PAIRWISE OXIDATIVE DEAROMATIZATION AND N-HYDROXYCARBAMATE DEHYDROGENATION: MOLECULAR COMPLEXITY VIA AN ACYLNITROSO DIELS–ALDER CYCLOADDITION CASCADE INSPIRED BY TETRODOTOXIN

I. Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin. Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. Drawing inspiration from the complex natural product tetrodotoxin, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso DielsAlder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. II. Oxidative Dearomatization/Acylnitroso Diels–Alder Cycloaddition Cascade: An Approach Toward the Total Synthesis of (±)-Tetrodotoxin Tetrodamine, a common conceptual intermediate en route to tetrodotoxin, represents a challenging synthetic target due to its densely functionalized cyclohexane core. Capitalizing on the latent functionality embedded within the benzenoid nucleus, we deploy an oxidative dearomatization/acylnitroso Diels–Alder cycloaddition cascade to access a highly functionalized cyclohexanone intermediate bearing structural and stereochemical features in common with tetrodamine.Doctor of Philosoph