Total Synthesis Of Racemic Tetrandrine And Asymmetric Synthesis Of Drug-Active Molecular Analogs Containing Octahydro [3,4-c] Bipyrrole Structures

The first part of this paper:Study on total synthesis of racemic tetrandrineObjective:We have established a new synthetic route for the total synthesis of racemic tetrandrine,which is highly efficient,economical and green.It provides a reference route for industrial mass production of optically pure tetrandrine and reduces the market pressure.Methods:In this project,the optimal reaction route was constructed by comparing the results of each reaction step using industrial grade 5-bromovanillin and4-hydroxyphenylacetic acid as starting materials.At the same time,the optimal results of each reaction step were scaled up in appropriate amounts to investigate the feasibility of industrial mass production.Thus,a simple and mature process route was obtained.Results:（1）The optimal reaction conditions for the synthesis of intermediate amide condensate are:2-（4-（benzyloxy）-3-bromo-5-methoxyphenyl）ethan-1-amine:2-（3-bromo-4-（toluenesulfonyloxy）phenyl）acetic acid=（1:1.1）,N’N-carbonyldiimi-dazole（CDI）（1.4 equiv）,rt,2 h,85%yield.（2）The optimal reaction conditions for the synthesis of the first step of the Ullmann coupling intermediate were:8-bromo-1-（3-bromo-4-methoxybenzyl）-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydrois oquinoline:8-bromo-1-（3-bromo-4-methoxybenzyl）-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline=（1:1.5）,Cu I（0.2 equiv.）,N,N-dimethylglycine（0.6 equiv.）,Cs₂CO₃（3.0 equiv.）,DMF,N₂,130°C,3 days,27%yield.（3）The optimal reaction conditions for the synthesis of the racemic tetrandrine were:Cu Br·SMe₂（2.0 equiv.）,Cs₂CO₃（2.5 equiv.）,4（?）MS,pyridine,Ar,150°C,4 days,16%yield.（4）Gram-scale scale-up experiments were completed for most of the steps,and the corresponding intermediates were obtained in good to high yields.（5）The total synthesis of racemic tetrandrine was completed in 19 steps in this route with a total yield of 0.06%.Conclusion:A new 19-step synthetic route for the total synthesis of racemic tetrandrine was developed using technical 5-bromovanillin and 4-hydroxyphenylacet-ic acid as starting materials with an overall yield of 0.06%.The route provides a reference for the synthesis of optically pure tetrandrine in later stages.The second part of this paper:Asymmetric synthesis of drug-active molecular analogs containing octahydro[3,4-c]bipyrrole structuresObjective:The asymmetric synthesis of drug-active molecular analogs containing octahydro[3,4-c]bipyrrole structures using catalytic asymmetric 1,3-dipolar[3+2]cycloaddition reactions for the desymmetrization of prechiral compounds is expected to provide a source of compounds for natural product synthesis as well as drug synthesis,which is expected to provide potential applications for the pharmaceutical as well as biological industries.Methods:（1）Using isatin and maleic anhydride as raw materials,the N-arylma-leimides and N-2,2,2-trifluoroethylisatinone imides were synthesized first according to the technical route based on three important technical indicators of yield,enantioselectivity and diastereoselectivity.（2）Using N-arylmaleimide and N-2,2,2-tri-fluoroethylisatinone imines as raw materials,the optimal reaction system was constructed by screening copper catalysts,ligands and solvents.（3）Different N-arylmaleimides and N-2,2,2-trifluoroethylisatinone imines were selected to examine the general applicability of the technical route.（4）Gram-scale experiments were conducted to investigate the feasibility of industrial applications based on the obtained standard products containing octahydro[3,4-c]bipyrrole skeleton.（5）To perform derivatization experiments on two of the obtained compounds containing octahydro[3,4-c]bipyrrole structures to provide a reference for the synthesis of more drug molecules containing such skeletons.Results:（1）A laboratory pilot synthesis process was established to synthesize 23octahydro[3,4-c]bipyrroles in the best technical route,and several polycyclic compounds containing octahydro[3,4-c]bipyrrole skeletons were synthesized in high yields of 99%,97%enantioselectivity and>20:1 diastereoselectivity.（2）Gram-level reaction products were obtained in 90%yield with high enantioselectivity（99%）and high diastereoselectivity（>20:1）of standard products containing octahydro[3,4-c]bip-yrrole skeletons.（3）A total of two derivatives containing octahydro[3,4-c]bipyrrole drug-active analogues were obtained with high enantioselectivity（94%,97%）as well as high diastereoselectivity（>20:1）under a well-established synthetic process.Conclusion:As a result of this project,an asymmetric synthesis method for the construction of drug-active analogs containing octahydro[3,4-c]bipyrrole structures using N-（2-tert-butylphenyl）maleimide and N-2,2,2-trifluoroethylisatinone imide as substrates was established.Meanwhile,gram-scale reactions and derivatization experiments exemplify more application possibilities of this synthetic technique.