(PPh3)3]‚2EtOH catalyst giving 82% ee.8a Very recently,
Shibasaki’s group has accomplished the highly enantiose-
lective reductive aldol reaction of allenic esters to ketones
in up to 99% ee.8b Thus, reductive aldol reactions with
ketones are still developing and have room for improvement
for substrate scope, yields, and enantioselectivity.
We have developed a highly enantioselective reductive
aldol reaction with acrylates using aldehydes as acceptors
by chiral rhodium-bis(oxazolinylphenyl) catalysts, Rh-
(Phebox), which show several excellent profiles such as
exceptional anti-selectivity, lower catalyst loading (<1 mol
%), and catalyst recoverability.9 We have, therefore, taken
on a difficult and significant challenge using ketones as
acceptors.
Table 1. Asymmetric Reductive Aldol Reaction of Ethyl
Cinnamate and Acetonea
1/hydrosilane/acetone (mmol) yield ee
entry hydrosilane
(mL, acetone)
(%) (%)
1
2
Me2PhSiH
1.5/1.6/1.0a
29
23
71
78
72
60
83
33
19
54
94
93
92
95
95
96
97
95
91
94
3.0/3.0/1.0a
3b
4c
5c
6c
7c
8c
9c
10c
1.5/1.6/1.0b
1.0/1.3/2.7 (0.2 mL)
1.0/1.3/6.8 (0.5 mL)
1.0/1.3/13.6 (1.0 mL)
1.0/1.3/2.7 (0.2 mL)
1.0/1.3/2.7 (0.2 mL)
1.0/1.3/2.7 (0.2 mL)
1.0/1.3/2.7 (0.2 mL)
MePh2SiH
Et2MeSiH
(EtO)2MeSiH
TMDSd
a Rh(Phebox-ip) cat. (0.01 mmol, 1 mol %), toluene (2.0 mL) as a solvent,
50 °C, 0.5 h, yield based on acetone. b No toluene. c No toluene, yield based
on 1. d TMDS: tetramethyldisiloxane.
The reaction was carried out at 50 °C by addition of Me2-
PhSiH (1.6-3.0 equiv) into a mixture of ethyl cinnamate 1
(1.5-3.0 equiv) and acetone (1.0 mmol, yield based on
acetone) in toluene solvent (2 mL) with the catalyst Rh-
(Phebox-ip) (1 mol %) (Table 1, entries 1 and 2). The
reactions finished within 0.5 h and resulted in enantioselec-
tivities of 93-94%, but the yields of the aldol product 2
were disappointingly very low, where the conjugate reduction
of the cinnamate predominately proceeded to produce the
dihydrocinnamate. After several trials, concentrated condi-
tions with no solvent were found to improve the yield to
71% (entry 3). Eventually, based on the optimization of the
quantity of acetone toward the cinnamate (1.0 mmol) (entries
4-6), 2.7-13.6 equiv of acetone (0.2-1.0 mL) operated well
to give 60-78% yields with 95-96% ee. MePh2SiH, among
other hydrosilanes, attained the highest ee of 97% with a
yield of 83% (entry 7), whereas alkyl- and alkoxysilanes
resulted in lower yields (entries 8-10).
(3) Cu and In catalysts (nonasymmetric): [Cu]: (a) Ooi, T.; Doda, K.;
Sakai, D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133-2163. (b) Chiu,
P.; Leung, S. K. Chem. Commun. 2004, 2308-2309. Review: (c) Chiu, P.
Synthesis 2004, 2210-2215. [In]: (d) Shibata, I.; Kato, H.; Shida, T.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711-714. (e) Miura,
K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985-1989.
(4) Rh and Ir catalysts (asymmetric): (a) Taylor, S. J.; Duffey, M. O.;
Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528-4529. (b) Zhao, C.-X.;
Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829-1831.
(c) Russell, A. E.; Fuller, N. O.; Taylor, S. J.; Aurriset, P.; Morken, J. P.
Org. Lett. 2004, 6, 2309-2312. (d) Fuller, N. O.; Morken, J. P. Synlett
2005, 1459-1461.
Table 2. Asymmetric Reductive Aldol Reaction of Several
Cinnamates and Acetonea
(5) References 2a (intermolecular) and 3b (intramolecular). For hydrogen-
mediated intramolecular aldol reaction between ketone and enone, see: (a)
Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146. (b) Koech,
P. K.; Krische, M. J. Org. Lett. 2004, 6, 691-694. (c) Jang, H.-Y.; Krische,
M. J. Acc. Chem. Res. 2004, 37, 653-661.
(6) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225-4228.
Nonasymmetric: Lam, H. W.; Murry, G. J.; Firth, J. D. Org. Lett. 2005, 7,
5743-5746. Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A.
F.; Prieto, O.; Luebbers, T. Org. Lett. 2006, 8, 3729-3732.
entry
3
R
X
4
yield (%)
ee (%)
1
2
3
4
5b
6
7
8
3a
3b
3c
3d
3e
3f
Me
i-Pr
Bn
t-Bu
Ph
Et
H
H
H
H
H
CF3
Cl
4a
4b
4c
4d
4e
4f
83
82
82
36
28
64
62
81
96
98
96
97
<1
97
97
96
(7) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem.,
Int. Ed. 2006, 45, 1292-1297.
(8) (a) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2006, 47, 1403-1407. (b) Zao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 14440-14441.
(9) (a) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem.
Soc. 2005, 127, 6972-6973. (b) Ito, J.; Shiomi, T.; Nishiyama, H. AdV.
Synth. Catal. 2006, 348, 1235-1240. (c) Shiomi, T.; Ito, J.; Yamamoto,
Y.; Nishiyama, H. Eur. J. Org. Chem. 2006, 5594-5600. The chiral
rhodium-bis(oxazolinylphenyl) catalysts, Rh(Phebox), can readily be
prepared by reaction with the corresponding bis(oxazolinyl)benzenes and
rhodium chloride; see: (d) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.;
Shiomi, T.; Itoh, J.; Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem.
Eur. J. 2006, 12, 63-71.
3g
3h
Et
Et
4g
4h
OMe
a Rh(Phebox-ip) cat. (0.01 mmol, 1 mol %), no solvent, acetone (0.2
mL, 2.7 mmol), 3 (1.0 mmol), silane (1.3 mmol), 50 °C, 0.5 h, yield based
on 3. b Acetone (0.4 mL).
1652
Org. Lett., Vol. 9, No. 9, 2007