Rh-,Ni-catalyzed Asymmetric Hydrogenation Of α-functionalized Ketones

Chiral alcohol compounds and their derivatives are ubiquitous in our daily life and production.Asymmetric(transfer)hydrogenation of ketones is currently one of the most effective methods for preparing chiral secondary alcohol compounds.In the past 20 years,many efficient and highly selective catalytic systems have emerged for the asymmetric(transfer)hydrogenation of ketones,which has greatly promoted the industrial preparation of chiral alcohols.In the past decade,the technology of asymmetric(transfer)hydrogenation of ketones has become more and more mature,and the successive establishment of inexpensive metal catalytic systems has brought new vitality to the field.However,the reduction of some challenging substrates,such as pre-chiral linear aliphatic ketones and some special functionalized ketones,is still unsolved,so it is necessary to explore new catalytic systems to solve practical problems.This thesis mainly studies the synthesis of alcohol compounds with two consecutive chiral centers,including the following aspects:A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl-α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors.With the current Rh(Ⅲ)catalyst system,a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities(up to 99%yield,up to 99:1 dr).Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(Ⅲ)catalyst.A catalytic protocol for the enantio-and diastereoselective reduction of α-substituted-β-keto carbonitriles is described.The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers.A wide range of α-substituted-β-keto carbonitriles were obtained in high yields(94%-98%)and excellent enantio-and diastereoselectivities(up to >99% ee,up to >99:1 dr).The origin of the diastereoselectivity was also rationalized by DFT calculations.Furthermore,this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.In thesis,an efficient and high enantioselective asymmetric transfer hydrogenation of 3-hydroxy-4-substituted maleimide derivatives was successfully developed.For chiral3-hydroxy-4-substituted-maleimides,the Rh catalyst can complete the reaction with a TON of up to 2 000,and the reaction product,substituted succinimide has excellent enantioselectivity and diastereoselectivity(up to >99% ee and up to >99:1 dr).Importantly,this method enables the synthesis of cis-and trans-configured substituted succinimides by ingeniously controlling the alkali content in the reaction system.Furthermore,the establishment of this methodology also provides an efficient route for the synthetic development of chiral pyrrolidine derivatives,which are key intermediates of many chiral natural products and pharmaceuticals.Chiral α-hydroxy-β-lactams are key fragments of many bioactive compounds and antibiotics,so that the development of efficient synthetic methods for these compounds is of great value.The highly enantioselective dynamic kinetic resolution(DKR)of α-keto-β-lactams was realized via a novel proton shuttling strategy.A wide range of α-keto-β-lactams were reduced efficiently and enantioselectively by Ni-catalyzed asymmetric hydrogenation,providing the corresponding α-hydroxy-β-lactams derivatives with high yields and enantioselectivities(up to 92% yield,up to 94% ee).Deuteriumlabelling experiments indicate that phenylphosphinic acid plays a pivotal role in the DKR of α-keto-β-lactams by promoting the enolization process.The synthetic potential of this protocol was demonstrated by its application in the synthesis of a key intermediates of Taxol and(+)-epi-Cytoxazone.