In 1972, two antifungal agents, myriocin and thermozymocidin, were isolated from Myriococcum albomyces NRRL 3858 (1) and Albomyces 20,349 (2) respectively. They were both identified as 2-amino-2-hydrox y methyl-3,4-dihydroxy-14-0x0-eicos-6-enoic acid (3, 4). Some ambiguity remained concerning their identity and relative stereochemistries. Their absolute configuration was not reported. Bagli et al. (3) suggested the stereochemistry 1 for anhydromyriocin, whereas Kuo and Wendler (5) assigned the configuration 2, based on spectral comparison of various synthetic racemic isomers of the lactonic ester 3 with Bagli's products. This was in accord with the relative stereochemistry obtained by X-ray diffraction for thermo~ymocidin.~ We decided to synthesize anhydrothermozymocidin from chiral precursors, and compare it to the y-lactone derived from natural myriocin, thus (a) confirming the identity or nonidentity of the two compounds and (6) proving their absolute and relative configuration. -
Synthetic ApproachThe best candidate for a precursor seemed to be arabinose which already contains the desired uicdiol in a threo configuration and of which both D and L isomers are available. In the approach described, the two main problems were (a) elongation of the pentose at C-1 by at least one carbon atom permitting the introduction of a trans double bond and the hydrocarbon chain, and (b) selective protection of the 4-hydroxy function, allowing its conversion at a later stage to a ketone and hence to a cyanoamine and amino acid.We first studied the use of phosphorus ylids on partially protected pentofuranoses, hoping to effect simultaneous homologation at C-1 and opening of the sugar, thus allowing subsequent protection of the free hydroxyl group. The use of stabilized ylids is limited by the ease with which the products cyclize via a Michael-type addition (6), restricting the choice of hydroxyl protecting groups. It was our experience that although nonstabilized ylids react sluggishly with closed sugars, others, of intermediate reactivity, such as thiomethylmethylenetriphenylphosphorane, did give the desired intermediate. However, we also found that hydrolysis of the resulting terminal vinyl sulfides to the free aldehydes presented major difficulties.We then decided to use the sugar in the open form and concentrate on the homologation itself. We describe several approaches involving (a) attempted displacement of mesylate or iodide functions with an acetylenic anion (6 + 7 + 8 + 9 +); (b) a two-carbon elongation via a stabilized ylid leading to a carboxylic acid, followed by oxidative decarboxylation and ultimately the -formation of a terminal phosphonium salt (6+ 11+ 12+ 13+ 19 +); (c) formation, via a Wittig reaction, of a model a$-unsaturated ketone followed by reduction, with a borane reagent, of the corresponding tosylhydrazone accompanied by migration of the double bond (6 + 14 + 15 + 16); and finally, (d) the method which proved to be the most practical: a one carbon elongation using nitromethane addition with eventual ...
