protected α-amino acid
with o-phenylenediamine, cyclization to benzo[d]imidaz-
ole, N-methylation, and Boc-group removal. The stereo-
chemical outcomes of the aldol process can be affected by
the configuration and steric bulk of the α-amino acid res-
idue. The highest enantiomeric excesses achieved were 65
and 62% for the aldol reaction between 4-nitrobenzalde-
hyde and acetone or cyclohexanone, respectively. In view
of the current wide interest in optically pure amines, we
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Bureš, F.; Šimon, P.; Schweizer, W. B. Tetrahedron:
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Bureš, F.; Mlostoń, G. Tetrahedron: Asymmetry 2012, 23,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 491–494