Research And Application Of Metal Catalysis In The Construction Of Nucleosides And Nitrogenous Heterocyclic Compounds

In nucleoside chemistry,C-2? modified nucleosides have displayed promising anticancer and antiviral activities.So far,there are few successful examples reported for the synthesis of C-2? modified nucleosides,thus an efficient,practical and simple synthetic method is urgently needed,especially for carbohydrate donor absence of neighboring group participation at C-2?.Therefore,it is important to develop a concise and efficient method to construct chemical library of C-2? modified nucleosides for drug candidate screening.In present dissertation,we designed the introduction of ortho-alkynyl benzoate group on D-ribose 2-position to develop a new approach for constructing C-2? nucleoside derivatives.The ortho-alkynyl benzoate can efficiently act as neighboring participating group to facilitate synthesizing ?-nucleoside in the Vorbrüggen glycosylation,which could be selectively removed under the catalysis of gold(I).Further derivatization of the obtained C-2' hydroxyl nucleosides can give a series of C-2' modified nucleosides.Firstly,using 1,3,5-O-tri-benzoyl-?-D-ribose as the starting material,the ortho-alkynyl benzoate group was introduced to C-2 hydroxyl of the ribose with high yield.Then,Vorbrüggen glycosylation with a series of nucleobases were carried out.The results showed that ortho-alkynyl benzoate group was an effective neighboring participation group to facilitate synthesis of ?-nucleoside.Then,after extensive screenng of gold catalysts and subsequent optimization of reaction conditions,it was found that Ph3 PAu TFA was the most efficient catalysis for activation of ortho-alkynyl benzoate group to release the corresponding nucleoside and isocoumarin with high yield and complete selectivity.Furthermore,the gold-catalyzed reaction mechanism was proposed by combining the experimental results and H2O18 isotope tracking.After established ortho-alkynyl benzoate group as new neighboring participation group,it‘s potential application was firstly verified by synthesis of anti-tumor drug Fludarabine.Using 1,3,5-O-tri-benzoyl-?-D-ribose as starting material,Fludarabine was prepared in 7 steps and 37% overall yield using ortho-alkynyl benzoate as protecting group of C-2 hydroxyl.The newly developed synthetic strategy successfully solved the dilemma of currently reported synthesis of Fludarabine,such as high cost of starting material,poor selectivity and difficulty in separation,and may have potential industrial application.In order to further expand the utilization of gold(I)-catalyzed ortho-alkynyl benzoate in nucleoside synthesis,tetra-O-acetyl-?-D-ribose was used as raw material and ortho-alkynyl benzoates were introduced on the 2-hydroxyl and 5-hydroxyl of ribose respectively.After Vorbrüggen glycosylation with thymine,the ortho-alkynyl benzoate group was removed smoothly in the presence of 5% Ph3 PAu TFA.Thus,first total synthesis of naturally occurring marine nucleoside Kipukasin D was achieved with 15.7% overall yield in 9 steps.This practical approach avoided effectively the transesterification between 2? position and 3? position.Furthermore,this nucleoside synthesis strategy was also suitable for the synthesis of disaccharide nucleoside.At last,9-(2-O-?-D-ribofuranosyl-?-D-ribofuranosyl)adenine and 9-(2-O-?-Dribofuranosyl-?-D-galactopyranosyl)adenine were smoothly prepared with corresponding trichloroacetimidate as glycosylation donors after smoothly removing the ortho-alkynyl benzoate group.Finally,in order to enrich the diversity of C-2? nucleosides,the application of transition metals in the construction analogues of nucleobase was also studied.Through screening of catalysts and optimization of reaction conditions,it was found that 1-sulfonyl-1,2,3-trizaoles could be effectively activated by Rh2(OAc)4 to form ?-imino Rh(II)carbenes intermediate.Then,a diversity of substituted dihydropyrazines were obtained via the transannulation of ?-imino Rh(II)carbenes with 2H-azirines.The structure of obtained dihydropyrazine was unambiguously confirmed by single crystal X-ray diffraction.According to the experimental results,the possible reaction mechanism was proposed.Furthermore,the dihydropyrazine products can be converted to pyrazines under basic conditions in excellent yield.