Open Access11-Step and Scalable Total Synthesis of Hamigeran M Enabled by Five C–H Functionalizations
Author(s) -
Baiyang Jiang,
Mingji Dai
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c11060
Subject(s) - chemistry , borylation , negishi coupling , metalation , oxazole , halogenation , electrophile , hydroxylation , stereochemistry , moiety , total synthesis , combinatorial chemistry , medicinal chemistry , organic chemistry , catalysis , aryl , alkyl , enzyme
We report the convergent total synthesis of (±)-hamigeran M, enabled by five C-H functionalization reactions and proceeding in 11 steps in 3.9% overall yield. The C-H functionalizations include a hydroxy-directed C-H borylation, one C-H metalation-1,2-addition, one C-H metalation-Negishi coupling, a late-stage oxazole-directed C-H borylation-oxidation, and one electrophilic bromination. Two of these five C-H functionalizations forged strategic C-C bonds in the seven-membered ring of hamigeran M. The oxazole-directed C-H borylation-oxidation was unprecedented and ensured a late-stage hydroxylation. Other key steps include a tandem Suzuki reaction-lactonization to join the cyclopentane building block with the aromatic moiety and a hydrogen-atom transfer reaction to reduce a challenging tetrasubstituted double bond.