(+) - Table Wampee Amide Antipodal Selective Synthesis And Its Analogues

(-)-clausenamide, the levo contra part of the natural product racemic clausenamide has already been proved to have nootropic activities in an array of varied biological tests and is now under Phase I clinical trial for its potential in treatment of Alzheimer’s disease (AD). Its diastereomer (+)-epi-clausenamide, nevertheless, showed twice the magnitude of LTP enhancement as that of (-)-clausenamide and thereby a more promising nootropics. Moreover,(-)-3-deshydroxyl-epi-clausenamide was identified as an inhibitor of17β-hydroxy-steroid dehydrogenase Ⅱ (17β-HSD Ⅱ) and therefore could be useful in preventing the onset of osteoporosis. Previous work has accomplished the synthesis of these two biologically active molecules. However, all the routes designed were based upon chiral resolution and the routes were lengthy and difficult to handle. Hence, a convenient approach to these two molecules is necessary which also will help facilitate biological studies. For this reason, we finished the following work in this dissertation:1. Based upon Barbas’work, asymmetric synthesis of (+)-epi-clausenamide was designed in which organocatalytic asymmetric Michael reaction was the key step to build the stereochemistry of the target molecule. Although not successful, and the yield of Michael addition reaction was much low, this work explored some possibility that the route designed is rather proper and makes sense.2. Starting from D or L-pyroglutamic acid, or D or L-serine, enantioselective synthesis of the two molecules was investigated in which C4-Ph was assembled through Heck coupling. The reactant of Heck coupling was synthesized separately from chiral pyroglutamic acid and chiral serine. The one started from the later proved to be successful. However, the yield of Heck coupling was so much low that optimization even didn’t work out. Mechanistic explanation was tried and Heck coupling based route had to be given up.3. Again starting from D or L-serine, and also based upon coupling reaction, Suzuki-Miyaura reaction based enantioselective synthesis of the two molecules was investigated and proved to be successful. Wherein a previously unknown Suzuki-Miyaura reaction was optimized.