Abstract
Natural products (NPs), especially alkaloids, have revolutionized medicine. We applied the diverted total synthesis (DTS) to access the analogues of quinazolinone alkaloids (Luotonin, Rutaecarpine, Vasicinone and Bouchardatine etc.) and 2-aminoimidazole (Oroidin, Hymenidin etc.) alkaloids to identify leads for drug discovery. The efforts are delineated herein, and the thesis is divided into four chapters. Chapter I describes formimidamide chemistry to access 4/5-aroyl-2-aminoimidazoles as the simplified analogues of UMD lead which itself is an analogue of oroidin, a marine natural product with microbial biofilm inhibition activities that we had developed as a lead in our earlier efforts. These 4, 5-aroyl analogues were found to be only moderately active against the bacterial strains (P. aeruginosa, and S. aureus) tested. Chapter II describes the successful extension of our formimidamide chemistry in identification of a facile synthetic route to access 3-aryl/alkenyl/alkynyl substituted imidazo[1,2-a]pyridines from readily available benzyl/allyl/propargyl halides and 2-aminopyridine as substrates. Computational analysis of the reaction mechanism suggested the preference of an intramolecular Mannich type addition (Baldwin allowed 5-exo-trig cyclization) over a pericyclic 1,5-electrocyclization (anti-Baldwin 5-endo-trig process). The Chapter III describes a facile super acid catalyzed regioselective aza-Nazarov cyclization strategy of quinazolinonyl enones to access tricyclic enols. Reaction optimization studies revealed the importance of proton availability to access either linear (in proton rich environment) or angular tricyclic enols (in a relatively proton poor environment). In silico analysis of the reaction mechanism suggested that the kinetic and thermodynamic controls could account for the selective production of angular and linear tricycles, respectively. The linear tricyclic enols were successfully employed to amass a focused library of C-ring substituted luotonin and vasicinone analogues while the angular tricyclic enols obtained under proton deficient conditions were converted angular luotonins. The library of all the analogues were tested for their efficiency to inhibit topoisomerase I, a molecular target of luotonin, and the assay results revealed that the analogues were topo I inert. In Chapter IV, efforts towards the total synthesis of rutaecarpine and its analogues have been described. The linear tricyclic enols synthesized in Chapter III were utilized to access nor-rutaecarpine analogues via Fischer indole synthesis. We have also attempted total synthesis of rutaecarpine via homo azaNazarov reaction on cyclopropanoyl quinazolinone, however, we met with failures though interesting side reactions were observed. Finally, further cyclization studies on advanced imine intermediate revealed heating in neat triflic acid would lead to rutaecarpine. Further efforts to access the C-ring substituted rutaecarpines via cyclopropanated quinazolinonyl enones followed by homo aza-Nazarov cyclization and Fischer - Indolization are in progress.