Syntheses,Structure Characteristics And Applications Of C₇N Aminocyclitol Derivatives

The C7N aminocyclitol family is a relatively new class of natural products that is increasingly gaining recognition due to their significant biomedical and agricultural uses.Based on the systematic review of previous researches,this dissertation mainly contains two parts:1)a new practical approach from(+)-valienamine to(+)-valiolamine via diastereospecific epoxidation and highly regioselective ring-opening is improved;2)three classes of C7N aminocyclitol derivatives,including 1,2,3-triazoles,thioethers and thioureas are designed and synthesized.In Chapter 1,the essential role natural products play in the discovery of new pharmaceuticals and the structures and properties of typical aminocyclitols are introduced briefly.Reviewed in details in Chapter 2 are the concise history of development of validamycins and the preparation of typical C7N aminocyclitols using fermentation processes or chemical syntheses.The modifications and diversifications of C7N aminocyclitols and their applications are also summarized in this chapter.Taking advantage of epoxide's characteristics,a new practical procedure from(+)-valienamine to(+)-valiolamine via diastereospecific epoxidation and highly regioselective ring-opening is improved in Chapter 3.By means of employing higher-boiling solvent and adding radical inhibitor,the disadvantages such as long reaction time and low conversion of valienamine pentaacetate are solved smoothly,and the yield of epoxide is improved from initial 30%to 96%.The configuration of epoxide group is confirmed to be ? as expected by using single crystal X-ray diffraction.Meanwhile,the mechanism model of substrate-directable epoxidation is also built based on the experimental phenomena.Under acid condition,three 5-halogen valiolamine pentaacetates are obtained via regioselective ring-opening of epoxide,and the mechanism model of abnormal ring-opening of epoxide is also built.After dehydrohalogenation and deprotection,the 5-halogen valiolamine pentaacetates are converted to(+)-valiolamine,which could give voglibose by reductive amination with 1,3-dihydroxyacetone,according to reported procedure.This efficient and practical synthesis of(+)-valiolamine starting from readily available(+)-valienamine in 5 steps and up to 80%total yield in gram-scale quantities circumvent laborious purification of products using chromatographical separation.In Chapter 4,Cu(?)-catalyzed diazotransfer reaction and Cu(?)-catalyzed azide alkyne 1,3-dipolar cycloaddition(CuAAC)"click chemistry" is used to synthesis C7N aminocyclitol derivatised 1.2.3-triazoles.In the course of this work,-N=N-moiety is trasnferred into C7N aminocyclitols,employing imidazole-1-sulfonyl azide as the diazo-transfer reagent catalyzed by Cu(?),Zn(?)and Ni(?)with moderate to good yields.The structure of compound 4-32 is confirmed by single crystal X-ray diffraction.The obtained azidocyclitols are linked with various terminal alkynes under modified Meldal's condition(CuI/DIPEA/DMF)with good to execellent yields,in the absence of any ligand or promotion tools such as microwave or ultrasound.The stereo-and regio-chemistry of the products are confirmed through 2D-NMR(NOESY and HMBC of representative product 4-40a).The one-pot syntheses of the corrensponding 1,2,3-triazoles,as more efficient and safe procedures are also investigated and give moderate to good yields.The reaction between valienamine epoxide pentaacetate and thiophenols catalyzed by tertiary amines and LiClO4 has been studied as described in Chapter 5.The yields of products is improved significantly,and the mechanism model of ring-opening with thiophenols in the presence of DIPEA and LiClO4 is also built based on the experimental phenomena.Furthermore,nine new thioether derivatives of valiolamine are prepared under optimized condition,and the structure of 5-9j is comfirmed by single crystal X-ray diffraction.Moreover,the reaction between valienamine epoxide pentaacetate and sodium azide,giving 5-azido valiolamine,is also studied in this chapter.In the CuAAC reaction of and 5-azido valiolamine and terminal alkyne,the atropisomerism of adduct due to the sterically hindered substrate is observed.This dissertation research also focuses on synthesis of thiourea derivetives of C7N aminocyclitols.The details of synthesis and characterization are found in Chapter 6.Ten new thiourea-derivatised aminocyclitols are prepared using the addition of C 7N aminocyclitols and phenyl isothiocyanates.The region-specific N-acetylation in the peracetylated products is comfirmed by single crystal X-ray diffraction.Moreover,the atropisomerism of ortho-phenyl thiourea derivatives due to the hindered rotation about single bond between thiourea and phenyl is also observed.The approximate energy barrier to rotation is 63.01 kJ/mol,which is obtained by molecular simulation on Gaussian 09 software.