*3.2. Synthetic Procedures.*

3.2.1. General Procedure for the Small-Scale Aldol Condensation Between Aldehydes **2** and Ketones **1**

The aldol reaction was carried out in a 2 mL vial. In a typical reaction, the vial was charged at room temperature with the reactants in the following order: (*S*)-proline (0.03 mmol), methanol (40 μL), water (10 μL), the selected ketone **1** (1.5 mmol), and the selected aldehyde **2** (0.3 mmol). The flask was capped with a stopper and sealed. Then, the reaction mixture was stirred at room temperature for the desired time. The conversion was monitored by TLC (Merck, Darmstadt, Germany) and 1H-NMR (a small portion was taken, diluted, and immediately analyzed) (Agilent, Santa Clara, CA, United States). Then, the mixture was filtered on a short pad of silica with ethyl acetate and concentrated under reduced pressure.

The product conversion with respect to the limiting aldehyde and the diastereomeric ratio were determined by 1H-NMR in CDCl3 on the crude mixture. The enantiomeric excess was determined by chiral stationary phase (CSP)-HPLC (Agilent, Santa Clara, CA, United States) on the crude mixture.

The study of the solvent role (Tables 1–3), the study of the e ffects of ketone amount (Table 4), and the protocol application to other ketones (Table 5) were carried out following this general procedure.

#### 3.2.2. Procedure for the Aldol Condensation Between Benzaldehyde **2d** and Cyclohexanone **1a** on 10 mmol Scale

The aldol reaction was conducted in a 25 mL flask. The flask was charged with (*S*)-proline (115 mg, 1 mmol), methanol (1.33 mL), water (330 μL), and cyclohexanone **1a** (5.18 mL, 50 mmol) and the mixture was allowed to stir for 10 min at room temperature. Then, the mixture was cooled at 0 ◦C and benzaldehyde **2d** (1.02 mL, 10 mmol) was slowly added by means of a syringe. The flask was capped with a stopper and sealed. The reaction mixture was stirred at room temperature for 30 h. Then, the mixture was filtered on a pad of silica with ethyl acetate and concentrated under reduced pressure. The conversion (85%) with respect to the limiting aldehyde and the diastereomeric ratio (90:10) were determined by 1H-NMR in CDCl3 on the crude mixture. The obtained residue was purified by column chromatography (ethyl acetate/cyclohexane = 2:8 as the eluent) to a fford the product **3ad** in 78% yield. The enantiomeric excess (95% *ee*) was determined by CSP-HPLC on the pure product.

3.2.3. Procedure for the Aldol Condensation between Benzaldehyde **2d** and Cyclohexanone **1a** on 100 mmol Scale (Table 6)

The aldol reaction was conducted in a 250 mL flask. The flask was charged with (*S*)-proline (1.15 g, 10 mmol), methanol (13.33 mL), water (3.33 mL), and cyclohexanone **1a** (51.8 mL, 500 mmol) and the mixture was allowed to stir for 15 min at room temperature. Then, the mixture was cooled at 0 ◦C and benzaldehyde **2d** (10.2 mL, 100 mmol) was slowly added by means of (*i*) addition funnel (addition rate = 45 min), or (*ii*) syringe for slow addition (addition rate = 6 h). Then, the flask was capped with a stopper and sealed. The reaction mixture was stirred at room temperature. The reaction performance was monitored over time (a small portion was taken, diluted, and immediately analyzed); the product conversion with respect to the limiting aldehyde and the diastereomeric ratio were determined by 1H-NMR in CDCl3 on the crude mixture, and the enantiomeric excess was determined by CSP-HPLC on the crude mixture. After 49 h, the first reaction (addition rate = 45 min) was stopped, the reaction mixture (total volume = 79 mL) was divided in six portions, and they were treated as described in Table 8 (see below for details).

#### 3.2.4. General Procedure for the Study of Reaction Outcome as a Function of Reaction Time (Table 7)

The aldol reaction was conducted in a 100 mL flask. The flask was charged with (*S*)-proline (575 mg, 5 mmol), methanol (6.67 mL), water (1.67 mL), and cyclohexanone **1a** (25.9 mL, 250 mmol) and the mixture was allowed to stir for 15 min at room temperature. Then, the mixture was cooled at 0 ◦C and the desired aldehyde **2** (50 mmol) was slowly added by means of an addition funnel. Then, the flask was capped with a stopper and sealed. The reaction mixture was stirred at room temperature. The reaction performance was monitored over time (a small portion was taken, diluted, and immediately analyzed); the product conversion with respect to the limiting aldehyde and the diastereomeric ratio were determined by 1H-NMR in CDCl3 on the crude mixture, and the enantiomeric excess was determined by CSP-HPLC on the crude mixture. At the reported time (Table 7), the mixture was filtered on a pad of silica with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/cyclohexane = 2:8 as the eluent) to afford the pure product (**3ad**: 76% yield, **3am**: 67% yield, **3ai**: 43% yield).

#### 3.2.5. Procedure for the Aldol Condensation between Benzaldehyde **2d** (50 mmol) and Cyclohexanone **1a** (2 equivalents, 100 mmol)

The aldol reaction was conducted in a 100 mL flask. The flask was charged with (*S*)-proline (575 mg, 5 mmol), methanol (6.67 mL), water (1.67 mL), and cyclohexanone **1a** (10.36 mL, 100 mmol) and the mixture was allowed to stir for 15 min at room temperature. Then, the mixture was cooled at 0 ◦C and benzaldehyde **2d** (5.1 mL, 50 mmol) was slowly added by means of an addition funnel. Then, the flask was capped with a stopper and sealed. The reaction mixture was stirred at room temperature. The reaction performance was monitored over time (a small portion was taken, diluted, and immediately analyzed); the product conversion with respect to the limiting aldehyde and the diastereomeric ratio were determined by 1H-NMR in CDCl3 on the crude mixture, and the enantiomeric excess was determined by CSP-HPLC on the crude mixture. After 99 h, the reaction was stopped and it was filtered on a pad of silica with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/cyclohexane = 2:8 as the eluent) to a fford the product **3ad** in 76% yield. The enantiomeric excess (91% *ee*) was determined by CSP-HPLC on the pure product.
