Organic Syntheses Procedure

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Org. Synth. 2011, 88, 317-329

DOI: 10.15227/orgsyn.088.0317

(S_a,S)-N-[2´-(4-METHYLPHENYLSULFONAMIDO)-1,1´-BINAPHTHYL-2-YL]PYRROLIDINE-2-CARBOXAMIDE: AN ORGANOCATALYST FOR THE DIRECT ALDOL REACTION

Submitted by Santiago F. Viózquez, ¹Gabriela Guillena¹, Carmen Nájera¹, Ben Bradshaw², Gorka Etxebarria-Jardi², and Josep Bonjoch².

Checked by David Hughes.³

1. Procedure

A. (S_a)-N-[2´-Amino-(1,1´-binaphthyl)-2-yl]-4-methylbenzene-sulfonamide (1). A 250-mL round-bottomed flask equipped with a 3-cm oval PTFE-coated magnetic stir bar is charged with (S_a)-(–)-1,1'-binaphthyl-2,2'-diamine (3.13 g, 11.0 mmol, 1.0 equiv), dichloromethane (130 mL), and pyridine (10 mL, 124 mmol, 11 equiv). To the stirred solution is added p-toluenesulfonyl chloride (2.03 g, 10.7 mmol, 0.97 equiv) in one portion (Note 1). The flask is sealed with a rubber septum through which is inserted an 18-gauge inlet needle, which is connected to a nitrogen line and a gas bubbler, and a thermocouple probe (Note 2). The brown solution is stirred at 22 °C for 10 h (Note 3). The reaction solution is concentrated by rotary evaporation (40 °C bath temperature, 20 mmHg) to an oil that is transferred to a 500-mL separatory funnel with EtOAc (200 mL). The organic layer is washed with 2M HCl (5×30 mL) (Note 4), then vacuum-filtered through a bed of sodium sulfate (40 g) in a 150-mL medium-porosity sintered glass funnel. The filter cake is washed with EtOAc (2 x 40 mL). The filtrate is concentrated in a 500-mL round-bottomed flask by rotary evaporation (40 °C bath, 20 mmHg), then further dried under vacuum (20 mmHg) at room temperature for 14 h to afford 1 as a pink foam (4.7 g, 82% purity, 80% yield) which is used directly in the next step (Notes 5 and 6).

B. (S_a,S)-t-Butyl 2-[(2´-(4-methylphenylsulfonamido)-(1,1´-binaphthyl)-2-yl-carbamoyl]pyrrolidine-1-carboxylate (2). A 250-mL round-bottomed flask equipped with a 3-cm PTFE-coated magnetic stir bar is charged with (S)-N-(t-butoxycarbonyl)-L-proline (3.00 g, 13.9 mmol, 1.6 equiv), anhydrous THF (100 mL), and triethylamine (1.42 g, 14.0 mmol, 1.6 equiv) (Note 7). The flask is sealed with a rubber septum through which is inserted an 18-gauge inlet needle, which is connected to a nitrogen line and a gas bubbler, and a thermocouple probe (Note 2). The mixture is cooled to 3 °C with an ice-water bath and ethyl chloroformate (1.43 g, 13.2 mmol, 1.5 equiv) is added dropwise via a 3-mL syringe over 3 min where upon a fine white precipitate is formed (Note 8). The suspension is stirred 30 min at 0-5 °C and then a solution of 1 (4.7 g, 82 wt%, 3.85 assay g, 88 mmol, 1.0 equiv) in anhydrous THF (25 mL) is added dropwise over 5 min via a 40-mL syringe. After the addition, the rubber septum is replaced with a condenser fitted with a gas adapter connected to a nitrogen line and gas bubbler. The mixture is refluxed using a heating mantle for 12 h (Note 9). At the end of the reaction, the suspension is cooled to room temperature, filtered through a 60-mL medium-porosity sintered glass funnel, and the filter cake is washed with THF (2×25 mL). The combined filtrates are concentrated by rotary evaporation (40 °C bath temperature, 20 mmHg) in a 500-mL round bottomed flask and further dried under vacuum (20 mmHg) for 3 h to provide 2 (7.7 g, estimated 65% purity, 5.0 assay g, 90% yield) as a pink foam which is used directly in the next step (Notes 10-12).

