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Synlett 2006(10): 1580-1582  
DOI: 10.1055/s-2006-941602
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Total Synthesis of (-)-Galantinic Acid

Yann Bethuel, Karl Gademann*
Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland
Fax: +41(44)6321328; e-Mail: gademann@org.chem.ethz.ch;
Further Information

Publication History

Received 2 March 2006
Publication Date:
12 June 2006 (online)

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Abstract

A concise, practical and stereoselective total synthesis of galantinic acid, constituent of the peptide antibiotic galantin, is reported. The title compound is obtained in six steps via Heathcock-Claisen condensation, Evans reduction and deprotection in 10% overall yield from protected serine. The route described herein thus constitutes the shortest and most efficient procedure for the preparation of the title compound disclosed so far.

Key words

amino acids - antibiotics - natural products - peptides - polyketides

    References and Notes

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9

Preparation and Selected Data for Compound 6:
n-BuLi (1.6 M solution in hexane, 2.90 mL, 4.60 mmol, 6.00 equiv) was added dropwise to a solution of i-Pr2NH (691 µL, 4.90 mmol, 6.40 equiv) in dry THF (2.00 mL) at 0 °C. The reaction mixture was stirred at this temperature for 10 min and then cooled to -78 °C. Then, t-BuOAc (623 µL, 4.60 mmol, 6.00 equiv) was added dropwise and the reaction mixture was stirred at this temperature for 1 h. The resulting enolate was cannulated into a solution of (3S,4S)-5-benzyloxy-4-benzyloxycarbonylamino-3-(tert-butyl-dimethylsilanyloxy)pentanoic acid methyl ester (5, 0.300 g, 775 µmol, 1.00 equiv) in dry THF (2.00 mL) at 0 °C. The reaction mixture was stirred 1 h at 0 °C, 30 min at r.t. and then quenched with sat. aq NH4Cl solution and the THF was evaporated. A mixture of NH4Cl-H2O (1:1) was added and the solution was extracted 3× with EtOAc. The combined organic layers were washed with sat. aq NH4Cl solution, dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (EtOAc-hexane, 1:7) gave 6 (274 mg, 581 µmol, 75% yield) as a colorless oil. R f = 0.34 (EtOAc-hexane, 4:6); [α]D 25 +0.2 (c 5.22, CHCl3). 1H NMR (300 MHz CDCl3): δ = 1.45 (s, 9 H), 2.65 (dd, 1 H, J 1 = 4.0 Hz, J 2 = 17.7 Hz), 2.79 (dd, 1 H, J 1 = 8.7 Hz, J 2 = 17.4 Hz), 3.33 (dd, 1 H, J 1 = 2.5 Hz, J 2 = 10.3 Hz), 3.35 (s, 2 H), 3.64 (m, 2 H), 3.76-3.86 (m, 1 H), 4.40-4.48 (m, 1 H), 4.51 (s, 2 H), 5.11 (s, 2 H), 5.39 (d, 1 H, J = 9.3 Hz), 7.28-7.36 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 28.0, 28.1, 46.6, 51.1, 53.3, 66.9, 67.3, 67.4, 71.0, 82.2, 127.5, 127.8, 128.3, 128.6, 136.2, 137.4, 156.3, 165.9, 203.0. IR: 3606-3187 (w), 2977 (w), 1744 (m), 1712 (s) cm-1. MS: m/z (%) = 494.2 (17) [M + Na]+, 394.2 (81) [M - CO2 t-Bu + Na]+. HRMS (MALDI): m/z calcd for C26H33NO7Na [M + Na]: 494.2149; found: 494.2141.

11

Preparation and Selected Data for Compound 7. A solution of 6 (135 mg, 0.290 mmol, 1.00 equiv) in MeCN (1.50 mL) was cooled to -35 °C and Me4N(OAc)3BH (534 mg, 2.03 mmol, 7.00 equiv) dissolved in MeCN-AcOH (1.00 mL/1.00 mL) was added. The reaction mixture was stirred at this temperature for 62 h. It was then warmed to 0 °C and a sat. solution of Na-K tartrate was added. The solution was stirred at this temperature for 4 h. The phases were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Flash chromatography (hexane-EtOAc, 6:4) gave 7 (111 mg, 0.235 mmol, 81%) as a colorless oil. R f = 0.38 (EtOAc-hexane, 1:1); [α]D 25 +0.35 (c 0.86, CHCl3). 1H NMR (300 MHz, CDCl3): 1.46 (s, 9 H), 1.50-1.60 (m, 1 H), 1.64-1.78 (m, 1 H), 2.39 (d, 2 H, J = 5.6 Hz), 3.43 (m, 1 H), 3.58 (d, 1 H, J = 3.73 Hz), 3.67 (d, 2 H, J = 4.1 Hz), 3.72 (m, 1 H), 4.18-4.30 (m, 2 H), 4.50 (s, 2 H), 5.10 (s, 2 H), 5.51 (d, 1 H, J = 9.3 Hz), 7.20-7.40 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 28.2, 39.7, 42.3, 54.2, 65.4, 66.8, 68.8, 72.2, 73.6, 81.3, 127.6, 127.8, 127.8, 127.9, 128.0, 128.4, 136.3, 137.3, 156.4, 172.2. IR: 3636-3117 (w), 2977 (w), 1715 (s) cm-1. MS: m/z (%) = 496.2 (41) [M + Na]+, 440.2 (100) [M - 2H2O + H]+. HRMS (MALDI):
m/z calcd for C26H35NO7Na [M + Na]+: 496.2306; found: 496.2299.

12

Ref. 5d describes the synthesis of protected galantinic butyl ester in eight steps from a commercially available serine derivative. We found that the deprotection of this butyl ester under basic conditions results in partial decomposition, epimerization, lactone formation and dehydration. The use of an acid-labile protecting group such as in the route presented in this letter thus greatly facilitates deprotection and thus the preparation of target galantinic acid.