A Build-Couple-Pair method to synthesize sulfur-containing macrocycles, in particular macrocyclic sulfamoyl carbamates and aza sulfonates, is reported. This approach focuses on the construction of diverse building components to subsequently generate a variety of novel <i>S</i>-macrocycles through a series of reactions we term “Click, Click, Cyclize.” Amino/alcohol components are first constructed to bear alkene and alkyne moieties (Build). Each component then undergoes subsequent regioselective condensation into a bifunctional sulfonyl coupling reagent (Click, Click/Couple), followed by an intramolecular cyclization through ring-closing metathesis (RCM) or ring-closing enyne metathesis (RCEM), resulting in the generation of macrocyclic sulfamoyl carbamates and aza sulfonates in an atom economical fashion (Cyclize/Pair). The initial utilization of this method resulted in eight novel <i>S</i>-macrocycles, while many options for diversification have yet to be explored. Future efforts include synthesizing diversely functionalized amino/alcohol components to further functionalization after the cyclization step for diversified library synthesis.

Development of a build-couple-pair strategy to macrocyclic sulfamoyl carbamates and aza sulfonates

ACS Spring 2022

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