RESUMO
Anthracyclines are archetypal representatives of the tetracyclic type II polyketide natural products that are widely used in cancer chemotherapy. Although the synthesis of this class of compounds has been a subject of several investigations, all known approaches are based on annulations, relying on the union of properly prefunctionalized building blocks. Herein, we describe a conceptually different approach using a polynuclear arene as a starting template, ideally requiring only functional decorations to reach the desired target molecule. Specifically, tetracene was converted to (±)-idarubicinone, the aglycone of the FDA approved anthracycline idarubicin, through the judicious orchestration of Co- and Ru-catalyzed arene oxidation and arenophile-mediated dearomative hydroboration. Such a global functionalization strategy, the combination of site-selective arene and dearomative functionalization, provided the key anthracycline framework in five operations and enabled rapid and controlled access to (±)-idarubicinone.
Assuntos
Idarubicina/análogos & derivados , Naftacenos/química , Idarubicina/síntese química , Idarubicina/química , Estrutura Molecular , EstereoisomerismoRESUMO
An asymmetric Diels-Alder reaction methodology was employed to construct the tetracyclic structure of the anthracyclinone. A five-step sequence was needed to furnish the target (+)-8-hydroxy-8-methylidarubicinone.
Assuntos
Antraciclinas/síntese química , Idarubicina/análogos & derivados , Idarubicina/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Feminino , Humanos , EstereoisomerismoRESUMO
In the present work, a new chiral pool approach has been developed for the synthesis of anthracyclinones. Thus, enone 8, readily available from l-rhamnose, has been converted via addition of 2,5-dimethoxybenzyllithium to the carbonyl group and a series of six reactions into a suitably protected aldehyde 21. The SnCl(4)-promoted stereospecific cyclization of the latter afforded enantiopure key intermediate 22. Silylation of benzylic hydroxyl of 21 followed by anodic oxidation and selective hydrolysis gave ketoacetals 25 and 26 to which 3-cyano-1(3H)-isobenzofuranone 27 was annelated. Removal of the isopropylidene group in the resulting 28, subsequent oxidation of the C(13) hydroxyl and full deprotection led to idarubicinone (4).
Assuntos
Antraciclinas/síntese química , Técnicas de Química Combinatória , Idarubicina/análogos & derivados , Idarubicina/síntese química , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oxirredução , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A versatile and efficient synthetic route to 4-demethoxyanthracyclinones has been utilized in the preparation of a number of aglycons having 9-alkyl, 9-(hydroxylalkyl), or 9-carbamoyl substituents. Silver trifluoromethanesulfonate catalyzed coupling of these aglycons with various daunosamine derivatives has yielded a series of novel anthracyclines which have been evaluated as antitumor agents. 9-Alkylanthracyclines 22, 23, 33, and 34 have higher efficacy vs L-1210 leukemia than the parent 4-demethoxydaunorubicin (21), or the natural anthracyclines daunorubicin (1) and doxorubicin (2). 9-(Hydroxyalkyl) derivatives have in most cases high efficacy but are slightly less potent than 21. 9-Methyl analogue 22 has higher efficacy vs P388 leukemia than other anthracyclines tested, while 9-(hydroxymethyl) derivative 37 retains similar efficacy to anthracyclines 1, 2, and 21 but is considerably more potent. The N-substituted 9-carbamoylanthracyclines are devoid of antitumor activity.