The synthesis of a regioselectively protected staurosporine aglycone

Staurosporine and related indolo[2,3-a]carbazoles have been the subject of intensive research due to their potent biological activities, especially the potent inhibition of protein kinase C (PKC). They represent a challenging synthetic target specifically in terms of differentiation between the two indole nitrogens. This differentiation problem can be addressed by having orthogonal protecting groups on the indole nitrogens of the staurosporine agylcone, known as staurosporinone, which can then be selectively deprotected for further manipulations, or by having a single regioselectively protected nitrogen. The goal of this research was to investigate pyridazino[4,5- b]indoles and pyrrolo[3,4-b]indoles as diene systems in inverse electron demand Diels-Alder reactions with alkynyl dienophiles, and to apply this chemistry to the synthesis of regioselectively monoprotected staurosporine aglycone.; First, a new route to pyrrolo[3,4-b]indoles was discovered via the reductive ring contraction of pyridazino[4,5-b]indoles with the hope that they could be utilized as indolo-2,3-quinodimethane equivalents in Diels-Alder reactions. With the new concise synthesis of pyrrolo[3,4- b]indoles, they were utilized in cycloadditions with benzyne, but were not sufficiently reactive for application to the staurosporine problem with other, less reactive dienophiles, so attention turned to the pyridazino[4,5- b]indoles.; During efforts to utilize pyridazino[4,5-b]indoles as a starting point for the synthesis of staurosporinone, a new transformation converting esters to ketones in a single step was discovered. This new reaction was employed to synthesize new unsymmetrically 3,6-disubstituted 1,2,4,5-tetrazines also for application in the synthesis of the staurosporine aglycone.; Transformation of dimethyl pyridazino[4,5-b]indole 1,4-dicarboxylate via a key intramolecular Diels-Alder reaction gave the ABCD ring system of staurosporinone. A Curtius rearrangement applied to the C4 acid after deesterification followed by intramolecular palladium-catalyzed aryl amination afforded the regioselectively protected staurosporinone. The 1H-indolo[2,3- a]pyrrolo[3,4-c]carbazole ring system, staurosporinone, was thus synthesized starting from indole and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in eight steps.