Following the turn of the millennium, the role of asymmetric covalent organocatalysis has developed into a scalable, synthetic paradigm galvanizing the synthetic community toward utilization of these methods for more practical, metal–free syntheses of natural products. A myriad of reports on asymmetric organocatalytic modes of substrate activation relying on small, exclusively organic molecules are delineating what has now become the multifaceted field of organocatalysis paving the way to a vast array of reaction types.
α,β–Unsaturated acylammonium salts, generated in situ from commodity acid chlorides and a chiral isothiourea organocatalyst, comprise a new and versatile family of chiral dienophiles for the venerable Diels–Alder (DA) cycloaddition. Their reactivity is unveiled through a highly diastereo– and enantioselective Diels–Alder/lactonization organocascade that generates cis– and trans–fused bicyclic γ– and δ–lactones bearing up to five contiguous stereocenters. Moreover, the first examples of DA–initiated, stereodivergent organocascades are described delivering complex oxa–bridged trans–fused tricyclic γ–lactams found in bioactive compounds. An evaluation of various experimental and computational parameters was performed in order to derive a more detailed understanding of what renders this process selective. The utility of this methodology is showcased through a concise approach to the core structures of glaciolide, isatisine A and nonpeptidyl ghrelin–receptor inverse agonists, and formal syntheses of indoprofen, dihydrocompactin, fraxinellone, trisporic acids, and trisporols