Ir-catalyzed Asymmetric Hydrogenation Of Ketones And Its Applications In The Green Synthesis Of Drugs

Chirality exists in all aspects of the world.Chiral alcohols being a key synthetic building block for many important drug molecules.They are obtained by chiral resolution,CBS borohydride reactions and enzyme catalysis.However,these methods often suffer from low efficiency,high catalyst loading and harsh reaction conditions.Transition metalcatalyzed asymmetric hydrogenation of ketones has the advantages of high efficiency,high stereoselectivity,high atomic economy and greenness.It is one of the most efficient and convenient methods for the preparation of such chiral compounds.There are still some challenging substrates for which hydrogenation is difficult to achieve.In addition,the high catalyst loading required for some reactions would be very detrimental to largescale industrial applications.The key to metal catalysts lies in chiral ligands.The development of new efficient chiral ligands is a powerful tool to solve existing problems.In this thesis,asymmetric hydrogenation of ketones catalyzed by iridium was explored,and chiral compounds such as chiral diols,chiral lactones and chiral aryl alcohols were constructed efficiently and with high stereoselectivity through the screening of experimental conditions.Several chiral phosphine ligands with an oxaspirocyclic backbone have been designed and synthesized to achieve the enantioselective construction of cyclic diaryl alcohols.The details are as follows:The chiral synthesis of 20 examples of 1,4-diols was achieved using 1,4-diones as substrate,an iridium complex as metal catalyst,methyl tert-butyl ether as solvent and 10mol% KOH at S/C = 1 000,with product yields up to 99%,dr values up to 100:1,ee values up to >99% and turnover numbers of model substrates up to 40 000.This method was subsequently applied to the construction of chiral 1,2-ethanediols and 1,5-pentanediols.Chiral mono-alcohol intermediate was captured during the experiment,which helped to suggest the reaction mechanism of stepwise hydrogenation.Chiral lactones are widely found in natural products and pharmaceutical molecules,and the development of efficient synthetic methods for their synthesis is of great application.In this paper,the construction of a total of 24 chiral lactones,including benzofused lactones,γ-lactones and biaryl-bridged lactones,were achieved by hydrogenation and lactonization using ketoesters as substrates,metal iridium complex as catalyst at S/C= 200,tetrahydrofuran or dichloromethane as solvents,supplemented with KOH or Me OK.The yields of lactones up to 99% and ee values up to 99%.Compared to previous methods,the reaction is carried out at room temperature,the catalytic loading is as low as 0.5 mol% and the substrate range is wide.The method not only applies the iridiumcatalyzed hydrogenation system to the chiral synthesis of benzo-fused lactones and γ-lactones,which are widely found in natural products and pharmaceuticals,but also,achieves the construction of chiral biaryl-bridged lactones with atropisomerism.Asymmetric hydrogenation of diaryl ketones without substitution at the orthoposition is still difficult to achieve.We aimed at cyclic diaryl ketone substrates.After trying numerous complexes of iridium metals,the corresponding chiral alcohols could not be obtained with high enantioselectivity.After continuous design,synthesis and optimization of chiral oxa-spirocyclic phosphine ligands,O-SpiroPABQ with a benzoquinoline was eventually found to be a superior ligand for this reaction,resulting in a model product with an ee value of 96%,and the ee values of the expanded chiral alcohols were almost always above 90% and up to 99%.The iridium complex was found to be a novel phosphine-nitrogen-nitrogen-carbon(PNNC)complexation mode.This efficient and highly enantioselective hydrogenation method achieves the chiral synthesis of cyclic diaryl alcohols and provides an efficient method for the synthesis of key intermediates of the latest generation of anti-influenza drugs,baloxavir.The high cost of metal catalysts is a constraint to their widespread use in industry.In addition to the application of inexpensive metals,shortening the steps of ligand synthesis and improving the efficiency of synthesis,reducing the catalyst loading would also help to greatly enhance the application of metal complexes.We applied the complexes of iridium metal and the chiral oxa-spiro ligand O-Spiro PAP as catalysts to achieve the chiral synthesis of three important intermediates of crizotinib,lorlatinib and pibrentasvir with low catalyst loadings,good reactivity and stereoselectivity(TON above 5 000,ee values up to 99% and dr values >20:1).It provides a new and efficient method for the industrial synthesis of these drug intermediates.