These natural products stimulated the investigation into a convergent pyridine synthesis approach because of their biological activities. The limonoid alkaloids have been found to act on PTP1B, which is a thoroughly investigated yet historically challenging protein to target for therapeutic intervention. Although PTP1B is classically a target for diabetes, as it regulates insulin production, it has also been shown to play a complicated role in a number of signaling pathways related to obesity More recently, PTP1B overactivation has been shown to lead to neuronal cell death through several downstream events, 12 which hastens the pathological development of neurodegenerative diseases such as Alzheimer's disease. Several pieces of data mark PTP1B and associated proteins as promising new targets for neurodegeneration: (1) PTP1B overactivation deactivates tropomyosin receptor kinase B (TrkB), which is essential in promoting neuronal cell survival and growth through binding to its ligand, brain-derived neurotrophic factor (BDNF); (2) PTP1B inhibition augments the BDNF signaling pathway, and was shown to ameliorate schizophrenia-like behaviors in Lmo4-deficient mice; (3) in a separate study, pharmacological inhibition of PTP1B with trodusquemine prevented hippocampal neuron loss and spatial memory deficits in a mouse model for Alzheimer's Disease (hAPP-J20 mice); 17 (4) encouragingly, inhibition of PTP1B is demonstrated to be a safe mode of action based on other indications in Phase 1 and Phase 1b studies with trodusquemine. The limonoid alkaloids are structurally novel inhibitors of PTP1B and do so through an unknown mechanism of action (granatumine A, IC50 = 23 µM). Our long-term interest in these molecules derives from the hypothesis that they may bind to an uncharacterized allosteric site. We recently documented the chemical synthesis of several limonoid alkaloids including xylogranatopyridine B (1-1) 2f and granatumine A (1-2), 2g through a late-stage pyridine synthesis. The development of such approaches enabled both an efficient access to these natural products and related analogs for SAR studies. Herein we describe the evolution of the synthetic strategies toward these limonoid alkaloids, as well as structural revision of several related natural products guided by NMR-computation. Preliminary PTP1B inhibitory activities of several limonoid alkaloids and their synthetic analogs are also reported.