Angewandte
Communications
Chemie
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C H Activation
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Enantioselective C H Olefination of a-Hydroxy and a-Amino
Phenylacetic Acids by Kinetic Resolution
Kai-Jiong Xiao, Ling Chu, and Jin-Quan Yu*
Abstract: Significant progress has been made in the past
N-protected amino acid (MPAA) ligands cannot be applied to
the preparation of important chiral derivatives of mandelic
acids and phenylglycines.[8b]
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decade regarding the development of enantioselective C H
activation reactions by desymmetrization. However, the
requirement for the presence of two chemically identical
Enantiopure a-hydroxy and a-amino phenylacetic acids,
also known as mandelic acids and phenylglycines, respectively,
are important structural motifs found in many pharmaceut-
icals and biologically active compounds such as the antibiotics
cefamandole, cephalexin, and vancomycin.[11] Enantioen-
riched mandelic acid and phenylglycine derivatives can also
be utilized as catalysts, as well as chiral building blocks in
organic synthesis.[12] As a consequence, asymmetric syntheses
of these two families of compounds have received much
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prochiral C H bonds represents an inherent limitation in
scope. Reported is the first example of kinetic resolution by
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a palladium(II)-catalyzed enantioselective C H activation and
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C C bond formation, thus significantly expanding the scope of
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enantioselective C H activation reactions.
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D
evelopment of enantioselective C H activation reactions
is a significant and challenging task in catalysis and organic
synthesis as they offer new disconnections for asymmetric
synthesis.[1] Among various approaches,[2–7] the palladium-
attention.[13,14] An early example of asymmetric hydroxylation
[15]
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of benzylic C H bonds of chiral epoxides and the recent
II
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catalyzed desymmetrization of prochiral C H bonds has
development of enantioselective C H iodination using Pd /
emerged as a promising avenue that can lead to a wide range
of enantioselective carbon–carbon[8,9] and carbon–heteroa-
tom bond-forming reactions.[10] However, desymmetrization
MPAA catalysts demonstrate the feasibility of achieving
kinetic resolution[16] through C H hydroxylation and iodina-
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tion. Herein, we report a palladium(II)-catalyzed enantiose-
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is only suitable for substrates containing two prochiral C H
lective C H olefination of a-hydroxy and a-amino phenyl-
bonds, thus limiting the structural diversity that can be
accessed by this approach. For example, the previously
reported (Figure 1a) enantioselective palladium(II)-cata-
acetic acids through kinetic resolution to afford enantiomer-
ically enriched olefinated mandelic acids and phenylglycines
(Figure 1b). The remaining starting materials are further
enantioselectively olefinated using chiral MPAA ligands, with
the opposite configuration, to give the enantiomer in high
enantiomeric purity. Notably, these chiral molecules are not
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lyzed C H olefination of diphenylacetic acids using mono-
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accessible through desymmetrization of prochiral C H bonds
or other asymmetric methods.[13,14] To the best of our knowl-
edge, this reaction is the first example of kinetic resolution by
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C H activation and C C bond formation.
We commenced our studies by exploring the enantiose-
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lective C H olefination/kinetic resolution of the racemic
pivaloyl (Piv) protected 3-chloromandelic acid rac-1a with
methyl acrylate as the coupling partner (Table 1; see the
Supporting Information for screening of the O-protecting
group). It was found that in the presence of Boc-l-Ala-OH
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(L1) as the ligand, the enantioselective C H olefination of
rac-1a under aerobic conditions afforded the desired product
2a1 with 89% ee at 18% conversion, thus corresponding to
a selectivity factor (s)[17] of 21 (entry 1). Encouraged by this
promising result, we screened a variety of Boc-protected
amino acid ligands with different side chains (L1–L6). The
s factors were gradually improved with the increase of the
steric bulk on the side chains (entries 1–6). In particular, both
Boc-l-Tle-OH (L5) and Boc-l-Thr(t-Bu)-OH (L6) gave
superior s factors of 38 (entries 5 and 6). As the hydroxy
group on threonine (H-l-Thr-OH) could provide a valuable
handle for structural modifications, this amino acid was
selected as the ligand backbone for further tuning. Firstly, we
investigated the effect of different N-protecting groups. While
Fmoc-l-Thr(t-Bu)-OH (L8) provided a similar s factor to that
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Figure 1. Enantioselective C H activation reactions.
[*] Dr. K.-J. Xiao, L. Chu, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institution
10550 N. Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Supporting information for this article is available on the WWW
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2856 –2860