J. Org. Chem. 1996, 61, 1817-1821
1817
Syntheses of (-)-Isocitric Acid Lactone and (-)-Homoisocitric Acid. A New Method of Conversion of Alkynylsilanes into the Alkynyl Thioether and Corresponding Carboxylic Acids Carole Schmitz, Anne-Claire Rouanet-Dreyfuss, Marie Tueni, and Jean-Franc¸ ois Biellmann* Laboratoire de Chimie Organique Biologique associe´ au CNRS, Universite´ Louis Pasteur, Faculte´ de Chimie, 1 rue Blaise Pascal, 67003 Strasbourg, France Received June 12, 1995X
A simple, stereoselective synthesis of natural isocitric and homoisocitric acids from a common alkynylsilane correlates the stereochemistry of these acids. Starting with dimethyl D-malate dianion, methyl 2-hydroxy-3-carbomethoxy-6-(trimethylsilyl)-5-hexynoate (6a) was prepared with a good stereoselectivity (threo/erythro 90/10). Oxidative cleavage of the triple bond provided isocitric acid lactone (8′) in 15% overall yield starting from D-malic acid diester 1. The synthesis of homoisocitric acid relied on a new method of conversion of alkynylsilane to alkynyl thioether, which is converted to the carboxylic acid of the same chain length. Addition of benzenesulfenyl chloride to (trimethylsilyl)alkyne 6b and elimination of trimethylsilyl chloride gave the corresponding thioether 10, which by acid hydrolysis gave homoisocitric acid (11) in a 24% yield from D-malic acid ester. This novel method of conversion of alkynylsilane to the corresponding acid was illustrated with several other alkynyltrimethylsilanes. Introduction Isocitric acid (8), which is an intermediate in the Krebs cycle,1 is produced from citric acid by acotinase2 and is converted into R-ketoglutaric acid by isocitric acid dehydrogenase. Of the four stereoisomers of isocitric acid, only the (-)-D-threo isomer is a substrate for acotinase and for the NADP+-linked isocitrate dehydrogenase from porcine heart3 and NAD+-linked enzyme from bovine heart.4 Racemic isocitric acid was first prepared by R. Fittig,5 and two other syntheses of racemic isocitric acid were reported later.6,7 The absolute configuration of isocitric acid lactone has been established by a stereoselective synthesis based upon the condensation of methyl (-)-trans-epoxysuccinate with dimethyl malonate.8 A stereoselective synthesis of isocitric acid lactone relying on the stereoselective alkylation of L-malic acid9,10 has been reported. Homoisocitric acid (11) is involved in the R-aminoadipate pathway of lysine synthesis in yeasts and certain fungi. The synthesis of homoisocitric acid from homocitric acid is catalyzed by homoaconitate hydratase.11 The enzymatic conversion of homoisocitric acid into R-ketoadipic acid is catalyzed by homoisocitric acid dehydrogenase.12 Racemic homoisocitric acid has been synthesized by condensation of diethyl glutarate with diethyl oxalate to triethyl 2-oxaloglutarate, which was reduced to the corresponding hydroxy ester and saponified to the racemic free acid.13 The absolute configurations of the Abstract published in Advance ACS Abstracts, December 15, 1995. (1) Plaut, G. W. E.; Sung S. C. J. Biol. Chem. 1954, 207, 305. (2) Rose, I. A.; O’Connell, E. L. J. Biol. Chem . 1967, 242, 1870. (3) Ochoa, S. Enzymes 1951, 929. (4) Plaut, G. W. E.; Sung, S. C. Methods Enzymol. 1955, 1, 710. (5) Fittig, R.; Miller, H. E. Ann. Chem. 1889, 255, 43. (6) Wislicenus, W.; Nassauer, M. Ann. Chem. 1885, 285, 1. (7) (a) Greenstein, J. P. J. Biol. Chem. 1935, 109, 529. (b) Greenstein, J. P. J. Biol. Chem. 1936, 116, 463. (8) Kaneko, T.; Katsura, H. Chem. Ind. (London) 1960, 1188. (9) Compound 8: [R]D -60 (H2O, c 1.03) (lit. [R]D +61.7 (H2O, c 0.985) for the enantiomer) Aebi, J. D.; Sutter, M. A.; Wasmuth, D.; Seebach, D. Liebigs Ann. Chem. l983, 2114. (10) Seebach, D.; Wasmuth, D. Helv. Chem. Acta 1980, 63, 197. (11) Strassman, M.; Ceci, L. N. J. Biol. Chem. 1966, 241, 5401. (12) Strassman, M.; Ceci, L. N. J. Biol. Chem. 1965, 240, 4357. X
0022-3263/96/1961-1817$12.00/0
Scheme 1
four isomers of homoisocitric acid have been established by synthesis from the corresponding 2-hydroxy-3-cyclohexenecarboxylic acids14 of known absolute configuration.15 The threo D isomer of homoisocitric acid is a substrate for homoisocitric acid dehydrogenase.16 However further study of the enzymes involved in this biosynthetic pathway is hampered by the unavailability of the intermediates: homoisocitric and homocitric acids. The enzymes involved in this specific biosynthetic pathway are targets for inhibitors, potential antibiotics, and fungicides. The aim of our work17 was to develop a specific synthesis of the (-)-D-threo isomers of isocitric and homoisocitric acids. Our synthesis starts from D-malic acid and correlates the stereochemistry of isocitric and homoisocitric acids. It constitutes the first chiral synthesis of (-)-D-homoisocitric acid and illustrates a novel method of conversion of alkynylsilanes to their carboxylic acids. (13) Yamashita, M. J. Org. Chem. 1958, 23, 835. (14) Compound 11: [R]D -10 (c 2.05, acetone) (lit. [R]D -8 to -13 (c 1.22, acetone). Chilina, K.; Thomas, U.; Tucci, A. F.; McMichael, K. D.; Stevens, C. M. Biochemistry 1969, 8, 2846. (15) Febrer, M. A.; Gomis, P.; Pascual, J. An. R. Soc. Esp. Fis. Quim. 1964, 60B, 671. (16) Rowley, B.; Tucci, A. F. Arch. Biochem. Biophys. 1970, 141, 499. (17) Schmitz, C. Ph.D. Thesis, ULP, 1992. (18) Schmitz, C.; Rouanet-Dreyfuss, A. C.; Tueni, M.; Biellmann, J. F. Tetrahedron Lett. 1992, 33, 4911.
© 1996 American Chemical Society
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J. Org. Chem., Vol. 61, No. 5, 1996
Schmitz et al. Scheme 2
Figure 1.
In a previous paper18 we reported our preliminary findings on the synthesis of isocitric and homoisocitric acids making use of this method.
Scheme 3
Results and Discussion Our approach19 to homoisocitric acid (11) (Scheme 1) is based on the procedure used by Seebach for the synthesis of isocitric acid.9 Reaction of D-malic dimethyl ester (1) dianion with 1-bromo-3-butene gave the alkylation product 2 in 15% yield (threo/erythro selectivity of 80/20). Acetylation of the hydroxy function of compound 2 (85%), oxidation of the double bond (68%), and subsequent deprotection of the alcohol and esterification of the free acid functions gave the homoisocitric acid triester 5 (90%). In view of the low overall yield of 5 (
