Antifungal Activity And Synthesis Of Chiral Secondary Amines By The Tandem Reaction Of Asymmetric Hydrogenation And Direct Reductive Amination

Since the manufacture of L-dopa was realized as the first successful industrial-scale asymmetric catalytic process,asymmetric hydrogenation(AH)has become the main driving force for asymmetric catalysis,and the most frequently utilized homogeneous enantioselective catalytic tranformation in large scale.The striding progress in AH research was evinced by Knowles and Noyori winning the Nobel Prize.At the other hand,direct reductive amination(DRA)is currently the most practical method for the synthesis of chiral amine drugs.It can construct the C-N bond in one step,and the byproduct is only H2 O.As both AH and DRA share the same reductant,H2,we propose to combine these two reactions to make the procedure for the synthesis of chiral amino compounds more concise and proficient.The research must solve two main challenges: establishing a new catalytic system capable of reducing C=N and C=C bonds;effectively inhibiting the reduction of aldehydes and olefins.We envisioned that combination the two steps may help to tackle those problems.One is the application of an ideal transition metal which could efficiently coordinate and reduce both the imine bond and the olefin bond.The other is the addition of appropriate additives which facilitates the imine formation and the following reduction,and alleviate the inhibition effect from the amine reactant,imine intermediate and the amine product on the catalyst.We have successfully tandemed two efficient reactions,AH and DRA,in one-pot,which share the common reductant,namely hydrogen gas.Catalyzed by the rhodium-Segphos complex,the DRA of aldehydes and the AH of prochiral olefins took place sequencially to afford the chiral amino compounds.The main contents are as follows:1.With 2,3-diphenyl acrolein as the standard substrate,aniline as the ammonia source,Rh-(R)-Seg Phos as the catalyst,and hydrogen gas as the reducing agent,the best reaction conditions are screened out: the reaction temperature is 60 ?,the pressure of hydrogen gas is 50 atm,reaction time is 24 h,using a mixed solution of methyl acetate and N,N-dimethylformamide with the ratio of 4:1,adding 0.3 equivalents of chlorobenzenesulfonic acid,0.05 equivalents of sodium hexafluoroantimonate,and 4 ? molecular sieve.To our delight,both the yield and ee value of chiral secondary amine,N,2,3-triphenylpropylamine,are up to 98%.2.Under the optimized reaction conditions,the catalytic effect of Rh-(R)-Seg Phos on 27 kinds of ?,?-unsaturated aldehydes and aniline was investigated.The results showed that: whether the substituents were on the para-or meta-positions of the corresponding products were obtained with more than 95% ee and 90% yields,regardless of their electron-donating or electron-withdrawing properties;but when the substituents were on ortho-positions or as 1-naphthyl group,the reaction required higher catalyst loading or reaction temperature,probably due to the greater steric hindrance.The additive set and catalytic system also worked well for heteroaromatic substrate and aliphatic group substituted.It is worth mentioning that protic groups –OH and –NHAc,and reducible group –CN were well-tolerated in the reactions.3.Under the optimal reaction conditions,the catalytic effect of the system on standard substrates and 11 types of amines was investigated.The results exhibited that: all selected anilines,with substituents at para-,meta-and ortho-positions,or having electronic-withdrawing or electronic-donating groups,reductively coupled with the 2,3-diphenylacrylaldehyde substrate smoothly to afford the desired products with excellent ees(up to 99%)and yields(up to 98%).Notably,the protic hydroxyl group again tolerated in this transformation.In addition,sterically hindered anilines,with ortho-substituents and 1-naphthyl group,were all suitable nitrogen sources for the successful convertion of standard substrate.4.To further explore the utility of this AH and DRA combination strategy,we next made efforts on the transformations of these N-(2,3-diarylpropyl)aniline products.Using 3y and 3n as starting materials,two kinds of ubiquitous chiral compounds,1-(4-methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroquinoline and 3-benzyl-1-(4-methoxyphenyl)indoline were successfully afforded via Buchwald-Hartwig cross-coupling reaction with 94% and 96% ee,respectively.5.The inhibitory activity of 15 kinds of chiral amines against 6 series of plant pathogenic fungi was screened by the mycelium linear growth rate method.To our disappointed,their inhibitory activities were not ideal.In summary,combination of asymmetric hydrogenation and direct reductive amination into one step,40 types of chiral secondary amines were prepared efficiently with the yield of 98% and the enantioselectivity of 99%,which indicates that the catalytic system with excellent practicality and applicability.Catalyzed by Rh-(R)-Segphos,2,3-diphenyl acrolein first undergoes a direct reductive amination reaction,followed by an asymmetric hydrogenation reaction to obtain the chiral secondary amine.It can be concluded that the Rh salt as precursor can reduce the C=C bond and C=O bond.The addition of 30 mol% of 4-chlorobenzenesulfonic acid facilitates the formation of the corresponding imine and reduction of the C=N bond and C=C bond.This research not only establishes a succinct and efficient new protocol for the synthesis of chiral secondary amines,but also enriches the compound library of chiral secondary amines.Furthermore,it provides theoretical basis and technical support for the synthesis of best-selling chiral amine drugs and biologically active natural products with chiral amine sacffold.