Development of synthetic methods to access potentially bioactive substituted 3-, 4-, 5-membered rings and macrocycles

Abstract

The development of biologically active compounds with enhanced three-dimensional character is an important strategy for expanding chemical space beyond conventional planar molecular architectures. This account describes synthetic approaches to strained-ring and macrocyclic compounds using transition-metal catalysis and biocatalysis. Substituted 3-, 4-, and 5-membered rings were synthesized through transition-metal-catalyzed cross-coupling reactions of Grignard reagents with alkyl, vinyl, and aryl halides. In particular, nickel-catalyzed cross-coupling of protected 2-iodo-D-ribals with diverse Grignard reagents provided functionalized products that were subsequently transformed into nucleosides. Cobalt catalysis enabled the synthesis of substituted cyclopropanes and cyclobutanes from the corresponding strained-ring Grignard reagents and alkyl halides, whereas copper catalysis afforded substituted bicyclo[1.1.1]pentanes. In addition, enantio- and chemoselective enzymatic reductions of unsaturated 3- and 4-membered rings were achieved using ene reductases (EREDs). As an approach to macrocyclic architectures, [n]paracyclophanes were synthesized from tricyclic dienes and activated alkynes through a one-pot Diels–Alder/retro-Diels–Alder sequence. Collectively, these synthetic strategies provide efficient access to structurally diverse, three-dimensional strained-ring and macrocyclic scaffolds with potential applications in medicinal and pharmaceutical chemistry.