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Synlett 2004(4): 714-716  
DOI: 10.1055/s-2004-817770
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short Synthetic Approach to Chiral Serine Azido Derivatives

Gautam Panda*, N. Venugopal Rao
Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, K1A 0R6, Canada
e-Mail: gautam_panda@lycos.com ; e-Mail: bapi@rocketmail.com;
Further Information

Publication History

Received 26 December 2003
Publication Date:
17 February 2004 (online)

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Abstract

We report a new synthetic methodology for the synthesis of chiral serine azido derivatives through a conversion of N-protected (Boc, Cbz and Fmoc) serine amino acid into its corresponding Weinreb amide. Thus, acidity of the α-proton of the serine is reduced and it allows nucleophilic addition reaction onto Weinreb amide to furnish chiral serine azido derivatives.

Key words

serine azido esters - Weinreb amide - Mitsunobu reaction - azido aldehyde - LiOH-H2O2 - hydrolysis - Fmoc group

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1

Present Address: Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India, e-mail: gautam_panda@lycos.com.

11

Typical Procedure for Mitsunobu Reaction: A mixture of Fmoc-Ser-Weinreb amide ester 4c (2.01 g, 5.4 mmol) and Ph3P (2.13 g, 8.1mmol) in anhyd THF (120 mL) was cooled in an ice bath. A solution of DEAD (1.46 g, 8.1 mmol) in THF (18 mL) was added dropwise. After mixing of the solution for 5 min, a HN3-toluene solution (8.7 mL, 16.2 mmol) was slowly added. The mixture was allowed to warm to r.t. and stirred for 8 h. The solvent was removed in vacuo. The oily residue was purified by column chromatography (hexane-EtOAc, 1:1) to provide product 5c (2.0 g, 93%). [α]D 25 = +12.50 (c = 1.0, EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.7 (d, J = 8 Hz, 2 H), 7.5 (d, J = 8 Hz, 2 H), 7.4 (d, J = 8 Hz, 2 H), 7.2 (d, J = 7.8 Hz, 2 H), 6.1 (br s, 1 H), 5.0 (br s, 1 H), 4.4 (m, 3 H), 4.2 (m, 2 H), 3.8 (s, 3 H), 3.6 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 169.6, 156.2, 151.3, 144.1, 144.0, 141.9, 130.5, 128.6, 128.1, 127.5, 127.4, 125.5, 120.5, 120.3, 108.3, 68.0, 67.7, 62.8, 62.4, 52.6, 51.6, 47.4. MS: m/z = 395 [M+]. Anal. Calcd: C, 60.75; H, 5.35; N, 17.71. Found: C, 61.01; H, 5.21; N, 17.88.
Typical Procedure for Hydrolysis of 5c: To a solution of azide 5c (75 mg, 0.189 mmol) in THF (3mL) and H2O (1 mL) were added LiOH (7 mg, 0.283 mmol) and H2O2 (0.1 mL, 1.51 mmol) and the reaction mixture was stirred at 0 °C for 8 h. The mixture was quenched by sat. solution of Na2SO3 at 0 °C and THF was removed in vacuo. CH2Cl2 was added to remove any unchanged starting material. The aqueous phase was acidified with NH4Cl and extracted twice with EtOAc. The crude acid 1c was obtained which was purified through column chromatography (58 mg, 88%).

