Expeditious Total Syntheses Of Camptothecin-Family Alkaloids

Cancer is one type of highly lethal deseases threatening human health today. Recent research indicates it is keeping increase in the incidence and leads the death toll rising. Drug is one of the useful clinical protocols among all cancer treatments. With increase of effective anticancer drugs and improvement of treatment strategies, drug treatment plays a much more importmant role in the integrative cancer treatments.Camptothecin, a pentacyclic alkaloid isolated from Camptotheca acuminata by Wall and co-workers, elicited widespread interests due to its potent antitumor activity. Irinotecan and Topotecan, which were developed from natural camptothecin by appropriate structural modifications, have been used to treat a number of cancers in clinical practice. In addition, several other camptothecin analogues also have been studied at various stages of clinical trials. Although a considerable number of total syntheses of camptothecin and its derivatives have been reported to date, most of them are lengthy, of low overall efficiency and high cost as compared to natural sources. To achieve a more pratical and efficient total synthesis of camptothecin-family alkaloids, we attempted in this work to explore and develop a new strategy to synthesize camptothecin and its derivaties.(1) In 2007, a mild and efficient Hendrickson reagent-promoted cascade methodology was developed by us and successfully employed in the synthesis of camptothecin and luotonin A in high overall yield. On the basis of this work, we continued completing the total syntheses of 22-hydroxyacuminate and 14-azacamptothecin. Compared to the previous achievements, the synthetic efficiencies have been greatly improved.(2) Since multiple air-sensitive organometallic reagents were used in the preparation of the key pyridone precursor (the D/E ring of CPT), most previous syntheses are not applicable for the large-scale synthesis. In order to achieve a more practical and efficient total synthesis, we disclosed an additional new route for expedient total syntheses of camptothecin and 10-hydroxycamptothecin. In this study, a novel cascade combining an organocatalyst-inititated Michael addition with an aldol condensation was developed and applied in the one-step construction of the A/B ring (quinoline derivative) of CPT. Formation of the D/E ring of camptothecin was accomplished by an intramolecular reverse electron demand oxa Diels-Alder reaction under heating conditions. These syntheses will be of great value for the future endeavor for an alternative supply of CPT alkaloids.