Open AccessConcise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis
Author(s) -
Christine Jérôme,
Ulrike Nettekoven,
Miroslav Kovačevič,
Zdenko Časar
Publication year - 2021
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.1c01614
Subject(s) - enantioselective synthesis , chemistry , hydrosilylation , moiety , catalysis , annulation , nitrile , acetophenone , derivative (finance) , combinatorial chemistry , stereochemistry , organic chemistry , financial economics , economics
A concise six-step asymmetric synthesis of nearly enantiomerically pure ramelteon was developed from a monocyclic precursor with a 17% overall yield and a 97% ee in the asymmetric step. The synthetically challenging tricyclic 1,6,7,8-tetrahydro-2 H -indeno[5,4- b ]furan core of ramelteon was assembled by using Ir-catalyzed O -vinylation and Rh-catalyzed vinyl ether annulation through directed C-H bond activation, while the chirality was introduced with enantioselective reduction of an α,β-unsaturated nitrile moiety under hydrosilylation conditions using a Cu II /Walphos type catalyst. The presented methodology represents the shortest synthetic approach to ramelteon.