Synthesis Of β-Functionalization α-Hydroxy Phosphonate Compounds Based On Pudovik Reaction

Organophosphorus compounds are widely used in pharmaceutical chemistry,material chemistry,pesticides,military and other fields.α-hydroxy phosphonates are a class of organophosphorus compounds with P-C bonds and hydroxyl groups attached to α-carbon atoms,which have attracted much attention due to their rich biological activities.In addition,the chiral properties of α-carbon atoms in α-hydroxy phosphonates often play a very important role,so the asymmetric synthesis of α-hydroxy phosphonates has always been one of the research hotspots in the field of organophosphorus chemistry.On the other hand,the introduction of another reactive functional group,such as halogen,ester group,carbonyl group,etc.on the β-position carbon atom of α-hydroxy phosphonates,undoubtedly has significant potential application value for the synthesis ofα-hydroxy phosphonates with more diversified chemical structure.At present,in addition to traditional biosynthesis methods,there are few efficient asymmetric catalytic chemical synthesis methods of α-hydroxy phosphonates,and there are few reports on α-hydroxy phosphonates with active substituents at β-sites.Pudovik reaction is a kind of classical organophosphorus reaction to construct P-C bond,which can form P-C bond through phosphite ester and carbonyl substrate and obtain alcohol hydroxyl functional group.Pudovik reaction is one of the most common synthesis strategies of α-hydroxyl phosphonates at present.On the basis of previous studies on Perkow correlation reactions,the research group further carried out feasibility exploration on the synthesis of β-functionalized α-hydroxy phosphonates and their small molecules catalyzed asymmetric reactions based on Pudovik reaction.The main results are as follows:1.Asymmetric synthesis of chiral β-chloro-α-hydroxy phosphonates catalyzed by cinchona alkaloidsHalogens,as a class of excellent leaving groups,allow α-hydroxy phosphonates to be further targeted to synthesize organophosphorus molecules with higher activity.In this paper,ketones were used as substrates to introduce chlorine functional groups into the β-site of α-hydroxy phosphonates.In dichloromethane,β-chloro-α-hydroxy phosphonates was synthesized by reaction of triethylamine(10 mol%)with phosphite ester at room temperature.After obtaining racemic β-chlorine-α-hydroxy phosphonates,we focus on the chiral problem of α-carbon atom in α-hydroxy phosphonate.Cinchona alkaloid,as a kind of organic small molecule catalyst,shows remarkable catalytic ability in Pudovik addition reaction due to its advantages of pseudo-enantiomer form and cheap availability.In this paper,25 kinds of cinchona alkaloids with different structures were optimized by using diphenylphosphine oxide and α-chlorophenone as template substrates.Finally,it was found that in toluene,DHQD-2PHAL(2.5 mol%)with piperazine ring was used as the catalyst and the reaction was carried out at 0℃.The enantioselectivity of the purified product was up to 90% EE after recrystallization in ethanol solution at-20℃.On this basis,12 β-chlorine-α-hydroxy phosphonates andβ-chlorine-α-hydroxyphosphonate with different substituent groups were synthesized,with ee value up to 94%.2.Synthesis of β-p-toluene sulfonyloxy-α-hydroxy phosphonate based on Pudovik reactionP-toluene sulfonyloxy(Ts O-)is the most commonly used nonhalogen leaving group,which is prone to nucleophilic substitution reactions to form new C-C and C-X chemical bonds.In this paper,α-ptoluene sulfonyloxy acetophenone was prepared by Koser reagent HTIB,which was cheap and easy to obtain.Then,the Pudovik reaction conditions were optimized and screened by using it as template substrate.It was found that in toluene solvent,triethylamine(10 mol%)was used as catalyst to react with phosphite diester at room temperature.The target compound can be obtained in high yield without column chromatography.The reaction showed good applicability for substituents on benzene rings and phosphonate substrates containing P-C bonds.On this basis,a total of 21 compounds including β-toluene sulfonyloxy-α-hydroxy phosphonates,α-hydroxy hypophonates and α-hydroxytrisubstituted phosphonate were synthesized.