FULL PAPER
Abstract: The first palladium-catalyzed
enantioselective oxidation of secondary
alcohols has been developed, utilizing
the readily available diamine (À)-spar-
teine as a chiral ligand and molecular
oxygen as the stoichiometric oxidant.
Mechanistic insights regarding the role
of the base and hydrogen-bond donors
have resulted in several improvements
to the original system. Namely, addi-
tion of cesium carbonate and tert-butyl
alcohol greatly enhances reaction rates,
promoting rapid resolutions. The use of
chloroform as solvent allows the use of
ambient air as the terminal oxidant at
238C, resulting in enhanced catalyst se-
lectivity. These improved reaction con-
ditions have permitted the successful
kinetic resolution of benzylic, allylic,
and cyclopropyl secondary alcohols to
high enantiomeric excess with good-to-
excellent selectivity factors. This cata-
lyst system has also been applied to the
desymmetrization of meso-diols, pro-
viding high yields of enantioenriched
hydroxyketones.
Keywords: alcohols
· asymmetric
catalysis · oxidation · palladium ·
synthetic methods
Introduction
(Scheme 1).[12] Employing molecular oxygen as the sole stoi-
chiometric oxidant, high yields of aldehydes and ketones
were obtained for a variety of alcohols. These conditions
The oxidation of alcohols to carbonyl compounds is one of
the most fundamental reactions in organic chemistry.[1]
Many different systems have been developed using a wide
variety of oxidants.[2] Until recently, however, catalytic enan-
tioselective variants have been largely unexplored.[3,4] The
limited number of these alcohol oxidations is somewhat un-
derstandable, since this process is inherently complexity-
minimizing.[5] While many enantioselective oxidative trans-
formations involve the selective creation of stereogenicity
from prochiral starting materials by transfer of a heteroatom
to the organic substrate (e.g., epoxidation, dihydroxylation,
sulfide oxidation),[6] enantioselective alcohol oxidation re-
quires the selective destruction of a stereocenter in a stereo-
ablative kinetic resolution process.[7,8] Kinetic resolutions
have the ability to provide compounds of high enantiomeric
excess for even modestly selective processes at higher levels
of conversion. Furthermore, the ready availability of a wide
range of racemic alcohols, the prevalence of chiral alcohols
in organic synthesis, and the potential for product recycling
by a simple reduction could make an oxidative kinetic reso-
lution of alcohols a synthetically useful process for the pro-
duction of enantioenriched materials.
Scheme 1. Uemuraꢁs oxidation of alcohols.
were attractive for a number of reasons. Molecular oxygen,
essential for cellular respiration in all aerobic organisms, is
an inexpensive, abundant, and environmentally benign oxi-
dant. The lack of additional co-oxidants simplified reaction
complexity, producing water as the sole byproduct. Also,
pyridine was found to be critical to the reaction both as
ligand and base. Uemura reported no catalytic activity in
the absence of pyridine, indicating a strong ligand accelera-
tion effect. We anticipated that the use of chiral ligands in
the place of pyridine could lead to significant enantiodiscri-
mination in the oxidation, while the ligand acceleration
could minimize racemic background oxidation by other pal-
ladium(II) species that could be present in the reaction. Fi-
nally, the non-coordinating nature of toluene could limit sol-
vent displacement of a chiral ligand from the palladium
center.
The proposed mechanism for the oxidation involves alco-
hol substitution and deprotonation of a palladium(II) com-
plex to generate intermediate palladium alkoxide
(Scheme 2). Subsequent b-hydride elimination from this
complex forms the product ketone and palladium hydride 2,
which then reacts with oxygen and another equivalent of al-
cohol to reform 1. Efforts by a number of researchers have
further clarified this mechanism.[13–15]
As part of a general program directed toward enantiose-
lective oxidation, we chose to pursue palladium(II) as a cat-
alytic metal for this process. Not only is palladium catalysis
prevalent in a variety of enantioselective transformations,[9]
but a number of systems involving palladium have been ap-
plied to the aerobic oxidation of alcohols.[10,11] Particularly
intriguing was a report by Uemura of racemic alcohol oxida-
tion utilizing a palladium(II) catalyst and pyridine in toluene
1
[a] Dr. D. C. Ebner, Dr. J. T. Bagdanoff, Dr. E. M. Ferreira,
Dr. R. M. McFadden, Dr. D. D. Caspi, Dr. R. M. Trend,
Prof. B. M. Stoltz
Based on this previous report of alcohol oxidation, we re-
cently developed a palladium-catalyzed oxidative kinetic
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis
Division of Chemistry and Chemical Engineering
California Institute of Technology
resolution of secondary alcohols.[16,17] Utilizing [Pd
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amine (À)-sparteine, a variety of alcohols were resolved to
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Chem. Eur. J. 2009, 15, 12978 – 12992
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12979