Chemistry Letters Vol.32, No.7 (2003)
585
References and Notes
In order to evaluate the effect of water on enantioselectiv-
ity, 2c was first dried in vacuo at 70 ꢁC followed by the subse-
quent addition of the wet dichloromethane solvents prepared
with a calculated amount of water and 3-phenylpropanal at
room temperature. The solutions were cooled to ꢂ20 ꢁC and 1
was added at the temperature. Consequently, the enantioselec-
tivity was improved as the water content increased and the op-
timal enantioselectivity was observed when water amounted to
ten equivalents of the catalyst (Table 1). The results obtained in
the presence of water were highly reproducible.16
1
a) M. Asaoka, N. Sugimura, and H. Takei, Bull. Chem. Soc. Jpn.,
52, 1953 (1979). b) C. W. Jefford, D. Jaggi, and J. Boukouvalas,
Tetrahedron Lett., 28, 4037 (1987).
2
a) D. W. Brown, M. M. Campbell, A. P. Taylor, and X. Zhang, Tet-
rahedron Lett., 28, 985 (1987). b) G. Casiraghi, L. Colombo, G.
Rassu, and P. Spanu, Tetrahedron Lett., 30, 5325 (1989). c) T.
Bauer, Tetrahedron: Asymmetry, 7, 981 (1996).
3
4
T. Fukuyama and L. Yang, Tetrahedron Lett., 27, 6299 (1986).
M. A. Brimble, M. T. Brimble, and J. J. Gibson, J. Chem. Soc., Per-
kin Trans. 1, 1989, 179.
5
6
H. Kitajima and T. Katsuki, Synlett, 1997, 568.
a) D. A. Evans, C. S. Burgey, M. C. Kozlowski, and S. W. Tregay,
J. Am. Chem. Soc., 121, 686 (1999). b) D. A. Evans, M. C.
Kozlowski, J. A. Murry, C. S. Burgey, K. R. Campos, B. T.
Connell, and R. J. Staples, J. Am. Chem. Soc., 121, 669 (1999).
Table 1. Effect of water on enantioselectivity in the addition
reaction of 1 to 3-phenylpropanal with 2ca
´
M. Szlosek, X. Franck, B. Figadere, and A. Cave, J. Org. Chem.,
´
Entry Water/2c Yield/% anti:syn % ee (anti) % ee (syn)
7
8
9
63, 5169 (1998).
This addition is a Mukaiyama aldol-like reaction with dienol silyl
ether.
´
M. Szlosek and B. Figadere, Angew. Chem., Int. Ed. Engl., 39, 1799
(2000).
1
2
3
4
5
2
3
6
10
12
96
96
96
91
96
52:48
51:49
46:54
39:61
39:61
84
86
90
95
93
52
61
79
89
89
10 Metallosalens possessing a binaphthyl unit are referred to as sec-
ond-generation metallosalens: Y. N. Ito and T. Katsuki, Bull. Chem.
Soc. Jpn., 72, 603 (1999).
11 a) J. Mihara, T. Hamada, T. Takeda, R. Irie, and T. Katsuki, Synlett,
1999, 1160. b) K. Aikawa, R. Irie, and T. Katsuki, Tetrahedron, 57,
845 (2001). c) J. Mihara, K. Aikawa, T. Uchida, R. Irie, and T.
Katsuki, Heterocycles, 54, 395 (2001).
aIsolated yield of a mixture of anti- and syn-products.
bDetermined by HPLCanalysis using chiral column (DAICEL
CHIRALPAK AS-H, hexane/isopropanol = 9/1).
The reactions of other alkanals were also examined at
ꢂ20 ꢁC in the presence of water (Table 2).17 The reactions of
non-branched alkanals gave anti- and syn-products of high en-
antiomeric excesses (>94% and >88%, respectively), while the
enantiomeric excess of the products derived from cyclohexane-
carboxaldehyde was somewhat diminished (Entry 4). However,
diastereoselectivity was only modest in all instances. These re-
sults suggested that the chiral salen ligand effectively blocked
one enantioface of the coordinated alkanal, which 1 approached
from its open side far-off the stereocontrolling unit of the li-
gand. In contrast, enantioselectivity of the addition of 1 to benz-
aldehyde was moderate (Entry 5). This suggested that the retro-
addition occurred rapidly in this reaction even in the presence of
water, probably because the bond was cleaved at the benzylic
position in the retro-addition.
