Stereoselective and Divergent Construction of β‑Thiolated/Selenolated Amino Acids via Photoredox-Catalyzed Asymmetric Giese Reaction

Sulfur
and selenium occupy a distinguished position in biology
owing to their redox activities, high nucleophilicity, and acyl transfer
capabilities. Thiolated/selenolated amino acids, including cysteine,
selenocysteine, and their derivatives, play critical roles in regulating
the conformation and function of proteins and serve as an important
motif for peptide design and bioconjugation. Unfortunately, a general
and concise method to attain enantiopure β-thiolated/selenolated
amino acids remains an unsolved problem. Herein, we present a photoredox-catalyzed
asymmetric method for the preparation of enantiopure β-thiolated/selenolated
amino acids using a simple chiral auxiliary, which controls the diastereoselectivity
of the key alkylation step and acts as an orthogonal protecting group
in the subsequent peptide synthesis. Our protocol can be used to prepare
a wide range of β-thiolated/selenolated amino acids on a gram
scale, which would otherwise be difficult to obtain using conventional
methods. The effect of our chemistry was further highlighted and validated
through the preparation of a series of peptidyl thiol/selenol analogues,
including cytochrome c oxidase subunit protein 7C
and oxytocin.