Chiral Phosphoric Acid-catalyzed Asymmetric Biomimetic Reduction Of Hydroxypyrimidine Derivatives

Chiral dihydropyrimidinones(DHPMs)is an important class of prevalent skeleton structures in pharmaceutical chemistry,wherein the C4 chiral center plays a pivotal role in the biological activity and efficacy of these compounds.The preparation of chiral DHPMs always relies on three-component condensation of aldehyde,acetoacetate and urea,which is named as Biginelli reaction.However,most of the successful examples are focused on furnishing the 4-aryl substituted chiral center.Considering the wide applications of such compounds in medicinal chemistry,to develop new methods to synthesize various chiral DHPMs,especially the unreported chiral DHPMs with alkyl or heteroatom substituted at C4 chiral centers,is of great significance and highly desirable for drug discovery.In this dissertation,the synthesis of chiral DHPMs with novel structures through asymmetric biomimetic reduction of hydroxypyrimidines is discussed in detail.First,using chiral phosphoric acid as the catalyst and Hantzsch ester as the hydrogen source,the asymmetric biomimetic reduction of hydroxypyrimidine with a symmetric structure was realized to yield the corresponding DHPMs with high enantioselectivities(up to 99%ee).Also,the reaction was scaled up to gram scale without loss of reactivity and enantioselectivity.In addition,by changing the hydrogen source,the hydroxypyrimidines with unsymmetrical structure were successfully reduced to the chiral 4-methyl substituted DHPMs with excellent regioselectivities and moderate enantioselctivities(rr>20:1,up to 78%ee).Second,employing the chiral phosphoric acid as catalyst and the Hantzsch ester as hydride donor,the chiral DHPMs with 4-alkyl chiral center were prepared in high regioselectivities and enantioselectivities(up to 98%ee)through biomimetic reduction of N-substituted pyrimidinones.This reaction still gave a high yield and enantioselectivity even in a gram scale.In addition,chiral guanidine compounds with potential biological activity were synthesized by using the resulted DHPMs as the starting materials.Last,the combination of DDQ oxidation and asymmetric biomimetic reduction enabled the deracemization reaction of DHPMs containing phosphonate substituents at C4-position.Using a racemic mixture as starting material,the enantiomeric enriched products were able to be obtained with high yields and high enantioselectivities(up to 96%ee)in one pot.This kind of novel chiral DHPMs compounds have not been reported yet.