The Catalytic Asymmetric Mukaiyama–Michael Reaction of Silyl Ketene Acetals with α,β-Unsaturated Methyl Esters

α,β-Unsaturated esters are readily available but challenging substrates to activate in asymmetric catalysis. We now describe an efficient, general, and highly enantioselective Mukaiyama–Michael reaction of silyl ketene acetals with α,β-unsaturated methyl esters that is catalyzed by a silylium imidodiphosphorimidate (IDPi) Lewis acid

Asymmetric Counteranion-Directed Lewis Acid Catalysis with α,β-Unsaturated Esters

The fundamental substrate class of α,β-unsaturated esters offers extraordinary synthetic potential for carbon-carbon bond forming reactions, such as cycloadditions and conjugate additions, however is rarely applied in asymmetric catalysis due to its relatively low reactivity. By expanding the concept of silylium-ACDC to non-silicon transfer reactions (catalytic in silicon), the introduction of chiral C–H acids into asymmetric catalysis and the identification of two distinct families of imidodiphosphorimidates (IDPi) catalysts, we could report unprecedented highly enantio- and diastereoselective Diels–Alder and Mukaiyama– Michael reactions of simple α,β-unsaturated methyl esters. The developed extremely active chiral Lewis acids represent the most efficient catalysts for asymmetric Diels–Alder reactions of α,β-unsaturated esters to date while tolerating a very broad scope on a variable scale with catalyst loadings as low as 0.1 mol%

Asymmetric Lewis acid organocatalysis of the Diels-Alder reaction by a silylated C-H acid

Silylium ion equivalents have shown promise as Lewis acid catalysts for a range of important C-C bond-forming reactions. Here we describe chiral C-H acids that upon in situ silylation, generate silylium-carbanion pairs, which are extremely active Lewis acid catalysts for enantioselective Diels-Alder reactions of cinnamates with cyclopentadiene. Enantiomeric ratios of up to 97: 3 and diastereomeric ratios of more than 20: 1 are observed across a diverse set of substitution patterns with 1 mole percent (mol %) of C-H acid catalyst and 10 mol % of a silylating reagent. The results show promise for broad applications of such C-H acid-derived silylium ion equivalents in asymmetric Lewis acid catalysis

Scalable and Highly Diastereo- and Enantioselective Catalytic Diels−Alder Reaction of α,β - Unsaturated Methyl Esters

Despite tremendous advances in enantioselective catalysis of the Diels−Alder reaction, the use of simple α,β-unsaturated esters, one of the most abundant and useful class of dienophiles, is still severely limited in scope due to their low reactivity. We report here a catalytic asymmetric Diels−Alder methodology for a large variety of α,β-unsaturated methyl esters and different dienes based on extremely reactive silylium imidodiphos-phorimidate (IDPi) Lewis acids. Mechanistic insights from accurate domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) calculations rationalize the catalyst control and stereochemical outcome

Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon-carbon bond forming reaction

The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon-carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counter-anion-directed Lewis acid catalysis mechanism