Coordination Inclusion Of Cyclodextrin / Active Organic Molecules - Cyclohexylbenzene Alanine Asymmetric Synthesis

Cyclodextrins and their derivatives (CDs) are the most important class of host compounds in host-guest chemistry in the area of supramolecular chemistry. They have many merits such as the unique structure of "hydrophobic interior hollow and hydrophilic outer surface", the biological affiliation, the good solubility in water and can be modified chemically. So CDs can encapsulate active molecules to form host-guest complexes or supramolecular species. This usually enhances and improves the water solubility, stability and bioavailability of the encapsulated active organic molecules. Therefore, it is of great importance to study the complex behaviors of active organic products with cyclodextrins.Optically active amino acids are fundamental building blocks for the preparation of peptide Pharmaceuticals and many natural product molecules. Due to the asymmetric synthesis of non-natural amino acids can be used for designing and screening peptide drugs and studying the structure-activity relationship, the organic chemists have paid great attentions to synthesize these compounds for years. Therefore, design and synthesis of non-natural amino acids that can explore their chain conformations have very important significance.This thesis describes studies towards the inclusion complexation behavior, binding ability, characterization, stabilization and solubilization effect of cyclodextrins (CDs) with gibberellin acid (GA3) and its derivatives (GA-13315and GA-13315CDO-4-MOBE). In addition, a pair of novel Boc protected β-branched non-natural amino acids were designed and synthesized by use of the chiral auxiliary4(R/S)-4-pheny1-oxazolidin-2-one according to the basic synthesis route and method of Evans and Hruby in this thesis.This thesis is composed of five chapters.In Chapters1, a review of the preparation, characterization and their applications of the cyclodextrin complexes is presented. The study on the complex behaviors of cyclodextrins with the active organic molecules in recent years is also reported.In Chapters2, several kinds of inclusion complexes between natural, modified cyclodextrins (a-CD, β-CD, γ-CD, HPβCD, SEBβCD and enβCD) and guest molecule gibberellin acid were prepared. The binding behavior, characterization and binding ability were investigated in both solution and the solid state by means of XRD, DSC,1H and2D NMR, SEM and UV-vis spectroscopy. The results showed that natural CDs possessed the higher binding constants, the water solubility and stabilization of GA3can be improved obviously after forming inclusion complex with cyclodextrins (Scheme1).In Chapters3, the water-soluble inclusion complexes formed by GA-13315, which is one of gibberellin derivatives possessed antitumor active, with β-cyclodextrin and its derivatives (2-hydroxypropyl-(β-cyclodextrin, HPβCD and sulfobuty ether-β-cyclodextrin, SBEpCD), which are safety in pharmacy, were researched. The binding ability, characterization, solubilization and stabilization effect of GA-13315with CDs were also studied (Scheme2).In Chapters4, the water-soluble inclusion complexes were prepared by the reaction of gibberellin derivative (GA-13315CDO-4-MOBE) with β-cyclodextrins and its derivatives (sulfobuty ether-β-cyclodextrin, SBEPCD). The inclusion mode was deduced according to the1D and2D NMR (ROESY) data. The characterization of inclusion complexes was carried out in the solid state by means of DSC, TG and XRD. The results showed that the water solubility and stability of GA-13315CDO-4-MOBE can be enhanced greatly after forming inclusion complex with cyclodextrins (Scheme3).In Chapters5, a series of active intermediates1a/1b-4a/4b and the novel chiral α-amino acid derivatives ((2R/3S) or (2S/3R)2-(tert-butoxycarbonylamino)-3-cyclo hexyl-3-phenylpropanoic)5a/5b with hindered conformation were synthesized. In the synthesis, easily available trans-cinnamic acid was used as starting material, and the reaction was controlled stereoselectively by use of chiral auxiliary. The synthetic process includes a series of key reactions, such as ammonolysis, asymmetric Michael addition reaction, direct azidation, one pot of hydrogenation and amine protection, as well as alkaline hydrolysis. The overall yields can reach10-20%and de90%(Scheme4).