NEW SYNTHESIS OF MEROMYCOLIC ACID

The meromycolic compound, cis-19,20:cis-35,36-bis(methylene)tetrapentacontanoic acid, has been prepared by a branching synthesis starting with l-halo-16-(tetrahydropyranyloxy)-cis-8,9-methylenehexadecane, which was obtained in two ways. One sequence, starting with 1,14-dichloro-7-tetradecyne, proceeded by cyanide chain elongation and hydrolysis to 8-hexadecenedioic acid and methylenation of the dimethyl ester. Reduction of the cyclopropane diester product with lithium aluminum hydride afforded the glycol 1,16-dihydroxy-ct's-8,9-methylenehexadecane which was then masked at one end by attaching the tetrahydropyranyl group. The remaining open hydroxyl was converted to bromide by tosylation and displacement of tosyloxy with bromide ion so as to arrive at the desired l-bromo-16-(tetrahydropyranyloxy)-cis-8,9-methylenehexadecane. In a different approach, the corresponding chloro derivative compound was synthesized by starting with l-hydroxy-3-nonyne. Base-catalyzed isomerization, by shifting the triple bond to the end of the chain, formed l-hydroxy-8-nonyne. This was converted to its tetrahydropyranyl derivative and then alkylated with 1,7-dichloroheptane to give l-chloro-16-(tetrahydropyranyloxy)-8-hexadecyne. Half-hydrogenation followed by methylenation with diethylzinc-methylene diiodide furnished the necessary intermediate, l-chloro-16-(tetrahydropyranyloxy)-ds-8,9-methylenehexadecane. The synthesis continued by elaborating l-halo-16-(tetrahydropyranyloxy)-ds-8,9-methylenehexadecane in two directions to obtain moieties that were eventually recombined. Along one branch, the Grignard reagent of the halo compound was allowed to react with methylcopper(I) followed by undecyl iodide to form l-(tetrahydropyranyloxy)-ci's-8,9-methyleneheptacosane, which with triphenylphosphine dibromide gave l-bromo-cis-8,9-methyleneheptacosane. Along the other branch, the same Grignard reagent after treatment with methylcopper(I) was allowed to couple with methyl 11-iodoundecanoate. The coupling product, methyl 27-(tetrahydropyranyloxy)-ds-19,20-methyleneheptacosanoate, was converted in two steps to methyl 27-iodo-cis-19,20-methyleneheptacosanoate. Finally, the two fragments were combined to form methyl meromycolate by forming the Grignard reagent of l-bromo-cis-8,9-methyleneheptacosane, introducing methylcopper(I) to generate the disubstituted cuprate(I) complex, and by coupling with the iodo methyl ester. This synthesis, by furnishing product in an uncorrected overall yield of 6-8%, represents a practical source of meromycolic acid, which we need as a starting material for projected syntheses of cord factor. Hexacosanoic acid, also required for the further work, was conveniently reached by coupling pentadecylmagnesium bromide via its methylcopper complex with methyl 11-iodoundecanoate and saponifying the product. © 1979, American Chemical Society. All rights reserved.