C. (S_a,S)-N-[2´-(4-Methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide (3). The 500-mL flask containing crude 2 (7.7 g, 65% purity, 7.9 mmol) from the previous step is equipped with a 3-cm oval PTFE-coated magnetic stir bar and charged with dichloromethane (80 mL) (Note 13). The flask is sealed with a rubber septum through which is inserted an 18-gauge inlet needle, which is connected to a nitrogen line and a gas bubbler, and a thermocouple probe (Note 2). Trifluoroacetic acid (16 mL, 208 mmol, 26 equiv) is added dropwise via a 20-mL syringe over 3 min, and the mixture is stirred at 20-22 °C for 1 h (Notes 14 and 15). At the end of reaction, the solution is cooled to 3 °C using an ice-water bath and the septum is removed and replaced with a 125-mL addition funnel to which is added 2.5 M sodium hydroxide (80 mL). The NaOH solution is added dropwise to the reaction mixture over 10 min (Notes 16 and 17). The mixture is transferred to a 250-mL separatory funnel, and the bottom organic layer is separated. The aq. layer is back extracted with dichloromethane (40 mL). The organic layers are combined and dried with sodium sulfate (100 g) (Note 18), then vacuum filtered through a 150-mL medium porosity sintered glass funnel into a 500-mL round bottomed flask. The filter cake is washed with dichloromethane (2x60 mL). The combined filtrate is concentrated by rotary evaporation (40 °C bath, 20 mmHg) to ~80 mL, then silica gel (30 g) is added, and the mixture is evaporated to a free-flowing powder. The material is purified by column chromatography (Note 19) with a final concentration in a 250-mL round bottom flask. The material is dried under vacuum (room temperature, 20 mmHg, 14 h) to provide 3 as a white solid (3.9-4.1 g). A 3-cm oval PTFE-coated stir bar and dichloromethane (8 mL) are added to the flask and the contents are warmed in a 40 °C water bath to dissolve the product, and then the flask is cooled to room temperature and is equipped with a 60-mL addition funnel. The mixture is stirred as hexanes (40 mL) are added through the addition funnel over 30 min. Crystallization occurs after 10 mL of hexanes is added, and the mixture becomes a thick slurry as the remainder of the hexanes is added. The slurry is stirred 12 h at ambient temperature and then is vacuum-filtered into a 60-mL sintered glass funnel. The filter cake is washed with 5:1 hexanes: dichloromethane (15 mL) and then is air-dried to constant weight to afford (S_a,S)-N-[2´-(4-methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide (3) as a white crystalline solid (3.8-4.0 g, step yield 89-94%, 3-step yield 65-68%) (Notes 20-22).

2. Notes

1. The following reagents and solvents in Step A were used as received: (S_a)-(–)-1,1'-binaphthyl-2,2'-diamine (Sigma-Aldrich, 99%), dichloromethane (Fisher, ACS reagent, 99.5%), EtOAc (Fisher, ACS reagent, 99%), pyridine (Sigma-Aldrich, 99%), and p-TsCl (Acros, 99%).

2. The internal temperature was monitored using a J-Kem Gemini digital thermometer with a Teflon-coated T-Type thermocouple probe (12-inch length, 1/8 inch outer diameter, temperature range -200 to +250 °C). There was no exotherm on addition of p-TsCl.

3. The reaction was monitored by thin layer chromatography on silica gel (EMD, silica gel, grade 60, F₂₅₄) with 1:1 EtOAc:hexanes as the eluent and visualization with UV. The diamine starting material has R_f = 0.5 (blue fluorescence) and the tosyl product has R_f = 0.6. The bis-tosyl by-product co-elutes with the mono-tosylate product. The mono- and bis-tosyl products can be separated by TLC by using an eluent of 1:6 EtOAc:hexanes and 3 elutions (bis-Ts, R_f = 0.45; mono-Ts, R_f = 0.40).

4. The acid wash removes unreacted (S_a)-(–)-1,1'-binaphthyl-2,2'-diamine, which can be recovered as follows. The combined acidic washes are neutralized with 2.5N NaOH until pH 8-10 and then are extracted with dichloromethane (3 × 30 mL). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated by rotary evaporation (40 °C, 20 mmHg) to give 0.30 g (10%) of (S_a)-Binam.

