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·PPh3 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 yieldenabling the completion of the first synthesis
of oleandrin in 17 steps (1.2% yield) from testosterone.
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