Study On The Synthesis Of Optical Active Neoclausenamide Derivatives And Cycloclausenamide

Both neoclausenamide and cycloclausenamide are kind of active lactam ingredients derived from Clausena lansium（Lour.）Skeels,and also have been demonstrated to be able to protect liver from impairments.Nevertheless,there are still inadequate studies on their preparations and structure activity relationships.In order to provide samples for their phar-macological research,new gateways to synthesis optical active neoclausen-amide derivatives and cycloclausenamide are described in this thesis after summarizing related known methods.More than that,preparations for key intermediates in those synthesis routes were further optimized in the study.A synthesis approach,sort of preparation for optical active clause-amide,earlier devised by our research team was first adopted to give optical active neoclausenamidone in good result,which was started from cinnamic acid that successively subjected to Oxone epoxidation,resolution,acylation,and cyclization.After improving the synthesis of involved inter-mediates,an elaborate investigation of stereoselective reductions on the C₆carbonyl of（+）-neoclausenamidone was contributed to prepare optical act-ive neoclausenamide and epi-neoclausenamide.Several stereoselective re-ductions,such as Metal complex hydrogen compounds reduction（including sodium borohydride,lithium tri-sec-butylborohydride,lithium triethylboro-hydride,diisobutyl aluminium hydride）,Meerwein-Ponndorf-Verley reduc-tion（MPV reduction）,Corey-Bakshi-Shibata reduction（CBS reduction）,were screened,however,lithium triethylborohydride reduction and CBS reduction were discovered showing good yield and strong stereoselectivity.This five-step synthesis presented two products in an overall yield of 10%and excellent enantiomeric excess（>99%）separately,and has advantages of low cost as well as simple operation.Then a cinnamic acid derivative instead of cinnamic acid were succes-sively came under Oxone epoxidation,resolution,acylation,and cycli-zation to generate a neoclausenamidone derivative that connecting a 4-chlorobenzyl group on the basis of the above synthesis way.An inves-tigation pointing at the Oxone epoxidation of cinnamic acid derivative with1-chloroacetone,according to references,was completed,providing theα,β-epoxycinnamic acid derivative that was going to be resoluted.The reso-lution was successfully achieved at PEA/acetone after several chiral base resolution agents had been screened.The final product,3-hydroxy-（trans-4-chlorobenzyl-5-benzoyl）-N-methyl-γ-lactam,was obtained in a total yield of 6.7%and good enantiomeric excess（>99%）.Compared with known analogous derivatives,the chlorobenzyl functional group installed on neo-clausenamidone is able to exert higher reaction activity and provide a novel pivot of the structure modification of neoclausenamide.Making use of the aforementioned preparation reported by our rese-arch team again,a synthesis commenced with Oxone epoxidation followed by a series of resolution,acylation,cyclization,and reduction simply pre-sented（+）-clausenamide as an intermediate.Afterwards an intramolecular dihydroxy dehydration endocyclization utilizing the intramolecular Mitsu-nobu reaction acting upon（+）-clausenamide directly produced the target（-）-cycloclausenamide in a yield of 56%and satisfactory enantiomeric excess（>99%）.In contrast with the conventional eleven-step synthesis（2%overall yield）of（-）-cycloclausenamide,this six-step synthesis（6.8%overall yield）not only shortens the preparation procedures,since there is neither pre-protection nor sulfonylation arising from the intermediate（+）-clausenamide,but also possesses milder reaction conditions and better efficiency.