5. The mono-tosylate 1 is approximately 82% pure (80% yield), containing 7 wt% EtOAc and 11 wt% of the bis-tosylate by-product as determined by ¹H NMR analysis of the Ts methyl groups of the mono- and bis-tosylated species:¹H NMR (400 MHz, CDCl₃); mono-tosylate 1: δ: 2.32; bis-tosylate: δ: 2.40. This bis-tosylate by-product is difficult to separate by standard column chromatography due to overlap of the peaks using a more polar eluent and tailing of the early eluting bis-tosylate into the mono-tosylate peak using a less polar eluent. The submitters reported preparation of a purified sample by column chromatography on silica gel eluting with hexane/EtOAc, 6:1, following a literature report.⁴ The checker purified a 100 mg crude sample by reverse-phase preparative HPLC using the following conditions: column, YMC-pack ODS-AQ, 5um, 150×20 mm I.D; mobile phase, linear gradient elution: 25% MeCN/75% water to 55% MeCN/45% water over 15 min; flow rate, 25mL/min; sample dissolved in MeCN at 10mg/mL;1 mL per injection. Fractions eluting between 7-9 min were concentrated by rotary evaporation to remove the organic phase (bath temperature 35 °C, 10 mmHg). The remaining aqueous layer was lyophilized, affording 24 mg of mono-tosylate 1.

6. Mono-tosylate 1 has the following spectroscopic properties: ¹H NMR pdf(400 MHz, CDCl₃) δ: 2.32 (s, 3 H, CH₃), 3.29 (br s, 2 H, NH₂), 6.42 (d, J = 8.4 Hz, 1 H), 6.67 (s, 1 H, NH), 6.94-7.09 (m, 5 H), 7.20-7.25 (m, 2 H), 7.37-7.43 (m, 3 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 8.7 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 8.13 (d, J = 9.0 Hz, 1 H); ¹³C NMR pdf(100 MHz, CDCl₃) δ: 21.7, 109.9, 118.2, 119.7, 121.8, 122.7, 123.6, 125.6, 125.9, 127.35, 127.37, 127.5, 128.37, 128.39, 129.7, 129.9, 130.9, 131.5, 133.0, 133.8, 133.9, 136.5, 142.9, 143.8; LC-MS calcd for [M + H]⁺ 439.5; found, 439.2.

7. The following reagents and solvents in Step B were purchased from Sigma-Aldrich and used as received: N-(t-butoxycarbonyl)-L-proline (>99%), triethylamine (99.5%), THF (ACS reagent, >99%, inhibited with 250 ppm BHT), and ethyl chloroformate (97%).

8. Addition of ethyl chloroformate results in a slight exotherm from 3 °C to 5 °C.

9. The progress of the reaction can be monitored by TLC (EMD, silica gel, grade 60, F₂₅₄) with 1:1 EtOAc:hexanes and visualization with UV (starting material 1 has R_f = 0.45 and the Boc-proline product 2 has R_f = 0.3); however, the end of reaction cannot be determined by TLC since the unreactive bis-tosylate carried forward from step A co-elutes with the mono-tosylate. NMR of the crude reaction mixture is uninformative due to broad peaks caused by Boc rotamers. Therefore, the end of reaction was assessed by deprotecting the Boc group and determining the amount of mono-tosylate that remained unreacted by ¹H NMR. A ~20 mg aliquot of the reaction mixture was evaporated then dissolved in 0.5 mL of CDCl₃ followed by addition of 0.2 mL of TFA. The sample was reacted for 15 min at room temperature then analyzed by ¹H NMR. The Ts-methyl group was diagnostic for assessing reaction completion: bis-tosylate, d 2.42; product 3, d 2.45; mono-Ts 1, d 2.52.

10. Given the broad peaks in the ¹H NMR spectrum (Note 12) the purity of the crude material from step B could not be estimated by NMR. The rough purity and yield estimates are based on the 65% recovery of material when subjected to flash chromatography in a separate experiment (Note 11).

11. Compound 2 (2.33 g crude weight) can be purified by column chromatography using 85 g silica gel (Fisher, 230-400 mesh, 60 Å) packed as a slurry with 2:1 hexanes: EtOAc, and eluted with 2:1 hexanes: EtOAc (600 mL), 1:1 hexanes:EtOAc (200 mL), and 1:2 hexanes: EtOAc (200 mL), taking 40 mL fractions. The desired product is obtained in fractions 16-23, (R_f = 0.3, 1:1 hexanes:EtOAc), which are combined and concentrated by rotary evaporation (40 °C, 20 mmHg) to give, after vacuum drying at room temperature to constant weight, 1.68 g of 2 (~90% purity, 65% recovery) as a pink foam.

