Asymmetric Hydrogenation Of Challenging Unsaturated Carboxylic Acids And Its Application In Drug Synthesis

Optical active carboxylic acids are a significant class of organic compounds and versatile intermediates,which widely exist in natural products,bioactive moleculars and pharmaceuticals.As we all know,catalytic asymmertric hydrogenation has been recognized as one of the most efficient,atom economic and environmental friendly approaches to various chiral compounds.In the past five decades,the classes of substrates in asymmetric hydrogenation expanded greatly with the prosperous development of chiral phosphine ligands.Therefore,asymmetric hydrogenation can be applied to the synthesis of various kinds of compounds.Since the first successful application of asymmetric hydrogenation to industrial production of L-DOPA,asymmetric hydrogenation has become one of the most common and mature catalytic asymmetric methods applied to industrial production.Chemists all over the world has made great efforts to the research on asymmetric hydrogenation of unsaturated carboxylic acids to chiral carboxylic acids.Despite impressive progress has been achieved in this area such as excellent catalytic effects and enatioselectivities,the scope of substrates remains limited,especially some challenging unsaturated carboxylic acids.Consequently,It’s meaningful and demanding work to explore effective catalytic systems to the asymmetric hydrogenation of challenging unsaturated carboxylic acids and employ the asymmetric hydrogenation systems to drug synthesis.Herein,two challenging unsaturated carboxylic acids were synthesized and reduced by Rh-catalyzed asymmetric hydrogenation with great enatioselectivities and yields.Besides,(R)-flobufen and the intermediate of sacubtril were synthesized concisely with high yields by applying asymmetric hydrogenation as key procedures.The research contains three parts.(1)Highly chemo-and enatioselective hydrogenation of α-substituted-γ-keto-α,β-unsaturated carboxylic acidsChiral α-substituted-γ-keto carboxylic acids are building blocks in various drugs and natural products,such as anti-inflamatory drug(R)-flobufen and tanomastat.Potentially,asymmetric hydrogenation is the most direct way to chiralα-substituted-γ-keto-carboxylic acids.Asymmetrical hydrogenation of α-substituted-γ-keto-α,β-unsaturated carboxylic acids catalyzed by Rh-JosiPhos complex were realized for the first time with excellent chemo-and enantioselectivities(100% chemoselectivity,97-99% yield and 95->99.9% ee)which provided a new approach to chiral α-substituted-γ-keto carboxylic acids and favored the synthesis of bioactive moleculars.Moreover,the utility of this method was further demonstrated by the gram-scale synthesis of(R)-flobufen.(2)Highly regio-and enatioselective asymmetric hydrogenation of α-substituted conjungated diene acidsChiral α-substituted-γ,δ-unsaturated carboxylic acids,which contains one stereogenic center,carboxylic group and double bond,are versatile precursors in organic synthesis.However,highly regio-and enantioselective asymmetric hydrogenation of α-substituted conjungated diene acids proved to be extremely difficult,even for simple substrate sorbic acid.No related work has been reported until now.22 kinds of α-substituted conjungated diene acids can be readily synthesized by three methods,including a variety of δ and α-substituted conjungated diene acids.We realized the first regio-and enantioselective asymmetric hydrogenation by employing Rh-Trifer complex as catalyst.A series of chiral α-substituted-γ,δ-unsaturated carboxylic acids were obtained with absolute regioselectivity and excellent enantioselectivities(up to 98% yield and >99.9% ee),regardless of electronic properties and steric hindrance of the substituents at α andδ position of carboxylic group.Besides,we conducted a series of comparison and verification test and computational calculation.Firstly,we verified the excellent regioselectivity by hydrogenation of the hydrogenated product at the same condition.Secondly,we verified the significance of secondary interaction between the carboxylic group of substrate and dimethylamino moiety of Trifer by comparison the result of asymmetric hydrogenation of α-substituted conjungated diene acids and its ester.Thirdly,we conducted the computational calculation to provide a plausible explanation to the function of trimethylamine and reaction mechanism.(3)Application of asymmetric hydrogenation to the synthesis of sacubitril’s intermediateEntresto which was hailed as a breakthrough in the treatment of heart failure patients in 25 years was constituted of sacubitril and vasartan.The reported synthesis route of sacubitril has some drawbacks such as complicated steps,low overall yields and toxic reagents usage which limited its application to industrial production of sacubitril.Besides,we think it’s potentially rational to apply Rh-Trifer catalyzed asymmetric hydrogenation to sacubitril when we found hydrogenated product(R,E)-5-([1,1’-biphenyl]-4-yl)-2-methylpent-4-enoic acid is building block of sacubitril.In two steps,(2E,4E)-5-([1,1’-biphenyl]-4-yl)-2-methylpenta-2,4-dienoic acid was obtained by recrystallization with 91% yield.It’s readily transferred to(R,E)-5-([1,1’-biphenyl]-4-yl)-2-methylpent-4-enoic acid by Rh-Trifer catalytic system with 97% yield and 98% ee.The intermediate of sacubitril was available after successive hydroxylamine esterification,asymmetric intramolecular olefin aminochlorination and reductive dechlorination with 64% total yield.In conclusion,this thesis realized the highly chemo-and enantioselective hydrogenation of two series of challenging and valuable unsaturated carboxylic acids by screening catalysts and optimizing the catalytic conditions.In addition,the optimized catalytic system has been successfully applied to the synthesis of (R)-flobufen and the intermediate of drug sacubitril.