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.

Content1. General information S2 General informationAll starting materials and solvents were obtained from commercial suppliers and used without further purification. The organocatalysts examined in this study (QN-SA, 1a QN-TU, 1b QN-N-SQA, 1c QN-SQA 1d ) were obtained from the corresponding 9-epi-aminocinchona alkaloids according to the published procedures. Thin layer chromatography (TLC) was performed on silicagel plates (Merck, Kieselgel 60 F254 0.25 mm). Chromatographic purification of the products was carried out using Merck silica gel 60 (230-400 mesh). The 1 H NMR and 13 C NMR spectra were recorded on a Varian NMR Systems 300 spectrometer (300 MHz 1 H/ 75 MHz 13 C) and a Bruker Avance III 500 (500 MHz 1 H/ 125 MHz 13 C). Chemical shifts were reported in ppm downfield from tetramethylsilane (TMS). HPLC analyses for determination of the enantiomeric excess (ee) of the products were performed on a Varian Pro Star Series instrument equipped with an isostatic pump using a CHIRALCEL Column (250 × 4.6 mm). General procedure for the catalytic Michael additionThe catalyst HQN-SQA (6 mg, 1.0 mol%), brine (3.0 mL, saturated NaCl aqueous solution), and dimethyl malonate (2a, 228 μL, 2.0 mmol) were added to a 5 mL vial containing βnitrostyrene (1a, 150 mg, 1.0 mmol), and the reaction mixture was stirred vigorously at room temperature. After completion of the reaction (60 min for 1a), the reaction mixture was quenched with aqueous HCl (1 N, 1.0 mL) and extracted with CH 2 Cl 2 (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.The residue was purified by column chromatography on silica gel (EtOAc/hexanes 1:10) to afford the desired Michael addition product (3a, 278 mg, 99%). S33. Kinetic data for Figure 1 and Figure 2 Experimental procedure Michael addition on brine: Catalyst, brine (3.0 mL), and dimethyl malonate (2a, 228 μL, 2.0 mmol) were added to a 5 mL vial containing β-nitrostyrene (1a, 150 mg, 1.0 mmol), and the reaction mixture was vigorously stirred at room temperature. At specific time points, 100 μL of the sample was taken from the reaction mixture by syringe, quenched with aqueous HCl solution (1 N, 1 mL), and extracted with CDCl 3 (600 μL). The conversion was determined through 1 H NMR analysis by comparing the intensities of the peak in β-nitrostyrene 1a (δ 7.97, d, J = 13.7Hz, 1H) with the peak in the Michael adduct 3a (δ 4.24, td, J = 8.9 Hz and J = 5.7 Hz, 1H).Michael addition in CH 2 Cl 2 : Catalyst, CH 2 Cl 2 (3.0 mL), and dimethyl malonate (2a, 228 μL, 2.0 mmol) were added to a 5 mL vial containing β-nitrostyrene (1a, 150 mg, 1.0 mmol), and the reaction mixture was stirred at room temperature. At specific times, 100 μL of the sample was taken from the reaction mixture by syringe, quenched with aqueous HCl solution (1 N, 1 mL), and extracted with CH 2 Cl 2 (3 mL). The organic layer was concentrated and dissolved in CDCl 3 (600 μL), after which 1 H NMR analysis was performed.

Due to the high versatility of chiral cyanohydrins, the catalytic asymmetric cyanation reaction of carbonyl compounds has attracted widespread interest. However, efficient protocols that function at a preparative scale with low catalyst loading are still rare. Here, asymmetric counteranion-directed Lewis acid organocatalysis proves to be remarkably successful in addressing this problem and enabled a molar-scale cyanosilylation in quantitative yield and with excellent enantioselectivity. Also, the catalyst loading could be lowered to a part-per-million level (50 ppm: 0.005 mol%). A readily accessible chiral disulfonimide was used, which in combination with trimethylsilyl cyanide, turned into the active silylium Lewis acid organocatalyst. The nature of a peculiar phenomenon referred to as a “dormant period”, which is mainly induced by water, was systematically investigated by means of in situ Fourier transform infrared analysis.

The manipulation of the transition states of a chemical process is essential to achieve the desired selectivity. In particular, transition states of chemical reactions can be significantly modified in a confined environment. We report a catalytic reaction with remarkable amplification of stereochemical information in a confined water cage. Surprisingly, this amplification is significantly dependent on droplet size. This water-induced chirality amplification stems from the hydrophobic hydration effects, which ensures high proximity of the catalyst and substrates presumably at the transition state, leading to higher enantioselectivity. Flow and batch reactors were evaluated to confirm the generality of this water-induced chirality amplification. Our observation on efficient chiral induction in confined water cages might lead to an understanding of the chirality amplification in the prebiotic era, which is a key feature for the chemical evolution of homochirality.

In this report, we demonstrate that self-aggregation is an intrinsic problem of bifunctional organocatalysts, especially in the case when the substrates do not have functional groups which are able to bind strongly with catalyst. Due to their self-association phenomena, the enantioselectivity of bifunctional catalysts dramatically decreases with increasing catalyst concentration or decreasing temperature. Thus, when the substrate concentration is kept constant, the enantioselectivity of bifunctional catalysts dramatically increases with decreasing catalyst loading. The ee values obtained at different catalyst concentrations are fairly consistent with the diffusion coefficients (D) of the catalysts, strongly indicating that their degree of self-association plays a crucial role in determining their enantioselectivity.