6776
J . Org. Chem. 1998, 63, 6776-6777
epibromohydrin. The HKR methodology is also shown to
be applicable to a variety of important glycidol derivatives.
Epihalohydrins are susceptible to racemization catalyzed
by adventitious halide ion, and this stands as a critical issue
in any kinetic resolution of these substrates. Indeed, this
racemization pathway has been used to advantage in the
resolution of epichlorohydrin with TMSN3 catalyzed by the
Cr analogue of 1.6 In that case, racemization was rapid
enough relative to the ring-opening pathway to allow for a
dynamic kinetic resolution affording the ring-opened product
in 76% yield and 97% ee. In contrast, racemization of
epichlorohydrin was found to take place only very slowly
relative to hydrolysis under hydrolytic conditions with Co
catalyst 1 (eq 2). This racemization was suppressed by
P r a ctica l Access to High ly En a n tioen r ich ed
C-3 Bu ild in g Block s via Hyd r olytic Kin etic
Resolu tion
Michael E. Furrow, Scott E. Schaus, and
Eric N. J acobsen*
Department of Chemistry and Chemical Biology, Harvard
University, Cambridge, Massachusetts 02138
Received J uly 9, 1998
Kinetic resolution (KR) can be a highly effective strategy
for the preparation of optically pure compounds, particularly
if the corresponding racemates are readily available and a
practical procedure for KR can be applied.1 In this light,
the recently disclosed hydrolytic kinetic resolution (HKR)
reaction catalyzed by (salen)Co complex 1 (eq 1) constitutes
addition of THF as solvent, thereby allowing the HKR of
(()-epichlorohydrin with 0.50 equiv of H2O to provide both
epoxide and diol in 96% ee and in isolated yields of 44% and
50%, respectively (eq 3). Enantiopure epichlorohydrin (>99%
ee) could be obtained in 42% isolated yield by resolution
under the same conditions using 0.55 equiv of water. In both
cases, catalyst 1 could be regenerated and reused with no
loss of activity or enantioselectivity (see the Supporting
Information).
a very attractive approach toward the preparation of enan-
tiopure terminal epoxides.2 The features of the HKR include
the following: the use of water as the nucleophile for epoxide
ring opening; the high accessibility of racemic terminal
epoxides; the low loadings and recyclability of the com-
mercially available catalyst;3 and the ease of product separa-
tion from unreacted epoxide due to large boiling point and
polarity differences.
Epihalohydrins and glycidol derivatives are particularly
attractive substrates for HKR because the racemates are
available inexpensively and on a large scale, and the chiral
three-carbon (C-3) building blocks derived from these com-
pounds are extremely versatile synthetic intermediates. In
the initial report on the HKR,2 epichlorohydrin was the only
C-3 substrate evaluated and its resolution was described to
afford recovered epoxide in 44% yield and 98% ee, but the
diol was obtained in only 38% yield and 86% ee. In this
paper, we describe a highly optimized protocol for the HKR
of epichlorohydrin to provide either epoxide or diol in >99%
ee,4,5 as well as the highly efficient dynamic HKR of
The HKR product of epichlorohydrin, chloropropane diol
3, is also a very valuable chiral C-3 building block,7 and
conditions were sought for its production in high optical
purity. The HKR of epichlorohydrin at reduced temperature
and lower conversion (-10 °C, 0.3 equiv of H2O) gave (R)-3
in 98.7% ee and 27% yield (eq 3). This corresponds to a
selectivity factor in the HKR of epichlorohydrin of at least
218. Enantiopure (R)-3 (>99% ee) was easily obtained by
HKR of epichlorohydrin to >99% ee with (S,S)-1, as de-
scribed above, followed by vacuum distillation of the epoxide
and THF and subsequent ring opening of the resolved
epoxide using (R,R)-1. This sequence, which takes advan-
tage of the equal availability of both enantiomers of catalyst
1, provides an attractive route to (R)-3 or (S)-3 in 41% overall
isolated yield from racemic epichlorohydrin (eq 4).
(1) Kagan, H. B.; Fiaud, J . C. In Topics in Stereochemistry; Eliel, E. L.,
Wilen, S. H., Eds.; Wiley: New York, 1987; Vol. 14, pp 249-330.
(2) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N. Science
1997, 277, 936.
(3) (S,S)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
cobalt(II): Aldrich catalog no. 47, 460-6. (R,R)-N,N′-Bis(3,5-di-tert-butyl-
salicylidene)-1,2-cyclohexanediaminocobalt(II): Aldrich catalog no. 47, 459-
2. The corresponding Co(III) complex 1 is generated either in situ in the
HKR or in a discrete step by exposure of the Co(II) complex to air in the
presence of AcOH. See the Supporting Information for complete experi-
mental details.
(4) For an alternative route to enantioenriched epichlorohydrin em-
ploying asymmetric catalysis, see: Takeichi, T.; Arihara, M.; Ishimori, M.;
Tsuruta, T. Tetrahedron 1980, 36, 3391.
In contrast to the slow rate of racemization observed for
epichlorohydrin under HKR conditions, epibromohydrin was
found to undergo racemization relatively rapidly. Thus, at
(5) For the synthesis of enantiopure epichlorohydrin by enzymatic
resolution of 2,3-dichloro-1-propanol, see: Kasai, N.; Tsujimura, K.; Suzuki,
T. J pn. Patent J P 02 257 895, 1990; Chem. Abstr. 1991, 114, 41064q.
(6) Schaus, S. E.; J acobsen, E. N. Tetrahedron Lett. 1996, 37, 7937.
(7) For the synthesis of 3 and 4 by asymmetric dihydroxylation, see:
Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448.
S0022-3263(98)01332-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/05/1998