DOI: 10.1002/chem.201000302
Highly Recyclable Chemo-/Biocatalyzed Cascade Reactions with Ionic
Liquids: One-Pot Synthesis of Chiral Biaryl Alcohols
Vincent Gauchot,[a] Wolfgang Kroutil,[b] and Andreea R. Schmitzer*[a]
The growing need for more sustainable technologies has
placed increased attention on the integration of organic
chemistry with biocatalysis to develop effective multistep,
one-pot chemical reactions. Cascade reactions, in general,
are attractive synthetic strategies because they save time
and materials, while producing less waste when compared
with the traditional method of carrying out each chemical
transformation and its required purification and characteri-
zation individually.[1–3] We wished to employ biocatalysis in
cascade reactions in combination with metal catalysts be-
cause biocatalysis provides the advantages of easily intro-
ducing perfect stereo- and regioselectivity. However, inte-
gration of biocatalysis in chemical cascade reactions is ex-
pected to be problematic because many organic intermedi-
ates are poorly soluble in the aqueous reaction medium and/
or display toxic effects on the biocatalyst. A solution to
these challenges is to exploit a biphasic solvent system with
nonmiscible liquid phases in which the biocatalyst is not per-
manently in contact with the organic molecules. However,
using commonly used organic solvents as part of the bipha-
sic system may also damage the biocatalyst itself.[4]
make them superior to many organic solvents applied in
whole-cell biotransformations.[6,7] In addition, the use of ILs
as reaction media for biotransformations has led to higher
operational stabilities with enantioselectivities and catalyst
activities that are generally equivalent to those observed in
organic solvents.[8,9]
We demonstrate herein that performing cascade reactions
with biocatalysis in conjunction with transition-metal cataly-
sis, employing ILs in the biphasic system, is possible. Specifi-
cally, we report a cascade reaction sequence that is a highly
enantio- and diastereoselective synthesis of biaryl alcohols
by employing a Suzuki coupling followed by an alcohol de-
hydrogenase (ADH) catalyzed reduction in a biphasic
system containing ILs. Moreover, we demonstrate the recy-
clability of the biphasic system up to four cycles with only a
negligible deactivation of reactivity and selectivity.
The combination of a palladium-catalyzed cross-coupling
reaction with an asymmetric enzyme reduction has recently
been performed in aqueous medium.[10] Based upon this
precedent, we investigated the possibility of performing a
one-pot, two-step synthesis of biaryl alcohols in a biphasic
system. The first step of the cascade (Suzuki coupling) was
performed in the IL phase, since Suzuki couplings can be
augmented in terms of catalytic activity and stability when
performed in ILs.[7] The second step of the cascade sequence
was an ADH-mediated reduction at the aqueous/IL inter-
face. Some precedent exists for the use of whole-cell bioca-
talysis in ILs. The activity and selectivity of W110A secon-
dary ADH from Thermoanaerobacter ethanolicus has been
studied in organic solvents and ILs in both mono- and bi-
phasic media.[11] In addition, the asymmetric reduction, in
both water and ILs, of hydrophobic phenyl-ring-containing
ketones has also been demonstrated by employing the over-
expressed, highly organic solvent tolerant ADH-A from
Rhodococcus ruber DSM 44541.[12] We chose to employ
lyophilized cells of E. coli containing the overexpressed
ADH-A for our purpose. These cells had already demon-
strated high specificity and activity in ILs for a broad set of
aromatic ketones.
The unique properties of room temperature ionic liquids
(ILs), such as nonvolatility, nonflammability, and in many
cases, high thermal and chemical stability, have made them
an environmentally attractive alternative to organic sol-
vents.[5] The surprising noninvasive effects on cellular mem-
branes of hydrophobic ILs in biphasic IL/water systems
[a] V. Gauchot, Prof. Dr. A. R. Schmitzer
Department of Chemistry, Universitꢀ de Montrꢀal
C.P. 6128 Succursale Centre-ville, Montrꢀal
Quꢀbec, H3C 3J7 (Canada)
Fax : (+1)514-343-7586
[b] Prof. Dr. W. Kroutil
Department of Chemistry
Organic and Bioorganic Chemistry University of Graz
Heinrichstrasse 28, 8010 Graz (Austria)
Supporting information for this article is available on the WWW
6748
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6748 – 6751