Metal-Free meta-Selective Alkyne Oxyarylation with Pyridine N-Oxides: Rapid Assembly of Metyrapone Analogues

Xiangyu Chen; Stefan A Ruider; Rolf W Hartmann; Leticia González; Nuno Maulide

doi:10.1002/anie.201607988

Metal-Free meta-Selective Alkyne Oxyarylation with Pyridine N-Oxides: Rapid Assembly of Metyrapone Analogues

Angew Chem Int Ed Engl. 2016 Dec 5;55(49):15424-15428. doi: 10.1002/anie.201607988. Epub 2016 Nov 9.

Authors

Xiangyu Chen¹, Stefan A Ruider^{1

2}, Rolf W Hartmann³, Leticia González², Nuno Maulide¹

Affiliations

¹ Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, 1090, Vienna, Austria.
² Institute of Theoretical Chemistry, University of Vienna, Währinger Strasse 17, 1090, Vienna, Austria.
³ Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research, Campus E8.1, 66123, Saarbrücken, Germany.

PMID: 27862782
DOI: 10.1002/anie.201607988

Abstract

An efficient metal-free oxyarylation of electron-poor alkynes with pyridine N-oxides has been developed. This transformation affords meta-substituted pyridines analogous to the drug metyrapone in high regioselectivities. Density functional theory (DFT) calculations provided important insight into the mechanism. Evaluation of the inhibitory properties revealed the most active CYP11B1 inhibitor of these derivatives, with two-digit nanomolar inhibitory activity akin to that of metyrapone.

Keywords: 11β-hydroxylase (CYP11B1); alkynes; density functional calculations; oxyarylations; pyridine N-oxides.

Publication types

Research Support, Non-U.S. Gov't