Research On Synthesis Of Natural Products Penicillide And Its Analogues

Up until now, most of the leads or scaffolds for drug discovery are still derived or inspired from natural products existing in animals and plants, microorganisms and marine organisms because of their beneficially therapeutic activities and diverse structures. Therefore, how to discover more effective candidates by deriving or modifying those natural products is always the hot research field for organic and medicinal chemists.Penicillide was isolated from the mycelia extracts of a fungus culture in1974, which displayed activity against CETP (Cholesteryl Ester Transfer Protein). Recently, its derivative1developed by the researchers in Bayer was demonstrated to have potent inhibition against CETP. Inspired by these promising results, we continued our work on the structural modification of compound1and expected to discover novel CETP inhibitors.This thesis focuses on developing a concise synthetic pathway to the dibenzodioxocinone parent core, and accomplishing the total synthesis of Penicillide and its analogues based on the strategy of "me too" drugs design. The important results are shown as followed: 1. Design and synthesis of Penicillide derivativesIn this thesis, the structural modification is mainly focused on two sites at the parent core of penicillide. Because little modification of aromatic fragment B has been reported so far, there is need to modify the fragment B to exploit new CETP inhibitors. Thus, two fragments A or B was first synthesized respectively, after assembling the two fragments to construct the penicillide core, and then further derivation was performed. According to the route, the hydrophilic groups such as methanesulfonyl and ethanesulfonyl are firstly introduced into the parent core (R2); Secondly, the secondary alcohols and the alkyl side chain (R3=OH, R4=alkyl) has been modified in order to find out whether a hydrogen bond interaction exists in the the small molecule or between the samll molecule and CETP, which would influence the pharmacophore conformation of CETP inhibitors binding with CETP.In the synthesis of the N-containing analogues (Y=N), fragment B (R1Y=NO2) such as o-nitrophenol was proved not to couple with fragment A by Ullmann coupling reaction, instead, phenolic hydroxyl in fragment B is unexpectedly methylated by fragment A, and thus a preliminary substituent effect was investigated in this noteworthy reaction; due to unsuccess with Ullmann coupling reaction, aromatic ring nucleophilic substitution was subsequently studied with the corresponding fluoro fragment A (Br→F) and fragment B in order to contruct the N-containing diaryl ether skeleton.2. Synthesis of (±)-penicillideOn the basis of the above successful route,(±)-penicillide was obtained in9.4%yield based on45(R1Y=BnO, PX=CH2OTHP, R2=Me) through a convergent approach, in which Negishi coupling, Ullmann coupling and Mukaiyama esterification were key steps. In addtion, the preparation of45(R1Y=BnO, PX=CH2OTHP, R2=Me) was improved via a modified and easy-handling synthetic route and the yield increased from31%to41%.In this thesis, the total118compounds were synthesized, and among them,12compouds were target molecules and68compounds were not reported before. All of them were confirmed by NMR and MS, and the target compounds and new intermediates were characterized by1H-NMR,13C-NMR,19F-NMR (if necessary) and HRMS.