Formation of α-chiral centers by asymmetric β-C(sp3)-H arylation, alkenylation, and alkynylation.
The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Qing-Feng
QF
Wu
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Peng-Xiang
PX
Shen
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Jian
J
He
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Xiao-Bing
XB
Wang
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Forrest
F
Zhang
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Qian
Q
Shao
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Ru-Yi
RY
Zhu
Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA.
Claudio
C
Mapelli
Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA.
Jennifer X
JX
Qiao
Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA.
Michael A
MA
Poss
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. yu200@scripps.edu.
Jin-Quan
JQ
Yu