Organocatalytic (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes: a facile access to enantioenriched 1,2-oxazinanes†

Abstract

The first asymmetric (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes has been demonstrated by secondary amine catalysts. While the other ortho-substituents gave 1,2-oxazinanes, ortho-hydroxy ones provided a novel class of tetrahydrochromeno-1,2-oxazine cores via rare 1,3-aryl migration, followed by cyclization. An unusual type of asymmetric approach was also recognized.

Graphical abstract: Organocatalytic (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes: a facile access to enantioenriched 1,2-oxazinanes Nitrogen-containing enantioenriched heterocycles are ubiquitous structural frameworks that are present in a diverse range of biologically active molecules.1 Among them, chiral 1,2-oxazinanes attracted significant attention owing to their presence in several natural products which exhibit potent biological activities.2 Therefore, a number of methodologies have been developed over the decades for their enantioselective construction by various research groups; however, most of them involve nitrones as a main precursor.3

Nitrones are one of the most useful and easily available starting materials for the construction of various biologically important nitrogen- and oxygen-containing heterocycles.3 Especially, their ability to undergo 1,3-dipolar cycloaddition has attracted remarkable attention from synthetic organic chemists in the past few decades.3 In 2005, Sibi and coworkers reported the first enantioselective (3+3)-cycloaddition of nitrones with cyclopropane dicarboxylates in the presence of Ni(ClO4)2 and a chiral ligand to obtain tetrahydro-1,2-oxazines with high enantiomeric excesses (Scheme 1a).4 Henceforth, several groups utilized this moiety for the asymmetric cycloaddition reaction to achieve enantioenriched heterocyclic frameworks.3 A substantial development has been made for metal-catalyzed enantioselective cycloaddition reactions in the last two decades, but organocatalytic cycloaddition with nitrones has rarely been reported.5 At the very beginning of this century, the first organocatalytic 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes was reported by MacMillan's group using a chiral imidazolidinone based secondary amine catalyst.5a Since this pioneering work, only a few asymmetric transformations were studied with nitrones; however, most of them are (3+2)-type cycloaddition.5 Evidently, organocatalytic enantioselective (3+3)-cycloaddition reactions with nitrones are still underexplored. Recently, in 2020 Shi et al. reported the first organocatalytic (3+3)-cycloaddition reaction of nitrones with 2-indolylmethanols in an asymmetric manner by utilizing the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA) (Scheme 1b).6 In a different way, we sought to develop an enantioselective (3+3)-cycloaddition of nitrones by utilizing secondary amine-based organocatalysis with an appropriate three-carbon reacting partner.