12. At ambient temperature compound 2 is a mixture of 2 rotamers that cause broad peaks in the ¹H NMR and ¹³C NMR spectra. The following NMR data were collected at 360 K where the rotamers had partially coalesced. ¹H NMR pdf(600 MHz, 360 K, DMSO-d₆) δ: 0.76 (br s, 1 H), 1.06 (br s, 1 H), 1.32 (s, 9 H, C(CH₃)₃], 1.39 (br s, 1 H), 1.67-1.73 (m, 1 H), 2.38 (s, 3 H, CH₃), 2.74 (br s, 1 H), 3.08 (app q, J = 8.3 Hz, 1 H), 4.00 (dd, J = 8.9, 3.0, 1 H), 6.70 (d, J = 8.5 Hz, 1 H,), 6.88 (d, J = 8.5 Hz, 1 H), 7.13-7.16 (m, 1 H), 7.20-7.25 (m, 3 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.43-7.46 (m, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.88 (br d, J = 8.6 Hz, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.96-7.99 (m, 2 H), 8.08 (d, J = 8.8 Hz, 1 H), 8.52 (br s, 1 H, NH), 8.78 (br s, 1 H, NH). ¹³C NMR pdf(150 MHz, 360K, DMSO-d₆) δ: 20.4, 22.1, 27.6, 29.4, 45.8, 60.0, 78.5, 122.4, 123.7, 124.5, 124.7, 124.8, 125.3, 125.93, 125.95, 126.3, 127.4, 127.5, 128.3, 128.7, 128.9, 130.9, 131.0, 131.9, 132.1, 133.3, 134,5, 137.7, 142.5, 153 (br), 171.2.

13. The following reagents and solvents in Step C were used as received: trifluoroacetic acid (Sigma-Aldrich, >99%), dichloromethane (Fisher, ACS reagent, 99.5%), silica gel (Fisher, 230-400 mesh, 60 Å), EtOAc (Fisher, ACS reagent, 99%), and hexanes (Fisher, ACS reagent, >98.5%).

14. During the TFA addition, the temperature decreases from 22 °C to 19 °C.

15. Reaction progress can be monitored by TLC using 2:1 EtOAc:hexanes as eluent and visualized by UV. An aliquot of the reaction mixture is quenched into a mixture of 0.5 mL of 2N NaOH and 0.5 mL of dichloromethane with the bottom organic layer sampled for TLC. R_f product 3, 0.3; R_f starting material, 2, 0.8; R_f bis-tosylate, 0.9.

16. Addition of NaOH is exothermic and should be added at a rate to keep the internal temperature below 35 °C to prevent boiling of dichloromethane.

17. At the end of the NaOH addition, the pH is checked by pH paper and should be 8-10. If below 8, additional NaOH is added.

18. The organic layer is hazy due to the retention of a second phase water that is not completely removed upon drying with sodium sulfate.

19. A 6-cm diameter glass column is slurry-packed (2:1 EtOAc:hexanes) with silica gel (200 g). Crude product 3 co-mixed with silica is slurried in 2:1 EtOAc:hexanes and added to the top of the column. The column is topped with 0.5 cm of sand, then eluted with 2:1 EtOAc:hexanes (500 mL), 3:1 EtOAc:hexanes (500 mL), and EtOAc (1 L), taking 100 mL fractions. The chromatography is monitored by TLC (EtOAc, R_f 0.5). The product elutes in fractions 9-15, which are combined and concentrated by rotary evaporation (40 °C water bath, 20 mmHg) in a 1-L flask, then transferred to a 250-mL round-bottomed flask for the final concentration. The white solid is dried under vacuum (20 mmHg) at room temperature for 28 h to constant weight (3.9 - 4.1 g).

