General Method for the Synthesis of α- or β-Deoxyaminoglycosides Bearing Basic Nitrogen

The introduction of glycosides bearing basic nitrogen is challenging using conventional Lewis acid-promoted pathways owing to competitive coordination of the amine to the Lewis acid promoter. Additionally, because many aminoglycosides lack a C2 substituent, diastereomeric mixtures of O-glycosides are often produced. Herein, we present a method for the synthesis of alpha- or beta-2,3,6-trideoxy-3-amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of alpha- and beta-forosamine, pyrrolosamine, acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. alpha-Linked products are obtained in 60-96% yield and with >50:1 selectivity. beta-Linked products are obtained in 45-94% yield and with 1.7->50:1 stereoselectivity. Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored beta-products at low temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.

Automated summary

A strategy for the synthesis of alpha- or beta-2,3,6-trideoxy-3-amino and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor has been presented. This strategy involves reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides, providing high yields and selectivities for the desired products. Furthermore, donors with axial amine substituents favored beta-products at low temperatures, establishing a general strategy for synthesizing O-glycosides bearing basic nitrogen.