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Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation
Author(s) -
Schütznerová Eva,
Oliver Allen G.,
Slough Greg A.,
Krchňák Viktor
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201702461
Subject(s) - iminium , solid phase synthesis , constraint (computer aided design) , phase (matter) , chemistry , combinatorial chemistry , materials science , organic chemistry , catalysis , mathematics , biochemistry , geometry , peptide
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.