Stereoselective Total Synthesis of (-)-Galantinic Acid

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

• 1 Shoji J. Sakajaki R. Wakisaka Y. Koizumi K. Mayama M. Matsurra SJ. J. Antibiot.  1975,  28:  122 
• 2a Sakai N. Ohfune Y. Tetrahedron Lett.  1990,  29:  4151 
• 2b Sakai N. Ohfune Y. J. Am. Chem. Soc.  1992,  114:  998 
• For didemnins, see for example:
• 3a Rinehart KL. Gloer JB. Hughes RG. Renis HE. McGovern JP. Swynenberg EB. Stringfellow DA. Kuentzel SL. Li LH. Science  1981,  211:  933 
• 3b Dolastatin 10: Pettit GR. Kamano Y. Herald CL. Tuinman AA. Boettner FE. Kizu H. Schmidt JM. Baczynskyj L. Tomer KB. Bontems RJ. J. Am. Chem. Soc.  1987,  109:  6883 
• 4 See, for example: Kondo SI. Akita E. Sezaki M. J. Antibiot.  1966,  19:  137 
• 5a Ikota N. Heterocycles  1991,  31:  521 
• 5b Kumar JSR. Datta A. Tetrahedron Lett.  1999,  40:  1381 
• 5c Kiyooka S. Goh K. Nakamura Y. Takesue H. Hena MA. Tetrahedron Lett.  2000,  41:  6599 
• 5d Moreau X. Campagne J.-M. Tetrahedron Lett.  2001,  42:  4467 
• 5e Raghavan S. Reddy SR. J. Org. Chem.  2003,  68:  5754 
• 5f Kumar Pandey S. Kandula SV. Kumar P. Tetrahedron Lett.  2004,  45:  5877 
• 6 For example: ref. 2a, 13 steps from protected serine; ref. 5f, 12 steps from propanediol; ref. 5e, 18 steps from a propargylic epoxide. Moreau and Campagne obtained a semi-protected ester derivative of 1 in six steps overall (ref. 5d)
• 7a Gademann K. Bethuel Y. Angew. Chem. Int. Ed.  2004,  43:  3327 ; Angew. Chem. 2004, 116, 3389; there are numerous methods for the stereoselective preparation of β-hydroxy-γ-amino acids, so-called statins
• Reviews:
• 7b Javier Sardina F. Rapoport H. Chem. Rev.  1996,  96:  1825 
• 7c Vera MD. Joullié MM. Med. Res. Rev.  2002,  22:  102 
• 7d See also: Brenner M. Seebach D. Helv. Chim. Acta  2001,  84:  1181 
• 7e Jouin P. Castro B. Nisato D. J. Chem. Soc., Perkin Trans. 1  1987,  1177 
• 8a Hubbs JL. Heathcock CH. J. Am. Chem. Soc.  2003,  125:  12836 
• 8b Earlier works used reduced amounts of enolate, see, for example: Lynch JE. Volante RP. Wattley RV. Shinkai I. Tetrahedron Lett.  1987,  28:  1385 
• 10 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

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.