The Investigation Of The Enantioselective Hydrophosphonylation Reaction Of Pentacoordinated Hydrospirophosphranes With Aromatic Aldehydes

It is well known that α-hydroxyphosphonates are a kind of important organophosphorus compounds.Its derivatives show a variety of biological and physiological activities,such as the inhibitory effect on a variety of enzymes,and they are also a class of very important synthetic intermediate.In general,only one of the enantiomers of α-hydroxyphosphonates is active in the racemic mixture.Therefore,the synthesis of optically active α-hydroxyphosphonates and their effective preparation methods are of theoretical significance and practical value.Furthermore,pentacoordinated hydrospirophosphranes can be used as model compounds to study the stereochemistry of pentacoordinated phosphorus compounds because of their unique spatial structures,chemical properties and simple and convenient synthetic methods.At the same time,pentacoordinated hydrospirophosphranes have inhibitory effect on tyrosinase.Therefore,this paper firstly studied the stereoselective hydrophosphonylation reaction of pentacoordinated hydrospirophosphranes with aromatic aldehydes to obtain α-hydroxyspirophosphranes,while pentacoordinated hydrospirophosphranes were used as a novel chiral organic skeleton substrate to induce the stereoselectivity.First,two pairs of hydrospirophosphranes were synthesized from L-valine and isoleucine,and then the products were separated by column chromatography to obtain single configuration products.The hydrophosphonylation reaction of pentacoordinated hydrospirophosphranes with aromatic aldehydes was firstly investigated.The reaction conditions were optimized,such as the type of base,the ratio of reactants,reaction solvent and the amount of base.Under the optimized condition,24 novel αhydroxyspirophosphranes were obtained by expanding substrates,and their structures were charaterized by NMR and HRMS spectra.Secondly,the phosphorus configuration of α-hydroxyspirophosphrane products was deduced by means of NMR method.And then the single crystal structure of product 3b-4 further confirmed that the phosphorus configuration of products was Δp configuration,and the chiral carbon formed in the reaction was R configuration.Then the difference in stereoselectivity of the hydrophosphonylation of pentacoordinated hydrospirophosphoranes with different phosphorus configurations with benzaldehyde proved that the reaction was induced by the phosphorus chirality of substrate.According to the effect of solvents on the hydrophosphonylation reaction,it was speculated that the stereoselectivity of the hydrophosphonylation reaction of pentacoordinated hydrospirophosphranes with aromatic aldehydes was possibly controlled by the hydrogen bond interaction between the reactants through the control of the attack direction of the nucleophile.Finally,the hydrophosphonylation reaction mechanism of pentacoordinated hydrospirophosphranes with different phosphorus configurations with aromatic aldehydes was proposed based on the experimental and single crystal results.For the hydrospirophosphranes with ΔP configuration,two N-H groups on the pentacoordinated phosphorus anion formed hydrogen bonds with aldehyde carbonyl group to activate substrate.Pentacoordinated phosphorus anion attacked the Re face of the aldehyde carbonyl group from the backside since the smaller steric hindrance behind P-H bond,and then the product with R configuration was produced.For the hydrospirophosphranes with ΛP configuration,the carbonyl group could be attacked from the Re or Si face by pentacoordinated phosphorus anion since the larger steric hindrance behind P-H bond,and the products with R configuration and S configuration were all obtained.The proposed mechanism will be helpful to further explore enantioselective hydrophosphonylation reaction using pentacoordinated hydrospirophosphranes as a novel chiral organic framework,and to synthesize more optically active organic compounds.Furthermore,the results will also contribute to the development of pentacoordinate phosphorus compounds.