Design And Synthesis Of Phosphorus Ligands For Asymmetric Hydrogenation And Hydroformylation

The development of asymmetric hydrogenation and hydroformylation largely relies on the exploration of new chiral phosphorus ligands.The asymmetric hydrogenation or hydroformylation of a series of new substrates was realized based on the development of new chiral phosphorus ligands.Particularly,some of these reactions have been applied into the industrial productions.However,there are no universal ligands and the substrate scope is always limited due to the matching effects between ligands and substrates.As a result,the exploration of more efficient and selective ligands with wide substrate scope for asymmetric hydrogenation and hydroformylation is always highly required.Moreover,to date,only a very narrow substrate scope(namely terminal and cis-1,2-disubstituted alkenes)was addressed in asymmetric hydroformylation.Efforts into the exploration of other types of substrates are highly desirable.In this thesis,we documented the development and application of phosphorus ligands for asymmetric hydrogenation and hydroformylation.And our work focuses on the development of new phosphine ligands.The application of the newly developed ligands in asymmetric hydrogenation and hydroformylation was also explored.Moreover,we conducted the asymmetric hydroformylation of very challenging substrates.The detailed work is as follows.(1).By the incorporation of the noncovalent ion pair interaction,we developed a new ferrocenyl chiral phosphine ligands(Wudaphos).Excellent reactivities and enantioselectivities were achieved in the asymmetric hydrogenation of a-aryl and a-alkyl arylic acids utilizing the Wudaphos(ee up to 99%,TON up to 20,000).The chiral drugs like Naproxen and Ibuprofen as well as other bioactive molecules and the Roche ester have been obtained.Moreover,a series of control experiments were conducted and the proposed 3D model was built to account for the critical roles of the ion pair noncovalent interaction between ligand and substrate and also the "three hindered quadrant" model.(2).The new chiral ferrocenyl SPO-Wudaphos was developed via the incorporation of the noncovalent ion pair and H-bond interactions.Utilizing the SPO-Wudaphos ligand,the asymmetric hydrogenation of ?-methylene-?-keto acrylic acids was realized for the first time(ee up to>99%,TON up to 5,000).The intermediate for the synthesis of the chiral drug cryptophycin was obtained via the in-situ lactonization of the hydrogenation product of the compound 2a.At last,a series of control experiments and DFT calculations were conducted,which revealed the important roles of ion pair and H-bond nocovalent interactions between ligand and substrate.(3).Based on the backbone of the TCFP ligand,we have developed a new chiral ferrocenyl bisphosphorus ligand t-Bu-Wudaphos by the incorporation of the noncovalent ion pair interaction.The t-Bu-Wudaphos is a highly air stable solid and no chiral HPLC resolution is needed in the synthesis,which overcomes the drawbacks of the TCFP ligand.The Rh/t-Bu-Wudaphos exhibited excellent reactivities and enantiselectivities in the asymmetric hydrogenation of a-methylene-y-keto carboxylic acids(>99%Conv.;up to>99%ee).Control experiments revealed that the ion pair interaction between the ligand and substrate is critical.(4).The first triphosphorus ligand was developed for rhodium catalyzed linear hydroformylation.The triphosphoramidite ligand has two identical coordination modes with rhodium,which results in much better chelating ability.The triphosphoramidite ligand exhibited much better selectivities(for 1-octene,l/b = 415,TON = 9,200;for 1-hexene,l/b ?471,TON = 7,400)compared with the bisphosphoramidite ligand.And the selectivities are also comparable to those obtained with the tetraphosphoramidite ligand.(5)A new triphosphorus ligand Tribi was developed for highly selective linear hydroformylation.The synthesis of the Tribi ligand is very efficient and can be scaled up(>350 g).The triphosphorus ligand exhibited much better selectivities compared with the Bisbi ligand.And the selectivities are also comparable to those obtained with the Tetrabi ligand.Moreover,the Tribi ligand was applied in the hydroformylation of butene mixtures,which affords a new way for the manufacture of the new plasticizer with higher molecular weight and lower toxicity.A new method for the substitution of PPh3 ligand for industrial use was also developed.(6).The first interrupted intramolecular hydroaminomethylation was developed.The challenging substrate,trans-3-substituted-N-Ts-allylic amines were employed as the substrates.And a series of chiral pyrrolidinones and pyrrolidines were obtained in high yields,excellent regioselectivities(>99:1)and enantioselectivities(up to 96%)by the one-pot interrupted intramolecular hydroaminomethylation followed by oxidation or reduction.It was found that the cis or trans configuration of the substrates has no influences on the enantioselectity and the cis and trans mixture was also well tolerated.A series of synthetic transformations were conducted,demonstrating the high utilities of our method.The current method has also been applied in the synthesis of the chiral drugs Venakalant and Enablex.