Copper-Catalyzed Asymmetric Cyclizative Sulfinamidation: Forging Indole-Based Stereogenic Sulfur(IV) Centers and Atropisomeric Chirality

The structural prominence of indole-based sulfur-containing
compounds
in pharmacologically relevant substances stems from their versatile
biofunctional capabilities. Despite their significance, the stereogenic
elements embedded in these structures have frequently been overlooked
in drug discovery endeavors primarily due to the absence of efficient
synthetic methodologies. Here, we introduce a groundbreaking strategy
for the enantioselective synthesis of indole-based sulfinamides via
a copper-catalyzed asymmetric nucleophilic cyclization and sulfinamidation
reaction. Utilizing ortho-alkynylanilines and sulfinylamines,
this method achieves a broad spectrum of sulfinamides with complete
atom economy, establishing a new paradigm in synthetic efficiency.
Our approach not only facilitates the formation of S-chirogenic sulfinamides
but also concurrently constructs products featuring both stereogenic
sulfur and atropisomeric chirality. Comprehensive mechanistic investigations,
complemented by density functional theory (DFT) calculations, provide
deep insights into the reaction mechanism, particularly in elucidating
the S-stereogenic and atropisomeric control during the cyclization
and sulfinamidation processes.