An efficient dynamic kinetic resolution requires that
racemization be faster than highly enantioselective transfor-
mation of the racemic starting material.12 The (DHQD)2-
AQN-catalyzed racemization and alcoholysis of 5-phenyl
dioxolanedione meets this requirement, thus allowing an
efficient dynamic kinetic resolution of the racemic dioxo-
lanedione at -78 °C. In contrast, alcoholysis of R-phenyl
UNCA 1a with (DHQD)2AQN was found to be a highly
enantioselective, but normal, kinetic resolution at -78 °C,
indicating that the rate of racemization is negligible compared
to the rate of alcoholysis of 1a (krac, kfast, kslow).7 The
challenge for realizing a cinchona alkaloid-catalyzed dynamic
kinetic resolution of UNCA (Scheme 1) is to accelerate the
Our hypothesis was confirmed by results from ethanolysis
of 1a with (DHQD)2AQN at various temperatures. As the
temperature was raised from -78 to 34 °C, the rate of
racemization increased relative to that of alcoholysis, as
shown by the increasing enantiomeric ratio (er) of amino
ester 2 at complete conversion of racemic 1a (entries 2-7,
Table 1). At 34 °C and with the addition of ethanol (1.2
Table 1. Acceleration of Racemization Relative to Alcoholysis
of UNCA 1a by Increasing Reaction Temperaturea
Scheme 1
entry
temp (°C)
time (h)
conv (%)
er of 2b
1
2
3
4
5
6
7
8c
-78
-78
-40
-20
0
23
34
34
2.0
336
22
3.0
1.0
0.3
0.2
2.0
48
100
100
100
100
100
100
100
97:3
56:44
61:39
66:34
72:28
78:22
79:21
93:7
a Unless otherwise noted, the reaction was performed by treatment of
1a (0.05 mmol) with (DHQD)2AQN (20 mol %) and ethanol (10.0 equiv)
in ether (3.5 mL) at the indicated temperature; see Supporting Information
for details. b Determined by HPLC analysis; see Supporting Information.
c Ethanol (1.2 equiv) was added as a solution in ether (1.0%, v/v) over 1.0
h; see Supporting Information for details.
racemization relative to the alcoholysis while maintaining
the large difference between kfast and kslow
.
Our kinetic studies indicate a general base catalysis
mechanism for the (DHQD)2AQN-catalyzed alcoholysis of
UNCA 1,7 which involves the catalyst, UNCA 1, and the
alcohol in a termolecular transition state (Scheme 1). On the
other hand, the racemization involving 1 and (DHQD)2AQN
is a bimolecular reaction (Scheme 1). The entropy of
activation for the termolecular alcoholysis is expected to be
more negative than that for the bimolecular racemization
(∆S‡alcoholysis < ∆S‡racemization). We reasoned that
reinforcing this difference in the respective entropy of
activation for the racemization and the alcoholysis by raising
the reaction temperature could lead to a significantly ac-
celerated racemization relative to the alcoholysis.
equiv) over 1 h, the ee values of 1a and 2 were found to be
nearly constant throughout the course of the reaction at 0-5
and 86% ee, respectively, indicating that the racemization
became faster than the alcoholysis under this condition (entry
8, Table 1). Further optimization by substituting ethanol with
allyl alcohol resulted in a highly efficient dynamic kinetic
resolution at room temperature, converting racemic 1a to allyl
amino ester 3a in 91% ee and essentially quantitative yield
(entry 1, Table 2).
The scope of the dynamic kinetic resolution was found to
be general. Transformations of various racemic R-aryl
UNCAs 1 into the corresponding optically active amino
esters (R)-3 with (DHQD)2AQN were conveniently and
rapidly achieved at room temperature in excellent enantio-
selectivity and 93-98% yields (Table 2). Complete conver-
sion of racemic 1i to (S)-3i was achieved with (DHQ)2AQN
but in only 74% ee at room temperature. The ee of (S)-3i
was, however, found to be 85% at 20% conversion of 1i,
indicating that the unsatisfactory dynamic kinetic resolution
was caused by the relatively slow racemization of 1i with
(DHQ)2AQN. The dependence of the relative rates of
(9) Reviews on dynamic kinetic resolutions: (a) Huerta, F. F.; Minidis,
A. B. E.; Ba¨ckvall, J.-E. Chem. Soc. ReV. 2001, 30, 321. (b) Faber, K.
Chem. Eur. J. 2001, 7, 5005. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV.
1996, 25, 447. (d) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475. (e)
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68,
36.
(10) For metal-catalyzed efficient dynamic kinetic resolutions see: (a)
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892. (b)
Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya,
H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J.
Am. Chem. Soc. 1989, 111, 9134. (c) Schaus, S. E.; Jacobsen, E. N.
Tetrahedron Lett. 1996, 37, 7937.
(11) For a study of dynamic kinetic resolutions of azlactones, see: Liang,
J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(12) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993,
115, 144.
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Org. Lett., Vol. 4, No. 19, 2002