Synthesis Of New Chiral Ligands And Their Application In Asymmetric Transfer Hydrogenation Of Aromatic Ketones

The second chiral alcohol which can be prepared by many ways is a kind of important intermediate in the synthesis of drug, pesticide and spice etc,a great of progress with fruitful results has been made by previous investigators, especially for the asymmetric hydride reaction .However, asymmetry transfer hydrogenation under mild conditions was just successfully reported in recent years, even so, there are still many difficulties for practical application. Thus, it is pivotal to design excellent chiral ligands and select ordinary catalytic conditions. On this background, we designed and synthesized some kinds of new chiral ligands, their properties on asymmetric transfer hydrogenation of aromatic ketones were also studied carefully.1. 9-Amino(9-deoxy)epicinchonine was synthesized from cinchonine through the Mitsunobu reaction and treated with 8-quinolinesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride respectively to give four chiral sulfonamides, these sulfonamides were used as ligands for transfer hydrongenation of acetophenone.The optimal catalytic conditions and results are as follow: for 9-(8-quinoline sulfonamino)-(9-deoxy)epicinchonine: the higheat yield (90.8%) can be obtained when acetophenone/Ru/KOH(mole ratio)=50/1/1.25;for 9-(benzene sulfonamino)-(9-deoxy) epicinchonine,9-(toluene sulfonamino)-(9-deoxy) epicinchonine and 9-(p-chlorobenz- ene sulfonamino)-(9-deoxy)epicinchonine: the higheat yields(60.9%,96.0%,45.5% respectively) can be obtained when acetophenone/Ru/KOH=50/1/2.5.All the reactions were occurred with isopropanol as both hydrogen source and solvent at 80℃for 48 h, KOH was used as a base, all of which obtained no enantioselectivities.2. Chiral amino amides hydrochloride were easy to synthesize with Boc as the protection group for the amino group of L-proline, then diamines were doubly acylated with Boc-L-proline with condensation agents(DCC) to provide the Boc-protected bisamides, N-Boc-protecting groups were removed selectively and afforded dihydrochloride at the same time with dry HCl in methanol. Their application to asymmetric transfer hydrogenation of acetophenone in aqueous media was researched. The optimal catalytic condition is keton/Ru/L /HCOONa=100/1/1/500,used degassed water as solvent at 40℃for 24 h, the classic conversion rate for N,N′-Bis[(L)-prolyl]ethylenediamine dihydrochloride(98.2%), for N,N′-Bis[(L)-prolyl] phenylenediamine dihydrochloride(75.2%),for 4,4′-N,N'-Bis[(L)-prolyl] diaminodiphe- nyl ether dihydrochloride(97.7%), for 4,4′–N,N′-Bis[(L)-prolyl] diamino- biphenyl dihydrochloride(97.7%) was achieved, and 33.4%, 55.8%, 64.1%, 70.4% enantiomeric excess was obtained respectively, through the experiments the excellent ligand was screened and afforded excellent conversion rates and good enantioselectivities in asymmetric transfer hydrogenation of aromatic ketones .3. New chiral amino alcohols (1S,2R)-1-(N-methyl-cyclohexylamine)-2-hydroxy -7,7-dimethyl bicyclo[2.2.1] heptane and (1S,2R)-1-(N-methyl-piperidyl)-2-hydroxy- 7,7-dimethyl bicyclo[2.2.1] heptane were synthesized from (+)-camphor. After sulfonation of the camphor, 10-camphorsulfonic acid was first synthesized , followed by reaction with thionyl chloride, potassium permanganate to obtained (1S)-7,7- dimethyl bicyclo[2.2.1] heptane -1- carboxyl -2- Keto by step gradually, treated the product with thionyl chloride to form acyl chloride , after the operation of amidation and reduction to give products.The new ligands had been applied in transfer hydrogenation of acetophenone without any catalytic activities. Treated the amino alcohols with HCl/CH3OH to obtained two chiral amino alcohols hydrochloride, both of them were used in transfer hydrogenation. However, only 2.8% of conversion rates without enantioselectivities were obtained.