Synthesis of chiral spiro-heterocyclic azides via asymmetric [4+2]cycloaddition of conjugated vinyl azide

Abstract

Chiral spiro-heterocyclic scaffolds are prevalent in numerous bioactive molecules and pharmaceuticals, yet their asymmetric synthesis remains rare. In this study, we achieved a highly enantioselective and diastereoselective [4+2]-cycloaddition reaction of 1-(1-azidovinyl)-cyclohex-1-ene with aurones and (E)-alkenyloxindoles mediated by chiral N,N′-dioxide/metal complexes. This approach efficiently delivered enantioenriched [6,5] spiro-heterocyclic azides with three contiguous stereocenters with good yields and excellent stereoselectivities. The derivatization of the products yielded valuable functional groups and structures, such as seven-membered lactams, diols, and ketones, underscoring the utility and versatility of this methodology. Possible transition state models were proposed to elucidate the observed stereo-induction.