Tetrahedron Letters
Oxidative kinetic resolution of racemic alkyl aryl carbinols
by an electronically tuned chiral nitroxyl radical
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Shohei Hamada, Yoshiyuki Wada, Takahiro Sasamori, Norihiro Tokitoh, Takumi Furura, Takeo Kawabata
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1
has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbi-
nols (s = up to 23).
Received 10 December 2013
Revised 31 January 2014
Accepted 4 February 2014
Available online 12 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Nitroxyl radical
Oxidation
Kinetic resolution
Alcohols
Hydride shift
Kinetic resolution of racemic alcohols is an alternative to asym-
metric reduction of the corresponding ketones for obtaining opti-
cally active alcohols. An advantage of kinetic resolution is being
able to produce optically active compounds with extremely high
enantiomeric purity under the proper control of the reaction con-
version.1 Acylative kinetic resolution of racemic alcohols has been
extensively developed.2 Oxidative kinetic resolution of racemic
alcohols has also been well developed employing organometallic
catalysts.3 On the other hand, oxidative kinetic resolution using
metal-free oxidation catalysts have been relatively unexplored.
Several chiral nitroxyl radical oxidation catalysts have been devel-
oped and effectively used for the oxidative kinetic resolution of
racemic alcohols.4 Here, we report a new method for oxidative ki-
netic resolution of racemic alcohols with chiral nitroxyl radical oxi-
dation catalyst 1.
We have developed racemic-1 as a nitroxyl radical oxidation
catalyst based on the electronic tuning strategy.5,6 Although cata-
lyst 1 has tetrasubstituted carbons adjacent to the nitroxyl radical
catalytic center, which usually resulted in poor catalytic activity
for the oxidation of secondary alcohols due to the steric reasons,7
1 could effectively promote oxidation of various secondary alco-
hols8 because of the presence of electron-withdrawing ester
groups (electronic tuning effect).5 A rate-determining hydride
transfer mechanism was proposed for the oxidation of bezylic
alcohols catalyzed by 1 based on the kinetic isotope effects and
Figure 1. Hydride shift (A) and nucleophilic attack of the oxygen atom (B) at the
key step of the oxidation of alcohols with the oxoammonium species derived from
nitroxyl radical oxidation catalysts.
Hammet plots. (Fig. 1).5,9 A hydride attached to the chiral center
of the substrate alcohol was supposed to be transferred directly
to the oxoammonium species derived from 1. On the other hand,
in most cases of the oxidation reactions catalyzed by nitroxyl rad-
icals, the reaction proceeds via a nucleophilic attack of an oxygen
atom of the hydroxy group to the oxoammonium species (B) fol-
lowed by proton-abstraction.4,7,8,10 The difference in the oxidation
mechanisms depending on the catalysts may result in the differ-
ence in the substrate scope of the oxidative kinetic resolution.
These stereochemical backgrounds prompted us to develop a
method for oxidative kinetic resolution of racemic alcohols pro-
moted by optically active 1.
⇑
Corresponding author. Tel.: +81 774 38 3190; fax: +81 774 38 3197.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.