Enantioselective Formation of Isoxazolidines via Brønsted-Base Catalyzed (3 + 2) Annulation of Cyclopropanes with Nitrosoarenes

Abstract

Enantioselective transformations of donor–acceptor cyclopropanes have opened a new chemical space for the construction of enantioenriched molecules. This work presents the first catalytic enantioselective synthesis of isoxazolidines─a privileged key-structure in organic and medicinal chemistry─through a Brønsted-base catalyzed (3 + 2) annulation of donor–acceptor cyclopropanes with nitrosoarenes. The reaction concept is general, scalable to gram-scale, and enables the reaction between cyclopropanes, substituted with ketones, aldehydes, esters, thioesters, or sulfones, and nitrosoarenes with different substitution patterns, yielding isoxazolidines in generally excellent yields (up to 98%) and enantioselectivities (up to 97% ee). For the (3 + 2) annulation of β-cyclopropyl ketones with nitrosobenzenes, a Hammett study was conducted to elucidate the role of substituents on enantioselectivity. The isoxazolidines can undergo different transformations, such as oxidative cleavage of the N-PMP-group or N–O bond cleavage by LiAlH₄, where the two cyano groups are key-functionalities, as this reaction also provided the simultaneous didecyanation and reduction of the carbonyl, affording attractive 5-amino-1,3-diols, a scaffold present in drugs like atorvastatin. Finally, a mechanistic model is proposed to account for the stereochemical outcome of the (3 + 2) annulation.