Synthesis Of Oxa-spirocyclic Diphosphine Ligands And Their Applications In Asymmetric Hydrogenation Of Unsaturated Carboxylic Acids

Nowadays,transition metal catalyzed asymmetric synthetic methodology is one of the most important methods to obtain chiral compounds.Since chirality originates from chiral ligands used in the area of asymmetric catalysis,the design and synthesis of chiral ligands with novel skeleton have always been the hot issue in this field.During the past few decades,chiral ligands based on spiro skeletons have graduately developed into the efficient ones,leading to high reaction activity and excellent stereoselectivity for many types of catalytic asymmetric reactions such as asymmetric hydrogenation,asymmetric allylic substitution and so on.To my best knowledge,some chiral spiro ligands and their related catalysts provide an efficient and environmentally friendly synthetic route for the industrial production of chiral drugs.Herein,a novel structurally unique oxa-spirocyclic diphenol was synthesized by constructing the all-carbon quaternary center at an early stage and then undergoing double intramolecular nucleophilic aromatic substitution to form the spiro skeleton.Besides,five novel chiral oxa-spirocyclic diphosphine ligands with different substituents were synthesized,and the bite angle of the most simple one was determined to be 99.2~o by the X-ray diffraction analysis.In order to find out the bite angle effect in asymmetric hydrogenation,reactions about ruthenium-catalyzed hydrogenation of tiglic acid with several common chiral diphosphine ligands were conducted,showing that the enantioselectivity was improved with the increasing bite angle.Next,it was demonstrated that the complexes formed by ruthenium acetate with oxa-spirocyclic diphosphine ligands had a excellent chiral inducing ability and a wide substrate scope in asymmetric hydrogenation of tri-and tetra-substituted?,?-unsaturated carboxylic acids.Impressively,the standard reaction condition was quite simple.Usually the modification on the phenyl group of the ligand was not necessary to achieve high enantioselectivity,and only the solvent methanol without any other additive was needed.Finally,the catalyst was successfully applied in construction of core structures of chiral drugs including Sacubitril,Paroxetine and Femoxetine.Notably,asymmetric hydrogenation of the intermediate for block buster drug Sacubitril resulted in a turnover number of 30000 and a diastereoselectivity of99/1.