12

Typical Procedure for DIBAL-H Reduction: To a solution of 5a,b (Boc dervative; 110 mg, 0.402 mmol, Cbz dervative 155 mg, 504 mmol) in anhyd THF (5 mL) at -78 °C was added DIBAL-H (0.68 mL for Boc, 0.85 mL for Cbz) and the reaction micture was stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and extracted with EtOAc. Column chromatography over silica gel furnished 6a (50 mg, 50%) and 6b (72 mg, 50%). Spectral data: 4a: 1H NMR: δ = 5.8 (br s, 1 H), 4.8 (br s, 1 H), 3.8 (m, 1 H), 3.7 (br s, 2 H), 3.3 (s, 3 H), 2.9 (s, 3 H), 1.4 (s, 9 H). MS: m/z = 248 [M+]. Anal. Calcd; C, 48.38; H, 8.12; N, 11.28. Found: C, 49.00; H, 9.00; N, 10.28. 5a: [α]D 25 = +2.9 (c = 1.0, EtOAc). 1H NMR: δ = 5.1 (br s, 1 H), 4.9 (br s, 1 H), 3.9 (m, 1 H), 3.1 (m, 2 H), 3.2 (s, 3 H), 3.0 (s, 3 H), 1.4 (s, 9 H). 13C NMR: δ = 169.9, 155.5, 80.5, 61.2, 61.0, 52.7, 51.0, 32.5, 28.6 MS: m/z = 273 [M+]. Anal. Calcd for C, 43.95; H, 7.01; N, 25.63. Found: C, 44.00; H, 7.89; N, 24.96. 6a: [α]D 25 = +12.0 (c = 1.0, EtOAc). 1H NMR: δ = 9.0 (s, 1 H), 6.2 (m, 1 H), 5.2 (s, 2 H), 1.4 (s, 9 H). MS: m/z = 214 [M+]. 9b: 1H NMR: δ = 8.0 (s, 1 H), 7.4-7.2 (m, 5 H), 5.1 (br s, 2 H), 3.8 (m, 1 H), 3.7 (s, 2 H), 3.2 (s, 3 H), 3.0 (s, 3 H). MS: m/z = 282 [M+]. Anal. Calcd: C, 44.85; H, 6.59; N, 26.15. Found: C, 44.0; H, 7.00; N, 26.10. 5b: [α]D 25 = +0.3 (c = 1.0, EtOAc). 1H NMR: δ = 7.4-7.2 (m, 5 H), 6.0 (br s, 1 H), 5.1 (br s, 2 H), 4.9 (m, 1 H), 3.8 (s, 3 H), 3.5 (d, J 1 = 6 Hz, J 2 = 2 Hz, 2 H), 3.1 (s, 3 H). 13C NMR: δ = 169.9, 156.2, 136.54, 128.9, 128.5, 128.4, 67.4, 62.7, 62.5, 52.5, 51.5, 32.5. MS: m/z = 307 [M+]. Anal. Calcd: C, 50.81; H, 5.58; N, 22.79. Found: C, 51.01; H, 5.68; N, 22.99. 1b: [α]D 25 = +9.0 (c = 1.0, EtOAc). 1H NMR: δ = 7.4-7.2 (m, 5 H), 6.9 (br s, 1 H), 5.1 (m, 2 H), 4.0 (br s, 1 H), 3.8 (m, 2 H). MS: m/z = 264 [M+]. Anal. Calcd: C, 50.00; H, 4.58; N, 21.20. Found: C, 50.89; H, 4.78; N, 21.55. 6b: [α]D 25 = +8.8 (c = 1.0, EtOAc). 1H NMR: δ = 9.0 (s, 1 H), 7.4-7.2 (m, 5 H), 7.1 (m, 1 H), 6.4 (s, 1 H), 5.6 (s, 1 H), 5.1 (s, 2 H). MS: m/z = 248 [M+]. Anal. Calcd: C, 53.22; H, 4.87; N, 22.57. Found: C, 53.99; H, 4.99; N, 23.99. 4c: 1H NMR: δ = 7.7 (d, J = 8 Hz, 2 H), 7.5 (d, J = 8 Hz, 2 H), 7.4 (d, J = 8 Hz, 2 H), 7.2 (d, J = 7.8 Hz, 2 H), 6.1 (br s, 1 H), 5.8 (br s, 1 H), 4.3 (s, 2 H), 4.2 (m, 1 H), 3.8 (m, 1 H), 3.7 (m, 2 H), 3.2 (s, 3 H), 2.9 (s, 3 H). 13C NMR: δ = 163.1, 156.9, 144.2, 144.1, 141.6, 141.5, 128.8, 128.1, 127.4, 125.5, 125.2, 120.3, 67.5, 63.5, 62.0, 53.3, 47.5, 39.0, 36.9, 34.2, 32.5, 31.8. MS: m/z = 370 [M+]. Anal. Calcd: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.00; H, 6.99; N, 8.89.