12 In 1H NMR analysis, the protons at the carbinol carbons in the syn-
products derived from octanal, cyclohexanecarboxaldehyde, and
benzaldehyde have been reported to appear in ca. 0.1–0.3 ppm
higher than the corresponding protons in the anti-products
(Ref. 9). The relative configurations of the products derived from
other aldehydes were tentatively assigned according to this report.
13 E. M. Carreira, in “Comprehensive Asymmetric Catalysis III,” ed.
by E. N. Jacobsen, A. Pfaltz, and H. Yamamoto, Springer, Berlin
(1999), Vol. 29.1, p 997.
14 For the previous discussions of water effect on asymmetric
Mukaiyama aldol reactions, see: a) M. Sodeoka, K. Ohrai, and M.
Shibasaki, J. Org. Chem., 60, 2648 (1995). b) O. Fujimura, J. Am.
Chem. Soc., 120, 10032 (1998). c) S. Kobayashi, S. Nagayama, and
T. Busujima, Tetrahedron, 55, 8739 (1999). d) Y. Yamashita, H.
Ishitani, H. Shimizu, and S. Kobayashi, J. Am. Chem. Soc., 124,
3292 (2002).
15 The effects of water might be manifold. We cannot rigorously ex-
clude the possibility that water could prevent A from promoting the
non-enantioselective reaction (Ref. 13 and 14c). Coordination of
water and hydration of the counter anion would also change the cat-
alyst structure as suggested by the reviewers. After this manuscript
was submitted, however, secondary alcohols have been found to be
effective as additives and enantiomeric alcohols to produce the
same additive effect. Thus, the coordination of the hydroxylic in-
gredients to the catalyst is unlikely to be significant for the change
of the stereochemical outcome. The utilities of alcoholic additives
are currently under investigation.
16 The reaction with complex 2a in the absence of water did not pro-
ceed, but the reaction in the presence of water showed high enan-
tioselectivity [54%, anti:syn = 41:59, 92% ee (anti) and 90% ee
(syn), at ꢂ20 ꢁC].
In conclusion, we were able to demonstrate that second-
generation cationic (R,R)-Cr(salen) complexes catalyze addition
reaction of 1 to alkanals in the presence of water in a highly en-
antioselective manner, though diastereoselectivity of the reac-
tions remains insufficient. Further study on the reaction
mechanism is under way.
1) catalyst, H2O
R-CHO
R
O
CH2Cl2, -20 °C
R
O
+
O
+
O
2) TFA
OH
1
syn
OH
anti
Table 2. Reactions of 1 and alkanals in the presence of 2ca
Yield/%b anti:sync %ee (anti)d %ee (syn)d
17 Typical experimental procedure: (R,R)-2c (2.8 mg, 2.5 mol%) was
dissolved in dichloromethane (250 mL) including 0.45 mL of water,
under nitrogen. To the solution was added aldehyde (0.10 mmol)
and the mixture was cooled to ꢂ20 ꢁC. 1 (20 mL, 0.12 mmol) was
added to the mixture and stirred for 24 h. The reaction mixture in-
cluding 4 and 5 was treated with TFA (10% THF solution), concen-
trated in vacuo, and chromatgraphed on silica gel (hexane/ethyl
acetate = 6/4) to give a mixture of the corresponding diastereo-
meric butenolide 5. The diastereomer ratio was determined by 1H
NMR (400 MHz) analysis. The enantiomeric excess of the resulting
butenolides was determined as described in footnote b in Table 1.
Entry
R
1
2
3
4
5
C
C
3(HCH2)5
3(HCH2)6
88
70
74
44
56
53:47
48:52
42:58
45:55
27:73
94
97
95
84
28
90
92
88
80
53
Ph(CH2)3
c-C6H11
C6H5
aReaction was carried in dichloromethane at ꢂ20 ꢁC with the
molar ratio of aldehyde:1:2c:H2O
=
1:1.2:0.025:0.25.
c
d
bFootnote a in Table 1. Ref. 12. Footnote b in Table 1.
Published on the web (Advance View) June 10, 2003; DOI 10.1246/cl.2003.584