Yne-Enones Enable Diversity-Oriented Catalytic Cascade Reactions: A Rapid Assembly of Complexity.

Abstract

A small-molecule collection with structural diversity and complexity is a prerequisite to using either drug candidates or chemical probes for drug discovery and chemical-biology investigations, respectively. Over the past 12 years, we have engaged in developing efficient diversity-oriented cascade strategies for the synthesis of topologically diverse skeletons incorporating biologically relevant structural motifs such as O- and N-heterocycles, fused polycycles, and multifunctionalized allenes. In particular, we have highlighted the use of simple, linear, and densely functionalized molecular platforms in these reactions.This account details our efforts in the design of novel molecular platforms for use in metal- and organo-catalyzed cascade reactions, which include 2-(1-alknyl)-2-alken-1-ones (yne-enones) for heterocyclization/cross-coupling cascades, heterocyclization/cycloaddition cascades, nucleophilic addition/cross-coupling cascades, nucleophilic addition/heterocyclization cascades, and so on. Moreover, this Account outlines corresponding mechanistic insights, computational information, and applications of these cascades in the construction of various highly substituted carbo- and heterocycles as well as highly functionalized acyclic compounds, e.g., allenes and dienes. In addition to yne-enones, we evolved the functional groups of our original yne-enones to provide a series of yne-enone variants, which resulted in products with complementary reactivities.The reactivity profile of the yne-enones is defined by the presence of an alkyne moiety and a conjugated enone unit and their mutual through-bond connectivity. Owing to the conceptually rapid development of carbophilic activation, we have identified a series of efficient catalytic systems consisting of metal catalysts, including Pd, Au, and Rh complexes, for diversity-oriented cascade catalysis, allowing various unprecedented reactions to be achieved through different-types of reaction intermediates, including all-carbon metal 1,n-dipoles, furan-based o-quinodimethanes (oQDMs), and allenyl-metal species. In addition to commonly known transition-metal catalytic activity, the Lewis acidity of these complexes is crucial to accomplish the corresponding transformation. In addition, highly enantioselective gold(I)-catalyzed heterocyclization/cycloaddition cascades of yne-enones and their variants were achieved by the application of bisphosphines (e.g., Cn-TunePhos), monophosphines, and our developed "Ming-Phos" as chiral ligands. Importantly, Ming-Phos ligands exhibited excellent performance in gold-catalyzed mechanistically distinct [3 + n]-cycloaddition reactions, in which the chiral sulfinamide moiety is possibly responsible for the interaction with the substrate to control enantioselectivity. Subsequently, we demonstrated that the easily prepared polymer-supported Ming-Phos ligand could be applied for heterogeneously gold(I)-catalyzed asymmetric cycloaddition with good stereocontrol. With metal-free catalysis, the divergent functionalization of yne-enones provides numerous synthetic outlets for structure diversification. For example, yne-enones are particularly attractive for use as precursors of various chiral and achiral heterocycles, such as pyrazoles, isoxazoles, pyrroles, and pyrans, etc.