Studies On The Synthesis Of Morphine Alkaloids

Morphine alkaloids with strong analgesic effects have been widely used as anesthetic agents in clinical practice.Morphine possesses a unique chemical structure,with five rings and one being an aza-bridged ring.It also contains five consecutive chiral centers,including a benzyl quaternary carbon chiral center.It is very challenging to develop a concise,practical and scalable method for asymmetric synthesis of morphine and related alkaloids in both academic research and industrial processes.In this dissertation,the asymmetric synthesis of morphine alkaloids was studied,in which chiral centers were introduced by asymmetric catalysis of small organic molecules and asymmetric induction of chiral tert-butanesulfinamide.Additionally,a new chemoselective process for the oxidation of primary alcohols and aldehydes has been developed,and this new method was also applied in the synthesis of Morphine and related alkaloids.This dissertation consists of four chapters.In chapter 1,the recent advance in the total synthesis of Morphine and relate alkaloids was summarized.Based on previous works,the new research plan for the synthesis of Morphine was proposed.In chapter 2,approaches toward the synthesis of Morphine and related alkaloids were explored.Firstly,the intramolecular 1,6-conjugated addition was introduced to construct the B ring of the morphine skeleton,then the A/B/E rings of the morphine skeleton were constructed.Secondly,asymmetric intramolecular 1,4-conjugated addition catalyzed by chiral amines was developed to construct the B ring of the morphine skeleton.The key all carbon quaternary center required for morphine alkaloids were also constructed by intramolecular alkylation.Thirdly,a highly diastereoselective Grignard addition of vinylmagnesium bromide towards Aryl/alkyl Ntert-butanesulfinyl imines were investigated and good d.r.values were obtained.In chapter 3,a new transition-metal-free process for the chemoselective oxidation of primary alcohols and aldehydes to the corresponding carboxylic acids was developed.Features of this oxidation are a new hydrogen transfer acceptor,namely the commercially available and cheap material 1-hydroxycyclohexyl phenyl ketone(1-HCPK).The oxidation process is practical and can be carried out on gram scale.The method was also applied in the synthesis of(-)-Morphine.In Chapter 4,the experimental operation and spectral data of intermediates involved in the synthesis process were recorded.