The catalytic asymmetric alkylation under phase-transfer conditions of various substrates (enones, a-fluoro ketones, glycineimines) promoted by chiral quaternary ammonium salts derived from cinchona alkaloids is described. A solvent-free phase-transfer catalysis is presented as well as a new type of polymer-supported phase-transfer catalyst derived from cinchona alkaloids.Asymmetric phase-transfer catalysis (PTC) is dominated by cinchona alkaloid derivatives, 1 though, other quaternary ammonium salts 2 and metal catalysis 3 have recently appeared as strong competitors. There are numerous reports on reactions that have been accomplished by enantioselective PTC, especially carbon-carbon bond formation (alkylation, 1a-f Darzens reaction, 1g,h Michael addition, 1i-k aldol reaction, 1l cyclopropanation 1m ), epoxidation, 1n-p and a-hydroxylation of ketones. 1q We present herein our contribution on the use of cinchona alkaloids in asymmetric PTC through three different reactions: 1) Michael addition onto enones, 2) construction of quaternary fluorinated carbon centers, 3) alkylation of the benzophenone imine of glycine tert-butyl ester. Both solution and solid-phase approaches were examined.Our interest in asymmetric PTC began during the synthesis of methyljasmonate in which the asymmetric key-step consisted of an enantioselective Michael addition of dimethyl malonate onto 2-pentylcyclohexenone. 4 The Michael adduct thus obtained was then decarboxylated in a racemization-free process (Scheme 1). This approach was selected among other possibilities, such as generating the malonate ion using chiral bases (magnesium amides or alkali alkoxides) or high pressure condensations in the presence of a chiral tertiary amine. Those two approaches were not efficient from the point of view of asymmetric synthesis, since the adducts were obtained in reasonable yields, but without any asymmetric induction. 5 A structure-enantioselectivity relationship study allowed us to select the following ammonium salts 1 and 2 derived from quinine and quinidine, respectively, as the most efficient chiral catalysts for this transformation (Figure 1).
Figure 1The best conditions, both in terms of yield and enantioselectivity, required the use of mild conditions: 1) presence of a mineral base (typically potassium carbonate), 2) reaction at mild temperature (room temperature or -20 °C), 3) absence of additional solvent (an excess of dimethyl malonate was used, and eventually recovered after the reaction). In the best case, an enantiomeric excess as high as 90% was obtained. 4 Since the method was both efficient and simple, we then decided to examine the scope and limitations of this system for other Michael additions. In a first set of experiments, we verified that the conditions used were specific for dimethyl malonate. Indeed, other nucleophilic agents were used (AcCH 2 COOMe, MeSCH 2 COOMe, tert-butyl malonate, methyl-tert-butyl malonate) in the same conditions (solvent-free reaction), with none of them giving the Michael addition. In a second ser...
