A total synthesis of the enantiomer of anhydromyriocin (anhydrothermozymocidin)

Abstract

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 ...

Flavovirin — a new antifungal antibiotic produced by the pyrenomycete Melanconis flavovirens

“…This was supported by mass spectra in which many significant fragmentations were similar (m/z 256, 237, 219, 113, 104 and 102). The advantage of this similarity was taken because the structure and configuration of myriocin has already been exactly characterized (ARAGOZZINI et al 1972, BAGLI et al 1973, JUST and PAYETTE 1980, PAYETTE and JUST 1981, BANFI et al 1982, 1983.…”

Stereoselective Total Synthesis of Serine Palmitoyl-CoA Transferase Inhibitors

“…Scheme 1 outlines the preparation of phosphonium salt 12 from cyclooctanone in seven steps and 11% overall yield. 9 Reaction of cyclooctanone with n-hexylmagnesium bromide gave tertiary alcohol 8, which was dehydrated in refluxing xylene in the presence of iodine to afford nhexylcyclooctene (9). Ozonolysis of a mixture of 9 containing cyclooctanone in ethanol followed by reductive work-up with sodium borohydride provided diol 10, which was converted into bromoacetal 11 by the following reaction sequence: selective oxidation of the secondary alcohol to a ketone with Br 2 /HMPA, 10 acetalization of the resulting ketone with 2,2-dimethyl-1,3-propanediol, and conversion of the primary alcohol to the corresponding bromide by treatment with N-bromosuccinimide (NBS) and triphenylphosphine in N,N-dimethylformamide.…”

“…The synthesis of the enantiomer of myriocin was achieved by Wittig reaction of the aldehyde prepared from 86 (Scheme 16) with phosphonium salt 12 (Scheme 1). 9,57 As shown in Scheme 36, oxidation of alcohol 86 with PCC followed by Wittig reaction with phosphonium salt 12 afforded cis-olefin 220. Alkene 220 (>90% cis) was converted into trans isomer 221 in 81% yield by epoxidation of 220 with MCPBA in cyclohexane, chromatographic separation of the major two enantiomers of cis-epoxides, and treatment of the resulting cis-epoxides with lithium diphenylphosphide and iodomethane in tetrahydrofuran.…”

Total Synthesis and Biological Activities of (+)-Sulfamisterin (AB5366) and its Analogues

“…Acid hydrolysis of a mixture of 11a and 12a gave the starting triol 9a in 87% yield, which could be reused to provide additional amount of 10a. Swern oxidation of 10a gave an aldehyde, which without purification, was reacted with Wittig reagent generated from phosphonium salt [10] 13 and n-BuLi to give 14a in 45% yield from 10a as a mixture of geometrical isomers (E : Zϭca. 1 : 4).…”

“…Evaporation of the solvents gave crude aldehyde (720.0 mg). To a solution of phosphonium salt 13 [10] (6.22 g, 10.4 mmol) in dry THF (19 ml) was added dropwise n-butyl lithium (1.59 mol/liter in hexane, 8.50 ml, 13.5 mmol) at Ϫ78°C and the mixture was stirred for 15 minutes at room temperature. After cooling at Ϫ78°C, to the mixture was added a solution of the crude aldehyde (720 mg) in THF (9 ml) dropwise via a cannula.…”