RadCrossSyn · Radical and Radical-Polar Crossover Logic in Terpenoid Synthesis

The synthesis of complex natural products has shaped the field of organic chemistry, with translational applications spreading further into medicinal, agrochemical, and material sciences. As the largest class of natural products, terpenoids play a variety of roles in mediating antagonistic and beneficial interactions macroscopically, i.e., among organisms, and microscopically, i.e., on a (sub)cellular level. They defend many species of plants, animals, and microorganisms against predators, pathogens, and competitors, and they are involved in conveying messages within these organisms.Facilitating and streamlining the access to the most complex terpenoids, heavily rearranged and highly oxidized triterpenoids, requires an understanding of Nature’s ways to biosynthesize these structures, i.e., of their biogenesis. Biomimetic synthesis can only then provide routes which outrival classical retrosynthetic planning. In the absence of a plausible biogenesis proposal, this strategy is not accessible, though.So far, biogenesis proposals have, in lieu of validated intermediates and enzymes, followed the paradigm of polar mechanisms and evoked standard textbook reactions involving ionic intermediates to account for skeletal rearrangements.The aim of this project is to disprove this paradigm and cross this perceived limit of reactivity.Thus, we will here provide chemical proof that terpenoid biogenesis is not sufficiently explained by polar mechanisms, but rather is an intricate interplay of radical and polar reactivity. The border we attempt to cross is the one between two very different chemical entities: radicals and ions.Development of radical-polar crossover logic will evolve robust and selective routes to access drugable triterpenoid natural products modulating the immune system, targeting cancer, and combating pathogens. Added value comes from the involvement of modern photoredox catalysis strategies to initiate radical-polar crossover cascades in sustainable fashion.