Straightforward Organocatalytic Enantioselective Protonation of Silyl Enolates by Means of Cinchona Alkaloids and Carboxylic Acids

Abstract

The combination of cinchona alkaloids and carboxylic acids provides a very simple chiral proton source. By using this system, enantioselective protonation of silyl enolates was achieved affording the corresponding ketones in high yields and in up to 75% ee.The enantioselective protonation of prochiral enol derivatives has emerged as a helpful tool to achieve optically enriched carbonyl compounds possessing a tertiary stereogenic carbon center at the a-position. 1 The successful development of various catalytic deracemization processes over the last fifteen years made this approach more synthetically useful and quite complementary to the catalytic enantioselective alkylation technology, generating nowadays increasing interest amongst the synthetic chemistry community. 2 We have recently reported the first organocatalytic enantioselective protonation of silyl enolates 2 by means of cinchona alkaloids and a 'latent source of HF'. 3 This organocatalytic approach offers unprecedented mild, neutral and metal-free conditions with excellent yields and high enantioselectivities of up to 92% (Figure 1a). 3 Mechanistically, the strategy relies on the in situ catalytic generation of a hydrogen fluoride salt 1-HF through the reaction between an acid fluoride and an alcohol in the presence of a chiral tertiary amine 1. As a result of the high silicon-fluoride affinity, the active catalytic species 1-HF can exert a specific silyl enolate activation mode (Figure 1c; X = F -) to promote the protonation of silyl enolate 2 along with the regeneration of the precatalyst 1.Within our continuing interest to develop a more straightforward and general approach for the organocatalytic enantioselective protonation of silyl enol ethers, we queried whether our methodology could be rendered more atom economic and operationally simpler by replacing the two-component, naked source of HF with a more readily handy proton source such as a simple carboxylic acid (Figure 1b).According to this new scenario, the protonation of a tertiary amine 1 by a carboxylic acid would generate the corresponding hydrogen carboxylate salt 1-RCO 2 H. This species should be a better protonating agent than the rather more acidic carboxylic acid itself, due to the cooperative activation of the silyl enolate 2 by the carboxylate counterion ( Figure 1c; X = RCO 2 -) through generation of either an enolate or a hypervalent silicate. 4 Considering this cooperative activation mode as a prerequisite for achieving high levels of stereoinduction, 3 the question then arose whether the carboxylate counter-anion would be capable to enhance the silyl enol ether nucleophilicity with similar efficiency as the fluoride ion did in our previous approach. Actually, the capacity of carboxylate anions to serve such an effective Lewis base catalyst has recently been proven by reports from the Fu 5 and Mukaiyama 6 groups dealing with the C-acylation of silyl ketene acetals and the catalytic Mannich-type reaction between trimethylsilyl enol ethers and aldimines, respectively.

Carboxylate Catalysis: A Catalytic O-Silylative Aldol Reaction of Aldehydes and Ethyl Diazoacetate

“…On the basis of our previous work on carboxylate catalysis in the enolization of thioesters with simple carboxylate catalysts such as tetramethylammonium pivalate (TMAP), we hypothesized that the diazoacetate aldol reaction should also be amenable to carboxylate catalysis. A few examples of catalytic systems involving carboxylate catalysts have been published, demonstrating diverse applications in C–C bond formation as well as in proton-transfer reactions . Herein we describe a particularly mild, catalytic method for the one-pot silylative diazoacetate aldol using a mild silylating agent ( N , O -bis­(trimethylsilyl)­acetamide, BSA) that gives the O -silylated aldol products in good yields even without any chromatographic purification.…”

“…A few examples of catalytic systems involving carboxylate catalysts have been published, demonstrating diverse applications in C–C bond formation as well as in proton-transfer reactions. 12 Herein we describe a particularly mild, catalytic method for the one-pot silylative diazoacetate aldol using a mild silylating agent ( N , O -bis(trimethylsilyl)acetamide, BSA) that gives the O -silylated aldol products in good yields even without any chromatographic purification.…”