Total Synthesis Of Paracaseolide A And Aphadilactones A-D And Structure Activity Relationship Study

This thesis was concerned with the studies on the total synthesis of natural product paracaseolide A(1) and aphadilactones A-D(89-92) with the key intermolecular Diels-Alder reaction. On the basis of total synthesis, the SAR study based on Paracaseolide A and design and synthesis of diacylglycerol acyltransferase 1(DGAT1) inhibitors based on aphadilactone C were carried out too. It mainly consists of the following two parts:Part 1 gaves a detailed introduction on the related research work about paracaseolide A. Firstly, biosynthetic pathway II of Paracaseolide A, hypothesized based on our comprehensive literature survey, and the biosynthetic pathway I hypothesized by Guo’s group were combined as a whole. And then, natural product Paracaseolide A has been successfully synthesized in total yield of 14% by the biosynthetic pathway I. Dimer compound 18 has also been successfully synthesized based on biosynthetic pathway II. And the following study was divided into two directions: dimer compound 18 transformed into Paracaseolide A and the SAR study of compound 18. At last, compounds 68 and 86 were found to have better CDC25 B and PTP1 B inhibit activity as well as selectivity compared to Paracaseolide A.Part 2 introduces the Aphadilactones A-D(89-92) related work. Started with commercially accessible 2-Methyl propenal and 2-Butyn-1-ol, we successfully constructed the dimer natural product Aphadilactones A-D in total yield of 6.6 % in 11 steps. And compounds 207-210 were designed and synthesized, which the lactone group of aphadilactone C was introduced into the PF-04620110 and AZD-7687, which have entered into the clinical research, and to verify whether the lactone in aphadilactone C played the same role as carboxylic group in PF-04620110 and AZD-7687.