Acetylenes in the Superbase-Promoted Assembly of Carbocycles and Heterocycles

In this Account, we briefly discuss the recently discovered and rapidly developing superbase-promoted self-organization reactions of several equivalents of acetylenes and ketones to afford complex compounds that represent promising synthetic building blocks common in natural products. Notably, acetylenes play a special role in these reactions because of their dual (acting as an electrophile and a nucleophile) and flexible reactivity. These unique properties of acetylenes are elegantly expressed in superbasic media, where acetylenes are more deprotonated and their electrophilicity increases as a result of complexation with alkali metal cations, with simultaneous enhancement of the nucleophilic reactants due to desolvation. Under these conditions, acetylenes behave as a driving and organizing force toward other reactants. Various combinations of nucleophilic addition to the triple bond and acetylene deprotonation in the presence of other reactants with dual reactivity (e.g., ketones) enables the self-organization of complex molecular architectures that are inaccessible by conventional reactions. Herein we analyze recent achievements in this area concerning the reactions of acetylenes with ketones in superbasic KOH/DMSO-type systems that selectively afford synthetically and pharmaceutically valuable carbo- and heterocycles. Most of the reactions are triggered by the nucleophilic addition of deprotonated ketones (enolate anions) to acetylenes (superbase-catalyzed C-vinylation of ketones with acetylenes, which was recently introduced by our group into a toolkit of organic chemistry). The β,γ-ethylenic ketones thus formed can then take part in cascade processes with ketones and acetylenes to afford either carbocycles (e.g., hexahydroazulenones, acyl terphenyls, functionalized and cyclopentenols) or heterocycles (e.g., furans, benzoxepines, dioxabicyclo[3.2.1]octanes, and dioxadispiro[5.1.5.2]pentadecanes), depending on the structure of the reactants and the reaction conditions. Most of these compounds are selectively built from several equivalents of ketones and acetylenes in different combinations, and despite the presence of two or more asymmetric carbons in the products, they are generated as single diastereomers. When other nucleophiles (hydroxylamine, hydrazines, guanidine, and oximes) and ketones are involved in these self-organization processes, the intermediate β,γ-ethylenic ketones allow the formation of diverse heterocyclic systems (pyrroles, isoxazolines, pyrazolines, aminopyrimidines, and azabicyclo[3.1.0]hexanes). The discovered unique chemical transformations do not require transition metal catalysts and proceed under mild and operationally simple conditions. Most of these syntheses involve cascade addition reactions and therefore represent pot-, atom-, step-, and energy-saving processes that meet the requirements of green chemistry. The significance of the approach discussed herein is that it represents a viable alternative to existing classic and modern transition-metal-based catalytic syntheses of some fundamental carbo- and heterocycles. This is demonstrated by its employment of readily available, inexpensive starting materials like acetylenes and ketones and simple, widely accessible superbasic systems such as KOH/DMSO, which serves as a highly active universal catalyst and auxiliary. As shown in this Account, as this approach has developed, the number of preparatively attractive methods for the synthesis of diverse and potentially useful compounds has rapidly ballooned. The impressive experimental results presented in this Account will hopefully draw the attention of large circles of organic chemists involved in the design of rational and ecologically sound synthetic procedures and thus increase the application of these techniques in medicinal chemistry and materials science.