Final Activity Report Summary - DRUG-DISCOVERY (Synthesis and screening of new small molecules with antibacterial activity: Discovery of novel biological targets)
Our aim in this DOS project was the exploitation of all the possibilities for chemical modifications of our starting materials. We chose aminoalkenes to play that role, which, despite of their simplicity, were susceptible of undergoing a wide range of chemical modifications. Between the possible transformations, we were interested in the study of the tandem sequence of reactions leading to bicyclic and tricyclic structures directly from the linear starting materials.
From these linear substrates, the preparation of a set of molecules that were still highly functionalised and therefore transformable was attempted. The linear alcohols type 5 were subjected to Mitsunobu reaction with N-(Boc)-p-toluenesulfonamide, in order to introduce the desired N-Boc moiety. The Boc protecting group was going to play an important role, allowing the cascade of reactions that would give rise to bicyclic and, especially, tricyclic systems (2 and 3) in one pot process. The choice of Boc for the protection of the nitrogen, allowed for the tandem deprotection and Michael addition sequence leading to the bicyclic structures 2 from structures type 7. By small variation in the reaction conditions, we could as well obtain the tricycles 3 from the structures 1, in a process that included tandem deprotection, Michael addition and Dieckmann condensation.
The stereochemistry of the final structures was determined using spectroscopic techniques and X-ray diffraction. A series of isomers of different size fused bicycles was prepared and the optimum conditions for the preparation of tricycles from the linear structures were settled. It is worth highlighting the importance of the reaction leading to the 6-6-6 tricycle 3b. This was a diastereoselective, four step tandem reaction, including N-Boc deprotection, double Michael addition and Dieckmann condensation, that afforded a diastereoisomer of this 6-6-6 tricyclic system that had not been prepared before and whose mechanistic implications deserved consideration. Furthermore, based on the previously reported synthesis of other isomers of the family of coccinellidae alkaloids, we envisaged 3b as a useful intermediate in the preparation of the natural product myrrhine, and we probed it by preparing both this alkaloid and its non-natural N-oxide.
The satisfying results of our research were that we achieved the optimisation of stereo-controlled tandem transformations which efficiently converted simple linear chains into complex cyclic structures. This kind of transformations constituted an area of current interest in organic synthesis research, which would be especially appreciated in case it had application in the synthesis of natural products. Furthermore, we applied this methodology for the preparation of a library of molecular probes with different stereochemistry and for the total synthesis of the alkaloid myrrhine.