Sequential EDA/HAT Enables C(sp3)-C(sp3) Cross-Dehydrogenative Coupling: Accessing Non-Canonical Amino Acids with
Krishnakumar Sachidanandan1, Cole Stenftenagel1, Alexander M Cluff1
1Department of Chemistry & Chemical Biology, Indiana University Indianapolis, Indianapolis, Indiana 46202, United States.
Abstract:
Current strategies for the alkylation of amino acids via C(sp3)-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(sp3)-C(sp3) 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.
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