Open AccessFrom Metallacycle-Mediated Annulative Cross-Coupling to Steroidal Tetracycles through Intramolecular C9–C10 Bond Formation
Author(s) -
Adam B Millham,
Chinmay P. Bhatt,
Glenn C. Micalizio
Publication year - 2020
Publication title -
organic letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.94
H-Index - 239
eISSN - 1523-7060
pISSN - 1523-7052
DOI - 10.1021/acs.orglett.0c02358
Subject(s) - chemistry , intramolecular force , stereochemistry , metallacycle , annulation , substitution (logic) , aryl , alkyl , organic chemistry , catalysis , x ray crystallography , physics , computer science , diffraction , optics , programming language
While semisynthesis is a common platform for medicinal investigation of steroidal systems, varying the nature of substitution and stereochemistry at C9 and C10 remains challenging. It is demonstrated here that de novo synthesis, enabled by a metallacycle-centered annulation reaction, provides a uniquely effective means of addressing this problem. In short, double asymmetric Friedel-Crafts cyclization proved most effective for establishing anti - relative stereochemistry (with respect to C13), while an intramolecular Heck reaction reliably delivered the syn - diastereomers with high selectivity. In addition, these studies reveal that this oxidative rearrangement is effective for establishing a C10 quaternary center boasting variable alkyl or aryl substitution.