ABSTRACT
Phosphines and phosphites are critical tools for non-metal desulfurative methodologies due to the strength of the P[double bond, length as m-dash]S bond. An overarching premise in these methods has been that stoichiometric (or excess) P(iii) reagent is required for reactivity. Despite decades of research, a desulfurative process that is catalytic in phosphine/phosphite has not been reported. Here, we report the successful merging of two thermal radical processes: the desulfurization of unactivated and activated alkyl thiols and the reduction of P(v) = S to P(iii) by reaction with a silyl radical species. We employ catalytic trimethyl phosphite, catalytic azo-bis(cyclohexyl)nitrile, and two equivalents of tris(trimethylsilyl)silane as the stoichiometric reductant and sulfur atom scavenger. This method is tolerant of common organic functional groups and affords products in good to excellent yields.
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. Oxidation-prone 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.
Subject(s)
Sulfhydryl Compounds , Ultraviolet Rays , Sulfhydryl Compounds/chemistry , Peptides/chemistry , ProteinsABSTRACT
We recently reported that acrylic acid (AA) induces the MPT in vitro, which we suggested might be a critical event in the acute inflammatory and hyperplastic response of the olfactory epithelium. The purpose of the present investigation was to determine if induction of the MPT is a general response to short-chain carboxylic acids or if there are critical physical chemical parameters for this response. Freshly isolated rat liver mitochondria were incubated in the presence of varying concentrations of selected carboxylic acids. All of the acids that we tested caused a concentration-dependent induction of the MPT, which was blocked by cyclosporine A. Although the C4 carboxylic acids were slightly more potent than the C5 acids, there was no correlation with the degree of saturation, the octanol/water coefficient (log P), or the dissociation constant (pK(a)) of the acids that we tested. We conclude that induction of the MPT in vitro is a general response to short-chain carboxylic acids having a pK(a) of 4 to 5.
