Study On Camphor-diol Induced Asymmetric Synthesis Of Chiral Organophosphorus Compounds

P-stereogenic compounds are an important class of organophosphorus compounds and have been widely applied in the fields of asymmetric transformations,agrochemistry and medicinal chemistry.The access to P-stereogenic motifs has always been considered as a very challenging and high attractive mission in modern organic synthesis.Whilst several chiral auxiliaries employed by the practical Jugé-Stephan methodology have been developed,new type of readily accessible ligands towards P-chirogenic building still remain much desirable.The most fundamental and critical issue in this strategy is the design and development of chiral auxiliaries with dual reactive functional groups.Currently,the commonly used chiral auxiliary groups are mainly 1,2-amino alcohols and1,2-thiols.However,most of these chiral auxiliaries are still sufferring from low-availability,difficult-preparation and weak-compatiblity so far.In this thesis,a powerful novel chiral template,camphor-derived 2,3-diols named as CAMDOL,was designed and synthesized from the commercially cheap camphorquinone.Divergent P（III）-and P（V）-chiral compounds were successfully afforded through this CAMDOL platform.The achieved results are briefly summarized as follows:1.Design and synthesis of camphor-diol chiral auxiliary.Based on the unique non-asymmetric scaffold of camphor,6 endo-type chiral CAMDOLs were designed and synthesized from the commercially cheap camphorquinone via stereospecific nucleophilic addition by RMg Br or RLi in 75%-85%yields at 50 g scale without column purification.On this basis,the P（III）and P（V）chiral centers were thus constructed efficiently by phosphorylation（phosphitylation）and/or by the oxidation with H₂O₂.2.Synthesis and transformation of chiral phosphinous acid boranes.Using camphor-derived phosphonite as substrate,the borane forms of dioxaphospholidines were prepared conveniently by Borane-methyl sulfide complex in high yields.Then,37 diverse chiral phosphinous acid boranes were successfully synthesized by the Jugé-Stephan reaction with Grignard reagent or lithium reagent with more than 90%ee values（up to99%ee）.Moreover,seven types of 10 P（III）and P（V）-chiral compounds,including the important ligands PAMP and DBT,were afforded efficiently in more than 95%ee values with excellent stereoretentive P-chirality through methylation of P（O）OH,substitution,deboronation,oxidation,and sulfuration reactions of the stable phosphinous acid borane synthon.To be emphasized,stereodivergent preparation of P-stereogenic phosphinous acid boranes can be easily achieved simply just by switching the organometallic reagents adding sequences or by using the different camphorquinone enantiomeric forms.3.Synthesis of P-chiral asymmetric phosphonothionates.Using the 2,3-diphenyl CAMDOL as substrate,17 camphor-derived thiophosphonate compounds were obtained with up to 20:1 diastereoselectivities under mild reaction conditions by the one-pot procedure.Furthermore,ring-opening reaction by RONa alcoholysis of phosphonothioates afforded10 P-stereogenic phosphonothionates with up to 95%ee values after comprehensive condition optimization.4.α-Asymmetric functionalization of camphor-phosphonates.Using the camphor-derived benzyl phosphonate as substrate,the P-chirality transferring feasibility was explored towards the formation of new C-C,C-F and C-S bonds,giving theα-carbon arylation,alkylation,acylation,fluorination and trifluoromethylsulfuration products including 26α-substituted phosphonates,12β-ketophosphonates,2α-fluorophosphonates and 2α-trifluoromethylsulfurophosphonates with up to 93%yield and 99:1 dr values.In summary,a new type of camphor-based chiral auxiliary CAMDOL was designed and synthesized from the commercially cheap camphorquinone.With this powerful chiral auxiliary,precise construction,controllable conversion,and effective delivery of P（III）-and P（V）-chiral centers were achieved,affording 14 types of 120 chiral phosphorus compounds possessing diverse chemical spaces with impressive stereocontrol performances,which exhibit extinct application prospect in synthetic chemistry,pharmaceutical chemistry and pesticide chemistry.