Cinchona alkaloid derivatives as chiral organocatalysts

Abstract

(A) The nucleophile-catalysed Staudinger reaction (not to be confused with its azide-reduction namesake) is a process of considerable interest from a medicinal chemistry standpoint. Lectka et al. were the first to report the catalytic asymmetric [2+2] cycloaddition of ketenes with imines to form a variety of β-lactam compounds. (Diagram Presented). (B) The reaction of imines with activated alkenes (the aza-Baylis-Hillman reaction) catalysed by modified cinchona alkaloids has been reported. The use of a modified Quinidine-derived catalyst, i.e. β-isocupreidine, allowed the reaction between 1,1,1,3,3,3-hexafluoroisopropylacrylate and aromatic imines 5 to proceed in good yield with high enantioselectivity. Interestingly, the corresponding aldehyde substrates (the Baylis-Hillman reaction) gave products with the opposite configuration. (Diagram Presented). (C) Gaunt and co-workers have described a novel enantioselective organocatalytic synthesis of functionalised cyclopropanes via intermediate ammonium ylides. These reactions yielded exceptional enantio- and diastereoselectivities with a range of functional groups. (Diagram Presented). (D) Cinchona alkaloids have been used as nucleophilic catalysts for the cycloaddition reactions involving ketenes and aldehydes. O-Trimethylsilyl derivatives of 1 and 2, along with structurally diverse aldehydes, provided access to a range of optically active β-lactones. (Diagram Presented). (E) Reaction of dihydroquinine with the β-keto ester 9 gives rise to a chiral ammonium enolate, which reacts with an electrophilic peroxide in a face-selective manner to form α-hydroxy-β-keto esters 10 with moderate enantioselectivity. Subsequent diastereoselective reduction of 10 affords anti-1,2-diols. (Diagram Presented). (F) The cinchona alkaloid derivative-catalysed desymmetrisation of meso-anhydrides in the presence of methanol is an efficient strategy for the synthesis of non-racemic dicarboxylic acid monoesters. The products were formed with high enantioselectivity (up to 98% ee) with 100% conversion of the anhydride using nucleophilic Sharpless AD ligands. (Diagram Presented). (G) Corey and Huang have developed a cinchona alkaloid derivative capable of catalysing the Strecker reaction of N-allyl-benzaldimines with HCN. This provides a concise, versatile route to a variety of α-amino acids. (Diagram Presented). (H) An example of a cinchona alkaloid-catalysed asymmetric α-halogenation/esterification transformation involving ketenes has also been described. Synthetically useful enantiopure α-chloroesters are readily accessible from commercially available acid chlorides using this process. (Diagram Presented).