Free‐Radical‐Based, Specific Desulfurization of Cysteine: A Powerful Advance in the Synthesis of Polypeptides and Glycopolypeptides

Abstract

Being specific: The specific conversion of Cys (seleno‐Cys) into Ala by a free‐radical‐mediated reduction can be achieved in an aqueous medium under mild conditions (see scheme, PG=protecting group). The conversion can be achieved in the presence of all 20 natural amino acids as well as a range of functional groups. This native chemical ligation followed by the Cys into Ala conversion will enable the synthesis of complex peptides and glycopeptides.

One-pot total chemical synthesis of human α-synuclein

“…Note that the N-terminus of peptide 3 was not N a -acetylated since we previously showed this modification to have no major impact on the native oligomeric state of a-syn. 20 Free-radical desulfurization 21 was then applied (see ESI †). The conversion of both cysteines at positions 30 and 69 occurred within 1 h of reaction as seen using MALDI-TOF MS with an observed mass of 14 464 Da (calc.…”

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

“…Both diastereomers were shown to effectively facilitate ligation and could be converted into the native Val residues upon radical desulfurization. [15] In 2009, Liu and co-workers reported the synthesis of a g-thiol Lys derivative 20 that could effectively mediate ligation at both the a-and e-amino groups of Lys.…”

“…Subsequent deprotection of the Cbz group would enable modification of the e-amino group in a second ligation step. Removal of the thiol auxiliary using a reductive [13] or radical [15] desulfurization protocol would then afford the doubly functionalized Lys residue. This innovative synthetic strategy is particularly attractive for the synthesis of peptides and proteins bearing post-translational modifications on the Lys side-chain, including acetylation, ubiquitylation, and methylation.…”

“…These findings explicitly established the core intellectual framework for the application of fully synthetic amino acid derivatives equipped with suitably positioned b-or g-thiol auxiliaries for use in ligation-desulfurization chemistry (Scheme 2). [13] Aided by the development of a milder, metal-free radical desulfurization protocol with broad functional group tolerance, [15] this perceptive notion has recently come to fruition, with the preparation of several suitably functionalized amino acid building blocks (Table 1). These compounds have augmented the scope and flexibility of chemoselective ligation methodologies.…”

Synthesis of Highly-strained Cyclic Tetrapeptides via Peptide Hydrazide Based Ligation

“…2012 年, 刘磊课题组在本刊发表了通过多肽 酰肼化学连接反应合成环状四肽分子的研究(图 2) [9] . 在 该工作中, 作者将多肽酰肼的分子内化学连接反应与 Danishefsky 等发展的自由基脱硫反应 [10] 相结合, 以高 产率合成了具有不同侧链官能团的环状四肽分子, 突显 出该方法在克服环肽结构张力方面的卓越能力. …”