Patent Publication Number: US-9844773-B2

Title: Picolinamide-cinchona organocatalysts and derivatives

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This Application is a 371 of PCT/IB2014/065128 filed on Oct. 7, 2014, which, in turn, claimed the priority of Portuguese Patent Application No. 107209 filed on Oct. 8, 2013, both applications are incorporated herein by reference. 
     TECHNICAL FIELD 
     The present application refers to an organocatalytic ketimine hydrosilylation process to chiral amines. 
     BACKGROUND 
     Organocatalysis is a subdivision of catalysis which relies on the use of wholly organic molecules as catalysts. These catalysts are very useful and have already made significant contributions in the production and discovery of new pharmaceuticals, agrochemicals and other high added value compounds (Alemán and Cabrera, 2013, MacMillan, 2008). The discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction was the starting point (Eder et al. 1971, Hajos et al. 1974). But only relatively recently has there been a renaissance of this field, when Barbas III, Lerner, List and MacMillan applied very successfully simple small molecule organocatalysts (for example, L-proline and derivatives and imidazolidinones) in intermolecular aldol and Michael addition reactions, etc. 
     In general the catalysts are optically pure and the reactions highly enantioselective. Organocatalysts based on the Cinchona skeleton are known, and very good results have been reported for a diversity of reactions, like, conjugate additions (Hiemstra e Wynberg, 1981), Michael additions and Mannich reactions (Ye et al., 2005, Tillman et al. 2006, McCooey and Connon 2005), and phase-transfer catalysis (Chinchilla et al. 2000) amongst other reactions. Picolinamide based organocatalysts have also been reported and have been exploited with success in the hydrosilylation reaction of N-substituted imines (Guizzetti et al. 2009, Zheng et al. 2007) and in asymmetric Biginelli reactions (Xu et al. 2012). 
     Many chiral amines have been shown to be biologically active. 45% of molecules that chemists are developing into drugs contain a chiral amine unit (Ritter, 2013), well known examples include: rivastagimine, rasagline, sertraline, indatraline (Hyttel and Larsen, 1985) cetirizine and cromakilm etc. 
     Picolinamides, which are amides derived from picolinic acid have been incorporated into a number of carbon skeletons and used very successfully as organocatalysts in a number of reactions. For example in the asymmetric Biginelli reaction (Xu et al. 2012) in which the bifunctional organocatalyst of formula I: 
                         
which contains a primary amine linked to a picolinamide unit, is used in the reaction:
 
     
       
         
         
             
             
         
       
     
     Another example is in the area of ketimine hydrosilylation using trichlorosilane as the reducing agent where the N-picolinoylaminoalcohol of formula II: 
                         
gave excellent results (Zheng et al. 2007) in the reaction with a catalyst loading of 10 mol %.
 
     
       
         
         
             
             
         
       
     
     There are other examples in the literature (Guizzetti et al. 2009, Bonsignore et al. 2013, Onomura et al. 2006 and Jones and Warner, 2012). However, there aren&#39;t any reports on the synthesis and use of N-alkylated cinchona picolinamides. 
     The catalytic asymmetric hydrosilylation reaction of ketimines is extremely useful from an industrially perspective, as it affords chiral amines (Nugent and El-Shazly, 2010, Ghose et al. 1999), amino acids and other high valued products. Traditionally, the hydrogenation of ketimines is conducted using metal based catalysts (Nishiyama and Itoh, 2000). For decades, catalysis by way of metals has been the dominant form of catalysis, the principle advantages are that a variety of transition metals and ligands can be used and the catalysts tuned on this basis, and the loadings are generally low. Despite these advantages, the downside is that these catalysts are expensive, generally unstable to oxygen/water and to recycling, some are toxic and they generally end-up in the final product in small quantities (Busacca et al. 2011). This is less of a problem for most organocatalysts. 
     Quite recently, a number of groups have used organocatalysts in the hydrosilylation of ketimines, and have obtained good yields and enantioselectivities (Jones and Warner, 2012, Malkov et al. 2006, Bonsignore et al. 2013, Wang et al. 2006 and Wu et al. 2008). In fact, this methodology was nicely shown to be a viable approach to the commercial herbicide; (S)-Metolachlor (Guizzetti et al., 2009). 
     There have been several reports to date on the use of supported organocatalysts, (Cozzi, 2006, Kristensen and Tore, 2010), including the use of magnetic nanoparticles (Gleeson et al. 2011). However there have been no reports on the immobilization of picolinamide organocatalysts or derivatives. 
     The present disclosure describes a novel type of picolinamide-cinchona organocatalyst that allows for the successful transformation of ketimines to chiral amines with very high enantioselectivities and with the highest TOFs reported for any particular organocatalyst to date. These organocatalysts have also been immobilized to a variety of solid supports, including magneto-nanoparticles. 
     SUMMARY 
     The present application describes a novel type of picolinamide-cinchona organocatalyst that allows for the successful transformation of ketimines to chiral amines with very high enantioselectivities and with the highest TOFs reported considering any known organocatalyst to date. Thus, this application describes an organocatalyst comprising the formula: 
                         
in which,
 
  represents a carbon-carbon single, double or triple bond;
 
R and R 2  represent, a hydrogen, an alkyl or alkyloxy chain, an aryl group, a nitro, a hydroxyl, an amine, a cyano or a halogen;
 
R 1  represents a hydrogen, an alkyl or an aryl group;
 
R 3  represents, an alkyl group;
 
the stereochemical configurations at C-8 and C-9, are the only ones that vary;
 
X represents, a halide, a triflate, a trifluoroborate, a PF 6 , a SbF 6  or a ClO 4 .
 
