Complete switch of product selectivity in asymmetric direct aldol reaction with two different chiral organocatalysts from a common chiral source

Full text of DOI:10.1021/ja807807p

Published on Web 12/04/2008
Complete Switch of Product Selectivity in Asymmetric Direct Aldol Reaction
with Two Different Chiral Organocatalysts from a Common Chiral Source
Keiji Nakayama† and Keiji Maruoka*,‡
Process Technology Research Laboratories, Daiichi Sankyo Co., LTD, Hiratsuka, Kanagawa 254-0014, Japan, and
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received October 3, 2008; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Synthesis of Two Different Chiral Organocatalysts
Design of new chiral organocatalysts to achieve efficient asym-
metric transformations has become increasingly important in current
asymmetric organocatalysis.1 In particular, development of a novel
approach for asymmetric synthesis of both enantiomers would be
very useful from a practical viewpoint by designing two different
chiral organocatalysts from a readily available compound as a
common chiral source. We here wish to report our case study on
this subject by the preparation of chiral organocatalysts 2 and 3
starting from common chiral intermediate 1 with the unique cis-
diamine structure.2 The chiral efficiency of these organocatalysts
was evaluated by their application to asymmetric direct aldol
reactions.3-5
Reagents and conditions: (a) MsOH, CH3CN; (b) Tf2O, Et3N;
(c) Pd/C, H2.
With the optimal reaction condition at hand, we further studied
the generality of asymmetric direct aldol reaction of various cyclic
ketones and substituted benzaldehydes in the presence of catalyst
2 or 3 as shown in Table 2. Both catalysts exhibited generally high
anti selectivity and excellent enantioselectivity in the asymmetric
direct aldol reactions. Here, use of catalyst 2 always gave anti aldol
products anti-5a∼i, anti-7a, and anti-9a with the (2S,1′R) config-
uration, while use of catalyst 3 afforded anti-6a∼i, anti-8a, and
anti-10a with the (2R,1′S) configuration.8 In case of cyclopentanone
substrate, the catalyst loading could be further reduced to 1 mol %
without losing the high anti selectivity and enantioselectivity (entries
20 and 22).
The requisite catalysts 2 and 3 can be easily prepared from 1
in a 3-step sequence as shown in Scheme 1. Asymmetric direct
aldol reaction of cyclohexanone and p-nitrobenzaldehyde cata-
lyzed by 2 was first carried out as a model experiment to find
the optimum reaction condition.6 Treatment of cyclohexanone
and p-nitrobenzaldehyde (4a) with 5 mol % of 2 in polar solvents
(DMSO, DMF, or CH3CN) at room temperature gave aldol
products 5a in very low yields, but the major isomer anti-5a
was found to exhibit high enantioselectivity (entries 1-3 in Table
1). Without solvent, the reaction proceeded smoothly to furnish
anti-5a as a major product with high enantioselectivity (entry
6). A noticeable increase in the reaction rate was attained by
the use of MeOH and i-PrOH (entries 7 and 8), and water solvent
was found to be superior in terms of reactivity and selectivity
(entries 9 and 10).7 Finally, the mixed solvents such as aqueous
DMSO, DMF, CH3CN, and THF were examined (entries 12-15),
and among these use of aqueous THF gave aldol products 5a in
almost quantitative yield with excellent enantioselectivity after
shorter reaction time (entry 15). In marked contrast, however,
A possible transition state model has been proposed as shown
in Figure 1 to account for the observed absolute configuration of
aldol product 5 (R ) H) or 6 (R ) H) and the high selectivity of
the catalyst 2 or 3.
Table 1. Asymmetric Direct Aldol Reaction of Cyclohexanone and
p-Nitrobenzaldehyde Catalyzed by 2a
entry
solvent
time (h)
% yield (anti/syn)b,c
% eed
1
2
3
4
5
6
7
8
DMSO
DMF
MeCN
THF
68
68
68
68
68
68
68
68
68
94
46
94
75
75
48
4 (-/-)
98/-
99/-
94/-
88/40
82/-
92/20
92/50
97/49
97/62
98/75
96/75
98/80
98/51
97/48
98/51
6 (-/-)
1 (-/-)
54 (75/25)
28 (-/-)
65 (76/24)
89 (80/20)
85 (90/10)
64 (91/9)
90 (93/7)
94 (87/13)
92 (91/9)
73 (85/15)
95 (88/12)
95 (94/6)
toluene
neate
MeOH
i-PrOH
H2O
9
10
11
12
13
14
15
sat NaCl
DMSO/H2O
DMF/H2O
MeCN/H2O
THF/H2O
switching catalyst 2 to 3 resulted in formation of the enantiomeric
aldols 6a in 96% yield (anti/syn ) 91:9), and the major anti
isomer anti-6a was found to be 98% ee with the opposite
absolute configuration.
a Unless otherwise specified, asymmetric direct aldol reaction of
cyclohexanone and p-nitrobenzaldehyde in the presence of 5 mol % of
catalyst 2 at room temperature under the given reaction conditions.
b Isolated yield of 5. c The anti/syn ratio of 5 was determined by 1H
NMR analysis. d Enantiopurity of aldol product 5 was determined by
HPLC analysis using a chiral column [DAICEL Chiralpak AD-H] with
hexane-isopropyl alcohol as solvent. e In cyclohexanone.
† Daiichi Sankyo Co.
‡ Kyoto University.
9
17666 J. AM. CHEM. SOC. 2008, 130, 17666–17667
10.1021/ja807807p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Direct Aldol Reaction of Cyclic Ketone and
Substituted Benzaldehyde Catalyzed by 2 or 3a
Figure 1. Proposed transition state of aldol reaction of cyclohexanone with
benzaldehyde catalyzed by 2 and 3. The geometry was optimized by the
PM5 method.
References
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(8) The absolute and relative configuration of the aldol products 5-10 was
determined by comparison with the following references (a) Suri, J. T.;
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Lipin´ski, R. Eur. J. Org. Chem. 2006, 3864. (c) Mase, N.; Nakai, Y.; Ohara,
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a Unless otherwise specified, asymmetric direct aldol reaction of
cyclohexanone and substituted benzaldehyde 4 in the presence of 5 mol
% of catalyst 2 or 3 at room temperature for 3-4 days. b Isolated yield.
c The anti/syn ratio was determined by 1H NMR analysis.
d Enantiopurity of anti aldol products was determined by HPLC analysis
using a chiral column [DAICEL Chiralpak AD-H, AS-H, and Chiralcel
OD-H] with hexane-isopropyl alcohol as solvent. e Use of 1 mol % of
catalyst 2 or 3 for 108 h.
In summary, we have succeeded in obtaining both enantiomeric
aldol products by using two different chiral organocatalysts 2 and
3, which are easily derived from common chiral source 1 with the
unique cis-diamine structure. This strategy is in principle applicable
to another catalytic system, and further effort to this end is currently
underway in our laboratory.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA807807P
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J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17667