Application Of Ring-Closing Metathesis Reaction In The Synthesis Of Alkaloid Fawcettimine And Macrocyclic Pharmaceutical Intermediates

The alkaloid fawcettimine is a homologue of the second-generation inhibitor of the acetylcholinesterase,Huperzine A,with potential anti-acetylcholinesterase activity.Because fawcettimine is a four rings fused compound and has two quaternary carbon centers,it is difficult to synthesize and is increasingly welcomed by chemical practitioners.The reported synthetic methods are all with the same strategy of the cleavage of C-N bond to give a tricyclic structure,but the synthetic steps are numerous.Thus,we have conceived a brand-new synthetic approach,the breakage of the carbon-carbon bond to give the twisted amide,a key intermediate with high reactivity.In this thesis,we explored the total synthesis of fawcettimine and investigated the selectivity of ring-closing metathesis reaction in the synthesis of its skeleton.This thesis is divided into four chapters:1.Studies on the total synthesis of fawcettimine.The substrates(R)-3-methylhex-5-ynoic acid and 6-azacyclodecene were synthesized.Alkynoic acid was synthesized by the following steps:synthesis of chiral auxiliary compound,asymmetric allylation,ozone oxidation,Corey-Fuchs reaction,and hydrolysis.6-Azacyclodecene was prepared by ring-closing metathesis(RCM).The alkynoic acid and nitrogen-containing olefins were then subjected to a cobalt-mediated[C2+C2+C1]cycloaddition(Pauson-Khand reaction)to give the key intermediate cyclopentane enone.2.Olefin metathesis condition optimization in the synthesis of nine-membered ring compounds.By two-step reaction,alkylation and RCM,the synthesis of nitrogen-containing nine-membered ring was completed.In the RCM reaction,the catalysts,solvents,and concentration conditions were optimized.The single crystal structures of the nine-membered ring and the dimerized 18-membered ring were obtained.In order to verify the structure of dimeric 18-membered ring,we chemically synthesized the 18-membered ring to obtain different ratios of the dimeric mixture ZZ/ZE/EE,and under certain conditions,the olefin configuration conversion was observed from Z.to E.3.Kinetic experiments of olefin metathesis reaction.We performed kinetic experiments on all substrates and provided evidence of conversion among EE-3.4a,EZ-3.4a and ZZ-3.4a.After lowering the temperature,the secondary metathesis is suppressed,so that the kinetic control of this RCM reaction was achieved with G1,and a reliable model is established to distinguish the kinetic or thermodynamic control in the RCM reaction.The kinetic experiments of Cat-Z,a highly Z-selective catalyst,confirms the kinetic control of this catalyst and the conversion capabiltity of Z-to E-olefins.4.Studies on the ring size selectivity in macrocyclic synthesis.The ring-closing metathesis(RCM)of ?,m,?-triene was employed for the syntheses of four slightly different EE-,EZ-,ZE-and ZZ-isomers of macrocycles with two far separated type I olefins.The ring size selectivity of a,co-vs.?,m/m,?-products in the RCM reaction of a,m,?-triene revealed that all types of isomeric a,?-products are favored for the 18-membered ring and above,and a,m/m,?-products are predominated for the 14-membered ring and less.For the 15-,16-and 17-membered rings,each of E/Z-selective RCM reactions of starting mE-and mZ-trienes has different performance under the optimized conditions.