Research Article

Ligand-Controlled C(sp3)–H Arylation and Olefination in Synthesis of Unnatural Chiral α–Amino Acids

Science  14 Mar 2014:
Vol. 343, Issue 6176, pp. 1216-1220
DOI: 10.1126/science.1249198

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A Palladium 1–2 Punch

Methods to replace carbon-hydrogen bonds directly with carbon-carbon bonds offer enticing prospects for streamlining the synthesis of organic compounds. The trouble is that it is hard to select any particular C-H bond and to avoid making complex mixtures of products. He et al. (p. 1216) report that a pair of powerful pyrimidine ligands induces a palladium catalyst to add aryl groups selectively to amino acid derivatives. One ligand promotes addition of a single aryl group to the β-carbon center; the other appends a second, potentially different aryl group to the same carbon—all in the same flask.

Abstract

The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp3)–H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp3)–H arylation using pyridine and quinoline derivatives: The former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of β-Ar-β-Ar′-α–amino acids with excellent levels of diastereoselectivity (diastereomeric ratio > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp3)–H olefination of a protected alanine.

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