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Synlett 2006(11): 1675-1678  
DOI: 10.1055/s-2006-947322
LETTER
© Georg Thieme Verlag Stuttgart · New York

Catalytic Asymmetric Cyano-Ethoxycarbonylation Reaction of Aldehydes Using a Novel C 2-Symmetric Chiral N,N′-Dioxide Titanium Complex

Qinghan Lia, Lu Changa, Xiaohua Liua, Xiaoming Feng*a,b
a Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. of China
b State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. of China
Fax: +86(28)85418249; e-Mail: xmfeng@scu.edu.cn;
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Publication History

Received 1 April 2006
Publication Date:
04 July 2006 (online)

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Abstract

The asymmetric addition of ethyl cyanoformate to a range of aldehydes was efficiently catalyzed by a easily prepared C 2-symmetric chiral N,N′-dioxide-Ti(IV) complex in high yields with up to 90% ee under mild conditions. A linear effect between the enantiopurity of the ligand and the enantiopurity of the product was observed.

Key words

C 2-symmetric chiral N,N′-dioxide ligand - ethyl cyanoformate - aldehydes - enantioselectivity - organotitanium

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General Procedure for the Preparation of C 2 -Symmetric Ν , N ′-Dioxide Ligands.
(a) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.3 g, 10.0 mmol) in CH2Cl2 was added Et3N (4 mL), isobutyl carbonochloride (1.44 mL, 10.0 mmol) at 0 °C under stirring After 25 min, the amine (10.2 mmol) was added. It was allowed to warm to r.t. and stirred for 8 h. The mixture was washed with 1 M KHSO4 (20 mL), sat. NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4 and concentrated. The residue in CH2Cl2 (25 mL) was added TFA (10 mL) and stirred for 2 h. Then, the solvent was evaporated, and H2O (20 mL) was added. The pH of the mixture was brought into the range of 8-10 by the addition of 2 M NaOH. The aqueous phase was extracted with CH2Cl2 (50 mL). The CH2Cl2 extracts were pooled, washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was used for next step directly.
(b) 2,6-Di(bromomethyl)-4-methylphenol (5.1 mmol) was added in one portion to a stirred and cooled solution of (S)-pyrrolidine-2-carboxamide (10.2 mmol) and K2CO3 (21 mmol) in dry DMF (8 mL). The ice bath was removed after the addition and the resulting solution was allowed to stir at r.t. for 12 h before it was diluted with H2O (50 mL) and Et2O (50 mL). The two phases were separated and the aqueous phase was extracted with Et2O three times and the combined organic phases were washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and evaporated. The residue was purified by silic gel column chromatography to give the foam product. Next, MCPBA (13 mmol) was added at -78 °C to a solution of the above product and anhyd K2CO3 in CH2Cl2. The resulting mixture was stirred at the same temperature and the reaction was monitored by TLC. After completion, the mixture was allowed to warm slowly to r.t. and filtered. The solvents were evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (Et2O-MeOH, 10:1 and Et2O-MeOH, 6:1) to afford the corresponding (2S,2′S)-1,1′-[(2-hydroxy-5-methyl-1,3-phenylene)di(methylene)]bis[N-(2-tert-butylphenyl)pyrrolidine-2-carboxamide]-N,N′-dioxide (1c).

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The following are the physical, NMR and HRMS data of 1c: mp 127-129 °C; [α]D 25 -7.3 (c 2.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.54 (s, 2 H), 7.25-7.33 (m, 4 H,), 7.07-7.15 (m, 4 H), 6.82 (s, 2 H), 3.82-3.85 (d, J = 12 Hz, 2 H), 3.59-3.62 (d, J = 12 Hz, 2 H), 3.30-3.34 (m, 2 H), 2.95-3.00 (m, 2 H), 2.39-2.46 (m, 2 H), 2.19 (s, 3H), 1.99-2.05 (m, 4 H), 1.76-1.79 (m, 4 H), 1.44 (s, 18 H,). 13C NMR (400 MHz, CDCl3): δ = 20.39, 24.01, 30.16, 30.56, 34.54, 53.83, 55.78, 67.42, 123.07, 125.89, 126.34, 126.58, 127.8, 129.74, 135.08, 142.76, 153.32, 172.28. HRMS: m/z calcd for C38H52N4O5: 657.4016 [M + H]+; found: 657.4005 [M + H]+.

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General Procedure for Asymmetric Addition of Ethyl Cyanoformate to Aldehydes. To a solution of 1c (16.4 mg, 0.025 mmol) and 4 Å MS (20 mg) in CH2Cl2 (0.5 mL) was added Ti(Oi-Pr)4 (1 M in toluene, 25 µL, 0.025 mmol) at r.t., then the mixture was stirred at 35 °C for 1 h under N2 atmosphere. To this solution aldehyde (0.25 mmol) and EtOCOCN (50 µL, 0.5 mmol) were added at -45 °C under N2 atmosphere. After the complete conversion of the aldehyde (monitored by TLC, 48-100 h), the crude product was purified by column chromatography on silica gel (PE-Et2O, 10:1) to give the corresponding cyanohydrin carbonates for further analysis.