A simple method for the conversion of carboxylic acids into thioacids with Lawesson’s reagent

Abstract

A one-step protocol for the conversion of carboxylic acids to thioesters, using Lawesson's Reagent, has been developed.Thioacids represent a well-established and versatile class of organic compounds. Due to their nucleophilicity, thioacids have found broad applications, for instance the synthesis of thiols and thioesters 1 as well as in reactions with azides and nitrosulfonamides. 2,3 The recognition that thioacids are not only exploitable nucleophiles, but also can function as overall acylating agents under mild conditions, has enabled the development of a number of new methods for the construction of simple amides, as well as amide bonds in the context of peptide ligations. 4In the course of a current program directed toward the synthesis of glycopeptides (and glycoproteins), 5 we recently disclosed several strategies which use thioacids as the coupling partners.6 The value of such methods depends on the accessibility of the thioacids. We have now directed our efforts to the development of a new and practical protocol for the selective installation of thioacid functionality.Among the current methods for synthesizing thioacids, three are most commonly used. One involves pre-formation of activated carboxylic acids, which are converted to thioacids by reaction with hydrosulfide (HS) anion. Another involves prior coupling of the carboxylic acid with either HSFmoc, HSTrt or HSTmob. Removal of the protecting group releases the target thioacid. 8 Finally, Boc solid phase peptide synthesis (SPPS) with a thioester solid support can be applied to the preparation of large peptide thioacids.9 The major limitations of these approaches include the toxicity of H 2 S, required recourse to activating agents, current commercial unavailability of HSFmoc and HSTmob, and the inconvenience factors associated with a multistep protocol to accomplish a simple -OH to -SH interconversion. We describe herein the development of a new and efficient one-step synthesis of thioacids from the corresponding carboxylic acids, using Lawesson's Reagent (LR).Lawesson's Reagent is commercially available, inexpensive, and widely used in organic synthesis, particularly for the transformation of a carbonyl functional group to its thiocarbonyl Correspondence to: Samuel J Danishefsky. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 10 Remarkably, there had been no systematic study investigating the preparation of thioacids by direct reaction between carboxylic acid and LR. As outlined in Scheme 1, we postulated that, perhaps, a carboxylic acid (1) could react with LR in a manner analogous to that observe...

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