美登霉素的3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基吡喃萘醌类似物的合成

Synthesis of 3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl pyranonaphthoquinone analogues of medermycin.

作者信息

Brimble Margaret A, Davey Roger M, McLeod Malcolm D, Murphy Maureen

机构信息

Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand.

出版信息

Org Biomol Chem. 2003 May 21;1(10):1690-700. doi: 10.1039/b301449p.

DOI:10.1039/b301449p

PMID:12926356

Abstract

The synthesis of an isomeric mixture of 4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl analogues 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin is described. The key 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 8 was prepared via Stille coupling of 6-(3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3-bromo-1,4- naphthoquinone 17 with (alpha-ethoxyvinyl)tributyl-stannane followed by hydrolysis and oxidation of the resultant hydroquinone 18. Bromonaphthoquinone 17 in turn was afforded by oxidative demethylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3- bromo-1,4,5-trimethoxynaphthalene 16 formed by regioselective bromination of 6-(4-acetyl-3-azido-2,3,6-trideoxy- beta-D-arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene 10. This latter naphthalene 10 was prepared via direct C-glycosylation of naphthol 12 with glycosyl donor 11 using BF3.Et2O in acetonitrile. The regioselectivity of the bromination of naphthalene 10 was independently determined by reductive monomethylation of the 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 22 to naphthol 23 followed by selective ortho bromination to bromide 24 and methylation to 16. Attempts to effect acetylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 and 3-bromo-6-(3-dimethylamino-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-1,4,5-trimethoxynaphthalene 26 via Stille coupling with (alpha-ethoxyvinyl)tributylstannane were low yielding thereby establishing the necessity to use an azido group as a latent dimethylamino group and a more electrophilic bromonaphthoquinone as the coupling partner for the Stille reaction. Addition of 2-trimethylsilyloxyfuran 9 to 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)- 5-methoxy-1,4-naphthoquinone 8 afforded the furofuran adducts 7 and 19 as an inseparable mixture of diastereomers. Oxidative rearrangement of this diastereomeric mixture using ceric ammonium nitrate afforded the inseparable diastereomeric furonaphthopyrans 6 and 20.

摘要

描述了C-糖基吡喃萘醌抗生素美登霉素的4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基类似物6的异构体混合物的合成。关键的3-乙酰基-6-(4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-5-甲氧基-1,4-萘醌8是通过6-(3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-3-溴-1,4-萘醌17与(α-乙氧基乙烯基)三丁基锡进行Stille偶联，然后将所得的对苯二酚18水解和氧化而制备的。溴代萘醌17又是由6-(4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-3-溴-1,4,5-三甲氧基萘16氧化脱甲基得到的，16是通过对6-(4-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-1,4,5-三甲氧基萘10进行区域选择性溴化而形成的。后者的萘10是通过在乙腈中使用BF3·Et2O使萘酚12与糖基供体11直接进行C-糖基化反应制备的。萘10溴化反应的区域选择性是通过将6-(4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-5-甲氧基-1,4-萘醌22还原单甲基化得到萘酚23，然后进行选择性邻位溴化得到溴化物24，再甲基化得到16来独立确定的。尝试通过与(α-乙氧基乙烯基)三丁基锡进行Stille偶联来实现6-(4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-3-溴-1,4,5-三甲氧基萘16和3-溴-6-(3-二甲基氨基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-1,4,5-三甲氧基萘26的乙酰化反应，产率较低，从而确定了有必要使用叠氮基作为潜在的二甲基氨基，并使用更具亲电性的溴代萘醌作为Stille反应的偶联伙伴。将2-三甲基硅氧基呋喃9加到3-乙酰基-6-(4-O-乙酰基-3-叠氮基-2,3,6-三脱氧-β-D-阿拉伯己吡喃糖基)-5-甲氧基-1,4-萘醌8上，得到呋喃并呋喃加合物7和19，它们是不可分离的非对映异构体混合物。使用硝酸铈铵对该非对映异构体混合物进行氧化重排，得到不可分离的非对映异构体呋喃萘并吡喃6和20。