Novel Short-Step Synthesis of Optically Active Tetronic Acids from Chiral α-Hydroxy Acids Mediated by 1-Hydroxybenzotriazole

Abstract

A novel method for the synthesis of functionalized γ-hydroxy acids and optically active tetronic acids is reported. The synthesis is simple and the compounds are produced in good yields (45-81%). Measurements of their optical rotations show that the reaction proceeds without or with partial racemization of the starting materials.

Key words

tetronic acids - γ-hydroxy acids - 1-hydroxybenzotri­azole - natural products

References

• 1 Pattenden G. Fortschr. Chem. Org. Naturst.  1978,  35:  133 
• 2 Booth PM. Fox CMJ. Ley SV. J. Chem. Soc., Perkin Trans 1  1987,  121 
• 3 Mittra A. Yamashita M. Kawasaki I. Murai H. Yoshioka T. Ohta S. Synlett  1997,  909 
• 4 Bourguet-Kondracki M.-L. Guyot M. Tetrahedron Lett.  1999,  40:  3149 
• 5 Holler U. Konig GM. Wright AD. J. Nat. Prod.  1997,  60:  832 
• 6 Clutterbuck PW. Raistrick H. Reuter F. Biochem. J.  1935,  29:  300 
• 7 Birkinshaw JH. Samant MS. Biochem. J.  1960,  74:  369 
• 8 Watanabe K. Tanaka T. Fukuhara K. Miyairi N. Yonehara H. Umezawa H. J. Antibiot.  1957,  10:  39 
• 9 Jones RCF. Duller KAM. Vulto SIE. J. Chem. Soc., Perkin Trans. 1  1998,  411 
• 10 Schobert R. Muller S. Bestmann H.-J. Synlett  1995,  425 
• 11a Effenberger F. Syed J. Tetrahedron: Asymmetry  1998,  9:  817 
• 11b Buhler H. Bayer A. Effenberger F. Chem.-Eur. J.  2000,  6:  2564 
• 12 Mitsos CA. Zografos AL. Igglessi-Markopoulou O. J. Org. Chem.  2000,  65:  5852 
• 13 Athanasellis G. Gavrielatos E. Igglessi-Markopoulou O. Synlett  2001,  1653 
• 17 Nolte MJ. Steyn PS. Wessels PL. J. Chem. Soc., Perkin Trans. 1  1980,  1057 
• 18 Petroliagi M. Igglessi-Markopoulou O. J. Chem. Soc., Perkin Trans. 1  1997,  3543 

14

Athanasellis, G.; Gavrielatos, E.; Igglessi-Markopoulou, O. Bull. Chem. Soc. Jpn. 2002, in press.

15

General Procedure for the Synthesis of Compounds4-21:
In a typical reaction, 10 mmol of the appropriate O-acetyl hydroxy acid 1a-e was treated with 10 mmol of 1-hydroxybenzotriazole 2 and 10 mmol DCC in anhyd THF (40 mL) at 0 °C for 1 h. The resulting suspension was refrigerated overnight at 3-5 °C. The precipitated solid (DCCU) was filtered off and discarded, the THF filtrate was added to a solution of 20 mmol NaH and 10 mmol of dimethyl malonate 3a, diethyl malonate 3b or butyryl acetate 3c in anhyd THF. The resulting mixture was stirred at r.t. for 2.5 h and then concd in vacuo. The obtained gummy solid was diluted with water and washed with diethyl ether. The aq extract was acidified with 10% HCl in an ice water bath to afford a white solid (1-hydroxybenzotriazole) which was filtered off. The aq filtrate was extracted with DCM (3 ×) and the combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo to afford either 3-substituted tetronic acids 4-6 as white solids or the C-acylation compounds
7-14 as oils. The oily products 7-14 were dissolved in methanol and treated with 10% HCl for 24 h (7 and 8) or 48 h (9-14) at r.t. to afford the corresponding tetronic acids
15-21 as white solids. The solid products were filtered off, washed with light petrol and dried in vacuo.

