Development of α-Selective Glycosylation with l-Oleandral and Its Application to the Total Synthesis of Oleandrin.

This letter describes the development of an α-selective glycosylation using l-oleandrose, a 2-deoxysugar that is frequently found in natural products, and its application to the total synthesis of the natural cardiotonic steroids oleandrin and beaumontoside. To improve the reaction diastereoselectivity and to minimize side-product formation, an extensive evaluation and optimization of the conditions leading to α-selective glycosylation of digitoxigenin with l-oleandrose-based donors was conducted. These studies led to the exploration of 8 different phosphine·acid complexes or salts and yielded HBr·PPh as the optimal catalyst, which provided in the cleanest α-glycosylation and produced protected beaumontoside in 67% yield. Subsequent application of these conditions to synthetic oleandrigenin afforded the desired α-product in 69% isolated yield─enabling the completion of the first synthesis of oleandrin in 17 steps (1.2% yield) from testosterone.