Phosphine-Dependent Photoinitiation of Alkyl Thiols under Near-UV Light Facilitates User-Friendly Peptide Desulfurization

Abstract

Peptides are steadily gaining importance as pharmaceutical targets, and efficient, green methods for their preparation are critically needed. A key deficiency in the synthetic toolbox is the lack of an industrially viable peptide desulfurization method. Without this tool, the powerful native chemical ligation reaction typically used to assemble polypeptides and proteins remains out of reach for industrial preparation of drug targets. Current desulfurization methods require very large excesses of phosphine reagents and thiol additives or low-abundance metal catalysts. Here, we report a phosphine-only photodesulfurization (POP) using near-UV light that is clean, high-yielding, and requires as little as 1.2 equiv phosphine. The user-friendly reaction gives complete control to the chemist, allowing solvent and reagent selection based on starting material and phosphine solubility. It can be conducted in a range of solvents, including water or buffers, on protected or unprotected peptides, in low or high dilution and on gram scale. Oxidationprone amino acids, π-bonds, aromatic rings, thio-aminal linkages, thioesters, and glycans are all stable to the POP reaction. We highlight the utility of this approach for desulfurization of industrially relevant targets including cyclic peptides and glucagon-like peptide 1 (GLP-1(7-36)). The method is also compatible with NCL buffer, and we highlight the robustness of the approach through the one-pot disulfide reduction/multidesulfurization of linaclotide, aprotinin, and wheat protein.

Cryptands on a Solid Support for the Separation of Europium from Gadolinium

“…A fluorenylmethyloxycarbonyl protecting group (Fmoc) analysis of cryptand loading was performed in triplicate experiments separately for cryptand-modified and unmodified NovaPEG amino resin following reported procedures, 49 and the results were used to quantify the amount of cryptand loaded onto the NovaPEG amino resin. UV−visible absorption of dibenzofulvene-piperidine adduct was measured at 301 nm using the Fmoc-deprotected solution.…”

A Hitchhiker’s Guide to Problem Selection in Carbohydrate Synthesis

“…Initially reported by Kent in 1994, the scope of NCL has since been enhanced by several enabling methodologies such as ligation at noncysteine residues, ligation with selenium containing amino acids, and metal-free chalcogen removal. These methods have enabled synthetic access to homogeneous glycoproteins. − These advances in NCL are discussed in recent reviews. , In addition, the Muir lab has published work on split inteins as a method for expressed peptide ligation. , Using flow chemistry, exceptional work in the Pentelute lab demonstrates automated synthesis of peptides up to 164 amino acids in length . Looking to the future, application of these advances to the synthesis of glycoproteins would be highly enabling.…”

Metal-free reductive desulfurization of C-sp3-substituted thiols using phosphite catalysis

“…9 Photoredox strategies 10 a , b avoid functional group incompatibility 10 a and may enable further functionalization of the substrate; however, they do require the use of expensive rare earth transition metal complexes, which may limit industrial scale applications. With only two exceptions, 10 d , e modern and non-metal strategies for thiol desulfurization 10,11 employ excess phosphine/phosphite reagents, whose aquatic toxicity 9 has limited their utility in >kg-scale processes. The last several years have seen a surge of interest in the potential of P( iii )/P( v ) catalysis, 12 largely focused on strategies to facilitate polar P( iii )/P( v ) = O cycles.…”