20. (S_a,S)-N-[2´-(4-Methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide (3) exhibits the following physical and spectroscopic properties: R_f 0.5 (EtOAc); [α]_D²⁵ -95 (c 1.0, CHCl₃); mp 196-197 °C, Lit^7d 191-192 °C; ¹H NMR pdf(400 MHz, CDCl₃) δ: 0.64-0.73 (m, 1 H), 1.15-1.28 (m, 2 H), 1.57-1.64 (m, 1 H), 1.74-1.84 (m, 1 H), 2.20-2.26 (m, 1 H), 2.35 (s, 3 H), 3.32 (dd, J = 4.0, 9.5 Hz, 1 H), 6.35 (br s, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.1, 2 H), 7.16-7.22 (m, 2 H), 7.37-7.46 (m, 4 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1 H), 8.06 (d, J = 9.0, 1 H), 8.19 (d, J = 9.0 Hz, 1 H), 8.82 (d, J = 9.0 Hz, 1 H), 9.31 (br s, 1 H); ¹³C NMR pdf(100 MHz, CDCl₃) δ: 21.7, 25.4, 30.7, 46.3, 60.7, 117.0, 119.4, 119.6, 120.8, 124.3, 125.3, 125.4, 125.8, 127.6, 127.8, 128.3, 128.8, 129.7, 130.3, 130.7, 130.9, 131.4, 132.3, 132.7, 133.9, 135.9. 136.7, 144.1, 173.5; Anal. calcd. for C₃₂H₂₉N₃O₃S: C, 71.75; H, 5.46; N, 7.84; Found: C, 71.41; H, 5.15; N, 7.73.

21. The checkers determined the enantiomeric purity by SFC using a Lux-4 column (150 x 4.6mm, 5um particle size); isocratic elution, 40% MeOH with 25 mM i-butylamine/60% CO₂; 3.0 mL/min flow; detection at 210 nm; 200 bar pressure; t_r (S,S)= 4.5 min; t_r (R,R)= 5.5 min; none of the enantiomer was detectable (ee >99%). The submitters determined enantiomeric purity by HPLC analysis at 254 nm using a Chiralpak AD-H column; isocratic elution, 80:20 hexanes: i-PrOH; 1mL/min: t_r (R,R)= 51 min, t_r (S,S)= 105 min. The (R,R)-enantiomer was prepared by the same procedure using (R_a)-(–)-1,1'-binaphthyl-2,2'-diamine and Boc-D-proline and exhibited the following physical properties: mp 195-197 °C; [α]_D²⁵ +93 (c 1.0, CHCl₃).

22. The diastereomeric purity (de) was determined to be >99% by ¹H NMR analysis in comparison to the (S_a,R)-diastereomer, which was prepared via the same procedure except that Boc-D-proline was used instead of Boc-L-proline. One aromatic proton in the (S_a,R)-diastereomer is upfield (6.54 ppm doublet) relative to the (S_a,S)-diastereomer (6.86 ppm doublet). The 6.54 ppm doublet was undetectible (<0.5%) in the (S_a,S)-diastereomer. The diastereomer (S_a,R)-N-[2´-(4-methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide exhibits the following physical and spectroscopic properties: mp 134-137 °C, Lit^7d 152-155 °C; [α]_D²⁵ + 6 (c 1.0, CHCl₃); ¹H NMR pdf(400 MHz, CDCl₃) δ: 1.50-1.55 (m, 2 H), 1.86-2.00 (m, 2 H), 2.30-2.34 (m, 1 H), 2.34 (s, 3 H), 2.57-2.62 (m, 1 H), 3.51 (dd, J = 4.5, 9.5 Hz, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 6.98 (dt, J = 1.1, 7.7 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 2 H), 7.20-7.23 (m, 1 H), 7.34-7.41 (m, 4 H), 7.89 (dd, J = 8.3, 11.0 Hz, 2 H), 7.99 (d, J = 9.0 Hz, 1 H), 8.06 (d, J = 9.0 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 8.80 (d, J = 9.0 Hz, 1 H), 9.65 (br s, 1 H, NH); ¹³C NMR pdf(100 MHz, CDCl₃) δ: 21.7, 26.1, 30.9, 47.0, 61.0, 117.6, 118.9, 120.0, 120.3, 124.7, 124.9, 125.6, 127.2, 127.3, 127.6, 128.3, 128.5, 129.8, 130.2, 130.7, 130.9, 131.2, 132.5, 132.9, 134.0, 135.8, 136.4, 144.0, 174.1. Safety and Waste Disposal Information All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.

