Synthesis And Application Of The α-Substituted Alkenylphosphonates

The structure ofα-substituted alkylphosphonates is present in many drug molecules.Study shows that substitution of a carboxylic acid unit by a phosphonic acid or phosphonate moiety in biologically active organic compounds is a promising strategy for increasing the potency and/or selectivity of the original activity,which is widely applied to the drug’s development and optimization.Moreover,many organophosphorus compounds can be synthesized via theα-substituted alkylphosphonates,including fosmidomycin derivatives.The major methods to synthesize theα-substituted alkylphosphonates include addition/elimination tandem reaction,decarboxylative condensation,transition-metal catalyzed cross-coupling reactions,hydrophosphinylation of the alkynes,and the radical reactions.However,there is no general and efficient protocol to incorporate alkyl,（hetero）aryl,alkenyl,and alkynyl substituents at theα-carbon of the ethenylphosphonates.Therefore,there is still much valuable work left in designing and synthesizing the electrophilic coupling partners,and it is also interesting to apply these electrophilic coupling partners to synthesize theα-substituted alkylphosphonates via the strategy of C-C coupling.Additionally,more concern will be devoted to a synthetic application of theα-substituted vinylphosphonates with the development of synthetic methods.This thesis consists of three parts,including the development of new class of electrophilic coupling partners,the synthesis of a wide range of theα-substituted alkenylphosphonates,and the synthesis of theα-substituted alkylphosphonatesand1-substitutedcyclopropylphosphonatesviatheα-substituted vinylphosphonates.The major research contents and results of every subject are as follows:（1）An efficient and versatile protocol to synthesize variousα-substituted vinylphosphonateswasdevelopedviapalladiumcatalyzedSuzuki cross-coupling reaction.Using theα-halo vinylphosphonates as the electrophilic coupling partners,Pd（OAc）₂/^tBu₃PH.BF₄ or Pd₂（dba）₃/SPhos as the catalyst,a wide range ofα-alkyl,aryl,heteroaryl,alkynyl substituted vinylphosphonates could be nicely accessed in 42%-99%yields under the mild conditions.A good functional group tolerance and a broad substrate scope were also demonstrated.The mode reaction could be scaled up to 50 mmol without decline in efficiency,and get accessed to diethylα-phenyl vinylphosphonate in 96%yield.（2）A new class of electrophilic coupling partners was developed.With theα-phosphonovinyl arylsulfonates as the electrophilic coupling partners,α-aryl vinylphosphonates could be smoothly accessed in 60%-99%yields via 7 mol%Pd（OAc）₂/15 mol%SPhos catalyzed Suzuki reaction of organoboronic acid in toluene.Under the same reaction conditions,α-（hetero）aryl and alkyl vinylphosphonates could be produced in 35%-99%yields with potassium trifluoroborates as the nuclephilic coupling partners in toluene/H₂O.（3）A general and efficient method to synthesize a wide range ofα-alkyl alkenylphosphonates was developed.Withα-（pseudo）halo alkenylphosphonates as the electrophilic coupling partners,variousα-alkyl alkenylphosphonates could be accessed in 56%-98%yields via 5 mol%Pd（OAc）₂/10 mol%SPhos catalyzed Negishi reaction in DMA.This reaction was suitable for primary alkyl organozinc reagents,a broad of benzylzinc reagents,and dimethylzinc,and could be compatible with many functional groups such as CN,Cl,CO₂Et.Additionally,this methodology was suitable to the gram-synthesis of the cross-coupling products.（4）A gentle and economical method to synthesize theα-substituted ethylphosphonates was developed via the CuH catalyzed reduction of theα-substituted vinylphosphonates.The CuH catalyst was generated in situ from the mixture of 10 mol%Cu（OAc）₂,10 mol%PPh₃ or 3-8 mol%BDP,and 3equivalent PMHS at 40 ^oC.This protocol features high selectivity because the hydrogenation only take place in the phosphono substituted C=C bond keeping untouched other functional groups such as C=C,NO₂,CN,COMe,and produced theα-alkyl or（hetero）aryl ethylphosphonates in 80%-99%yields.Moreover,this method could be well compatible with halogenated aryl.Compared with the acrylate,the hydrogenation of a vinylphosphonate is more difficult and reproducible.（5）As a good radical acceptor,photo-catalyzed reactions of theα-aryl vinylphosphonates were explored.With alkyl trifluoroborate or carboxylic acid as the alkyl radical precursors,Giese-type reaction of theα-aryl vinylphosphonates undergo smoothly under the standard conditions of 2 mol%Ir[dF（CF₃）ppy]₂（dtbbpy）PF₆ in DMSO 9 W blue LED stirring for 12 h,and get accessed to theα-aryl alkylphosphonates in 80%-95%yields.As a critical step,this protocol was successfully applied to the synthesis of the fosmidomycin derivative.A further study showed that cyclopropylphosphonates compounds couldbeaccessedwith2equivalentpotassium[18-Crown-6]bis（catecholato）-chloromethylsilicate as the chloromethyl radical precursor under the same standard conditions.Interestingly,this method was suitable for other Michael radical acceptors and 1-substitutent-1-aryl olefins,and get the1,1-disubstituted cyclopropanes in 34%-98%yields.