Synlett 2003(5): 0627-0630
DOI: 10.1055/s-2003-38355
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Highly Efficient Approach to 5-Alkyl-5-hydroxymethyl Substituted 4-O-Benzyl Tetramates

Franz F. Paintner*, Marcel Metz, Gerd Bauschke
Department Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, Haus C, 81377 München, Germany
Fax: +49(89)218077247; e-Mail: franz.paintner@cup.uni-muenchen.de;
Further Information

Publication History

Received 20 December 2002
Publication Date:
28 March 2003 (online)

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Abstract

4-O-Benzyl-5-methoxycarbonyl tetramates readily available by 5-methoxycarbonylation of 4-O-benzyl tetramates undergo highly regioselective alkylations with various alkyl halides to give 5-alkyl-4-O-benzyl-5-methoxycarbonyl tetramates in high overall yields. These can be efficiently converted into 5-alkyl-5-hydroxymethyl substituted 4-O-benzyl tetramates and further into the respective tetramic acids.

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Compund 5b was obtained in 96% yield from commercially available 4-benzyloxy-1,5-dihydropyrrol-2-one by acylation with di-tert-butyl dicarbonate (2.0 equiv) in the presence of Et3N (1.0 equiv) and DMAP (1.0 equiv) (CH2Cl2, r.t.).

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Typical Procedure: A solution of n-BuLi (1.6 M in hexane, 3.75 mL, 6.0 mmol) was added dropwise to a stirred solution of 5a (1.219 g, 6.0 mmol) in THF (60 mL) at -78 °C. After stirring for 1 h at -78 °C, methyl chloroformate (232 µL, 3.0 mmol) was added and the mixture was stirred for 3 h at
-78 °C. A 2.5% aq KH2PO4 solution (60 mL) was added, the resulting mixture was allowed to warm to r.t. and was extracted with CH2Cl2 (3 ¥ 100 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (n-hexane-EtOAc, 20:80) to give 6a (752 mg, 96%).
Methyl 3-benzyloxy-1-methyl-5-oxo-2,5-dihydro-1 H -pyrrole-2-carboxylate ( 6a): Colorless crystals. Mp 104 °C. 1H NMR (500 MHz, CDCl3): δ = 2.91 (s, 3 H, NCH3), 3.81 (s, 3 H, OCH3), 4.58 (s, 1 H, 2-H), 5.01 (s, 2 H, CH2Ph), 5.17 (s, 1 H, 4-H), 7.33-7.38 (m, 5 H, Harom). IR(film): ν = 1747, 1692, 1631 cm-1. MS (CI, CH4): m/z (%) = 262(100) [M + H+]. Anal. Calcd for C14H15NO4 (261.3): C, 64.36; H, 5.79; N, 5.36. Found: C, 64.27; H, 5.77; N, 5.34.

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Typical Procedure: A solution of 6a (653 mg, 2.5 mmol) in THF (35 mL) was added dropwise to a solution of LHMDS (1.0 M in THF, 2.63 mL, 2.63 mmol) in THF (40 mL) at -78 °C. After stirring for 1 h at -78 °C, CH3I (779 µL, 12.5 mmol) was added and the mixture was allowed to warm to r.t. and stirred for 16 h. A 2.5% aq KH2PO4 solution (50 mL) was added and the mixture was extracted with CH2Cl2 (3 ¥ 100 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (n-hexane-i-PrOH, 70:30) to give 9a (647 mg, 94%).
Methyl 3-benzyloxy-1,2-dimethyl-5-oxo-2,5-dihydro-1 H -pyrrole-2-carboxylate (9a): Colorless crystals. Mp 95 °C. 1H NMR (500 MHz, CDCl3): δ = 1.60 (s, 3 H, CH3), 2.81 (s, 3 H, NCH3), 3.73 (s, 3 H, OCH3), 4.99 (d, 1 H, J = 12.0 Hz, CH2Ph), 5.03 (d, 1 H, J = 12.0 Hz, CH2Ph), 5.12 (s, 1 H, 4-H), 7.31-7.40 (m, 5 H, Harom). IR(film): ν = 1739, 1682, 1631 cm-1. MS (CI, CH4): m/z (%) = 276(100) [M + H+]. Anal. Calcd for C15H17NO4 (275.3): C, 65.44; H, 6.22; N, 5.09. Found: C, 65.51; H, 6.37; N, 5.03.

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In case of lithium dienolate 8a, aggregation was indicated by the formation of a colorless precipitate, which gradually dissolved in the course of the alkylation reactions.