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 counteranion-directed Lewis acid catalysis mechanism.

A chiral squaramide has been supported onto a polystyrene (PS) resin through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and used as a very active, easily recoverable and highly reusable organocatalyst for the asymmetric Michael addition of 1,3-dicarbonyl compounds to b-nitrostyrenes. The PS-supported squaramide could be recycled up to 10 times.

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity.

When developing a synthetic methodology, chemists generally optimize a single substrate and then explore the substrate scope of their method. This approach has led to innumerable and widely-used chemical reactions. However, it frequently provides methods that only work on model substrate-like compounds. Perhaps worse, reaction conditions that would enable the conversion of other substrates may be missed. We now show that a different approach, originally proposed by Kagan, in which a collection of structurally distinct substrates are evaluated in a single reaction vessel, can not only provide information on the substrate scope at a much earlier stage in methodology development, but even lead to a broadly applicable synthetic methodology. Using this multi-substrate screening approach, we have identified an efficient and stereoselective imidodiphosphorimidate organocatalyst for scalable Diels–Alder reactions of cyclopentadiene with different classes of α,β-unsaturated aldehydes.