Orthogonal nucleophile-ordered assembly for modular access to enantiopure 1,2-amino alcohols.

The programmed assembly of multiple common chemicals with minimal reactivity differences into complex chiral architectures with high selectivity is a long-standing challenge in synthetic chemistry. Here we report a palladium-catalysed orthogonal multicomponent strategy that enables the sequential incorporation of two native N-H/O-H nucleophiles with similar reactivity into propargylic carbonates through a nucleophile-ordered assembly. Leveraging the tandem reactivity of the propargyl-palladium complex, this system functions as a sorting mechanism: stronger nucleophiles undergo outer-sphere addition to the propargyl-palladium intermediate, while weaker nucleophiles, guided by superior coordinating affinity, selectively attack the resulting allyl-palladium species through an inner-sphere mechanism. This strategy enables the precise recognition and ordered incorporation of diverse native nucleophile pairs, providing a platform and modular access to valuable chiral 1,2-amino alcohols and 1,2-diols with exceptional regio-, chemo-, Z- and enantiocontrol. This work demonstrates how subtle reactivity differences can be systematically harnessed for programmable complex synthesis from fundamental feedstocks.