Study On Asymmetric Synthesis Of Marine Natural Products Emericellamide A, B And Apratoxin E And E - Dehydroapratoxin A With Important Physiological Activities

The term "natural products" was originally referred to chemical substances found in animals, plants or microbes. It could be divided into terrestrial natural products and marine natural products according to its sources. Unlike the terrestrial environment, the bioactive secondary metabolites which generated in organism metabolism in the special marine eco-environments have attracted much more attention since they demonstrated significant novel chemical structures and notable biological activities. Therefore, preparation of secondary metabolites through asymmetric synthetic method not only overcame the disadvantages that limit further research because it is difficult to obtain adequate amount of them by separation from nature, but also serve as an important source in lead compound discovery. Besides, the diversity of structure synthesis also promoted the development of various disciplines such as pharmaceutical and biology.This dissertation is constituted of the following two parts:Part one:Total synthesis of Emericellamides A and B, two marine secondary metabolites which showed bioactivity against MRSA.1. An asymmetric synthesis of aldehyde 1-42 using Evan’s alkylation and asymmetric Aldol reaction starting from butenoic acid with highly stereo selectivity was developed, and then the HDMD unit was achieved using Wittig method over four steps. 2. Emericellamide A is successfully synthesized based on the detailed investigation of the condensation conditions of each unit. The overall yield is 5.4% for 19 linear steps.3. Preparation of non-peptide unit HTMD of Emericellamide B from the key intermidate 1-42 through HWE reaction and Evan’s alkylation. Emericellamide B is successfully synthesized based on this research. The overall yield is 2.7% for 26 linear steps.Part two:Synthesis of cyanobacterial metabolites Apratoxin E which exhibited potent cytotoxicity against cancer cell and asymmetric synthesis of E-Dehydroapratoxin A.4. Preparation of the terminal oefine 2-109 from y-butyrolactone based on Evan’s alkylation and CBS-catalyzed asymmetric reduction with 31% overall yield. We also developed a method for synthesis of homocysteine derivatives using glutamic acid as a chiral source.5. With high selective preparation of the compound 2-165 from olefine 2-109 and 2-145 through intermolecular RCM reaction using Grubbs catalyst, we achieved the non-peptide unit 2-170 by several steps from 2-165.6. The connection of each units of compound Apratoxin E was achieved, and preliminary asymmetric synthesis of Apratoxin E was completed.7. We obtained the non-peptide fragment of E-Dehydroapratoxin A based on the preceding research of the similar unit of Apratoxin E. The final compound E-Dehydroapratoxin A was then accomplished over 13 steps. The overall yield is 4.3% for 31 linear steps from y-butyrolactone.