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Reengineered BI‐DIME Ligand Core Based on Computer Modeling to Increase Selectivity in Asymmetric Suzuki–Miyaura Coupling for the Challenging Axially Chiral HIV Integrase Inhibitor
Author(s) -
Haddad Nizar,
Mangunuru Hari P. R.,
Fandrick Keith R.,
Qu Bo,
Sieber Joshua D.,
Rodriguez Sonia,
Desrosiers JeanNicolas,
Patel Nitinchandra D.,
Lee Heewon,
Kurouski Dmitry,
Grinberg Nelu,
Yee Nathan K.,
Song Jinhua J.,
Senanayake Chris H.
Publication year - 2016
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201600889
Subject(s) - chemistry , integrase , quinoline , selectivity , combinatorial chemistry , ligand (biochemistry) , asymmetric hydrogenation , coupling (piping) , stereochemistry , catalysis , enantioselective synthesis , organic chemistry , receptor , mechanical engineering , biochemistry , engineering , gene
Through a computer‐guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki–Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI‐DIME, leading to the discovery of the 3′,5′‐dimethyl‐substituted ligand which improved the atropisomeric selectivity of the Suzuki–Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates.