Radical-Mediated Reactions of α-Bromo Aluminium Thioacetals, α-Bromothioesters, and Xanthates for Thiolactone Synthesis

Abstract

Thiolactones have attracted considerable attention in recent years as bioactive natural products, lead compounds for drug discovery, molecular probes, and reagents for polymerisation. We have investigated radical-mediated C-C bond forming reactions as a strategy for thiolactone synthesis. Cyclisation of an α-bromo aluminium thioacetal was investigated under radical conditions. It was found that at low temperature, a radical fragmentation and rearrangement process occurs. A putative reaction mechanism involving a previously unreported aluminium templated thiol-ene step for the rearrangement process is presented. Cyclisation reactions of α-bromo thioesters and α-xanthate thioesters under radical mediated conditions furnished the desired thiolactones in moderate yields.

Atmospheric Oxygen Mediated Radical Hydrothiolation of Alkenes

“…Recognizing that by incorporation of a thioester, we are introducing a thiol in protected form, we were able to transform A13 to 5‐mercaptopentanoic acid ( F1 ) by subjecting the product of the hydrothiolation reaction to an acidic workup and affording the free thiol in 92 % yield (Scheme 4 A). This thiol can then easily be converted to a δ‐thiolactone by Steglich thiolactonization, delivering a class of compound important in numerous fields [17, 18, 69–75] . In addition to this, we also attempted the hydrothiolation of an alkyne (thiol‐yne reaction) [76, 77] .…”

“…This thiol can then easily be converted to a d-thiolactone by Steglich thiolactonization, delivering ac lass of compound important in numerous fields. [17,18,[69][70][71][72][73][74][75] In addition to this, we also attempted the hydrothiolation of an alkyne (thiol-yne reaction). [76,77] It wasfound that under slightly modified condition (6 equiv of AcSH and extended reaction time) that the bis-thioester F2-bis and the vinyl thioester F2-mono were formed in a1 :1.1 ratio (determined by 1 HNMR analysis of the crude reaction mixture) and were isolated in 44 %a nd 50 %y ield, respectively (Scheme4B).…”

Radical‐Mediated Approaches for the Synthesis of Thiolactones

“…An underexplored, though somewhat more direct route to thiolactones is the cyclization of C‐centered radicals generated from a thioester precursor onto a pendant alkene, as has been utilized to great effect in the preparation of lactones and lactams. Scanlan and co‐worker have explored various methods for the 5‐ exo‐trig cyclization of C‐centered radicals onto pendant alkenes for the synthesis of γ‐thiolactones [48] . It was found that α‐bromo aluminium thioacetals, although stable at low temperatures, could not undergo the Dénès modified Ueno‐Stork reaction to furnish thiolactols due to a competing radical fragmentation pathway.…”

5‐exo versus 6‐endo Thiyl‐Radical Cyclizations in Organic Synthesis

“…Thiolactones have proven highly valuable in synthesis and biology . The synthesis of thiolactones has been an area of interest for synthetic chemists for well over a century, with attention being reinvigorated recently . Unlike their homologues, lactones, the strategies that have thus far been developed for the synthesis of thiolactones are somewhat limited and underexamined .…”

“…[70,71] The synthesis of thiolactones has been an area of interest for synthetic chemists for well over a century, with attention being reinvigorated recently. [72][73][74][75][76] Unlike their homologues, lactones, the strategies that have thus far been developed for the synthesis of thiolactones are somewhat limited and underexamined. [72] The majority of methods reported for the synthesis of thiolactones involve the use of a lactone as starting material.…”