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Synlett 2007(5): 0795-0799  
DOI: 10.1055/s-2007-970765
LETTER
© Georg Thieme Verlag Stuttgart · New York

NOBIN-Prolinamide Organocatalyzed Enantioselective Direct Aldol Reaction: Remarkable Activity in Apolar Medium

Alessio Russo, Giovanna Botta, Alessandra Lattanzi*
Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano, Italy
Fax: +39(089)969603; e-Mail: lattanzi@unisa.it;
Further Information

Publication History

Received 5 December 2006
Publication Date:
08 March 2007 (online)

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Abstract

Amides easily obtained from enantiopure (R)- and (S)-NOBIN and l-proline have been shown to promote the enantioselective direct aldol reaction under low catalytic loadings (5 mol%), in apolar hexane as the solvent and using only a slightly higher ­molar excess of the acetone with respect to the aldehyde. Aldol products are isolated in good to high yields and up to 77% ee at room temperature.

Key words

aldol reaction - asymmetric organocatalysis - prolin­amides - NOBIN - apolar solvent

14

Procedure for the Synthesis of Catalysts 2 and 3
To a solution of N-carbobenzyloxy l-proline (320 mg, 1.26 mmol) in anyd CH2Cl2 (4 mL) and MeCN (4 mL) was added DMAP (80 mg, 1 mmol), EDC·HCl (368 mg, 3 mmol) at 0 °C under argon atmosphere. Stirring was mantained for 1 h, then (R)-or (S)-NOBIN (400 mg, 1.4 mmol) dissoved in anhyd DMF (2 mL) was cannulated in the reaction vessel and stirring was mantained for 3 d at r.t. The solvent was removed, the crude mixture was diluted with HCl solution (0.1 N) and extracted with CHCl3 (2 × 50 mL). The organic phase was then dried over Na2SO4. The crude mixture was purified by flash chromatography eluting with PE-Et2O (1:1) to PE-EtOAc (2:1) mixtures to give 400 mg (60%) and 380 mg (57%) yield, respectively, as white gummy compounds. To N-carbobenzyloxy-l-prolinamide (R)-NOBIN (400 mg) dissolved in anhyd MeOH (8 mL) was added Pd/C (10% w/w). The reaction mixture was stirred under H2 (1 atm) at 50 °C for 3 h. After cooling, the mixture was filtered over a pad of Celite®. The solvent was removed and the crude mixture was purified by flash chromatography eluting with CHCl3-MeOH (2:1) mixture to give 2 (266 mg, 90%) as a white solid. Compound 3 was obtained with the same yield.
Compound 2: mp 199-201 °C (dec.); [α]D 23 -46.7 (c 0.25, EtOH). IR (neat): 3203, 3056, 2870, 1670, 1506, 818, 751 cm-1. 1H NMR (400 MHz, CDCl3): δ = 9.70 (br s, 1 H), 8.62 (d, 1 H, J = 9.0 Hz), 8.03-7.80 (m, 5 H), 7.41-7.31 (m, 4 H), 7.25-7.21 (m, 1 H), 7.03-6.99 (m, 1 H), 3.55-3.50 (m, 1 H), 2.58-2.53 (m, 1 H), 2.32-2.28 (m, 1 H), 1.90-1.87 (m, 1 H), 1.81-1.76 (m, 1 H), 1.50-1.27 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 174.0, 152.0, 136.0, 133.3, 133.1, 132.8, 131.1, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0, 125.3, 125.2, 124.3, 123.6, 120.4, 117.8, 113.6, 60.5, 46.6, 30.6, 25.6. ESI-MS: m/z 383 [M + H+]. Anal. Calcd (%) for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.70; H, 5.96; N, 7.18.
Compound 3: mp 215-218 °C (dec.). [α]D 18 -25.8 (c 0.20, EtOH). IR (neat): 3232, 3056, 2972, 1661, 1505, 865, 749 cm-1. 1H NMR (400 MHz, CDCl3): δ = 9.72 (br s, 1 H), 8.75 (d, 1 H, J = 9.0 Hz), 8.07-7.80 (m, 5 H), 7.43-7.31 (m, 4 H), 7.24-7.20 (m, 1 H), 7.03-6.99 (m, 1 H), 3.57-3.52 (m, 1 H), 2.35-2.31 (m, 1 H), 1.84-1.80 (m, 1 H), 1.69-1.62 (m, 1 H), 1.54-1.48 (m, 1 H), 1.30-1.20 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 174.0, 151.9, 136.0, 133.3, 133.1, 132.8, 131.0, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0, 125.0, 124.9, 124.2, 123.7, 119.9, 117.8, 113.6, 60.6, 46.1, 30.6, 25.3. ESI-MS: m/z = 383 [MH+]. Anal. Calcd (%) for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.39; H, 5.62; N, 7.20.

16

Procedure for the Synthesis of Catalyst 6
N-Carbobenzyloxy-d-prolinamide-(R)-NOBIN (180 mg, 0.348 mmol) was stirred with Cs2CO3 (566 mg, 1.74 mmol) in MeCN (5 mL) at r.t. for 30 min. Then MeI (870 µL, 14 mmol) was added and the mixture was stirred for 18 h. The solvent was removed, the crude mixture was diluted with HCl solution (0.1 N) and extracted with CHCl3 (2 × 50 mL). The organic phase was then dried over Na2SO4. The crude mixture was purified by flash chromatography eluting with PE-EtOAc (6:4) to give 124 mg (67%) of the methylated product. Deprotection of this compound, carried out as previously reported for compound 2 and 3, furnished 88 mg (95%) of 6 as a white solid.
Compound 6: mp 167-171 °C (dec); [α]D 23 +33.9 (c 0.25, EtOH). IR (neat): 3443, 2927, 1658, 1507, 1249, 812, 753 cm-1. 1H NMR (400 MHz, CDCl3): δ = 9.70 (br s, 1 H), 8.05-7.85 (m, 6 H), 7.56-7.17 (m, 6 H), 3.95 (s, 3 H), 3.50-3.45 (m, 1 H), 3.37-3.32 (m, 2 H), 2.17-1.98 (m, 2 H), 1.33-1.20 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 173.0, 154.9, 138.2, 133.7, 133.0, 132.8, 131.0, 130.7, 129.5, 129.0, 128.5, 128.3, 127.6, 127.0, 126.0, 125.2, 125.1, 124.7, 124.0, 123.7, 115.5, 58.8, 58.3, 47.6, 29.9, 25.4. ESI-MS: m/z = 403 [M + H+]. Anal. Calcd (%) for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.92; H, 6.25; N, 7.21.

17

Typical Procedure for the Aldol Reaction
In a capped vial under air catalyst 3 (3.8 mg, 0.01 mmol), aldehyde (0.2 mmol) and hexane (400 µL) were added at r.t. To this stirred mixture, acetone (44 µL, 0.6 mmol) was added. Upon completion of the reaction, monitored by TLC, the reaction mixture was directly purified by flash chromatography (PE-EtOAc 90:10 to 60:40 mixtures) to provide aldol 5. Analytical data of aldols matched those reported in the literature. [5] [6]

18

For the sake of comparison, the optimized Gong’s catalyst at -25 °C in cyclohexanone furnished the aldol product as anti/syn 95:5 ratio in 83% yield. The anti-isomer was isolated in 79% ee. [6c]

21

One way to achieve this goal might be the employment of proper mixtures of hexane and ethereal cosolvents.