Some Thioester Syntheses Love DIC: A Case Study on Functionalizing Amino Acids with O-Protected Mercaptoethanol
Year: 2026
Type: preprint
Abstract: Thioesters can be made through the formal condensation of a carboxylic acid and a thiol. This is generally accomplished using the same activated ester intermediates employed for amide synthesis; however, the yields are often far lower for the thiols. As part of our effort towards generating new biocompatible polymers, we need to access thioesters of amino acids in high efficiency and found that literature conditions for analogous systems provided extremely poor yields. Consequently, herein, we report our coupling reagent screening study for making thioesters between functionalized carboxylic acids (in the form of differentially protected amino acids) and multifunctional thiols including TBS-protected 2-mercaptoethanol, Fmoc-protected cysteine, and various aliphatic and aromatic thiols. Although there is no universal answer, we found that DIC, supplemented (or not) with HOBt in DMF reproducibly, and in the hands of multiple experimenters provided only with the written protocol, produced the highest yield both on small (low mg) and multigram scale.
Source: ChemRxiv
Institutions: University of Windsor, WE-SPARK Health Institute
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7204829329