The Synthesis Of Novel C-Nucleoside Analogues Via Three-Component One-Pot Biginelli Reaction

A C-nucleoside is a nonnatural nucleoside, in which the sugar moiety andheterocyclic base are linked via C-C bond instead of C-N. With better stability of the C-Cbond, C-nucleoside analogues are more stable than N-counterparts in acid-catalyzed orenzymatic hydrolysis. Due to the similarity with the natural nucleosides and the stability,C-nucleoside analogues have been studied in the area of biochemistry and medicinalchemistry.This dissertation deals with the application of a Biginelli reaction in synthesis ofpolycyclic nucleoside analogues.It is divided into two chapters.In the first chapter, bioactivity and chemosynthesis of C-nucleoside analogues werereviewed.Biginelli-type reactions have been especially useful in the synthesis ofC-nucleoside analogues.Firstly, C-nucleoside analogues exhibit a wide range of biological activity,such asanti-virus and anti-cancer. Compared with N-nucleoside analogues, C-nucleosideanalogues have better stability in vitro. Secondly, the current synthetic strategies sufferpoor stereoselectivity, low yield and narrow applicable range. Finally, multi-componentBiginelli reaction has been used for the synthesis of monocyclic C-nucleoside analoguesin recent years.In the second chapter, we synthesized C-nucleoside analogues and established thelibrary via a one-pot Biginelli reaction.Firstly, the precursor was obtained through multi-step protection and transformationof functional group from the starting ribose.Then we synthesized R/S-thiazolo[3,2-a]pyridine C-nucleoside analogues via a FeCl3.6H2O catalyzed Biginelli reaction. Secondly,we studied the scopes of substrates and the reaction mechanism. The reaction conditions are mild, with high yield and good applicability. The details are summarized as follows:(1) a heterocyclic ring with electron donating groups can increase the reaction yield,while a bulky group can decrease the stereoselectivity;(2)1,3-dicarbonyl compound withelectron withdrawing groups can increase the reaction yeild;(3) when the ester groupbecomes larger, the reaction yield will be reduced slightly and the stereoselectivity willbe decreased.Finally, we synthesized a library of44products with yields22-85%via Biginellireaction. Thiazolo[3,2-a]pyridine,pyrido[1,2-a]pyrimidine and benzo[4,5]thiazolo[3,2-a]pyridine C-nucleoside analogues were obtained with debenzylation. This methodsprovides a simple and efficient synthetic strategy to establish libraries of pyrimidinepolycyclic C-nucleoside analogues.