Project Summary/abstract The nitrogen-containing heterocycle is a privileged motif that is found widely in compounds with medicinal properties, in both pharmaceuticals and natural products. More specifically, the most common nitrogen-containing heterocycle is the piperidine ring, which is present in a number of top-selling drugs. Accessing highly decorated piperidines rings is often challenging and can rely on multi-step synthesis for stereo-defined decoration of these rings. This proposal aims to leverage the strain-promoted reactivity found in azacyclic allenes for access to the highly decorated piperidine ring found at the core the natural product keramaphidin B. This natural product belonging to the manzamine family shows potent anticancer properties and only one reported synthesis is known, which proceeded in 1% yield for the product-generating step. The difficulty inherent in the synthesis can be understood by examining the complexity of the strained polycyclic alkaloid. The core of keramaphidin B is built on a piperidine ring fused to a [2.2.2] quinuclidine azabicycle. Challenging motifs in the compound include four contiguous stereocenters with one being a quaternary stereocenter that is a member of a macrocyclic ring. The two macrocyclic rings, 11- and 13-membered, each possess transannular strain and (Z)-olefin moieties. While these functionalities will be difficult to incorporate, using an unconventional enantioenriched azacyclic allene will address several of these challenges in a single step. In one (4+2) Diels– Alder cycloaddition reaction, two 2 C–C bonds will be accessed, while simultaneously setting the absolute stereochemistry of the quaternary center. As this step will occur intramolecularly between an azacyclic allene and a 2-pyrone, macrocyclization of the 13-membered ring will also be accomplished. Using this strategy as the key step should allow for a concise synthesis of keramaphidin B, in as few as 16 steps.