Ligand-Controlled C(sp3)-H Arylation and Olefination in Synthesis of Unnatural Chiral [alpha]-Amino Acids

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. [PUBLICATION 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[variant prime]-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. [PUBLICATION ABSTRACT]