¿SYNTHETIC STUDIES TOWARDS BIOACTIVE FUNGAL METABOLITES¿

The problem of the development of new pesticides is very urgent, mainly because of the appearance of pest forms resistant to permitted pesticides and for the strict requirements in terms of their safety for people and the environment. Small molecules produced in biological contexts have been, and still are, a large reservoir of new biologically active substances, which can become scaffolds for the discovery of new agrochemicals. The aim of this PhD work was to synthesize naturally occurring potentially antifungal and herbicidal compounds and to test their biological activity. Efforts mainly focused towards the total synthesis of Bulgarein, a fungal metabolite produced by the fungus Bulgaria inquinans. Bulgarein possesses a benzo[j]fluoranthene skeleton, that can be found in a number of polyketide-derived fungal metabolites endowed with significant biological activity, in particular inhibition of Topoisomerase I. As no attempt to synthesize any of these compounds has been reported in literature so far, a synthetic sequence to the benzo[j]fluoranthene nucleus has been developed. Crucial steps for our strategy include a Suzuki coupling followed by a McMurry ring closure. The approach is modular and rapid and can be utilized to synthesize natural products, biologically active analogues or building blocks for the preparation of materials. Following this strategy, the first total synthesis of the recently isolated natural product benzo[j]fluoranthene-4,9-diol was carried out. Efforts were made to adapt the sequence for the synthesis of Bulgarein and other variously substituted compounds with this skeleton. As a second topic in this research, attention was dedicated to another natural compound, Farinomalein A, a structurally rather simple maleimide isolated in 2009 from the entomopathogenic fungus Paecilomyces farinosus. Farinomalein shows potent inhibition of Phytophthora sojae, a plant pathogen that every year causes enormous damage to soybean crops. Recently, three new farinomalein derivatives (Farinomalein C, D & E) were isolated from an endophyte from the mangrove plant Avicennia marina, growing in Oman. Due to the interesting antifungal activity of this class of compounds, a practical synthesis of farinomalein A was developed, which may have value in the large-scale preparation of the natural compound. Starting from farinomalein A, all the three derivatives were successfully synthesized . The antifungal activity of the derivatives was evaluated against Cladosporium cladosporioides and other pathogenic fungi. An approach to the synthesis of Ascaulitoxin, a phytotoxic metabolite produced by the fungus Ascochyta caulina, was also developed.