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

Abstract

Metrics & More Article RecommendationsCONSPECTUS: 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 Nheterocycles, 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 metaland 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 allcarbon 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 d...

Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement

“…The broad range of synthesis applications of these heterocycles requires highly modular approaches that allow for selective modification of the entire substitution pattern (12 regioisomers in total) . While condensation chemistry has dominated classical furan syntheses in the past, modern synthesis strategies are primarily based on the cyclization of linear precursors employing transition-metal catalysts . We now demonstrate the simple and rapid conversion of readily available 2,5-di­hydro­thiophenes 4 into tetrasubstituted furans 7 at ambient temperatures under metal-free reaction conditions (Scheme B).…”

High-order dipolar annulations with metal-containing reactive dipoles

“…MCRDs derived from metal carbenoids are type-II dipolar synthons in which the metal is located in the anionic part. Inspired by pioneering work on carbonyl ylides generated from diazo or alkyne groups and carbonyl groups, 88,89 many research groups developed a wide range of HODA reactions using carbene-metal-derived MCRDs. 90 An overview of reaction pathways was shown in Fig.…”

Gold(i)-catalyzed diastereo- and enantioselective [4 + 3] cycloadditions: construction of functionalized furano-benzoxepins

“…Since Larock's seminal report, 4 catalytic transformations from readily available yne-enones, such as 2-(1-alknyl)-2-alken-1-ones, have emerged as a powerful and reliable tool towards furan derivatives. 5 Among the numerous reports, the in situ generated gold-furyl 1,3-dipole intermediates Int-1 via gold-mediated transformations of 2-(1-alknyl)-2-alken-1-ones played an important role because of their various applications as versatile synthons in the synthesis of furan-fused molecules (Scheme 1A). 5 e Thanks to the “gold rush” of gold catalysis in the last few decades, 6 gold-catalyzed asymmetric cycloadditions involving 2-(1-alknyl)-2-alken-1-ones have been well developed, furnishing novel ways of constructing chiral furan-fused frameworks, such as asymmetric [3 + 2] cycloadditions with olefins and [3 + 3] versions with nitrones, respectively (Scheme 1A).…”