Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates (original) (raw)

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 CC bonds, one CO 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-βlactonization. Synthetic transformations that rapidly assemble complexity are actively being pursued given the importance of these processes for improvements in synthetic efficiency. In this regard, domino, 1,2 tandem, 3 and most recently organocascade 4,5 processes have emerged as some of the most useful strategies for quickly generating structural complexity. 6,7 Such methods for the construction of 6-membered carbocycles are numerous and include a range of classical methods with the Robinson annulation, 8 the cationic polyene olefin cyclization, 9 and the venerable Diels-Alder reaction 10 serving as benchmarks. By contrast the construction of 5membered carbocycles falls short of such diverse and widely used methods. 11 While several elegant strategies exist for 5-membered carbocycle synthesis or annulation including the Pauson-Khand reaction, 12 trimethylenemethane [3+2] cycloaddition, 13 photochemical olefin-arene cycloaddition, 14 and the Nazarov cyclization, 15 most of these methods deliver cyclopentanes possessing no more than two stereogenic centers and most are not