Total Synthesis of (+)-Granatumine A and Related Bislactone Limonoid Alkaloids via a Pyran to Pyridine Interconversion

We report the first
total synthesis of (+)-granatumine A, a limonoid
alkaloid with PTP1B inhibitory activity, in ten steps. Over the course
of this study, two key methodological
advances were made: a cost-effective procedure for ketone α,β-dehydrogenation
using allyl-Pd catalysis, and a Pd-catalyzed protocol to convert epoxyketones
to 1,3-diketones. The central tetrasubstituted pyridine is formed
by a convergent Knoevenagel condensation and carbonyl-selective electrocyclization
cascade, which was followed by a direct transformation of a 2H-pyran to a pyridine. These studies have led to the structural
revision of two members of this family.