Angewandte
Chemie
DOI: 10.1002/anie.200902373
Kinetic Resolution
Kinetic Resolution of Quaternary and Tertiary b-Hydroxy Esters**
Derek J. Schipper, Sophie Rousseaux, and Keith Fagnou*
Despite remarkable advances in enantioselective synthesis,
the preparation of single enantiomer quaternary stereocen-
ters remains a challenging and important goal in organic
chemistry.[1] The difficulties associated with the use of ketone
electrophiles is illustrative, where attenuated reactivity,
challenging carbonyl enantiofacial differentiation, and dimin-
ished stability to retroaldol decomposition can explain, in
part, the wealth of techniques for enantioselective aldol
additions to aldehydes[2] compared to ketones.[3] In such
instances, kinetic resolution of a racemic product may be an
attractive alternative to enantioselective synthesis and
remains an important method of accessing enantiopure
material.[4,5]
chemistry should find application in the preparation of a wide
array of natural and synthetic organic molecules.
The unique reactivity of N-methylephedrine was inadver-
tently discovered while evaluating the feasibility of amine
catalyzed asymmetric decarboxylative ketone aldol reactions
[Eq. (1)].[14] While performing the addition of 1 to ethyl
Whereas the kinetic resolution of secondary alcohols has
been studied extensively,[4,5] there are few examples of
tertiary alcohol resolutions. In addition to enzymatic process-
es[6] which have limited substrate scope, Angione and Miller
have described a peptide based catalyst for the acylation of a-
amino alcohols.[7] Hoveyda, Snapper, and co-workers also
used a peptide based catalyst for selective silylation of 1,2-
diols, including three examples of tertiary alcohols,[8a] as well
as the desymmetrization of triols.[8b] Oestreich and co-workers
have shown that stereogenic silanes can be used to resolve
chiral donor-functionalized tertiary alcohols.[9] Matsunaga,
Shibasaki, and co-workers also developed a resolution of
tertiary nitroaldols through a retro-nitroaldol reaction cata-
lyzed by mixed La/Li heterobimetallic complexes.[10]
Recently, Shintani, Takatsu, and Hayashi reported a rho-
dium-catalyzed resolution of tertiary homoallylic alcohols.[11]
Herein, we demonstrate unique reactivity and selectivity
associated with (1S,2R)-N-methylephedrine in the resolution
of tertiary alcohols arising from ketone aldol reactions. Even
though the tertiary stereogenic center is three atoms removed
from the reactive site, high selectivities are observed—with
s factors in excess of 20 in many instances. The method is
technically simple to perform, and employs a cheap and
readily available[12] resolving agent (1S,2R)-N-methylephe-
drine (a chiral compound that is commonly used as a
stoichiometric chiral auxiliary in diastereoselective carbon–
carbon bond-forming processes).[13] Given the ease with
which these racemic aldol processes may be performed, and
the ease with which the products may be resolved, this
pyruvate in the presence of (1S,2R)-N-methylephedrine (2) as
a chiral base, significant levels of enantiomeric excess were
obtained when the reaction was allowed to proceed to
completion over several days. Further evaluation of this
process indicated that the enantiomeric excess had arisen
from a kinetic resolution of the racemic product.
Following the initial discovery, a broad range of readily
available chiral nucleophiles was evaluated for the kinetic
resolution of 3. With chiral alcohols such as 5–9, no reaction
was observed at room temperature in the absence of other
additives. In these cases, improved outcomes could be
obtained by the addition of one equivalent of triethylamine
and heating the reaction mixture to 608C (Table 1, entries 2–
6). From these screens, (R)-(À)-pantolactone (7) (Table 1,
entry 4) and (1S,2R)-N-methylephedrine (2) (Table 1,
entry 14) provided promising s factors of 3.7 and 3.5, respec-
tively. Whereas further optimization with 7 failed to produce
superior results, the continued evaluation of N-methylephe-
drine (2) revealed that by increasing the reaction temperature
to 608C, the selectivity factor could be dramatically improved
from 3.5 to 21 (Table 1, entry 16). This can be further
enhanced to 38 by using two equivalents of 2 (Table 1,
entry 17). The reaction progress occurs over several hours and
may be monitored by HPLC methods using a chiral stationary
phase. Conveniently, the reaction may be performed in
toluene without necessitating the exclusion of air or moisture.
These optimized conditions were applied to a variety of
compounds as illustrated in Table 2. In addition to 3, which
can be isolated in 49% yield and 94:6 enantiomeric ratio
(e.r.), other tertiary alcohol compounds can be effectively
resolved. A number of functionalities at the quaternary center
may be present, including alkyl (Table 2, entries 1 and 5), aryl
(Table 2, entries 2 and 4), ester (Table 2, entries 1–3), tri-
fluoromethyl (Table 2, entries 3 and 4), and ketone (Table 2,
entry 5) substituents. Although the method is optimized for
tertiary alcohol compounds, this method may also be applied
[*] D. J. Schipper, S. Rousseaux, Prof. Dr. K. Fagnou
Center for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie Curie, Ottawa, ON K1N 6N5 (Canada)
Fax: (+1)613-562-5170
E-mail: keith.fagnou@uottawa.ca
[**] We thank NSERC, the University of Ottawa, the Alfred P. Sloan
Fellowship, and the Research Corporation (Cottrell Scholar Award,
K.F.) for support of this work. D.J.S. and S.R. thank the Canadian
government for NSERC-PGS D and NSERC-USRA scholarships.
Angew. Chem. Int. Ed. 2009, 48, 8343 –8347
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8343