Table 2. Variation of the Solventa
Scheme 1. Design and Synthesis of BTM
entry
solvent
time (h)
% conv
s
1
2
3
4
5
CH2Cl2
tert-amyl alcohol
PhMe
THF
Et2O
7
24
24
24
24
45
11
31
0
45
35
32
2
a Conditions: 0.25 M 5b, 4 mol % of (R)-16, 0.75 equiv of (EtCO)2O,
0.75 equiv of i-Pr2NEt, solvent, Na2SO4, room temperature.
) 390) with Vedejs’ catalyst.5f We have also found that
BTM-catalyzed KR of cinnamyl alcohols, e.g., 10 (Table 1,
entry 22), produces moderate selectivities and slow reaction
rates.13
Variation of the reaction medium was studied next (Table
2). As in the case of CF3-PIP (1),6a chloroform was
confirmed to be the optimal solvent, whereas dichlo-
romethane, toluene, and especially tert-amyl alcohol gave
lower selectivities and reaction rates. Surprisingly, no ap-
preciable reaction was observed in diethyl ether or THF.
Because the geometry of BTM (16) was sufficiently different
from that of CF3-PIP (1) and Cl-PIQ (2), we also decided
to reexamine other carboxylic anhydrides (Table 3). Although
intermediate and the increased air humidity in the ice bath
where these experiments were performed. To test this
hypothesis, we purposely added a small amount of water to
the reaction mixture at room temperature and observed a
similar loss of activity.9 Careful exclusion of external
moisture and addition of sodium sulfate to the reaction
mixture allowed us to prolong the catalyst’s life at 0 °C and
thus achieve the anticipated improvement. We were pleased
to observe that the selectivity factor in the KR of 5b exceeded
100 (Table 1, entry 9). To provide fair comparison with the
previously used catalysts, we repeated the experiment with
1, 2, and 4 under the modified set of conditions and obtained
only slight improvement of selectivity over the previously
reported results. Use of the new catalyst allowed resolution
of substrates 5a-d, 6a, 7a, and 8 with enantioselectivities
higher than, or at least equal to, those ever obtained for these
substrates using nonenzymatic catalysts10,11 (Table 1, entries
9 and 13-18). Substrates 6b and 7b combining two structural
features known to lead to high enantioselectivity, the 1- and
2-naphthyl aryl moieties and the bulky tert-butyl alkyl
groups, were both resolved with selectivity factors of about
300 (Table 1, entries 19 and 20). Interestingly, o-tolylmethyl
carbinol 8 was acylated with much higher enantioselectivity
(s ) 209) than its unsubstituted phenyl analogue 5a (s )
80) (cf. Table 1, entries 13 and 18). Qualitatively similar
observations were made by Fu (s ) 71 and 43)12 and Vedejs
(s ) 188 and 45)5f with their respective catalysts, whereas
our first-generation catalyst 1 produced the same selectivity
(s ) 26) with both of these substrates.6a By contrast,
mesitylmethyl carbinol 9 (Table 1, entry 21) was acylated
with very poor selectivity (s ) 2.5), much lower than that
obtained with CF3-PIP (1) (s ) 20).6a Curiously, this very
substrate produced the highest selectivity ever observed (s
Table 3. Variation of the Anhydridea
entry
anhydride
time (h)
% conv
s
1
2
3
4
(MeCO)2O
(EtCO)2O
(i-PrCO)2O
(PhCO)2O
4
51
49
42
7
36
72
101
-1.5
2.75
18
24
a Conditions: 0.25 M 5b, 4 mol % of (R)-16, 0.75 equiv of anhydride,
0.75 equiv of i-Pr2NEt, CDCl3, Na2SO4, room temperature.
the use of acetic anhydride, as expected, led to reduced
selectivity, the bulkier isobutyric anhydride resulted in
notable improvement. This latter finding is in contrast to what
we had observed with CF3-PIP (1).6a,14 Despite the markedly
lower reaction rate at room temperature, compared with
propionic anhydride, it proved feasible to reach similar levels
of conversion at 0 °C at comparable reaction times (Table
4). Significantly increased selectivity factors were observed
in the case of substrates 5a, 5b, 6a, 7a, and 8 (Table 4, entries
1-5), whereas the reactions with the sterically hindered
carbinols 5d and 6b were too sluggish to reach respectable
conversions in 2 days (Table 4, entries 6 and 7). Both
propionic and isobutyric anhydrides can be recommended
for practical use: whereas the former is more general and
(9) See Supporting Information.
(10) The highest selectivities previously reported for these substrates
are: 5a, s ) 80 (ref 11); 5b, s ) 41 (ref 5g); 5c, s ) 99, corrected value
s ) 117 (ref 5f); 5d, s ) 117 (ref 5g); 6a, s ) 99, corrected value s ) 116
(ref 5f); 7a, s ) 74 (ref 5g); 8, s ) 188 (ref 5f). It should be noted that
high selectivity factors are difficult to determine precisely, and therefore,
these values should be treated as approximate.
(13) Preliminary experiments suggest that rapid catalyst deactivation is
responsible for the observed results. A more detailed study is currently
underway.
(14) Selectivity factor s ) 11 at 44% conversion was obtained with
substrate 5b using isobutyric anhydride in the presence of 2 mol % of CF3-
PIP (1), whereas propionic anhydride under identical conditions gave s )
36 at 42% conversion.
(11) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347.
(12) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.
Org. Lett., Vol. 8, No. 7, 2006
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