Traceless Solid-Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint-Assisted Cyclic Iminium Formation.

Natural products comprising chiral molecular scaffolds containing fused medium-sized cycles and macrocycles represent an important and relevant pharmacological target for the discovery and development of new drugs. Here, we describe traceless solid-phase synthesis of acyclic intermediates amenable to cyclization to medium (11) and large (12) fused rings. The key aspect of the synthetic strategy is incorporation of a specific conformation constraint that facilitates cyclization in favor of 11- and 12-membered rings rather than possible 7-membered ones. The role of constraints in preorganization required for cyclization is supported by computational analysis. The synthesis involves cyclic N-sulfonyliminium-nucleophilic addition chemistry as the key ring-forming reaction and proceeds with complete stereocontrol of the newly formed stereogenic center. We document the scope and limitations of this strategy in the synthesis of 11+5, 11+6, 11+7, and 12+6 fused rings representing molecular scaffolds with 3D architecture that mimic complex natural products.