The sulfonamide functional group is prevalent in pharmaceutical and agrochemical industries, finding application as diuretics, anti-inflammatory and anti-viral agents. However, the closely related aza-analogue of sulfonamides, sulfonimidamides, are far less explored. Sulfonimidamides have an array of advantageous properties compared to sulfonamides including, a stereogenic centre, multiple hydrogen bonding acceptor and donor sites, and an additional point of diversification allowing fine-tuning of physiochemical properties. These beneficial features of sulfonimidamides mean they can be applied as bioisosteres for sulfonamides as well as carboxylic acids. Furthermore, the presence of chirality at sulfur leads to the potential application of this unexplored motif as organocatalysis or incorporation into ligands. Previous strategies for the synthesis of sulfonimidamides have relied on the use of malodorous thiols in long sequential processes, limiting their applications. Only recently has using N-sulfinylamines as a reagent emerged as a useful strategy to access this class of compound, in a one-pot procedure. However the synthesis of enantioenriched sulfonimidamides is still challenging, requiring either preparative HPLC or a chiral auxiliary approach, which has caused a great limitation in the variation of enantioenriched sulfonimidamides observed to date. We have shown that configurationally labile sulfonimidamides are easily prepared and can be subjected to an asymmetric phase-transfer catalysed alkylation to give enantioenriched products in high yields. The reaction involves a novel C-N bond formation to set a sulfur stereogenic centre, using highly modular phase-transfer catalysts. Overall we have developed an operationally simple catalytic asymmetric synthesis of sulfonimidamides which we foresee being of particular interest to industry and the wider chemistry community.

Enantioselective synthesis of sulfonimidamides via organocatalysis

ACS Fall 2020 Virtual Meeting

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