A new Ugi-like MCR4 multicomponent reaction to access chiral hexa-substituted benzenes towards development of inhibitors of protein kinases

Mati Bardosh Gelman, Department of chemistry, Bar Ilan University, Ramat Gan, Israel
Ahmad Abdelhai, Department of chemistry, Bar Ilan University, Ramat Gan, Israel
Ronit Lavi, Department of chemistry, Bar Ilan University, Ramat Gan, Israel
Gerardo Byk, Department of chemistry, Bar Ilan University, Ramat Gan, Israel

Multicomponent reactions are of special interest because they can generate in a single reaction complex molecules, such as hetero aliphatic and hetero aromatic polycyclic rings, and can be adapted to parallel automated synthesis. The synthesis of complex molecules has an advantage when it comes to natural compounds and their derivatives. Special attention was devoted to Staurosporine, an indolo[2,3-a]carbazole alkaloid, which acts as non-selective inhibitor of protein kinases and induces apoptosis. Thus, its derivatives have potential applications for cancer treatment. Structurally, this compound is characterized by a hexa-substituted benzene ring with a fused indole ring and a fused lactam ring with a pendant sugar moiety. Two recent works deserved as driving forces for the synthetic strategy we present here: the first, a conceptually new strategy for the synthesis of the hexa-substituted benzenes. The key-step of the reaction was the generation in situ of a furan intermediate which upon the presence of appropriate dienophiles undergoes Diels Alder reaction resulting in a non-stable intermediate that after rearrangement produces hexa-substituted benzenes. The second, proposed the formation of substituted furans by reacting barbituric acid with isocyanides and aldehydes at room temperature. Herein we combined both approaches for obtaining novel hexa-substituted benzenes. The advantage of the new approach is that chiral derivatives can be easily obtained in one pot. We have developed a new “Ugi like” MCR4 by using chiral β-keto-γ-lactams as precursors. Some of the new molecules display significant biological activity in XTT viability assays in different cell lines.