Development of cascade reactions for the concise construction of diverse heterocyclic architectures

Heterocyclic structural architectures occur in many bioactive natural products and synthetic drugs, and these structural units serve as important intermediates in organic synthesis. This Account documents our recent progress in the development of cascade reactions to construct complex carbocycles and heterocycles. We describe the rational design of cascade reactions and in-depth investigations of their mechanism as well as their applications in the synthesis of drugs, natural products, and related molecular analogs. Relying on knowledge about the dipole-type reactivity of sulfur ylides, we have developed three different types of cascade reactions: a [4 + 1] annulation/rearrangement cascade, a [4 + 1]/[3 + 2] cycloaddition cascade, and a Michael addition/N-alkylation cascade. Using these processes, we can generate oxazolidinones, fused heterocycles, and pyrrolines starting with simple and readily available substances such as nitroolefins and unsaturated imines. We have also developed corresponding enantioselective reactions, which are guided by axial chirality and asymmetric H-bonding control. In addition, by relying on the reactivity characteristics of newly designed acrylate-linked nitroolefins, we have disclosed an asymmetric Michael/Michael/retro-Michael addition cascade using the combination of a protected hydroxylamine and a bifunctional organocatalyst. Using this methodology, we prepared chiral chromenes in good yields and with high enantioselectivities. Moreover, a series of double Michael addition cascade reactions with anilines, thiophenols, and benzotriazoles generated highly functionalized chromanes. Via mechanistically distinct cascade processes that start with vinyl-linked indoles, we have synthesized polycyclic indoles. Intermolecular cross-metathesis/intramolecular Friedel-Crafts alkylation cascades, promoted by either a single ruthenium alkylidene catalyst or a sequence involving Grubbs' ruthenium catalyst and MacMillan's imidazolidinone catalyst, converted ω-indolyl alkenes into tetrahydrocarbazoles, tetrahydropyranoindoles, and tetrahydrocarbolines. In addition, we constructed tetrahydrocarbazoles and tetrahydroquinones using organocatalytic Friedel-Crafts alkylation/Michael addition cascades that used 2-vinyl indoles as common starting materials. Most green plants carry out photosynthesis to produce organic substances relying on readily available and renewable solar energy. In a related manner, we have also developed two cascade reactions that merge visible light-induced aerobic oxidation with either [3 + 2] cycloaddition/oxidative aromatization or intramolecular cyclization. These processes lead to the formation of pyrrolo[2,1-a]isoquinolines and enantiopure tetrahydroimidazoles, respectively.