Organic Chemistry

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 PTP-1B inhibitory activity, in 10 steps. Over the course of this study, two key methodological advances were made: a cost effective procedure for ketone alpha,beta-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.

Version notes

Version 1.1 - computational study added


Thumbnail image of Granatumine-combined-4-26-19.pdf

Supplementary material

Thumbnail image of C3-epi XF (4).txt
C3-epi XF (4)
Thumbnail image of Diketone (8).txt
Diketone (8)
Thumbnail image of pyroangolensolide (14).txt
pyroangolensolide (14)