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

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′‐dimeth...

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Bibliographic Details
Published in:Advanced synthesis & catalysis 2016-11, Vol.358 (22), p.3522-3527
Main Authors: Haddad, Nizar, Mangunuru, Hari P. R., Fandrick, Keith R., Qu, Bo, Sieber, Joshua D., Rodriguez, Sonia, Desrosiers, Jean-Nicolas, Patel, Nitinchandra D., Lee, Heewon, Kurouski, Dmitry, Grinberg, Nelu, Yee, Nathan K., Song, Jinhua J., Senanayake, Chris H.
Format: Article
Language:English
Subjects:
asymmetric Suzuki reaction
Asymmetry
atropisomers
BI-DIME
Computer simulation
Coupling
heterocycles
Ligands
Mathematical models
phosphine ligands
Selectivity
Substrates
Suzuki coupling
Synthesis (chemistry)
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Summary: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.
ISSN:1615-4150
1615-4169
DOI:10.1002/adsc.201600889