to a significant extent (Table 1, entries 3 and 4). Substituting
isobutyric anhydride for propionic, which had sometimes
proved beneficial in the past,5c,d led to lower selectivities
and reaction rates with both catalysts (Table 1, entries 5 and
6). Replacing chloroform with THF or tert-amyl alcohol led
to significant rate accelerations in the case of 2, although
the selectivities diminished somewhat (Table 1, entries 7 and
9). As in the earlier study of benzylic alcohol substrates,5c
the reaction with catalyst 3 did not proceed at all when THF
was used as a solvent (Table 1, entry 8), whereas the use of
tert-amyl alcohol resulted in a comparable reaction rate but
lower selectivity (Table 1, entry 10). Overall, 3 was judged
to be superior to 2, and chloroform was once again confirmed
to be the solvent of choice. Although diisopropylethylamine
was not particularly detrimental to the performance of 3, it
did not offer any significant advantages, either, and therefore,
all subsequent reactions were carried out in its absence.
Investigation of the influence of the structure of the
substrate on the enantioselectivity of KR began with variation
of the steric bulk of the alkyl group R1. In contrast to our
earlier observations with secondary benzylic alcohols, the
selectivities decreased in the series Me f Et f i-Pr f t-Bu
(Table 2, entries 1-4). The same trend was found by Fu et
Table 1. Optimization of Reaction Conditionsa
time,
%
convn
entry catalyst
solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
base
h
s
1
2
3
2
3
2
3
2
3
2
3
i-Pr2NEt
i-Pr2NEt
none
none
none
none
none
none
1
5
52
52
41
59
34
47
46
0
19
28
18
31
10
21
15
-b)
14
17
2
3
4
45.5
10.5
92
21.5
6.5
24
7
5b
6c
7
8
9
10
THF
EtCMe2OH none
EtCMe2OH none
37
47
7
a General conditions: 0.25 M 4a, 0.010 M (R)-2 or (R)-3, 0.19 M (0.75
equiv) anhydride, 0.19 M (0.75 equiv) base (if any), 0 °C. b (i-PrCO)2O
was used instead of (EtCO)2O in these two cases. c Not determined.
much faster than with any classes of substrates we had
previously tested. The initial results were encouraging enough
with both catalysts, 2 being more reactive and 3 more
selective, as had been the case with benzylic alcohols5c (Table
1, entries 1 and 2). On the basis of Fu’s pioneering study,2c
we expected to observe improved selectivities and decreased
reaction rates in the absence of a stoichiometric base.
Remarkably, the base-free conditions led to differentiation
between catalysts 2 and 3. The selectivities in each case
remained at similar levels; however, the catalytic activity of
2 decreased dramatically, whereas that of 3 was not affected
Table 2. Variation of the Substratea
time,
h
%
convn
entry substrate
R2
R1
Me
Et
i-Pr
t-Bu
s
1b
2b
4a
4b
4c
4d
5
5
6
7
8a
8a
8b
8c
9a
9b
Ph
Ph
Ph
Ph
10.5
10.5
10.5
10.5
24
18
2
1.5
24
25
59
56
56
43
13
62
52
55
24
42
60
48
55
57
31
27
18
3b
(2) (a) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63,
2794. (b) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F.
M.; Fu, G. C. Chem. Commun. 2000, 1009. (c) Tao, B.; Ruble, J. C.; Hoic,
D. A.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 5091. (d) Fu, G. C. Acc.
Chem. Res. 2004, 37, 542.
(3) (a) Vedejs, E.; Daugulis, O.; J. Am. Chem. Soc. 1999, 121, 5813. (b)
Vedejs, E.; MacKay J. A. Org. Lett. 2001, 3, 535. (c) Vedejs, E.; Daugulis,
O. J. Am. Chem. Soc. 2003, 125, 4166.
(4) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154.
(5) (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226. (b) Birman, V. B.; Jiang, H. Org.
Lett. 2005, 7, 3445. (c) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (d)
Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem.
Soc. 2006, 128, 6536.
(6) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347;
(7) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005, 46, 2239.
(8) A single example (substrate 4a) reported in ref 7 proceeded with
low selectivity (s ) 6.6).
(9) Efficient KR of propargylic alcohols can be achieved using enzymes.
See, e.g.: (a) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113,
6129. (b) Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343.
(10) Enantioenriched propargylic alcohols are also prepared via asym-
metric synthesis. For enantioselective alkynylation of aldehydes, see: (a)
Pu, L. Tetrahedron 2003, 59, 9873 (review). (b) Wolf, C.; Liu, S. J. Am.
Chem. Soc. 2006, 128, 10996 (up-to-date list of references). For enantio-
selective reduction of R,â-acetylenic ketones, see: (c) Midland, M. M.;
McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980,
102, 867. (d) Brown, H. C.; Ramachandran, P. V.; Weissman, S. A.;
Swaminathan, S. J. Org. Chem. 1990, 55, 6328. (e) Matsumura, K.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738.
(11) Selectivity factor is defined as s ) k(fast-reacting enantiomer)/
k(slow-reacting enantiomer). See: Kagan, H. B.; Fiaud, J. C. Top.
Stereochem. 1988, 18, 249.
4b
9.5
5b
1-cyclohexenyl Me
1-cyclohexenyl Me
1-hexynyl
acetyl
n-butyl
n-butyl
cyclohexyl
tert-butyl
H
27
27
32
26
11
13
11
6.8
11
5.4
6c
7b
Me
Me
Me
Me
Me
Me
n-C5H11
n-C5H11
8b
9b
10d
11d
12d
13d
14d
23
19
6
2.5
TMS
a General conditions: 0.25 M substrate, CHCl3, 0 °C. b 0.010 M (4 mol
%) (R)-3, 0.19 M (0.75 equiv) (EtCO)2O. c 0.025 M (10 mol %) (R)-3,
0.38 M (1.5 equiv) (EtCO)2O. d 0.025 M (10 mol %) (R)-3, 0.19 M (0.75
equiv) (EtCO)2O.
al.2c Quantitative comparison, however, was clearly in favor
of catalyst 3, in terms of both the selectivity and the time
scale of KR experiments. Replacement of the phenyl group
with other unsaturated substituents was examined next.
Gratifyingly, the selectivities in all the cases examined
remained at similar levels (Table 2, entries 5-8). 1-Cyclo-
hexenyl derivative reacted rather slowly, which necessitated
higher catalyst and anhydride loadings (Table 2, entries 5
4860
Org. Lett., Vol. 8, No. 21, 2006