Download PDF
Synlett 2006(8): 1235-1239  
DOI: 10.1055/s-2006-939695
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Approach to Protected (4S,5R)-4-Hydroxy-5-(α-hydroxyalkyl)-2-pyrrolidinones

Xiang Zhou, Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical ­Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
Fax: +86(592)2186400; e-Mail: pqhuang@xmu.edu.cn;
Further Information

Publication History

Received 11 November 2005
Publication Date:
05 May 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

Starting from (S)-N,O-dibenzylmalimide (7), a versatile four-step approach to (4S,5R)-N-benzyl-4-benzyloxy-5-(α-hydroxyalkyl)-2-pyrrolidinones 9 is reported. The method consists of Grignard reagent addition, p-toluenesulfonic acid monohydrate-mediated dehydration, one-pot epoxidation-methanol ring-opening reaction and reductive demethoxylation. 2-Pyrrolidinones 9 were obtained with excellent trans-diastereoselectivity in the pyrrolidinone ring and low diastereoselectivity at the carbinol center.

Key words

dehydration - enamide - 2-pyrrolidinones - epoxidation - asymmetric synthesis

15

All new compounds (6 and 9) gave satisfactory analytical and spectral data.
General Procedure for the Synthesis of 9.
To a solution of the more polar diastereomer of 5 [12] (1.0 mmol) in CH2Cl2 (10 mL) was added 0.05 mmol of p-TSA. The mixture was stirred at r.t. for 1 h. Then the reaction was quenched with sat. aq NaHCO3 and extracted with CH2Cl2 (3 × 10 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with EtOAc-PE to give 6. To a solution of 6 (1.0 mmol) in a mixture of abs. MeOH (20 mL) and dry CH2Cl2 (10 mL) was added dropwise a solution of MCPBA (3.0 mmol) in CH2Cl2 (10 mL) at -78 °C under nitrogen atmosphere. After the mixture stirred for 1 h, it was allowed to reach r.t. and stirred overnight. Then, the reaction was quenched with a solution of aq Na2S2O3 (10%) and sat. NaHCO3. The mixture was extracted with CH2Cl2 (3 × 40 mL). The combined extracts were washed with brine, dried over anhyd Na2SO4, filtered and concentrated in vacuum. Filtration through a short pad of SiO2 eluting with EtOAc-PE gave 8 as a mixture of diastereomers. The diastereomeric ratios were determined either by flash chromatographic separation or by analysis of 1H NMR spectra of the crude mixture. To a cooled (-78 °C) solution of diastereomeric mixture of 8 (1.0 mmol) in dry CH2Cl2 (10 mL) were added dropwise triethylsilane (10 mmol) and BF3·OEt2 (10.0 mmol) under nitrogen atmosphere. After stirred for 6 h at the same temperature, the reaction was allowed to warm up and stirred at r.t. overnight. The reaction was quenched with sat. aq NaHCO3 and extracted with CH2Cl2 (3 × 20 mL). The combined extracts were washed with brine, dried over anhyd Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc-PE to give 9.
Selected physical and spectral data for 6d: [α]D 20 +62.0 (c 0.4, CHCl3). IR (film): 3060, 3023, 1719, 1674 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.80 (t, J = 7.3 Hz, 3 H, CH3), 1.22-1.38 (m, 2 H, MeCH2), 1.94-2.12 (m, 2 H, EtCH2), 2.68 (dd, J = 1.7, 17.8 Hz, 1 H, COCH2), 2.78 (dd, J = 7.0, 17.8 Hz, 1 H, COCH2), 4.42 (d, J = 11.2 Hz, 1 H, PhCH2O), 4.53 (d, J = 11.2 Hz, 1 H, PhCH2O), 4.70 (s, 2 H, PhCH2N), 4.74 (dd, J = 1.7, 7.0 Hz, 1 H, BnOCH), 4.84 (t, J = 7.5 Hz, 1 H, =CH), 7.20-7.40 (m, 10 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.6, 23.3, 28.7, 36.6, 43.4, 69.9, 70.2, 108.0, 127.0, 127.2, 128.0, 128.1, 128.3, 128.4, 128.5, 135.8, 137.3, 138.9, 173.1 ppm. MS (ESI): m/z (%) = 336 (100) [M + H+]. Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.81; H, 7.47; N, 4.00.
Selected physical and spectral data for 9d: major diastereomer: colorless oil; [α]D 20 +44.2 (c 1.0, CHCl3). IR (film): 3378, 3063, 3031, 1671 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.84 (t, J = 7.1 Hz, 3 H, CH3), 1.22-1.48 [m, 4 H, Me(CH2)2], 2.50 (dd, J = 1.3, 17.4 Hz, 1 H, COCH2), 2.80 (dd, J = 6.9, 17.4 Hz, 1 H, COCH2), 3.00 (br s, 1 H, OH), 3.40 (d, J = 4.9 Hz, 1 H, BnNCH), 3.78-3.84 (m, 1 H, CHOH), 4.18 (d, J = 15.0 Hz, 1 H, PhCH2N), 4.19 (dd, J = 1.3, 6.9 Hz, 1 H, BnOCH), 4.40 (d, J = 11.7 Hz, 1 H, PhCH2O), 4.48 (d, J = 11.7 Hz, 1 H, PhCH2O), 5.00 (d, J = 15.0 Hz, 1 H, PhCH2N), 7.20-7.40 (m, 10 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.9, 19.3, 34.8, 38.6, 44.2, 68.0, 68.8, 70.4, 71.9, 127.7, 127.8, 128.4, 128.8, 136.2, 137.5, 174.2 ppm. MS (ESI): m/z (%) = 376 (100) [M + Na+]; minor diastereomer: white crystals, mp 77-79 °C; [α]D 20 +13.9 (c 0.4, CHCl3). IR (KBr, pellet): 3394, 3062, 3031, 1669 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H, CH3), 1.10-1.32 [m, 3 H, Me(CH2)2], 1.42-1.52 [m, 1 H, Me(CH2)2], 2.33 (br s, 1 H, OH), 2.51 (d, J = 17.7 Hz, 1 H, COCH2), 2.75 (dd, J = 6.4, 17.7 Hz, 1 H, COCH2), 3.58 (d, J = 4.6 Hz, 1 H, BnNCH), 3.61-3.65 (m, 1 H, CHOH), 4.02 (d, J = 6.4 Hz, 1 H, BnOCH), 4.18 (d, J = 15.2 Hz, 1 H, PhCH2N), 4.42 (s, 2 H, PhCH2O), 5.02 (d, J = 15.2 Hz, 1 H, PhCH2N), 7.20-7.40 (m, 10 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.8, 19.2, 34.8, 38.2, 45.9, 67.8, 70.2, 71.3, 73.8, 127.5, 127.6, 127.7, 127.9, 128.4, 128.6, 136.3, 137.6, 174.3 ppm. MS (ESI): m/z (%) = 354 (67) [M + H+], 376 (100) [M + Na+]. Anal. Calcd for C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: C, 74.77; H, 7.94; N, 4.02.