3. Discussion

The first generation of BINAM-prolinamides was introduced by several groups in 2006 to use in direct asymmetric aldol reactions⁵ ⁶ ⁷ or other enantioselective processes.⁸ (S_a,S)-N-[2-(4-Methylphenylsulfonamido)-1,1´-binaphthyl-2´-yl]-pyrrolidine-2-carboxamide (3) is a novel BINAM-prolinamide-type organocatalyst⁵ that was developed by Nájera´s group⁹ and others^7d almost simultaneously. This (S_a)-binam-L-prolinamide sulfonamide derivative 3⁹ was designed by replacing one proline residue in the first generation catalyst⁷ with an acidic sulfonamide group that could activate the carbonyl group of the acceptor through hydrogen-bonding.¹⁰ The efficiency of this catalyst when used with a small amount of benzoic acid as an additive has been proven in several aldol reactions, including the intermolecular aldol reaction between aldehydes and ketones (A, Scheme 1), the cross-aldol reaction between aldehydes (B, Scheme 1), and the intramolecular aldol reaction for the synthesis of the Wieland Miescher ketone (WMK) and related analogues (C, Scheme 1).

Scheme 1. Aldol processes catalyzed by N-tosyl-(S_a)-binam-L-prolinamide 3

For all the processses, solvent-free reaction conditions could be applied using low catalyst loadings, obtaining the corresponding aldol products with good yields and diastereo- and enantioselectivities comparable to those achieved with other structurally similar catalysts¹¹ under different reaction conditions. For instance, the large-scale synthesis of the Wieland-Miescher ketone¹² requires only 1 mol% of catalyst 3 (see accompanying article).¹³

The preparation of catalyst 3 described here is a variant of those which already exist,⁹^,¹⁰ and offers the following advantages:

1) Minimal purification steps: only the final product needs to be purified by chromatography.

2) The amide bond formation is efficiently accomplished using ethyl chloroformate, which avoids the use of SOCl₂ to form the acid chloride or the need for expensive coupling agents that, moreover, are difficult to remove at the end of the reaction.

This preparation can be also applied to obtain the enantiomer of the desired product, (R_a,R)-N-[2´-(4-methylphenylsulfonamido)-1,1´-binaphthyl-2-yl]pyrrolidine-2-carboxamide, as well as the (R_a,S)- and (S_a,R)-diastereomers.

References and Notes

Dpto. Química Orgánica and Instituto de Síntesis Orgánica, Universidad de Alicante, Apdo 99, E-03080 Alicante, Spain. Financial support from the MICINN (projects CTQ2007-62771/BQU, CTQ2010-20387 and Consolider INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (PROMETEO/2009/038), University of Alicante and European Community (COST Action CM0905: Organocatalysis (ORCA)).
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain. Financial support from the MICINN (projects CTQ2007-61338/BQU, CTQ2010-14846/BQU.
The checker thanks Mirlinda Biba for measuring rotations, Zainab Pirzada for developing the chiral SFC assay, Bob Reamer for carrying out the high temperature NMR work on compound 2, and WuXi Pharmatech for the preparative HPLC separation of the mono- and bis-tosylates.
Chen, T; Gao, J; Shi, M. Tetrahedron 2006, 62, 6289-6294.
For general reviews of organocatalysis, see: (a) List, B. Chem. Commun. 2006, 819-824. (b) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47, 4638-4660. (c) Barbas III, C. F. Angew. Chem., Int. Ed. 2008, 47, 42-47. (d) MacMillan, D. W. C. Nature 2008, 455, 304-308. (e) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178-2189. (f) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167-178.
For reviews on the organocatalyzed direct aldol reaction, see: (a) Guillena, G.; Ramón, D. J. Tetrahedron: Asymmetry 2006, 17, 1465-1492. (b) Zlotin, S. G.; Kucherenko, A. S.; Beletskaya, I. P. Russ. Chem. Rev. 2009, 78, 737-784. (c) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600-1632.
For pioneering work using BINAM-prolinamides: (a) Gryko, D.; Kowalczyk, B.; Zawadzki, L. Synlett 2006, 1059-1062. (b) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 1493-1497. (c) Guizzetti, S.; Benaglia, M.; Pignataro, L.; Puglisi, A. Tetrahedron: Asymmetry 2006, 17, 2754-2760. (d) Ma, G.-N.; Zhang, Y.-P.; Shi, M. Synthesis 2007, 197-208.
(a) Xiong, Y.; Huang, X.; Gou, S.; Huang, J.; Wen, Y.; Feng, X. Adv. Synth. Catal. 2006, 348, 538-544. (b) Horillo Martínez, P.; Hultzch, K. C.; Hampel, F. Chem. Commun. 2006, 2221-2223.
Guillena, G.; Nájera, C.; Viózquez, S. F. Synlett 2008, 3031-3035.
For amide-based bifunctional organocatalysts in asymmetric reactions, see: Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 6145-6158.
(a) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez, S. F. Tetrahedron: Asymmetry 2007, 18, 2300-2304. (b) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez, S. F. J. Org. Chem. 2008, 73, 5933.
(a) Bradshaw, B.; Etxeberría-Jardí, G.; Bonjoch, J.; Guillena, G.; Nájera, C.; Viózquez, S. F. Adv. Synth. Catal. 2009, 351, 2482-2490; (b) Bradshaw, B.; Etxeberría-Jardí, G.; Bonjoch, J. J. .Am. Chem. Soc. 2010, 132, 5966-5967.
Bradshaw, B.; Etxeberría-Jardí, G.; Bonjoch, J.; Viózquez, S. F., Guillena, G.; Nájera, C. Org. Synth. 2011, 88, 330-341.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

