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Synthesis of 1-Omikron-Silylated 3-Azido- and 3-N-Trifluoroacetamido-2,3,6-trideoxy-L-arabino and L-lyxo-hexopyranoses, Convenient Glycosyl Donors for Preparation of Anthracycline Antibiotics and Related DNA-Binding Agents

Grynkiewicz G., Fokt I., Skibicki P., Przewloka T., Szeja W., Priebe W.

Polish Journal of Chemistry

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2005

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Vol. 79 / nr 2

335-347

EN

Over the years our studies have been aimed at the preparation of DNA-binding agents containing L-daunosamine, L-acosamine, or their derivatives, and we have found 1-Osilylated 2-deoxy-hexopyranoses to be very valuable as synthetic intermediates and glycosyl donors. We present here efficient strategies for the synthesis and separation of 1-O-silylated 3-azido- and 3-amino-2,3,6-trideoxy-L-hexopyranoses and the design of suitable glycosyl donors towards synthesis of doxorubicin analogs modified at C-4 and C-14. By using a set of known reactions, we generated a mixture of 3-azido-hexopyranoses with L-arabino and L-ribo configurations, hitherto practically unexplored as glycosylating reagents. Two new approaches are described for producing efficient and scaleable resolution of 1-O-silylated azides (epimeric at C-3). The selection of 4-O-protecting groups able to withstand glycosylation conditions, yet suitably labile to allow deprotection under acidic or mild basic conditions, led to strategically important glycosyl donors that allow preparation of previously inaccessible doxorubicin-based DNAbinding glycosides. The described use of 3-azido-2,3,6-trideoxyhexoses constitutes a new strategy for pre- and postglycosylation functionalization of anthracycline antibiotic precursors.

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New Strategies Towards Synthesis of Doxorubicin Analogs

Fokt I., Grynkiewicz G., Skibicki P., Przewloka T., Priebe W.

Polish Journal of Chemistry

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2005

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Vol. 79 / nr 2

349-359

EN

Most of the new drug candidates in the anthracycline class of antitumor antibiotics are a result of synthetic efforts involving modification of both the aglycone and sugar moieties. In such an approach, formation of a glycosidic bond is an important step that often becomes a limiting factor in the preparation of certain target structures and can also affect the efficiency of synthetic processes for obtaining analogs of anthracycline antibiotics of clinical interest. We have developed a general approach to de novo glycosylation of anthracycline aglycones leading to doxorubicin analogs with L-lyxo- and L-arabinomonosaccharides. Such glycosylation procedures are also effective in preparation of daunorubicin congeners. Specifically, we have explored the use of 1-O-silylated 3-azido-2,3,6-trideoxy-hexopyranoses as stable glycosyl donors and have successfully demonstrated the practical use of the 3-azido group to generate an amino function during the last steps of synthesis to allow easy generation of doxorubicin analogs.We have also shown that other known glycosyl donors can be conveniently generated from 1-O-silylated-hexopyranoses and can be used effectively to take advantage of a particular glycosidation and deprotection strategy.We describe two standard glycosylation procedures that were designed to attain the desired level of alfa-glycoside stereoselectivity and overall efficiency. Different glycosylation procedures were selected depending on the sugar synthon configuration and sensitive C-14 substitution in the target anthracycline aglycone. These achievements are exemplified by the use of previously unreported 3-azidosugar synthons of L-lyxo- and L-arabino- configuration protected by a 4-O-chloroacetyl group or an acid-labile triethylsilyl (TES) protecting group.

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Synthesis of Kedarosamine, a Sugar Portion of the Chromoprotein Antibiotic Kedarcidine

Priebe W., Skibicki P., Neamati N., Achmatowicz O., Grynkiewicz G., Szechner B.

Polish Journal of Chemistry

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1999

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vol. 73 nr 7

1143-1152

EN

Synthesis of the sugar portion (kedarosamine) of a recently discovered chromoprotein antitumor antibiotic and spiroketal-macrolide A82548A is described. Kedarosamine was prepared from readily available methyl A-L-rhamnoside. This route can also be used to prepare different glycosyl donors and analogues of kedarosamine potentially useful in the synthesis of biologically important congeners.