The Construction 6-Substituted 2-Hydroxy 3-Hydroxymethypiperidine And Asymmetric Synthesis Of (-)-Deoxoprosophylline

Natural products-piperidine alkaloids exist widely in the nature.Especially 2,6-disubstituted 3-hydroxypiperidine,plays a significant role in the pharmaceutical industry,and many of them show interesting pharmacological activities such as anesthesia,analgesia,anticancer,antibacterial,and other important biological activities,which have aroused wide interests among pharmacologists and chemists in recent years.Among this,the 2,6-disubstituted 3-hydroxymethypiperidine structure is commonly isolated in alkaloids of the Prosopis and Cassia families.These alkaloids are characterized by a hydrophobic group and two polar groups,from the structure can be regarded as a(nerve)sphingosine sebum membrane cyclic analogues.Therefore,as the unique structure compound in this kind of alkaloids,it has attracted more attention of late years.The most typical ones are the prosophylline separated from the Prosopis Prosopis africana in Savanna,west Africa,which have better antibacterial and anaesthesia activity.The results showed that the structure activity relationships of prosophylline and(-)-deoxoprosophylline were identical,which indicated that they have similar activity.In terms of structure,2,6-disubstituted 3-hydroxymethypiperidine is more illustrative,but the diastereoselective synthesis of chiral substituted in piperidines is of considerable difficulty,especially a polar C-2 hydroxymethyl substituted.According to this structure,a method for the preparation of compound 109 by an addition-cyclization process of the imine 108 with vinylmagnesium bromide which could obtained 20 g scale has been developed,and has been applied in the total synthesis of 2,6-disubstituted 3-hydroxymethypiperidine(-)-Deoxoprosophylline.This dissertation is constituted of the following two parts:1.A novel protocol to access 2,6-disubstituted 3-hydroxymethypiperidine scaffoldBased on the depth of the previous work,a novel method for the preparation of trans-5-hydroxy-6-ethenyl-2-piperidinone 112 by an addition-cyclization process of the imine 108 with vinylmagnesium bromide which could obtained 20 g scale has been developed.Besides,the stereogenic center at the C-6 position was controlled by ?-OTBS group of imine(R,SRS)-108.Then using the dihydroxylation-oxidation-reduction as key step,trans-5-hydroxy-6-hydroxymethyl-2-piperidinone was synthesized.2.asymmetric total synthesis of natural product multi-substituted(-)-deoxoprosophyllineDifferent routes to synthesis(-)-Deoxoprosophylline starting from chiral intermediate 114 have been developed.The compound was obtained by an addition-ring opening sequence of 114 with Grignard reagent and a cyclization process to realize the introduction of long chain at C-6.The advantages of this route are that there are fewer steps and shorter routes,but regrettably it is not selective.In this process,the synthesis of chiral amino alcohol 119 was realized by accident.The synthetic route of(-)-Deoxoprosophylline was improved for the problem of the previous synthesis strategy.(-)-Deoxoprosophylline was asymmetrically synthesized by asymmetric allylation and olefin metathesis sequences from compound 114.Eventually,(-)-Deoxoprosophylline was synthesized in 57% overall yield within 5 steps from 114.