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Atroposelective Synthesis of Axially Chiral 4-Aryl-isoxazolo[5,4-b]pyridines by Relay Catalysis
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DOI：10.1002/cjoc.70674.png)
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Abstract
En 中文
Heterobiaryl atropisomers represent a kind of highly valuable scaffolds in drug development and asymmetric catalysis. Although significant progress has been made in atroposelective construction of such kind of scaffolds, exploration of asymmetric synthesis of diverse novel heterobiaryl atropisomers is still desirable. Herein, we report a relay catalytic strategy for the atroposelective synthesis of a kind of novel axially chiral heterobiaryls. By relay catalysis of chiral phosphoric acid and silver nitrate, an atroposelective cascade reaction involving [3+3] cyclization of α-(3-isoindolinonyl) propargylic alcohols with 5-aminoisoxazoles or 5-aminopyrazole followed by ring-opening and proton transfer has been accomplished. This transformation allowed the construction of various novel axially chiral 4-aryl-isoxazolo[5,4-b]pyridines with low to moderate yields (20%–80%) in moderate to excellent enantioselectivities (38%–98% ee). Afterward, the absolute configurations of one product and the intermediate were determined by X-ray crystal structural analyses. Subsequently, a series of control experiments revealed a cascade reaction mechanism in which the central-to axial chirality conversion is the key step of the establishment of the atropisomerism.
Keywords:
Asymmetric synthesis
Relay catalysis
Phosphoric acid
Silver nitrate
Cascade reaction
4-Aryl-Isoxazolo[5,4-b]pyridines
Chirality conversion
Axial chirality
Heterobiaryl atropisomers
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