First Asymmetric Total Synthesis Of The Immunosuppressive Natural Products Ent-Ivorenolide A And Ivorenolide B

In the past half century, the research towards the experimental and clinical application of immunosuppressive agents, which have an inhibitory effect on human body’s immune response, has witnessed rapid development. Currently, immunosuppressive drugs are mainly applied in organ grafts, and in the treatment of other immunity-associated disorders such as rheumatoid arthritis and multiple sclerosis. Although the currently used immunosuppressants (e.g., cyclosporin A, cortisol, FK506, and rapamycin) have demonstrated undeniable clinical advantages, these drugs commonly cause serious sideeffects, such as liver and renal toxicity, increased susceptibility to infectious ailments, and decreased cancer immunosurveillance. Therefore, the exploration of new-generation immunosuppression drugs with high efficacy but fewer adverse effects remains an urgent challenge.Ivorenolide A and B are two new macrolides isolated from K. ivorensis. Both of them showed significant immunosuppressive activity. This thesis aims at the studies on the structure determination and the total synthesis of these two immunosuppressive active natural products, accordingly, the main contents could be divided into the following three parts: Chapter1. Overview of the history and research progress of immunosuppressive compounds. The history and development of the immunosuppressive compounds were briefly described. The currently used immunosuppressive compounds were summarized, and their efficacy and side effects were analyzed. Finally, the isolation and activity test of ivorenolide A and B were introduced.Chapter2. Structural elucidation and first asymmetric total synthesis of ent-ivorenolide A The structure of ivorenolide A was fully determined by NMR, HREIMS, IR and X-ray. Using cheap and readily available8-bromooctanoic acid, R-methyl lactate and propargyl alcohol as starting materials, the bioinspired asymmetric total synthesis of the enantiomer (2-1) of ivorenolide A was achieved in12steps with22%overall yield. Cadiot-Chodkiewicz coupling and Yamaguchi macrolide reaction were used as the key reactions to construct the lactone skeleton, and CBS chiral reduction as well as asymmetric epoxidation were used as the key steps to get the chiral centers. By comparison with the analysis data of natural product ivorenolide A, we identified its absolute configuration for (9R,10S,11R,16R,17S). Meanwhile, we also tested the immunosuppressive activity of ivorenolide A, its enantiomer2-1and the trans product2-29, and found that both ivorenolide A and its synthetic enantiomer2-1showed potent and selective immunosuppressive activities, with2-1being more potent than ivorenolide A. This finding not only have provided a novel macrolide scaffold for the development of immunosuppressive agents, but also got a theoretical basis for their structure-activity relationship study.Chapter3. Structural determination and the first asymmetric total synthesis of ivorenolide BThe structure of ivorenolide B was fully determined by NMR, HREIMS and IR. By use of RCM and Cadiot-Chodkiewicz coupling as the key reactions to build macrocyclic lactone skeleton, the consise and efficient asymmetric total synthesis of ivorenolide B and its three isomers was achieved in6steps through a convergent strategy with26%overall yield. By comparison with the spectroscopy data of natural product ivorenolide B, we identified the absolute configuration of ivorenolide B as3-1a (9R,1OS,11R,16S). Immunosuppressive activity test revealed that ivorenolide B has good anti-immune activity, but its three isomers3-1b,3-1c,3-1d and four trans products3-30a,3-30b,3-30c and3-30d have no anti-immune activity. These results also provide a theoretical basis for our research QSAR anti-immune activity.