Synthesis of a 2-deoxyglucosyl analogue of medermycin

Abstract

The synthesis of a 2-deoxyglucosyl analogue 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin 1 is described. The key 3-acetyl-6-(2-deoxyglucosyl)-1,4-naphthoquinone 7 is prepared from 6-(2-deoxyglucosyl)-1,4-naphthoquinone 21, which in turn is available by C-glycosylation of naphthol 18 with glycosyl donor 12 using BF₃·Et₂O in acetonitrile followed by oxidative demethylation of the derived methyl ether 20. An acetyl group is then introduced at C-3 on naphthoquinone 21 by reductive monomethylation to naphthol 22, ortho bromination to bromide 24, methylation to 9, followed by Stille coupling with α-ethoxyvinyltributyltin (and hydrolysis) to afford the 3-acetylnaphthalene 8. Addition of 2-(trimethylsilyloxy)furan 13 to naphthoquinone 7, formed from oxidative demethylation of the naphthalene 8, affords the furofuran adducts 25 and 26 as an inseparable mixture of diastereomers. Oxidative rearrangement of this diastereomeric mixture using cerium(IV) ammonium nitrate affords the unstable diastereomeric lactols 27 and 28 also as a 1:1 inseparable mixture. Reduction of these lactols 27 and 28 with triethylsilane and BF₃·Et₂O at −10 °C affords ethers 29 and 30 as a 1:1 mixture. Finally, conversion of ethers 29 and 30 to a 1:1 diastereomeric mixture of medermycin analogues 6 and 31 is achieved by treatment with boron tribromide which effects removal of the methoxy group at C-7, the benzyl ethers on the 2-deoxyglucose residue, and epimerisation at C-5.