Sequential EDA/HAT Enables C(sp<sup>3</sup>)–C(sp<sup>3</sup>) Cross-Dehydrogenative Coupling: Accessing Non-Canonical Amino Acids with Quaternary Carbon Centers from Activated and Non-Activated Alkanes
Krishnakumar Sachidanandan, Cole Stenftenagel, Alexander M. Cluff, Grace A. McAlary, Athul Joshy, Ben Niu, Sébastien Laulhé
Abstract
Current strategies for the alkylation of amino acids via C(sp 3 )–H functionalization require the use of transition metals, often in the presence of excess peroxides at high temperatures. Herein, we developed a unique electron-donor–acceptor (EDA) system using aryl halides and N -phenylglycine derivatives to achieve a C(sp 3 )–C(sp 3 ) cross-dehydrogenative coupling that gives access to noncanonical amino acids. This metal- and photocatalyst-free protocol enables functionalization of ethers and unactivated alkanes via a hydrogen-atom transfer (HAT) process performed by an in situ generated aryl radical. The reaction proceeds via radical–radical coupling, which enables the formation of sterically demanding quaternary carbon centers and delivers site-selective α-functionalized N -phenylglycine moieties even when appended to complex bioactive molecules or small peptides.