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.Protein tyrosine phosphatase 1B (PTP1B) has emerged as an exciting target for the treatment of many ailments, such as diabetes, cancer, and neurodegenerative diseases. 1 Granatumine A (6), a bislactone limonoid alkaloid isolated from the Chinese mangrove (Xylocarpus granatum), has shown moderate inhibitory activity against PTP1B, while the related limonoid alkaloid xylogranatopyridine B (1) was found to be inactive. 2 This increased potency may arise due to the synthetically demanding structural differences, namely the presence of an acid-labile C3 benzylic ether substituent and a reorganized A-ring with a fused lactone.

This review article describes how cationic rearrangement reactions can be used in natural product total synthesis as a case study for the many productive ways by which isomerization reactions are enabling for synthesis.

This manuscript describes predicted NMR shifts for the limonoid natural product xylogranatin F. The 1 H and 13 C NMR shifts of four diastereomers were evaluated by GIAO and hybrid DFT/parametric DU8+ methods. The results of the 1 H and 13 C NMR calculations for both the GIAO method and the DU8+ calculations suggest the revised structure that was recently reassigned by chemical synthesis. Furthermore, we show that while DU8+ provides superior accuracy with less computation time, GIAO points to the correct structure with more distinguishable data in this case study.