A Flexible Approach for the Asymmetric Synthesis of N-Protected (R)-5-Alkyl Tetramates and (R)-5-Alkyl Tetramic Acid Derivatives

Abstract

A flexible two-step asymmetric approach to N-protected (R)-5-alkyl tetramates and (R)-5-alkyl tetramic acid derivatives is described. The method is based on the diastereoselective alkylation of (R)-phenylglycinol derived tetramates 7 and 8, which are the first synthetic equivalents to chiral nonracemic tetramate 5-carbanionic synthons A.

Key words

asymmetric synthesis - alkylations - chiral auxiliaries - tetramates - tetramic acids

References

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23

Representative Procedure for the Alkylation of ( R )-7/8: To a solution of (R)-7 (104 mg, 0.42 mmol) in THF (8.4 mL, containing 0.37 mL of HMPA as a co-solvent) was added dropwise t-BuLi (0.67 mL, 1.5 M in pentane) at -78 ºC. After being stirred for 1 h, MeI (0.08 mL, 1.26 mmol) was added and the stirring continued for an additional 6 h at the same temperature. The reaction was quenched by sat. NH₄Cl. The resulting mixture was extracted with Et₂O, and the organic layers were washed with brine, dried over MgSO₄ and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel to give 9b (62 mg, colorless oil), its diastereomer (7 mg, pale yellow oil) (combined yield, 63%) and recovered 7 (7 mg, yield based on the recovered starting material, 68%). Compound 9b: [α]_D ²⁰ +19.4 (c 1.1, CHCl₃). IR (KBr): 3374, 2981, 2934, 1657, 1625, 1340, 1221, 1029 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.40-7.20 (m, 5 H, ArH), 5.18 (dd, J = 6.4, 7.7 Hz, 1 H, D₂O exchangeable, OH), 5.01 (s, 1 H, O=CCH=), 4.51 (dd, J = 3.1, 7.7 Hz, 1 H, PhCHN), 4.27 (ddd, J = 7.7, 7.7, 12.3 Hz, 1 H, HOCH ₂), 4.00 (m, 3 H, CH₃CH ₂O and HOCH ₂), 3.73 (q, J = 6.8 Hz, 1 H, CH₃CHN), 1.37 (t, J = 7.1 Hz, 3 H, CH ₃CH₂O), 1.28 (d, J = 6.8 Hz, 3 H, CH ₃CHN) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 176.42, 173.18, 138.34, 128.80 (2 C), 127.77, 127.05 (2 C), 93.35, 67.10, 64.91, 61.90, 57.17, 15.83, 14.06 ppm. MS (ESI): m/z (%) = 262 (13) [M + H⁺], 244 (5) [M + H⁺ - H₂O], 142 (100). HRMS calcd for [C₁₅H₁₉NO₃ + H]⁺: 262.1438. Found: 262.1440. Minor diastereomer of 9b: [α]_D ²⁰ +17.1 (c 1.1, CHCl₃). IR (KBr): 3367, 2981, 2932, 1659, 1625, 1340, 1222, 1029 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.40-7.20 (m, 5 H, ArH), 5.02 (s, 1 H, =CHC=O), 4.82 (dd, J = 3.8, 7.5 Hz, PhCHN), 4.21 (m, 1 H, HOCH ₂N), 4.09 (m, 2 H, HOCH ₂ and OH), 3.98 (m, 2 H, CH₃CH ₂O), 3.88 (q, J = 6.8 Hz, 1 H, CH₃CHN), 1.37 (t, J = 7.1 Hz, 3 H, CH ₃CH₂O), 1.14 (d, J = 6.8 Hz, 3 H, CH ₃CHN). MS (ESI): m/z (%) = 262 (100) [M + H⁺]. HRMS calcd for [C₁₅H₁₉NO₃ + H]⁺: 262.1438. Found: 262.1432.