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.

硫与硒凭借其氧化还原活性、高亲核性及酰基转移能力，在生物学领域占据重要地位。巯基化与硒醇化氨基酸（包括半胱氨酸、硒代半胱氨酸及其衍生物）在调控蛋白质构象与功能方面发挥关键作用，同时也是多肽设计与生物偶联的重要基序。遗憾的是，目前仍缺乏通用且简洁的方法来制备对映纯的β-巯基化/硒醇化氨基酸，这仍是一个尚未解决的难题。在此，我们报道一种光氧化还原催化的不对称合成方法，借助简单手性助剂即可制备对映纯的β-巯基化/硒醇化氨基酸：该助剂可调控关键烷基化步骤的非对映选择性，同时在后续多肽合成中充当正交保护基。本方案可实现克级规模的多种β-巯基化/硒醇化氨基酸合成，而这类化合物通过传统方法往往难以获取。我们通过合成一系列多肽巯基/硒醇类似物（包括细胞色素c氧化酶亚基蛋白7C (cytochrome c oxidase subunit protein 7C)与催产素 (oxytocin)），进一步凸显并验证了本化学方法的实用性。