(S_a)-(-)-1,1´-Binaphthyl-2,2´-diamine: (S_a)-(-)-1,1´-Bi(2-naphthylamine); (18531-95-8)

p-Toluenesulfonyl chloride: Benzenesulfonyl chloride, 4-methyl-; (98-59-9)

Pyridine; (110-86-1)

N-(tert-Butoxycarbonyl)-L-proline; (15761-39-4)

Ethyl chloroformate: Carbonochloridic acid, ethyl ester; (541-41-3)

Triethylamine; (121-44-8)

Trifluoroacetic acid; (76-05-1)

	Josep Bonjoch was born in Barcelona (Catalonia, Spain) in 1952. He received his Ph.D. degree (1979) under the supervision of Prof. Joan Bosch at the University of Barcelona, Faculty of Chemistry. He then moved to the Faculty of Pharmacy at the same University, where he was promoted to Associate Professor (1984) and subsequently became Full Professor of Organic Chemistry in 1992. His main research involves the synthesis of complex nitrogen containing natural products, as a motive for developing new synthetic methodology.
	Santiago Viózquez was born in Alicante (Spain) in 1981. He received his B.S. degree in chemistry at the Universidad de Alicante in 2006. He is now pursuing his Ph.D. at the Universidad de Alicante under the supervision of G. Guillena and C. Nájera. His research concerns asymmetric organocatalysis with prolinamides derivatives.
	Gabriela Guillena received her BSc degree (1993) from University of Alicante. After spending one year as postgraduate student in the group of D. Seebach at the ETH (Zurich), she returned to University of Alicante and received her MSc (1995) and PhD (2000) degrees under the supervision of C. Nájera. After two years as a postdoctoral fellow at research group of G. van Koten (University of Utrecht, Netherlands), she returned to the University of Alicante where she became Assistant Professor in 2003 and Associate Professor in 2008. Her current research interests are focused on new organic methodologies and asymmetric organocatalysis.
	Carmen Nájera obtained her B.Sc. (1973) from University of Saragossa and her PhD (1979) at the University of Oviedo under the supervision of J. Barluenga and M. Yus. She performed her postdoctoral work at the ETH (Zurich) with D. Seebach, at the Dyson Perrins Laboratory (Oxford) with J. E. Baldwin, at Harvard University with E. J. Corey, and at Uppsala University with J.-E. Bäckvall. She became Associate Professor in 1985 at the University of Oviedo and Full Professor in 1993 at the University of Alicante. Her scientific contributions are focused on synthetic organic chemistry such as sulfone chemistry, new peptide coupling reagents, oxime-derived palladacycles, asymmetric metal catalysis and organocatalysis.
	Ben Bradshaw was born in 1974 in Southport, England. He studied Chemistry at the University of Manchester, where he obtained his PhD in 2001 under the supervision of Professor John Joule. After postdoctoral work with Professor Jim Thomas on the total synthesis of the Bryostatins he joined the group of Professor Josep Bonjoch at the University of Barcelona. In 2008 he was promoted to the position of assistant professor where his research interests include the application of organocatalysis to the total synthesis of complex natural products.
	Gorka Etxebarria-Jardí was born in 1981 in Barcelona, Catalonia. He obtained his BSc in Chemistry (2004) and MSc in synthesis of antiretroviral nucleoside drugs (2005) from the University of Barcelona. In 2006, he joined the research group of Prof. Josep Bonjoch and is currently completing his Ph.D in asymmetric catalysis and natural product synthesis.

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