Synthese totale de la (±) negamycine

Abstract

A total synthesis of (±) negamycine 1 has been achieved in 14 steps from the acrolein dimer 6, which possesses the same carbon skeleton as the key intermediate lactone 4. Treatment of 2-acetoxymethyl 3,4-dihydro[2H]pyran 8, obtained from 6, with lead tetracetate gave the allylic hemiketal 15, which was converted into the corresponding anomeric methyl ethers 23. Hydroxylation of the double bond of 23 with mercuric acetate, occurred selectively at the γ-position and the resulting isomeric alcohols 24 were isolated as their dimesylates 25a and 25b. Condensation of sodium azide with the ( trans-derivative 25a resulted in the formation of the cis-diazide 26a by inversion of configuration at C 3. Hydrogenation of 26a followed by acetylation of the intermediate diamine gave the cis-diamide 28 having the required stereochemistry. Oxidation of the corresponding hemiketal 29 by means of silver silicate yielded the diacetamido-lactone 4, which was then hydrolysed into (±) δ-hydroxy β-lysine 2 by refluxing aqueous HCl. Under the conditions required to protect the amino-groups as benzylcarbamates, the lactone 30 was produced. However, 30 gave directly the hydrazine 36 by condensation with benzyl N-methyl-hydrazinoacetate in refluxing acetonitrile m the presence of SiO 2. Finally (±) negamycine was obtained by hydrogenolysis of the protecting groups of 36. The antibacterial activities of the racemic antibiotic have been compared, in vitro and in vivo, with those of the natural product and with gentamicine C.