Tunicamycin synthetic

Y. Fukuda, H. Sasai, and T. Suami, Synthetic approach toward antibiotic tunicamycins. 3. Methyl 3.4,7.8 letra () acetyl-10 ) bcn/yl 2-benzyloxycarbony amino-2,6-dideoxy-l 1,12,-0-isopropylidene-p-i.-dodecodialdo-(12R)-furanose-(12,9)-pyranosides-(l,5), Bull. Chem. Soc. Jpn. 55 1574 (1982). 

More recently, Danishefsky reported a fully synthetic route to tunicamin-yluracil (274) derived from tunicamycin (85JA7761) and hikosamine (284) (85JA7762). Cyclocondensation of the ribosederived aldehyde (260) (84JOC1955) (Scheme 35) with diene 259 under catalysis by Eu(fod)3 (83JA3716) afforded an 86% yield of the carbon-linked disaccharide 261. Ozonolysis of 261, followed by oxidative treatment and esterification, furnished the /3-hydroxy ester 262 and its benzyloxymethyl ether 263. 

A synthetic approach toward tunicamycin 267, based on this principle, has been reported. Tunicamycin shows a direct carbon link between C6 of a galactosamine residue and C5 of a uridine moiety. The formation of this link has been carried out by Wittig reactions on model compounds using Secrist s phosphorane [181]. As shown in Scheme 11.58, the phosphonium salt 263 was treated with lithium hexamethyldisilazane to generate the phosphorane, which was reacted with aldehyde 264. Reduction of the double bond and benzyl hydrogenolysis of 265 was followed by acetylation to provide the model compound 266. 

Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH2OH) were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-iV-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the 5-isomer of 170 (R = CH2OH) was a good inhibitor. ... 

---