In connection with studies directed towards the synthesis of the pyranonaphthoquinone antibiotic medermycin, C-aryl glycosides were prepared by C-glycosylation of naphthols with glycosyl donors. Boron trifluoride diethyl etherate proved to be a suitable Lewis acid to promote the C-glycosylation, and use of the azido glycosyl donor proved more successful than using the dimethylamino glycosyl donor. 5-Hydroxy-1,4-dimethoxynaphthalene underwent facile C-glycosylation with two particular glycosyl donors, whereas 3-bromo-5-hydroxy-1,4-dimethoxynaphthalene was not an effective coupling partner with the same glycosyl donors. These studies indicate that subtle steric and electronic effects need to be considered in order to fine-tune C-glycosylations when using highly functionalized glycosyl donors.
The synthesis of azido analogues 2a,2b of the pyranonaphthoquinone antibiotic medermycin 1 has been achieved in eight steps from naphthol 8 and azido glycosyl sugar 7 in 9.3% overall yield. Key steps include the direct BF 3 ×Et 2 O promoted C-glycosylation of naphthol 8, introduction of an acetyl group onto a bromonaphthoquinone via Stille coupling with (a-ethoxyvinyl)tributyltin, furofuran annulation of a naphthoquinone to a furonaphthofuran using 2-trimethylsilyloxyfuran 5 and oxidative rearrangement of a furonaphthofuran to a furonaphthopyran.Medermycin (1) was isolated from Streptomyces tanashiensis and possesses a pyranonaphthoquinone skeleton with an additional b-C-glycoside linkage to the amino sugar, D-angolosamine. 1 Medermycin 1 is highly active against several micro-organisms, 2 is effective against antibiotic resistant cell lines of L5178Y lymphoblastoma and Ehrlich carcinoma in mice, and exhibits inhibition of human leukemia K 562 cells. 3 Platelet aggregation is inhibited by medermycin (1), 4 as is protein and RNA synthesis. 5 The important biological activity reported for medermycin (1) together with its interesting structure, being a member of the pyranonaphthoquinone family of antibiotics 6 that also contains a C-glycoside moiety, renders it a suitable target for synthesis.To date only one long, thirty two step synthesis of medermycin (1) has been achieved by Tatsuta et al. 7 in which the pyranonaphthalene skeleton was assembled via addition of a sulfonyl-phthalide to an enone. The C-glycosidic linkage was introduced as a D-olivoside early in the synthetic sequence before the phthalide annulation step, rendering it necessary to manipulate the functional groups on the sugar moiety to give the desired D-angolosaminide amino sugar at the conclusion of the synthesis. Notably the dimethylamino group on the sugar was introduced via a four step sequence, two of which only proceeded in 37% yield. We therefore herein report an efficient synthesis of an azido analogue 2 of medermycin (1) in which the key C-glycoside linkage was constructed at an early stage in the synthesis using an azido-sugar as a latent dimethylamino group that could be unmasked at a later stage. The synthesis of this azido analogue provides an important analogue for probing structure-activity relationships and the mode of action of this class of compounds that have been proposed to act as bioreductive alkylating agents. 8 Synthetic methodology developed by this research group has established an efficient synthesis of several simpler members of the pyranonaphthoquinone family of antibiotics. [9][10][11] The key steps in these syntheses involved addition of 2-trimethylsilyloxyfuran to an activated 2-acetyl-1,4-naphthoquinone followed by oxidative rearrangement of the resultant furonaphthofuran ring system to a furonaphthopyran ring system. In order to apply this synthetic methodology to the C-glycoside antibiotic, medermycin (1), an effective method to introduce the aryl Cglycoside 12 moiety is required.Our synthetic approach to mederm...
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.
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