Design And Synthesis Of Parguesterol Analogue

Parguesterol is a kind of steroids isolated from the sponge Svenzea zeai of Caribbean Sea La Parguera, which shown that have anti-tuberculosis activity against mycobacterium tuberculosis H37Rv. However, because of the low content of Parguesterol in the natural resource, it is impossible to get a sufficient amount to conduct anti-TB experiments in vivo and new drug research by extracting. Therefore it is necessary to establish an efficient method for the synthesis of Parguesterol and its analogues.The purpose of this paper is to establish an atom-economic, efficient method for the synthesis of parguesterol and the analogues using hyodesoxycholic acid as starting material, provide the methodological and material basis for the synthesis of analogues with different side chains, and propose new direction for the design of other sterols with anti-TB activity. We can lay the foundation for the research of new anti-TB drugs with 5(6→7)abeo-AB nucleus.1. Synthesis of the key intermediateThe key intermediate was synthesized in 7 steps including methyl etherification, p-tolylsulfonyl etherification, nucleophilic substitution-trans-elimination, ozonization, intramolecular Aldol reaction, and protecting in the total yield of 70.3% using hyodeoxycholic acid as the starting material.2. Synthesis of the analoguesB-nor-5β-hydroxy-6β-dimethoxy-methyl-3β-tert-butyl alkyl dimethyl silicon oxy bile aldehydes was synthesized in 2 steps including LiBH4 reduction and swern oxidization in the yield of 91.4% using the key intermediate as starting materials.In summary, the analogues of parguesterol were efficiently synthesized. The method was characterized by easily available and cheap starting material, concise synthetic route, high yields, atom-economic, and laid the foundation for further development of novel antituberculous drugs.