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. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-, and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.
Mahboobi
Siavosh
S
Institute of Organic Chemistry, University of Mainz, D-55099 Mainz, Germany.
Eibler
Ernst
E
Koller
Markus
M
Kumar KC
Sunil
S
Popp
Alfred
A
Schollmeyer
Dieter
D