Chemoselective N-Alkylation of Di-N,O-protected Tyrosine through Specific Oxy-Anion Solvation by Non-Hydrogen Bonding Donor Solvents

Abstract

N-(2-Nitro-benzenesulfonyl) activated l-tyrosine methyl ester has been directly N-alkylated under solid-liquid phase-transfer catalysis (SL-PTC) conditions and in a coordinating non-hydrogen bonding donor (non-HBD) solvent, which reduces through specific solvation the nucleophilicity of the oxy-anionic center of the N,O-dianion formed by action of an anhydrous inorganic carbonate.

solvent effects - chemoselectivity - alkylations - amino acids - phase-transfer catalysis

References and Notes

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11

Typical Procedure for the N-Alkylation: Synthesis of l- N -Allyl- N -(2-nitrophenyl)sulfonyl Tyrosine Methyl Ester (11a). In a dried flask, lyophilized sodium carbonate (424 mg, 4 mmol) was added to a solution of 9 (380 mg, 1 mmol), allyl bromide (2a, 242 mg, 2 mmol) and tetrabutylammonium hydrogensulfate (34 mg, 0.1 mmol) in anhyd DMSO (2.5 mL). The heterogeneous mixture was stirred at 30 °C for 6 h, controlling by TLC analysis (EtOAc-hexane, 2:3), then the crude was diluted with EtOAc (10 mL), washed with an aq sat. solution of NH₄Cl (2.5 mL), then with brine (2 × 5 mL). The aqueous phases were extracted with EtOAc (5 × 5 mL); the organic phases were collected and washed with H₂O (5 mL), brine (2 × 5 mL) and dried over MgSO₄. The solvent was distilled under vacuum and the residue was purified by flash chromatography (EtOAc-hexane, 2:3). N-Allyl derivative 11a, pale yellow oil (412 mg, 98%); ee 100% [HPLC: column CHIRALPAK^® AD (Daicel); 25 °C; i-PrOH-hexane (15:85); flow 0.8 mL/min; λ = 266.8 nm; t _R 27.575 min]; [α]_D ²⁰ -23.6 (c 0.83, CHCl₃). ¹H NMR (CDCl₃): δ = 7.84 (d, 1 H, J = 7.6 Hz), 7.64 (d, 1 H, J = 7.6 Hz), 7.58-7.54 (m, 2 H), 7.07 (d, 2 H, J = 8.1 Hz), 6.68 (d, 2 H, J = 8.4 Hz), 5.85-5.71 (m, 1 H), 5.35 (br s, 1 H), 5.20 (dd, 1 H, J = 17.3, 1.3 Hz), 5.11 (dd, 1 H, J = 9.9, 1.8 Hz), 4.85 (t, 1 H, J = 7.4 Hz), 4.13-3.98 (m, 2 H), 3.56 (s, 3 H), 3.27 (dd, 1 H, J = 14.3, 7.7 Hz), 2.96 (dd, 1 H, J = 14.3, 7.6 Hz). ¹³C NMR-APT (CDCl₃): δ = 170.8 (CO), 154.7 (COH), 148.0 (CNO₂), 134.2 (CH=), 133.6 (CH), 133.2 (CSO₂), 131.6 (CH), 131.0 (CH), 130.4 (2 CH), 128.0 (C_Ph), 124.0 (CH), 118.5 (CH₂=), 115.4 (2 CH), 61.4 (CH-N), 52.2 (OCH₃), 48.8 (CH₂N), 35.5 (CH₂Ph). Anal. Calcd for C₁₉H₂₀N₂O₇S (420.44): C, 54.28; H, 4.79; N, 6.66. Found: C, 54.37; H, 4.76; N, 6.69.

12 Reichardt C. Solvents and Solvent Effects in Organic Chemistry   Wiley-VCH; Weinheim: 2003.  p.246-250