The aforementioned biosynthetic pathway takes a stereochemically dense mexicanolide (2-1) and inserts a highly functionalized pyridine at the center. A more effective synthetic approach to enable analog synthesis would be to dissect the pyridine in half, generating two fragments of similar complexity. We began our retrosynthetic analysis of xylogranatopyridine B (1-1) with structural simplification of the limonoid A-ring, which would give intermediate 3-1 (Scheme 3). In a forward sense, a selective benzylic oxidation and vicinal difunctionalization of 3-1 would allow for the introduction of requisite moieties. With access to the tetracyclic core (3-1) regarded as a key structural goal, it was hypothesized that the tetrasubstituted pyridine could be constructed by a variety of ring synthesis strategies. Accordingly, several pathways were considered and implemented. Initially, we planned that 3-1 could be obtained via a stepwise Risch pyridine synthesis, employing 1,3-diketone 3-2 and β-amino ketone hydrochloride 3-3, to assemble the C8-C30 and the critical N-C9 linkage. Further retrosynthetic reasoning led us to consider several cross-coupling approaches to synthesize the demanding pyridine core. A Stille coupling strategy between a stannane such as 3-4 and a vinyl triflate 3-5 could result in 3-1 after subsequent condensation of an ammonia equivalent and oxidative 6π-electrocyclization. Alternatively, initial formation of the challenging N-C9 bond followed by the C8-C30 bond, through a Liebeskind pyridine synthesis between 3-6 and 3-7, would fashion the central pyridine. 7c