Download PDF
Synlett 2006(15): 2419-2422  
DOI: 10.1055/s-2006-950431
LETTER
© Georg Thieme Verlag Stuttgart · New York

trans-4-Hydroxy-l-proline Hydrazide-Trifluoroacetic Acid as Highly Stereoselective Organocatalyst for the Asymmetric Direct Aldol Reaction of Cyclohexanone

Chuanling Chenga,b, Siyu Weia, Jian Sun*a
a Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax: +86(28)85222753; e-Mail: sunjian@cib.ac.cn;
b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Further Information

Publication History

Received 20 June 2006
Publication Date:
08 September 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

Protonated N′-benzyl-N′-l-prolyl-trans-4-hydroxy-l-proline hydrazide has been found to be superior to the l-proline hydrazide counterpart as the catalyst for the asymmetric aldol reaction of cyclohexanone and aromatic aldehydes, resulting in excellent ­diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to >99% ee).

Key words

proline hydrazide - enantioselectivity - diastereoselectivity - cyclohexanone - asymmetric direct aldol reaction

8

General Procedure for the Preparation of Catalysts 2-4:
To a solution of Boc-l-Pro-NHNH2 (for 2) or trans-4-(tert-butyldimethylsilyloxy)-Boc-l-Pro-NHNH2 (for 3 and 4; 8.0 mmol) in toluene (20 mL) was added benzaldehyde (935 mg, 8.8 mmol). The reaction mixture was stirred at r.t. for 24 h, and then concentrated under reduced pressure. The residue was dissolved in MeOH (80 mL), and 5% Pd/C (0.2 g) was added. After stirring under hydrogen (1 atm) for 1 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 3:1) to give N′-benzyl-Boc-l-proline hydrazide or N′-benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-l-proline hydrazide.
To a solution of N′-benzyl-Boc-l-proline hydrazide or N′-benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-l-proline hydrazide (2.0 mmol) in DMF (20 mL) were added Boc-l-Pro (for 4) or trans-4-hydroxy-Boc-l-Pro (for 2 and 3; 2.4 mmol), N,N-diisopropylethylamine (DIPEA, 700 µL) and HATU (922 mg, 2.4 mmol) at 0 °C. The reaction mixture was stirred at r.t. for 24 h, and then concentrated under reduced pressure. The residue was dissolved in EtOAc. The organic phase was then washed with sat. aq NaHCO3 and brine and dried over anhyd Na2SO4. After removal of solvent under reduced pressure, the residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 2:1) to give a white solid, which was then treated with a mixture of TFA-CH2Cl2 (1:2, 20 mL). After stirring at r.t. for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a H+ ion-exchange resin column with NH3·H2O (3.0 M) as eluent to give a crude product, which was further purified through column chromatography on silica gel (eluent: CH2Cl2 saturated with NH3 gas-MeOH, 10:1) to give the final product.

9

The following are the analytic data of catalyst 4: [α]D 25 -43.2 (c = 0.206, MeOH); mp 59-62 °C. 1H NMR (600 MHz, CD3OD): δ = 1.57-1.72 (m, 4 H), 1.88-1.95 (m, 2 H), 2.66-2.71 (m, 2 H), 2.84-2.86 (dd, J = 3.90, 11.94 Hz, 1 H), 3.01-3.05 (m, 1 H), 3.71 (q, J = 8.46 Hz, 2 H), 4.21 (s, 1 H), 4.54 (br s, 1 H), 4.75 (br s, 1 H), 7.17-7.25 (m, 5 H). 13C NMR (150 MHz, CD3OD): δ = 25.6, 30.0, 39.4, 46.5, 50.5, 54.7, 57.5, 58.0, 71.8, 127.6, 128.3, 128.8, 135.4, 174.2, 175.6. HRMS (ESI): m/z [M +H]+ calcd for C17H25N4O3: 333.1921; found: 333.1915.

10

Typical Procedure for the Aldol Reaction of Aldehydes with Cyclohexanone:
To a solution of 4 (12.6 mg, 0.04 mmol) in toluene (0.2 mL) were added cyclohexanone (210 µL) and TFA (3.1 µL, 0.04 mmol). After stirring at 0 °C for 15 min, aldehyde (0.2 mmoL) was introduced. The reaction was stirred at the same temperature until completion, and was then quenched with sat. aq solution of NH4Cl. EtOAc was added to dilute the mixture. The organic layer was separated, washed with brine, dried over anhyd MgSO4 and concentrated under reduced pressure. The residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 3:1) to yield the corresponding aldol products for further analysis.

11

Further investigations, including computational studies, are needed to fully understand why catalyst 4 is superior to 1. A plausible explanation is that the existence of the trans-4-hydroxyl group in 4, which had no obvious effect on the solubility of the catalyst, favors the catalytic conformation that led to the major diastereomer and enantiomer.