Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates

Abstract

With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres 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. Here, we describe a 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 up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael-Michael-aldol-β-lactonization.

Figure 1. Natural products and pharmaceutical agents bearing complex cyclopentanes and accessible cyclopentyl systems employing the described NCMAL process

a, Bioactive natural products and drugs including polycyclics possessing highly substituted cyclopentane cores (red). b, Natural products possessing β-lactone-fused cyclopentanes (red). c, Several diverse cyclopentane scaffolds accessible by the described nucleophile-catalyzed, Michael-aldol-β-lactonization (NCMAL) process.

Figure 2. Generation and reactivity of the chiral unsaturated acylammonium 3 with contrast to related chiral intermediates 4–6 and a proposed catalytic cycle leading to bicyclic-β-lactones 14

a, Proposed synthesis of α,β-unsaturated acylammonium intermediate 3 from acid chlorides 1 and nucleophilic amines 2. b, Related chiral intermediates include the acylammonium intermediate 4, ammonium enolate 5, and ammonium dienolate 6. c, The latent, triple reactivity of the α,β-unsaturated acylammonium 3 first leads to an ammonium enolate 7 following Michael addition. The latter nucleophilic intermediate leads to α-substitution delivering acyl ammonium 8 and final acyl substitution leads to overall functionalizaton of three carbons of an α,β-unsaturated acid halide 1. d, Proposed catalytic cycle employing a latent, triply-reactive species 10, such as the keto anion 11, possessing two nucleophilic and one electrophilic site, capable of reaction with unsaturated acyl ammonium 3 to form three bonds resulting in cyclopentanes 14 bearing a fused β-lactone through a Michael-aldol-lactonization organocascade process.

Figure 3. Rapid molecular complexity generation, structural modifications of cyclopentane products, and extensions of both accessible Michael donors and unsaturated acyl ammonium intermediates

[All NCMAL reactions were performed under standard reaction conditions shown in Table 2 unless noted otherwise.] a, Monocyclic Michael donors with acrylolyl chloride deliver tricyclic 5,5- and 5,6-fused cyclopentyl systems 14t and 14u; b, bridged tricylic cyclopentanes; and c, Truncated steroid intermediates through bis-decarboxylation; d, Mild Pd(0)-mediated reductive decarboxylations leads to cyano substituted cyclopentane 14x. e, Application of aldehyde-containing Michael donors. f, In situ generation of tosyl anhydrides delivers tricyclic 5,5,4-systems from starting carboxylic acids. Relative stereochemistry determined by X-ray analysis (Supplementary, Fig. S8).