A Short Synthetic Approach to Chiral Serine Azido Derivatives

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.

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

References

<A NAME="RG36503ST-1">1</A>

Present Address: Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India, e-mail: [e-mail].

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<A NAME="RG36503ST-11">11</A>

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%).

<A NAME="RG36503ST-12">12</A>

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.