Angewandte
Chemie
DOI: 10.1002/anie.201400170
Asymmetric Catalysis
Organocatalytic Asymmetric Hydrolysis of Epoxides**
Mattia Riccardo Monaco, Sꢀbastien Prꢀvost, and Benjamin List*
Abstract: The hydrolytic ring opening of epoxides is an
important biosynthetic transformation and is also applied
industrially. We report the first organocatalytic variant of this
reaction, exploiting our recently discovered activation of
carboxylic acids with chiral phosphoric acids via hetero-
dimerization. The methodology mimics the enzymatic mech-
anism, which involves an enzyme-bound carboxylate nucleo-
phile. A newly designed phosphoric acid catalyst displays high
stereocontrol in the desymmetrization of meso-epoxides. The
methodology shows wide generality with cyclic, acylic, aro-
matic, and aliphatic substrates. We also apply our method in
the first highly enantioselective anti-dihydroxylation of simple
olefins.
dihydroxylations of olefins such as that developed by Sharp-
less et al.[9]
Epoxide hydrolases exploit a bifunctional mode of action,
involving hydrogen-bonding to the epoxide oxygen and the
concurrent nucleophilic attack of an aspartate carboxylate to
deliver an enzyme-bound ester intermediate. Its subsequent
hydrolysis then leads to the final enantioenriched 1,2-diol
(Scheme 1a).[10] We recently described the first well-defined
T
he asymmetric hydrolytic ring opening of epoxides is an
important transformation in synthetic chemistry since the
produced chiral vicinal diols are valuable building blocks and
represent a common motif in natural products and pharma-
ceuticals.[1] However, the activation of the epoxide moiety and
the concomitant enhancement of the typically moderate
reactivity of oxygen nucleophiles render this reaction still
challenging. In fact, only three systems have previously been
described: Jacobsenꢀs cobalt–salen catalyst, a heterobimetallic
gallium-based complex by Shibasaki and co-workers, and
a scandium–bipiridine complex by Schneider et al.[2–4] All of
these methodologies exploit metal-based catalysts and the
activation of epoxides in enantioselective organocatalysis has
long been elusive.[5] The hydrolysis of epoxides is also very
important in the xenobiotic metabolism of living organisms
for the detoxification of exogenous substances.[6] This bio-
transformation is catalyzed by epoxide hydrolases that do not
require metal cofactors.[7] Encouraged by this observation and
motivated by our previous findings on the activation of
carboxylic acids in Brønsted acid catalysis,[8] we focused our
attention on the development of a novel organocatalytic
approach. Here we show that a newly designed chiral
phosphoric acid catalyzes a highly enantioselective carbox-
ylytic ring opening of meso-epoxides. The reaction can also be
used in a one-pot anti-dihydroxylation of Z-olefins, comple-
menting established methodologies for the asymmetric syn-
Scheme 1. Design of an organocatalytic, asymmetric hydrolysis of
epoxides.
activation of carboxylic acids in asymmetric organocatalysis.
We showed that the heterodimerization of a carboxylic acid
with a chiral phosphoric acid catalyst enhances and directs the
carboxylate nucleophilicity in an asymmetric opening of
aziridines.[8] We speculated that our approach should also be
suitable for the carboxylytic opening of epoxides (Sche-
me 1b), resembling the biological epoxide hydrolysis.[11]
At the outset of these investigations, we focused our
attention on the ring opening of cyclohexene oxide 1a with
benzoic acid, catalyzed by binol-derived phosphoric acids 3
(Scheme 2). Indeed, the reaction catalyzed by (S)-TRIP (3a)
afforded the desired product 2a in quantitative yield and
promising enantioselectivity (e.r. = 78.5:21.5, Scheme 2). An
initial screening of phosphoric acid catalysts revealed the
importance of bulky aromatic groups in the 3,3’ positions of
the binol backbone (see the Supporting Information,
Table S1). Since catalysts bearing ortho,ortho-disubstituted
aryl moieties were particularly effective in the transforma-
tion,[12] we realized that the development of new even more
sterically demanding phosphoric acid catalysts would be
crucial for our studies and potentially could also contribute to
the advancement of the field of asymmetric Brønsted acid
[*] M. R. Monaco, Dr. S. Prꢀvost, Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser -Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[**] Generous support by the Max-Planck-Society and the European
Research Council (Advanced Grant “High Performance Lewis Acid
Organocatalysis, HIPOCAT”) is gratefully acknowledged. We thank
the members of our mass spectrometry department for their
excellent service.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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