Research On The Synthesis Of Chiral γ-Secondary Amino Alcohols Via Asymmetric Hydrogenation

In recent years,the preparation of chiralγ-secondary amino alcohols has gained much attention due to their potential use as drugs and bioactive compounds.For example,they are important scaffolds for sphingolipids,antibiotics,anti-virus’endomannosidase inhibitors,anticancer agents,norepinephrine reuptake inhibiting antidepressants,inhibitors of D₂and HT₂receptors and cyclic sulfamidates which possess multiple uses.Additionally,chiralγ-secondary amino alcohols,in conjunction with metal salt complexes,are useful for asymmetric catalytic reactions.Owing to the atom efficiency and minimal environmental impact of asymmetric hydrogenation reactions,one of the most promising methods for the synthesis of chiralγ-secondary amino alcohols is via the hydrgoenation of prochiralβ-secondary amino ketones.We have developed a ruthenocenyl phosphino-oxazoline-ruthenium complex（^tBu-Ru PHOX-Ru）which has shown promising catalytic activity in many asymmetric reactions due to its dual reaction sites and large steric hindrance.We have previously carried out asymmetric hydrogenations ofβ-tertiary amino ketones andβ-imide ketones with the bimetallic ^tBu-Ru PHOX-Ru complex to give bothγ-tertiary andγ-primary amino alcohols,respectively,in quantitative conversions and with up to99.9%ee.Herein,we report that the ^tBu-Ru PHOX-Ru catalytic system could also be used for the asymmetric hydrogenation ofβ-secondary amino ketones for the direct synthesis ofγ-secondary amino alcohols.We first carried out the ^tBu-Ru PHOX-Ru-catalyzed asymmetric hydrogenation ofβ-（benzylamino）-1-phenylpropan-1-one under different reaction conditions.Therefore,the optimal reaction conditions were found to be the following:using DBU as a base,in Et OH,at 25 ^oC,under 50 bar H₂pressure.Under the optimized reaction conditions,the substrate scope was explored.^tBu-Ru PHOX-Ru was successfully used for the asymmetric hydrogenation of a series of unstableβ-secondary amino ketones,directly affording chiralγ-secondary amino alcohols in up to 99%yield and with 99%ee.Gram-scale reaction could be performed with a relatively low catalyst loading（up to 2000 S/C）,and the resultingγ-secondary amino alcohols can be used for the synthesis of several useful drugs and drug candidates.