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

Abstract

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.

Asymmetric Organocatalysis: The Emerging Utility of α,β‐Unsaturated Acylammonium Salts

“…34 ) were obtained in high enantiomeric purity and good yields using Birman’s homobenzotetramisole (HBTM) catalyst with ketomalonates and commodity acid chlorides. 15 Importantly, this organocascade highlighted the triple reactivity of the unsaturated acylammonium salt intermediate in its ability to participate first as an electrophile, then a nucleophile through the ammonium enolate, and finally as an electrophile through the acylammonium intermediate. The proposed organocascade involves generation of ammonium enolate 37 by the Michael addition of malonate anion 36 to the α,β-unsaturated acylammonium chloride 35 .…”

“…This results in a three component organocascade affording the complex cyclohexyl fused-tricyclic β-lactone 44 with four contiguous stereocentres with both high enantio- and diastereoselectivity (Scheme 8). 15 …”

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes

“…Romo et al were able to synthesize the required bicyclic fragment, as shown in Scheme 5 [25]. This synthetic methodology is a variant of the previously reported procedure by Zhong et al [26].…”

Utility and NMR studies of α,β-unsaturated acylammonium salts: synthesis of polycyclic dihydropyranones and a dihydropyridone

“…7 These N-heterocyclic carbene (NHC) catalyzed reactions require either a stoichiometric amount of oxidant or functionalized aldehydes or esters as starting materials and have focused primarily on acyclic 1,3-dicarbonyl compounds. 8 These limitations, coupled to our recent studies of chiral α ,β -unsaturated acylammonium salts enabling Michael-aldol-β -lactonization, 9 Michael-proton transfer-lactamization, 10 and Diels-Alder-lactonization 11 organocascades, prompted us to reinvestigate the original idea of making cyclic enol lactones from unsaturated acid derivatives through organocatalysis with achiral and chiral Lewis bases under mild conditions. 12 In particular, the use of mono-and bicyclic 1,3-dicarbonyls in these reactions have not been described and thus we focused on these substrates.…”