Asymmetric Transfer Hydrogenation Catalysts OH O OH 99% yield, 96% ee (S/C = 1000) OH 89% yield, 99% ee ( ) S/C = 300 >99% yield, 97% ee (S/C = 200) OH OH X OH 78% yield, 95% ee R (S/C = 200) (S,S)-Ru cat X = CN, N3, NO2 R = H, CH3, F 67-100% yield, 92-98% ee (S/C = 100-1000) OH OH N OH 97% yield, 95% ee ( ) 100% yield OH S/C = 200 dl:meso = 98.6:1.4, >99% ee OH O O (S/C = 1000) ( )n OR >99% yield, 98% ee (S/C = 200) R = CH(CH3)2, n = 0, 94% yield, 75% ee R = C2H5, n = 1, 94% yield, 93% ee R = C2H5, n = 3, 99% yield, 95% ee Asymmetric Transfer Hydrogenation Catalysts Contents Introduction ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 2 Asymmetric transfer hydrogenation of ketones ⋯⋯⋯⋯⋯⋯ 2 Asymmetric transfer hydrogenation of benzyls ⋯⋯⋯⋯⋯⋯ 5 Kinetic resolution of secondary alcohols ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 5 Asymmetric transfer hydrogenation of imines ⋯⋯⋯⋯⋯⋯⋯6 Standard operating procedures for the asymmetric transfer hydrogenation of ketones ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 7 Reference ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 8 Products ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 9 1 Introduction Optically active alcohols and amines are useful As organic compounds such as 2-propanol and formic intermediates of pharmaceuticals or pesticides. Chiral acid are used as hydrogen donors in this asymmetric ruthenium complexes with chiral diamine ligands, which reaction, this reaction can be easily implemented using were discovered by NOYORI Molecular Catalysis Project laboratory equipments such as flasks and is therefore of Exploratory Research for Advanced Technology highly versatile. (ERATO) by Japan Science and Technology Corporation KANTO CHEMICAL CO.,INC. launches of pre-formed (JST), are extremely effective catalysts for the chiral ruthenium complexes, which are easily handled asymmetric transfer hydrogenation of ketones 1)-11) and and can be used for this asymmetric transfer imines 9), 12), 13) leading to optically active alcohols and hydrogenation. amines with high optical purities in high yields. Asymmetric Transfer Hydrogenation Catalysts Chloro complexes Amide complexes RuCl[(S,S)-Tsdpen](η6-arene) Ru[(S,S)-Tsdpen](η6-arene) Ts Ts N Rn N Rn Ru Ru N Cl N H2 H Ts = SO2C6H4-p-CH3 Ts = SO2C6H4-p-CH3 1a ; Rn = 1-CH3-4-CH(CH3)2 3a ; Rn = 1-CH3-4-CH(CH3)2 1b ; Rn = 1,3,5-(CH3)3 3b ; Rn = 1,3,5-(CH3)3 1c ; Rn = 1,2,3,4,5,6-(CH3)6 RuCl[(S,S)-Msdpen](η6-arene) Ms N Rn Ru N Cl H2 Ms = SO2CH3 2a ; Rn = 1-CH3-4-CH(CH3)2 1. Asymmetric transfer hydrogenation of ketones 1)-10) (Synthesis of optically active secondary alcohols) 《Selection of hydrogen donors》 Organic compounds such as 2-propanol and formic acid the reaction which uses formic acid as a hydrogen donor can be used as the hydrogen donors for this reaction. is not reversible, and therefore even if the reaction is As the reaction in 2-propanol is reversible, the reaction is implemented with a high substrate concentration or high proceeded after adjusting the substrate concentration S/C, a high yield of optically active alcohols with high and S/C (the substrate/catalyst molar ratio). Conversely, optical purities can be obtained. C Kanto Kagaku 2 ●Reaction with the 2-propanol as a hydrogen donor 1), 4)-6), 8) O OH OH O (S,S)-cat + + Ar R Ar s R (CH3)2CHOH 93～98% yield (S,S)-cat = [RuCl2(mesitylene)]2－(S,S)-TsDPEN－KOH(mole ratio 1:2:5) OH OH OH OH R R R = CH3 97% ee R = m-Cl 98% ee 93% ee 98% ee R = C2H5 97% ee R = p -Cl 93% ee R = m-OCH3 96% ee ●Reaction with the formic acid as a hydrogen donor 2), 4) O OH (S,S)-1b Ar R Ar s R HCOOH/N(C2H5)3 28 ℃ 93～99% yield OH OH OH S/C = 200 R R = m-Cl 97% ee R = p -Cl 95% ee S/C = 1000 R = m-OCH3 98% ee S/C = 200 96% ee R = p -OCH3 97% ee 97% ee OH OH OH OH R S/C = 200 S/C = 200 S/C = 200 S/C = 200 83% ee 96% ee R = CH2 99% ee 70% yield, 83% ee R = (CH2)2 99% ee C Kanto Kagaku 3 《Selection of substrates》 In addition to the simple ketones referred to above, the such as a pyridyl group, carbon-carbon multiple bond or reaction can also proceed efficiently and without loss of an ester group, allowing the successful synthesis of the the functional group in the case of ketones that have a key intermediate of a carbonic anhydrase inhibitor, MK- functional group such as a carbon-carbon multiple bond 0417. Furthermore, the reaction of unsymmetrically or a heteroatom, producing optically active alcohols with substituted 1, 2- diketones leads