Abstract (eng)
Anthracyclines represent one of the most important antitumor drugs especially for the treatment of human solid tumors and leukaemias. Since their discovery in the 1950s, considerable efforts were accomplished towards the understanding of their mode of action and towards the synthesis of anthracyclines approved to be used in cancer therapy such as doxorubicin or idarubicin and new analogs.
Despite of the extensive efforts accomplished in the total synthesis of anthracyclines, especially of our target Idarubicin, industrial production is still done in a semi-synthetic manner. Therefore, elaboration of new total synthesis of Idarubicin able to be translated in an industrial process is very interesting.
In the presented work, a new total synthesis of idarubicinone 12 / idarubicin 6 is reported starting from the anthraquinone 83 and L-malic acid 96. In this synthesis the anthraquinone 83 was converted in 5 steps into the bromo derivative 88 in 49 % overall yields without the need of chromatography and L-malic acid 96 was converted to the compound 165 in 3 steps in 75 % overall yield.
The alkylation of the bromo derivative 88 with 165 led to 166 in 89% yield and excellent de (>99%). After several attempts to obtain the tetracyclic structure of the targeted anthracycline, the compound 166 was converted to the lactol 196 in 7 steps in 62 % overall yield from 166. Intramolecular cyclization of lactol 196 under Marschalk conditions at room temperature afforded the 7-deoxyanthracyclinone 211 in 67 % yield which was subjected to subsequent oxidation of the hydroxyl group at the position C-13 and hydroxylation at C-7, followed by epimerisation of the undesired epimer, to afford the aglycone of idarubicin 12 in 11% overall yield from 88 on a labor scale.
Glycosidation of 12 followed by subsequent cleavage of the protecting group present in the sugar moiety afforded idarubicin hydrochloride 6-HCl in 30% overall yield from 12.
Up-scaling of the sequence was also explored. Every step to the aldehyde 199a+b was carried out on a 10 g scale at least. Overall yield was slightly decreased from 23% to 18% but some chromatography steps were substituted by recrystalisation or trituration.
The described synthesis pathway may be suitable for the preparation of further known or new anthracycline derivatives.