Toward improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocenters in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Herein, we describe a novel Michael-aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C-C bonds, one C-O bond, two rings, and three contiguous stereogenic centers delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that unsaturated acyl ammonium intermediates have broad utility for the design of organocascade and multicomponent processes with the latter demonstrated by a Michael-Michael-aldol-β-lactonization.

An improved, tandem acid activation/aldol-lactonization process is described. This more practical protocol shortens reaction times for the construction of bicyclic β-lactones from ketoacids and implements the use of commercially available reagents p-toluenesulfonyl chloride (p-TsCl) as activator and 4-dimethylaminopyridine (4-DMAP) as nucleophilic promoter (Lewis base). Substrates with β-substituents, with respect to the carboxylic acid, consistently showed excellent levels of diastereoselectivity during the bis-cyclization event.

No abstract