Taking advantage of the high stereodiscrimination shown
by enzymes5 and the fact that resolution of racemic mixtures
is probably the most common technique used in the industrial
sector for the preparation of enantiomerically pure com-
pounds,6 we have considered the kinetic resolution of (()-
2a-d, compounds easily prepared by chemical reduction of
commercially available ketones 1a-d using sodium boro-
hydride in MeOH (Scheme 1). The chemical reduction
processes proceed smoothly obtaining the racemic 1-aryl-
2-propanols 2a-d in good to excellent yields after 1 h. This
simple chemical reaction is a more efficient alternative
than the previous synthesis reported for this family of
alcohols.3f,7
Table 1. Lipase-Mediated Kinetic Resolutions of Alcohols
(()-2a-d Using 3 equiv of Vinyl Acetate in THF at 30 °C and
250 rpm
entry
lipase
X
t (h) eeP (%)a eeS (%)a c (%)b
Ec
1
2
3
4
5
6
PSL-C I
F
6
4
8
8
8
9
89
95
71
89
67
95
95
55
96
95
>99
>99
52
37
58
51.5
60
61
PSL-C I Cl
CAL-B Cl
PSL-C I Br
CAL-B Br
PSL-C I OMe
72
22
65
36
51.5 >200
a Determined by HPLC. b c ) eeS/(eeS + eep). c E ) ln[(1 - c) × (1 -
eeP)]/ln[(1 - c) × (1 + eeP)].10
Additionally, bioreduction processes offer a new alterna-
tive for the production of enantiopure alcohols, particularly
substituted 1-phenylpropan-2-ols.7,11 To examine the scope
of this methodology, ketones 1a-d were stereoselectively
reduced using a set of alcohol dehydrogenases (ADH): T,
LB, CP, PR2, RS1, and A (Scheme 2). The best results are
summarized in Table 2.
Scheme 1
.
Chemical Synthesis and Lipase-Mediated Kinetic
Resolution of Racemic Alcohols 2a-d
Scheme 2. Bioreduction of Ketones 1a-d Followed by
Intramolecular Cyclization to Afford 2,3-Dihydrobenzofuran 4
Then, after a preliminary screening of enzymatic activity,
we found Pseudomonas cepacia lipase (PSL-C I), also known
as Burkholderia cepacia lipase, as the most efficient bio-
catalyst for the asymmetric preparation of (R)-acetates 3a-d
and (S)-alcohols 2a-d (Table 1). In the lipase-mediated
acetylation, stereochemistries were in accordance with Ka-
zlauskas’ rule8 and previous enzymatic studies carried out
with 2d.9 Vinyl acetate was used as adequate irreversible
acyl donor, observing moderate enantioselectivity values
when halogen atoms were present in the 2-position of the
phenyl ring (F, Cl, and Br). PSL-C I allowed the recovery
of the (R)-acetates 3a-d up to 89% ee in all cases (entries
1, 2, 4, and 6), obtaining the best results with the methoxy
derivative 2d. In general, CAL-B showed lower stereopref-
erence values, although in the case of compounds 2b,c (X
) Cl and Br, entries 3 and 5) made possible the recovery of
the (S)-alcohols in nearly enantiopure form (96-99% ee).
From all of the ADH tested, T, CP, RS1, and A led to the
production of the (S)-alcohols; meanwhile, LB and PR2
allowed the isolation of the complementary (R)-alcohols (see
also Table S4 in the Supporting Information). In general,
ADH CP and ADH A acted with higher levels of stereopref-
erence toward the formation of (S)-2a-d, observing slightly
higher activity values for ADH A. Comparing both lipase-
catalyzed and bioreduction processes we can conclude that
meanwhile the classical kinetic resolution of alcohols (()-
2a-d allows the recovery of both alcohol and acetate of
opposite configurations in good to excellent optical purities,
and these biotransformations are limited to a maximum 50%
isolated yield. In contrast, the bioreductions have led to the
isolation of the (S)-alcohols in enantiopure form and
quantitative yield, although any of the ADH tested has
allowed the recovery of enantiopure (R)-alcohols up to 43%
yield (see Table S4 in the Supporting Information). For all
the above reasons, bioreduction and lipase-catalyzed resolu-
tions can be considered as ideal complementary tools for
the production of enantiomerically pure compounds.
(5) (a) Asymmetric Organic Synthesis with Enzymes; Gotor, V., Alfonso,
I., Garc´ıa-Urdiales, E., Eds.; Willey-VCH: Weinheim, 2008. (b) Organic
Synthesis with Enzymes in Non-Aqueous Medium; Carrea, G., Riva, S., Eds.;
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(6) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kebeler, M;
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To examine the synthetic possibilities of the resulting
enantiopure alcohols, (S)-2a-d were reacted in different
268
.
(8) Kazlauskas, R. J.; Weissfoch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656.
(10) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
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