Research objectives and content
The objectives of the present proposal are the total synthesis of martinelline and martinellic acid, two alkaloids with a triciclic core of pyrrolo(3,2-c)quinolone system that had not been reported previously in any natural product. Both alkaloids were isolated in 1995 from the root of Martinella iquitosensis for Merck laboratory and show bradykinin B 1 and B2 receptor antagonist activity in studies made for a group at Merck. This year the group of Dr. Jones have started the synthesis of both alkaloids and recently has published a short, high-yielding synthesis of the tricyclic pyrroliquinoline core of martinelline. The key step of this synthesis was the radical cyclisation of an aryl radical onto a pyrrole ring. The present proposal calls for extending this radical cyclisation into a total synthesis of these interesting natural products, firstly in a racemic way and secondly in a enantiopure form. The successful completion of this project will represent an important step forward in the use of aryl radical chemistry in natural products synthesis and would open the way to the preparation of analogues of martinelline with enhanced biological activity.
Training content (objective, benefit and expected impact)
This project will provide excellent training in modern synthetic organic chemistry. It involves radical chemistry, organometallic chemistry and modern heterocyclic chemistry all carried out against the challenge of the synthesis of an unusual and interesting natural product. Chemist with expertise and training in this area are much sought after by the pharmaceutical and agrochemical industries.
Links with industry / industrial relevance (22)
The synthesis of martinelline and some of their analogues will be of significant interest to pharmaceutical companies and it is intended to use the strong links already in place via the host group to develop links with suitable companies. For example, intermediate compounds and any analogues synthesized will be submitted for biological testing at appropiate companies. These results could be of significant interest and may lead to the development of a new pharmaceutical product.