ABSTRACT
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.
ABSTRACT
Base-catalyzed rearrangement of 2H-indazoles 1-oxides, prepared by tandem carbon-carbon followed by nitrogen-nitrogen bond formations from easily accessible N-alkyl-2-nitro-N-(2-oxo-2-aryl-ethyl)-benzenesulfonamides using glycine, 2-nitrobenzenesulfonyl chlorides, and bromo ketones/acetates, yielded high purity quinazolines.
Subject(s)
Imino Acids/chemistry , Indazoles/chemistry , Ketones/chemistry , Nitrophenols/chemistry , Oxides/chemistry , Quinazolines/chemical synthesis , Sulfonamides/chemistry , Catalysis , Indazoles/chemical synthesis , Molecular Structure , Oxides/chemical synthesis , Quinazolines/chemistry , BenzenesulfonamidesABSTRACT
1,10-Phenanthroline is derivatized and ultimately immobilized on two different polystyrene/divinylbenzene solid supports using convenient methodology. All syntheses are amenable to semiautomatic processing and are scalable for high-throughput screening. A domino copper-catalyzed coupling-cyclization reaction is used to illustrate applicability in catalytic studies.