16

Spectroscopic and Analytical Data of Selected Compounds:
3-Methoxycarbonyl Tetronic Acid (4). 59% Yield, mp: 166-167 °C. IR (KBr): 1720/1703 (C=O), 1605 (C=C)
cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.96 (s, 3 H, COOCH₃), 4.81 (s, 2 H, CH₂) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 52.3 (COOCH₃), 66.0 (C-5), 100.2 (C-3), 167.0 (C-6), 169.4 (C-2), 189.4 (C-4) ppm. Anal. Calcd for C₆H₆O₅: C, 45.57; H, 3.80. Found: C, 45.49; H, 3.86.
4-Acetoxy-3-hydroxy-2-methoxycarbonyl-4-methyl-2-pentenoate (9). 78% Yield. IR (KBr): 1743/1739/1735/1732/1728/1724 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.58 (s, 6 H, 2 × CH₃), 2.05/2.06 (two s, 3 H, OCOCH₃), 3.77 (s, 6 H, 2 × COOCH₃), 4.96 (s, 0.5 H, O=C-CH), 13.38 (s, 0.5 H, OH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.2 (CH₃), 24.4 (CH₃), 41.1 (O=C-CH), 53.2 (COOCH₃), 59.5 (OCOCH₃), 77.8 (C-4), 84.7 (C-2), 164.5 (OCOCH₃), 170.1 (C-1), 197.7 (C-3) ppm.
3-Methoxycarbonyl-5-phenyl Tetronic Acid (15). 81% Yield, mp: 188-189 °C. [α]_D ²¹: +86.6 (c1, MeOH). IR (KBr): 1759/1716 (C=O), 1610 (C=C) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.97 (s, 3 H, COOCH₃), 5.84 (s, 1 H, HCPh), 7.39-7.44 (m, 5 H, PhH) ppm. ¹³C NMR (75 MHz, CDCl₃): (ppm) 52.7 (COOCH₃), 78.6 (C-5), 94.2 (C-3), 126.5/129.2/130.0/132.3 (phenyl carbons), 166.3 (C-6), 166.9 (C-2), 190.3 (C-4). Anal. Calcd for C₁₂H₁₀O₅: C, 61.54; H, 4.27. Found: C, 61.60; H, 4.21.
3-Ethoxycarbonyl-5-phenyl Tetronic Acid (16). 80% Yield, mp: 156-157 °C. [α]_D ²¹: +71.1 (c1, MeOH). IR (KBr): 1758/1714 (C=O), 1607 (C=C) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.41 (t, J = 7.5 Hz, 3 H, COOCH₂CH ₃), 4.43 (q, J = 6.6 Hz, 2 H, COOCH ₂CH₃), 5.83 (s, 1 H, HCPh), 7.39-7.44 (m, 5 H, PhH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.0 (COOCH₂ CH₃), 62.2 (COOCH₂CH₃), 78.5 (C-5), 94.2 (C-3), 126.5/129.2/129.9/132.4/(phenyl carbons), 166.3 (C-6), 166.6 (C-2), 190.3 (C-4) ppm. Anal. Calcd for C₁₃H₁₂O₅: C, 62.90; H, 4.84. Found: C, 62.98; H, 4.94.
3-Methoxycarbonyl-5-dimethyl Tetronic Acid (17). 50% Yield, mp: 118-120 °C. IR (KBr): 1748/1721 (C=O), 1625 (C=C) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.56 (s, 6 H, 2 × CH₃), 3.78/3.94 (two s, 3 H, COOCH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.6 (CH₃), 52.6 (COOCH₃), 80.9
(C-5), 99.9 (C-3), 165.5 (C-6), 167.0 (C-2), 194.6 (C-4) ppm. Anal. Calcd for C₈H₁₀O₅: C, 51.61; H, 5.38. Found: C, 51.79; H, 5.48.