Betaketothioesters in organocatalysis: Harnessing nucleophilic reactivity, the fluorophobic effect, and expanding the substrate repertoire

Abstract

The use of thioesters as nucleophiles marks a considerable change in organic synthesis. This new method, propelled by gentle enolization with minimal catalyst loading, results in enantiomeric excesses surpassing 95 % under ambient conditions, accomplishing total conversion in merely 6 h. Remarkably, this method eliminates the need for additional functional groups in nitroalkenes for efficient chirality transfer from the organocatalyst. The exceptional reactivity of thioesters, combined with their water tolerance, enables reactions utilizing the hydrophobic effect, resulting in reaction times as short as 15 min and products with slightly enhanced stereoselectivity compared to analogous reactions in dichloromethane. Additionally, reactions performed in perfluorinated solvents outpace their homogenous counterparts in organic solvents, delivering products in shorter time with comparable stereoselectivity. This work highlights the rare utilization of the fluorous effect in organocatalysis. Simple squaramides also exhibit remarkable catalytic activity in the reactions of beta-keto thioesters with alpha-bromo nitroalkenes. As little as 0.1 mol% of the catalyst leads to product formation with an 86 % yield (qNMR) and 93 % enantiomeric excess. Upscaling the reaction does not significantly affect the enantiomeric excess but leads to a slight decrease in yield from 82 % to 77 %. It has been demonstrated that thioesters react more rapidly than their ketoester counterparts, and the two-step reaction leading to dihydrofuran ring closure is entirely accomplished by extending the reaction time, eliminating the need for additional base. The examples presented here expand the range of substrates derived from carboxylic acid esters in catalytic reactions, suggesting the potential for the synthesis of challenging reactions in analogs of alkoxyl esters. Additional KS-DFT calculations shed more light on the reaction paths, rationalizing the observed stereochemical outcomes.