Stereodivergent Asymmetric Synthesis of α,β-Disubstituted β-Aminoalkylboronic Acid Derivatives via Group-Selective Protodeboronation Enabling Access to the Elusive Anti Isomer.

Abstract

Chiral β-aminoalkylboronates generate growing interest as versatile synthetic building blocks to access β-aminoalcohols and other useful compounds, and also as bioisosteres of β-amino acids in drug discovery. In this study, the lack of methodology to access both syn and anti diastereomers of optically enriched, acyclic α,β-disubstituted β-aminoalkylboronates is addressed with the development of a divergent, diastereoselective strategy for the monoprotodeboration of β-amino gem-bis(boronate) precursors. To this end, new reaction conditions were successfully optimized to provide the elusive anti diastereomer by inverting a sequence of desulfinylation and protodeboronation. The desired syn or anti isomers are isolated independently in good yields and excellent diastereoselectivity (up to >20:1 dr) for a wide scope of substituents. The diastereotopic group selectivity of the new conditions yielding the anti isomer is rationalized by invoking a reactive rotamer featuring two ammonium-boronate hydrogen bonds, which enables phosphate coordination to boron with a concomitant, stereoretentive protonation of the least sterically hindered C-B bond. The accessibility and utility of both diastereomers of these α,β-disubstituted β-aminoalkylboronates is exemplified with the functionalization of the amino group, stereospecific oxidation to β-amino alcohols and C-C bond transformations of the secondary alkylboronate, and the preparation of free boronic acids and hemiboronic heterocycles.