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.

amino acids - antibiotics - natural products - peptides - polyketides

References and Notes

<A NAME="RG08206ST-1">1</A> Shoji J. Sakajaki R. Wakisaka Y. Koizumi K. Mayama M. Matsurra SJ. J. Antibiot.  1975,  28:  122 

<A NAME="RG08206ST-2A">2a</A> Sakai N. Ohfune Y. Tetrahedron Lett.  1990,  29:  4151 

<A NAME="RG08206ST-2B">2b</A> Sakai N. Ohfune Y. J. Am. Chem. Soc.  1992,  114:  998 

For didemnins, see for example:

<A NAME="RG08206ST-3A">3a</A> Rinehart KL. Gloer JB. Hughes RG. Renis HE. McGovern JP. Swynenberg EB. Stringfellow DA. Kuentzel SL. Li LH. Science  1981,  211:  933 

<A NAME="RG08206ST-3B">3b</A> 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 

<A NAME="RG08206ST-4">4</A> See, for example: Kondo SI. Akita E. Sezaki M. J. Antibiot.  1966,  19:  137 

<A NAME="RG08206ST-5A">5a</A> Ikota N. Heterocycles  1991,  31:  521 

<A NAME="RG08206ST-5B">5b</A> Kumar JSR. Datta A. Tetrahedron Lett.  1999,  40:  1381 

<A NAME="RG08206ST-5C">5c</A> Kiyooka S. Goh K. Nakamura Y. Takesue H. Hena MA. Tetrahedron Lett.  2000,  41:  6599 

<A NAME="RG08206ST-5D">5d</A> Moreau X. Campagne J.-M. Tetrahedron Lett.  2001,  42:  4467 

<A NAME="RG08206ST-5E">5e</A> Raghavan S. Reddy SR. J. Org. Chem.  2003,  68:  5754 

<A NAME="RG08206ST-5F">5f</A> Kumar Pandey S. Kandula SV. Kumar P. Tetrahedron Lett.  2004,  45:  5877 

<A NAME="RG08206ST-6">6</A> 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)

<A NAME="RG08206ST-7A">7a</A> 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:

<A NAME="RG08206ST-7B">7b</A> Javier Sardina F. Rapoport H. Chem. Rev.  1996,  96:  1825 

<A NAME="RG08206ST-7C">7c</A> Vera MD. Joullié MM. Med. Res. Rev.  2002,  22:  102 

<A NAME="RG08206ST-7D">7d</A> See also: Brenner M. Seebach D. Helv. Chim. Acta  2001,  84:  1181 

<A NAME="RG08206ST-7E">7e</A> Jouin P. Castro B. Nisato D. J. Chem. Soc., Perkin Trans. 1  1987,  1177 

<A NAME="RG08206ST-8A">8a</A> Hubbs JL. Heathcock CH. J. Am. Chem. Soc.  2003,  125:  12836 

<A NAME="RG08206ST-8B">8b</A> Earlier works used reduced amounts of enolate, see, for example: Lynch JE. Volante RP. Wattley RV. Shinkai I. Tetrahedron Lett.  1987,  28:  1385 

<A NAME="RG08206ST-9">9</A>

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.

<A NAME="RG08206ST-10">10</A> Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

<A NAME="RG08206ST-11">11</A>

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.

<A NAME="RG08206ST-12">12</A>

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.