First Total Synthesis And Determination Of The Absolute Configuration Of A Novel Benzonaphthyridine Alkaloid The Synthesis Of The Key Intermediate Of Beraprost Synthesis Of Pyrroloquinoline Alkaloids

Benzonaphthyridines have drawn widespread concern due to their chemical reactivity and biological properties, e.g. anti-bacterial, anti-fungal and anti-cancer bioactivities. Especially since2009, benzonaphthyridines were found to be small molecule immune potentiators capable of stimulating or modulating an immune response and developed as vaccines against herorrhagic fever virus, e.g., Ebola virus.A novel benzonaphthyridine alkaloid was first isolated from a mangrove-derived S. albogriseolus by Xu in2010, which possesses a fused tricyclic heteroaromatic system, and belongs to diazaphenathrene family. Based on extensive NMR data analysis, mass fragment analysis and calculation of13C NMR shifts, its structure was determined to be1-N-methy1-3-methylamino-[N-butanoic acid-3’-(9’-methyl-8’-propen-7’-one)-amide]-benzo[f][1,7]naphthyridine-2-one. It is the first known natural product with the framework. However, its absolute configuration of3’in the side chain still remained unclear due to its insufficient supply. In order to fully elucidate the structure of this natural product and overcome the problem of minor amount, the total synthesis of the benzonaphthyridine could offer us the opportunity for confirming the stereoconfiguration and reproducing such compounds in large amount for biotest and further medicinal research.In conclusion, we have for the first time accomplished the total synthesis of the noval benzonaphthyridine alkaloid with an overall yield of1.6%in15steps from isatin. The spectroscopic data (1H and13C NMR) and specific rotation of the synthetic material were in good agreement with those of the natural product. And finally by using commercially available L-glutamic acid derivative as chiral pool, the absolute configuration of benzonaphthyridine alkaloid was assigned as3’S.In primary cytotoxicity test, this noval benzonaphthyridine alkaloid showed no inhibitory effects against AGS,3AO, Skdbip,97H, LM3at concentrations of45μg/ml. But it proved to be moderately active against HGC-27at a concentration of45μg/ml and inhibited the proliferation significantly. Beraprost sodium is an orally active PGI2analogue, which is more stable than the PGI2and has longer half-life. It has been one of the commonly used antiplatelet drugs, and was commonly used in the treatment of intermittent claudication, pain and cold flu symptoms which was caused by chronic arterial occlusive disease.There were several articles on its asymmetric synthesis have been published, and the main difficulty lies in asymmetric synthesis of cyclopenta[b]benzofuran-5-butyric acid skeleton structure. At present, the use of chiral resolution and asymmetric reaction is adopted as the normal asymmetric synthesis strategy. However, the former greatly increases the cost of its synthesis due to the expensive chiral resolving agents, while the latter possesses low synthesis efficiency for the multi-step asymmetric reactions. In order to find a more efficient synthetic route, we attempted to conduct the asymmetric synthesis of Beraprost.We have accomplished the formal synthesis of Beraprost with an overall yield of40%in7steps from (-)-Corey lactone diol. The synthesis involves the use of RCM cyclization and aromatization of cyclohexadiene. Pyrroloquinoline alkaloids have been studied as both synthetic targets to develop new methodologies and biological activities to discover new drugs. Recently, ammosamide B and lymphostin have been isolated as significant bioactive compounds. Ammosamide B was isolated from the marine Streptomyces strain CNR-698, and interest in it has been stimulated by its cytotoxicities in cancer cell cultures. Lymphostin was isolated from a culture broth of Streptomyces sp. KY11783. Lymphostin has been shown to inhibit both lymphocyte kinase and phosphatidylino-sitol3-kinase, and recently, it has been found to be a potent mTOR inhibitor.The biological activity, along with ammosamide B and lymphostin’s c, inspired us to synthesize them.We have already constructed the quinoline skeleton during Doebner-Von Miller reaction from1,5-difluoro-2,4-dinitrobenzene, and found an efficient method to synthesize tricyclic pyrroloquinoline skeleton for ammosamide B and lymphostin, which lays a foundation for the total synthesis and structural modification of them.