Synergistic Cu–amine catalysis for the enantioselective synthesis of chiral cyclohexenones † - Aix-Marseille Université Access content directly
Journal Articles Chemical Communications Year : 2015

Synergistic Cu–amine catalysis for the enantioselective synthesis of chiral cyclohexenones †


An unprecedented utilization of 1,3-acetonedicarboxylic acid as a 1,3-bis-pro-nucleophile and a reactive acetone surrogate in enantio-selective catalysis has been reported. By synergistically activating the ketodiacid by copper catalysis and an a,b-unsaturated aldehyde by amine catalysis, an efficient domino di-decarboxylative Michael/aldol/ dehydration sequence takes place leading to valuable chiral cyclo-hexenones in one single operation in 94 to 99% ee. To fulfil the ideal of eco-compatible reactions, scientists continuously need to discover innovative activation modes able to perform unprecedented cascade transformations from simple molecules to complex architectures with a perfect control of stereoeselectivity. 1 In that regard, synergistic catalysis where different catalytic species are able to selectively activate different reaction partners has recently demonstrated its potential in the discovery of new previously inaccessible chemical transformations notably pioneered by the work from the group of Krische. 2 In this particular field, association of copper salts with organo-catalysts has proven efficient for the stereoselective activation of numerous nucleophilic and electrophilic partners. 3 Notably, copper and iminium activation could be combined synergistically, providing an improved route for the preparation of b-chiral aldehydes. 4 1,3-Acetonedicarboxylic acid (1) is an intriguing molecule possessing two pendant carboxylic acid functions that can potentially be involved in double biomimetic-like decarboxylative enolate formation rendering the corresponding acetone a,a 0-dianion easily available. 5 Prepared on a large scale from raw material namely citric acid, it can act as a potential reactive di-nucleophilic acetone surrogate. 6 This property was famously applied by Robinson in his 1917 tropinone synthesis and has since then found intensive utilization in the synthesis of tropinone like skeletons. 7 But quite surprisingly, despite its huge potential and to our knowledge there are no examples involving 1 as an acetone a,a 0-dianion equivalent in enantio-selective catalysis. 8 To fill this gap, we initiated a research program to selectively activate this unexploited 1,3-bis-pro-nucleophile in enantioselective synthesis. We first focused on its unaddressed reactivity towards a,b-unsaturated aldehydes as electrophiles in a di-decarboxylative Michael/aldol/dehydration sequence leading to synthetically useful cyclohexenone derivatives, a class of versatile molecules used in natural product synthesis. 9 Earlier reports on the preparation of these chiral cyclohexenones required multiple steps such as kinetic resolution of chiral compounds. 10 Several groups reported on the organocatalytic condensation of functionalized ketones on a,b-unsaturated aldehydes, leading after cascade cyclization by Knoevenagel or Wittig reaction to chiral cyclohexenones. 11 Unfortunately, in all these examples, additional functional groups are present on the obtained cyclohexenone backbones and require subsequent steps for their removal (tert-butyl ester for example). Given the utility of this chiral cyclohexenone motif and its numerous applications , alternative direct access to this structure remains attractive and desirable. To efficiently apply 1, we initially hypothesized that a secondary amine organocatalyst might activate the electrophile through its iminium ion while a copper salt catalyst, known to promote decarboxylative aldolizations, would activate ketodiacid 1 triggering the overall domino sequence initiated by a decarboxylative Michael addition (Scheme 1). 12 Herein we present our results on the development of such biomimetic transformation as well as supplementary successive cascade functionalization of the formed cyclohexenone. We initiated our research by condensing 1 on cinnamalde-hyde 2a in the presence of an aminocatalyst able to promote the direct Michael addition via the corresponding iminium intermediate. Selected optimizations are presented in Table 1.
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hal-01224321 , version 1 (09-11-2015)



Adrien Quintard, Jean Rodriguez. Synergistic Cu–amine catalysis for the enantioselective synthesis of chiral cyclohexenones †. Chemical Communications, 2015, 51, pp.9523. ⟨10.1039/c5cc02987b⟩. ⟨hal-01224321⟩
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