Synthesis of pyrrolidin-2-ones and of staurosporine aglycon (K-252c) by intermolecular Michael reaction

Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Res ponsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its ag lycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrro lidin-2-ones, a group of compounds with many interesting biological propert ies are related to staurosporinone. The most important property is the inhi bition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, all ows the synthesis of pyrrolidin-2-ones by an intermolecular Michael additio n, starting from nitroethene derivatives and substituted acetate Michael do nors. With this method also enantioselective syntheses can be carried out u sing chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the bio logical activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, Substituted indole-, phenyl-, and py ridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-py rrolidine) could be detected. Just like the total synthesis of staurosporin one within three steps, the easiest and shortest approach reported up to no w, with good to moderate yields, this sequence allows highly diastereoselec tive syntheses, which open the easy access to a new family of compounds.