JOURNAL OF CATALYSIS 176, 569–571 (1998)
ARTICLE NO. CA982085
PRIORITY COMMUNICATION
Enantioselective Hydrogenation of Ketopantolactone: Effect
of Stereospecific Product Crystallization during Reaction
M. Schu¨rch, N. Ku¨nzle, T. Mallat, and A. Baiker1
Laboratory of Technical Chemistry, Swiss Federal Institute of Technology, ETH Zentrum, CH-8092 Zu¨rich, Switzerland
Received March 12, 1998; revised March 20, 1998; accepted March 25, 1998
The hydrogenation of ketopantolactone over cinchonidine-modi-
fied Pt/alumina hasbeen reinvestigated, focussingon themisleading
effect of stereospecific product crystallization during reaction at
medium to high conversions. The appropriate choice of reaction
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conditions afforded 91.6 ꢀ 0.5% ee to R-(-)-pantolactone.
ꢁ 1998
Academic Press
SCHEME 1
Key Words: enantioselective; hydrogenation; Pt/alumina; keto-
pantolactone; cinchonidine.
(CD, >98% , Fluka) and toluene (>99.7% , Riedel-de Hae¨n)
were used without further purification. A sieve fraction of
50–100 ꢀm of a 5 wt% Pt/Al2O3 catalyst (Engelhard 4759)
was used for all experiments. The catalyst was pretreated
before use in a fixed bed reactor by flushing with 12 ml
minꢂ1 nitrogen at 673 K for 30 min, followed by a reduc-
tive treatment in H2 for 90 min at the same temperature.
After cooling to room temperature in H2, the catalyst was
transferred to the reactor under argon. The metal disper-
sion after heat treatment was 0.27 as calculated from TEM
images (2).
The hydrogenation of KPL was carried out in a 100-ml
stainless steel autoclave (Parr) equipped with mechanical
mixing at a frequency of 700 minꢂ1. It was shown that the
rate of hydrogen uptake was independent of the mixing
frequency above 500 minꢂ1. The reaction temperature was
monitored by a temperature sensor in the solution. The
pressure was held at 70 bar by a computerized constant
volume-constant pressure equipment (Bu¨chi bpc 9901).
Conversion and ee were determined by an HP 5890A gas
chromatograph (GC) with a chiral WCOT cyclodextrin-ꢁ-
2,3,6-M-19 (Chrompack) capillary column. The estimated
standard deviation of the GC method was ꢀ0.5% . Before
analysis the reaction mixture was diluted with ethanol in
order to redissolve the product.
INTRODUCTION
(R)-pantolactone (R-PL) is an intermediate in the syn-
thesis of pantothenic acid (1). Oxidation of PL to ketopan-
tolactone (KPL) followed by the enantioselective hydro-
genation of KPL to R-PL provides an alternative route to
the presently applied three-step resolution process via the
open chain hydroxy-acid form. In a previous paper (2) we
reported the hydrogenation of KPL over a cinchonidine-
modified Pt/Al2O3 catalyst (Scheme 1), affording up to 79%
enantiomeric excess (ee), and we proposed a mechanistic
model for the reaction. An interesting feature of the reac-
tion was the rather poor reproducibility of the results no-
ticed under certain reaction conditions (2) and no feasible
explanation for the unusually high standard deviation could
be found. In a continuation of our effort to get more insight
into this industrially important reaction we have recognized
that the low solubility of the product in apolar solvents re-
sulting in stereospecific crystallization during reaction can
severelydistort the observed ee. Thiseffect willbe discussed
briefly below.
METHODS
Ketopantolactone (KPL, Hoffmann-La Roche) was dri-
ed by azeotropic distillation with toluene. Cinchonidine
The reference experiment shown in Fig. 2 has been
carried out in a magnetically mixed 100-ml autoclave
(Baskerville) equipped with a 50-ml glass liner and PTFE
cover (2). The reaction was followed by taking samples, fil-
tering off the catalyst and analyzing the liquid with GC.
1 To whom correspondence should be addressed. E-mail: baiker@tech.
chem.ethz.ch.
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0021-9517/98 $25.00
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Copyright ꢁ 1998 by Academic Press
All rights of reproduction in any form reserved.