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Formation of α-chiral centers by asymmetric β-C(sp3)–H arylation, alkenylation, and alkynylation

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Science  03 Feb 2017:
Vol. 355, Issue 6324, pp. 499-503
DOI: 10.1126/science.aal5175

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Expressed preferences among methyl groups

Targeting just one of the two equivalent branch ends in Y-shaped molecules is a particular challenge for catalysis. Enzymes manage to do it by grasping the whole molecule, octopus-like, but often enzymes cannot tolerate minor structural variations. Wu et al. produced an amide-directed palladium catalyst that, armed with oxazoline-derived chiral ligands, could reliably attack just one methyl member of isopropyl groups. The reaction successfully replaced C–H bonds with C–C bonds in a wide variety of aryl and vinyl coupling partners.

Science, this issue p. 499

Abstract

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.

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