Asymmetric Hydration of Non-Activated Alkenes
COMMUNICATION
ecules as additives in catalytic
amounts, which are known to
complex PdII components.[8] We
were pleased to find that when
adding only 2 mol% of 2,2ꢃ-bi-
pyridine as an enzyme-compati-
ble and metal-inhibiting ligand
of a palladium species, we suc-
ceeded in realizing the desired
one-pot process, which corre-
sponds to a “formal” asymmet-
ric hydration process. Starting
from styrene (1a), and in the
presence of a “chemoenzymatic
catalytic system”, consisting of
a palladium-type catalyst and
an alcohol dehydrogenase, the
desired phenylethan-1-ol (R)-
3a was formed in the one-pot
synthesis with excellent conver-
sion of 92% (for the biotrans-
formation; Scheme 4). Thus, the
overall conversion is now in the
range expected from the con-
versions obtained in the indi-
vidual reaction steps carried
out in a separated fashion, indi-
cating that by means of the ad-
ditive (“inhibiting ligand”) the
Scheme 4. Optimized chemoenzymatic one-pot process in water.
Scheme 5. Substrate scope of the one-pot process.
reaction
mixture
of
the
Wacker–Tsuji oxidation is (bio)compatible with the subse-
quent enzymatic reduction process. Besides 2,2ꢃ-bipyridine,
other organic molecules turned out to be highly suitable for
this process, such as thiourea and EDTA, which led to con-
versions of 93% and 92%, respectively, when being used in
a catalytic amount of 2 mol% (see the Supporting Informa-
tion for details).
Furthermore, an initial study on the substrate scope of
this new one-pot synthesis and formal asymmetric hydration
process has been carried out using thiourea (2 mol%) as an
economically very attractive additive (Scheme 5). In addi-
tion to styrene, which was transformed into (R)-phenyle-
than-1-ol in 68% yield and with an excellent enantiomeric
excess of 99% ee, substituted styrene derivatives also turned
out to be suitable substrates. When starting from p-methy-
lated styrene (1b), the resulting alcohol (R)-3b was ob-
tained in 50% yield and with 94% ee, whereas the use of p-
chlorostyrene (1c), as a substrate led to the desired product
(R)-3c in 62% yield and with 99% ee (Scheme 5).
In conclusion, a one-pot synthesis has been developed
that enables the direct one-pot conversion of (substituted)
styrene(s) of type 1 into (substituted) (R)-phenylethan-1-
ol(s), (R)-3, in a highly enantioselective manner. Such an
enantioselective synthesis of a secondary alcohol corre-
sponds formally to the reaction type of an asymmetric hy-
dration of a non-activated alkene. The key feature of this ef-
ficient one-pot process is the use of a “chemoenzymatic cat-
alytic system”, consisting of an enzyme-compatible palladi-
um species and an enzyme, instead of a single catalyst mole-
cule. This “chemoenzymatic catalytic system” enables a one-
pot, two-step process in water comprising a palladium-cata-
lyzed Wacker–Tsuji oxidation and subsequent enantioselec-
tive enzymatic reduction of the in situ-formed (substituted)
acetophenone(s) of type 2 under formation of (substituted)
(R)-phenylethan-1-ol(s), (R)-3. Thus, this process is a further
example of the power of chemoenzymatic one-pot syntheses
in water for challenging asymmetric transformations. In
future work, the expansion of the substrate scope of this
process technology, further process development, the mech-
anistic clarification of the additive effect, and scale up are
planned.[9]
Acknowledgements
The authors thank Evonik–Degussa GmbH, Amano Enzymes Inc., and
Oriental Yeast Company Ltd. Japan for generous support with chemicals.
Keywords: alcohols
· asymmetric hydration · enzyme
catalysis · palladium · synthetic methods
[1] Overviews: a) Catalytic Asymmetric Synthesis (Ed.: I. Ojima), 3rd
ed., Wiley, Hoboken, 2010; b) Houben-Weyl, Methods of Organic
Chem. Eur. J. 2012, 18, 1073 – 1076
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1075