Dartmouth professor Jimmy Wu and Forest Robertson recently published a streamlined synthesis of allylic thioethers from phosphorothioate ethers and alcohols in Organic Letters. Although the previous work of Skowronska, Krawczyk, and Tanaka included the conversion of phosphorothioate ethers into the corresponding alkenes, the nature of the phosphorothioate ethers had limited their methods.  Using functionally distinct phosphorothioate ethers, Wu and Robertson instead add an exogenous alkoxide in a single step to create thioethers.

Considering the prevalence and importance of thioethers in bioactive natural and pharmaceutical agents, this finding fills a relevant gap in research methods surrounding the formation of C-S bonds.  Interestingly, the presence of the C-S bond over C-C or C-O bonds can enhance functionality.     For example, “a single sulfur atom bonded to at least one allyl side chain” found in diallyl sulfide inhibits the formation of cancerous cells. Additionally, the antitumor properties of doxorubicin, a chemotherapy drug, depend on linkage thioethers between doxorubicin and a specific antibody.

Proposed Mechanism

Proposed mechanism

Wu and Robertson assert the reaction proceeds via an SN2 mechanism that begins with the alkoxide attacking the phosphorothioate ether to create both a phosphate and a thiolate.  Acting as a nucleophile, the thiolate then displaces the phosphate to yield the intended thioether (see above).  Wu and Robertson supported the SN2 conclusion with a nearly perfect yield of a stereoselective reaction.

Wu and Robertson also included the yields of the corresponding thioethers from various alcohols, which ranged from moderate to high.  They conducted all of the reactions overnight in methyl tert-butyl ether (MTBE) or tetrahydrofuran (THF) while using NaH as the base to deprotonate the alcohol initially.  The byproduct from the procedure is an odorless phosphate salt that can easily be removed, adding to the elegance of the synthesis.

Overall, the improved method provides a way to use readily available material to form molecules essential to the activity of many cancer-fighting drugs.