to optically active high optical purities. For example, acetylenic alcohol α-hydroxyketones or optically active 1, 2- diols with 97% ee can be obtained in a high yield by an separately depending on the reaction conditions. reaction of acetylene-ketone. The reaction of ketones Further, the reaction of acetophenone derivatives with a that have a furan ring or thiophene ring also proceed cyano group, azido group or nitro group in the second properly, resulting in alcohols with high optical purities. position also proceeds efficiently, producing optically Moreover ketone having a pyridyl group also react well, active alcohols. These compounds can be easily resulting in optically active pyridyl alcohol with 95% ee. reduced by usual reducing agents, leading to optically This reaction can also be applied to the reaction of active amino alcohols, which are useful synthetic ketones that have a multiple number of functional groups intermediates for pharmaceutical products. OH OH OH s s s R O OH O S X cat : (S,S)-3b cat : (S,S)-1b cat : (S,S)-1b cat : (R,R)-1b S/C = 200 S/C = 200 S/C = 200 S/C = 200 >99%, 97% ee4) >99%, 98% ee2), 4) 47%, 98% ee2), 4) X = S 95%, 99% ee 2), 4) X = SO2 95%, 98% ee OH OH O OH CO2CH3 OC H Cl N R （ ）n 2 5 N cat : (S,S)-1a cat : (S,S)-1a cat : (R,R)-1b S/C = 200 n = 1 94%, 93% ee4) S/C = 200 5) 2),4) >97%, 95% ee n = 3 99%, 95% ee2) 68%, 92% ee O OH OH X R = H ; X = CN 100%, 98%ee OH OH R R = H ; X = N3 65%, 92%ee 7) cat : (S,S)-1a cat : (S,S)-1a X : CN, N3, NO2 R = H ; X = NO2 90%, 98%ee S/C = 300 (10 ℃) S/C = 200 (40 ℃) cat : (S,S)-1a R = F ; X = NO2 95%, 96%ee 6) 6) 89%, 99% ee 78%, 95% ee S/C = 100－1000 (30 ℃) R = CH3 ; X = NO2 67%, 95%ee C Kanto Kagaku 4 2. Asymmetric transfer hydrogenation of benzyls 11) (Synthesis of optically active hydrobenzoins) Benzyls can be rapidly reduced at room temperature hydrobenzoins with high optical purities almost with a chiral ruthenium catalyst in a mixture of formic quantitatively. acid/triethylamine, producing optically active O OH (S,S)-1a Ar R Ar Ar Ar R HCOOH/N(C2H5)3 O DMF, 30－60 ℃ OH S/C = 1000－2000 Ar = C6H5 100%, dl:meso = 98.6:1.4, >99% ee Ar = p-CH3-C6H4 67%, dl:meso = 96.7:3.3, >99% ee Ar = p-CH3O-C6H4 75%, dl:meso = 94.4:5.6, >99% ee Ar = p-F-C6H4 100%, dl:meso = 94.2:5.8, >99% ee 3. Kinetic resolution of secondary alcohols 4), 12) As asymmetric transfer hydrogenation in 2-propanol is a the kinetic resolution of racemic alcohols using a chiral reversible reaction, it has previously been difficult to ruthenium catalyst, optically active alcohols with high implement the high enantioselectivities in the reduction optical purities are now obtainable. This method can of high-reduction-potential ketones with an electron also be applied to the synthesis of natural products donating group on the aromatic ring. However, through such as (-)-chokol G14) and (-) -pentenomycin15) . OH O O OH OH (S,S)-cat + + + Ar R Ar R Ar R CH3COCH3 racemic 28 ℃ unreacted alchol substrate catalyst time, h recovery, % ee, % config. kf/ks OH R R = H 3a 36 50 92 R >80 R = p-OCH3 3a 22 47 92 R >30 R = p-N(CH3)2 3b 30 44 98 R >30 OH R R = CH2 3a 64797R >40 R = (CH2)2 3a 64999R >50 S/C = 500 C Kanto Kagaku 5 4. Asymmetric transfer hydrogenation of imines 4), 15) Up until now, it has been difficult to achieve the efficient reduction of imines using this catalyst is efficient, and synthesis of optically active amines through the catalytic optically active amines with a high optical purities can be asymmetric hydrogenation of imines. However, the obtained in high yields. R2 R2 (S,S)- or (R,R)-cat R3 1 3 1 R NR HCOOH/N(C H ) R N 2 5 3 H solvent, 28 ℃ HN CH3O NH NH CH3O N H R 6 cat : (S,S)-1a cat : (S,S)-1a cat : RuCl[(S,S)-ArSO2dpen](η -benzene) S/C = 1000 S/C = 200 Ar = 1-naphthyl 97%, 94% ee (R ) R = CH3 86%, 97% ee (R ) S/C = 100 R = C6H5 83%, 96% ee (R ) 90%, 89% ee (S ) HN HN S X 6 6 cat : RuCl[(S,S)-ArSO2dpen](η -benzene) cat : RuCl[(S,S)-ArSO2dpen](η -benzene) Ar = 1-naphthyl Ar = 1-naphthyl S/C = 200 S/C = 200 72%, 77% ee (S ) X = S 82%, 85% ee (S ) X = SO2 84%, 88% ee (S ) C Kanto Kagaku 6 Standard operating procedures for the asymmetric transfer hydrogenation of ketones Example procedures are shown below for the 1) production of optically active alcohols by the reduction of the ketonic substrates 2) and 2) production of optically active hydrobenzoin from benzyl 11) , both using a chiral ruthenium catalyst in a mixture of formic acid and triethylamine.