     In an embodiment, the pyridyl ring of the above mentioned organocatalyst is fused with another benzene unit. 
     In another embodiment, the organocatalyst is immobilized with a suitable linker to a suitable support. 
     Still in a further embodiment, the linker is selected from the group comprising an alkyl, a polyoxyalkyl or a polyalkylsulfide chain and is linked to said organocatalyst at C-11 in (III). 
     In another preferred embodiment the support is selected from the group comprising silica gel, mesoporous silica, a soluble or insoluble polymer or a magnetic nanoparticle. 
     This application also describes the use of the described organocatalyst in catalytic asymmetric hydrosilylations of ketimines and derivatives. 
     Still in a further embodiment, the organocatalyst described above is used in the transformation of ketimines and derivatives into chiral amines with enantioseletivities up to 90% ee (enantiomeric excess). 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
       Without intent to limit the disclosure herein, this application presents attached drawings of illustrated embodiments for an easier understanding. 
         FIG. 1 . Coating of magnetic iron oxide nanoparticles with a silica layer. 
         FIG. 2 . Ketimines used in the hydrosilylation reaction with organocatalyst (IX). 
     
    
    
     DESCRIPTION OF THE EMBODIMENTS 
     The present application describes the preparation of novel chiral organocatalysts of formula III: 
                         
in which,
 
R and R 2  represent, a hydrogen an alkyl or alkyloxy chain, an aryl group, a nitro, hydroxyl, amine, cyano or a halogen;
 
R 1  represents a hydrogen, an alkyl or an aryl group;
 
R 3  represents, an alkyl group.
 
     The stereochemical configurations at C-8 and C-9, are the only ones that vary and the bond between C10 and C11 can be single, double or triple; 
     X represents, a halide, a triflate, a trifluoroborate, a PF 6 , a SbF 6  or ClO 4 . 
     The pyridyl ring can be fused with another benzene unit, according to the formula: 
     
       
         
         
             
             
         
       
     
     The chiral organocatalysts of formula III derive from the simple cinchona natural products, Cinchonidine (CD), Cinchonine (CN), Quinine (QN) and Quinidine (QD), where: 
     
       
         
         
             
             
         
       
     
     This invention also describes immobilized versions of (III), which are represented by formula IV. 
                         
in which,
 
R and R 2  represent, a hydrogen an alkyl or alkyloxy chain, an aryl group, a nitro, hydroxyl, amine, cyano or a halogen;
 
R 1  represents a hydrogen, an alkyl or an aryl group;
 
R 3  represents, an alkyl group. The pyridyl ring can be fused with another benzene unit;
 
     The stereochemical configurations at C-8 and C-9, are the only ones that vary and the bond between C11 and C12 can be single, double or triple; 
     X represents, a halide, a triflate, a trifluoroborate, a PF 6 , a SbF 6  or ClO 4 ; 
     L represents a suitable linker, which can be an alkyl, polyoxyalkyl or a polyalkylsulfide chain, attached to a suitable support, like, silica gel, mesoporous silica, a soluble or insoluble polymer or a magnetic nanoparticle. 
     The pyridyl ring can be fused with another benzene unit, according to the formula: 
     
       
         
         
             
             
         
       
     
     The organocatalysts of formula VIII and IX: 
                         
were synthesized, according to the reaction:
 
                         
starting from cinchonidine (CD) and with 9-amino-(9-desoxi)-epi-cinchonidine (V) as an intermediate. The methylated picolonic acids (VI) and (VII) were prepared according to the previous reaction and were coupled with 9-amino-(9-desoxi)-epi-cinchonidine (V) a reaction that involved thermal condensation. However, other methods which involve coupling agents like carbonyldiimidazole (CDI), Mukaiyama&#39;s reagent, oxalyl chloride, thionyl chloride, P(OPh) 3  in which Ph is phenyl, dicyclohexylcarbodiimide (DCC)/NIC, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/HOBt/diisopropylethylamine (DIPEA), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU)/DIPEA, including many other coupling methods can be used. Various solvents, which ideally should be anhydrous can be used, like, CH 2 Cl 2 , THF, toluene etc.
 
     In the case of the picolinic acid alkylations, numerous alkylating agents can be used, generally these are alkyl bromides, chlorides or iodides. However, Meerwein&#39;s reagent: triethyloxonium tetrafluoroborate, can also be used (to introduce an ethyl group). Alcoholic solvents give the best results. 
     
       
         
         
             
             
         
       
     
     The iodide salt (VI) was readily converted to the trifluoroborate salt (VII) by a simple ion exchange process. 
     The corresponding non-N-alkylated derivative (X) was also prepared in 75% according to the reaction (Allen et al. 2012): 
     
       
         
         
             
             
         
       
     
     However, the coupling procedures given above can be used for this purpose. 
     With regard to the synthesis of the immobilized organocatalysts of formula (IV). Our approach was the use of ene-diene click chemistry (Hoyle and Bowman, 2010) to attach the organocatalyst to a trimethoxysilane based linker and then to the solid support. Three solid supports were investigated, nanosilica, MCM-41 and magnetic nanoparticles. The attachment of the linker involves the ene-diene reaction between the N-methylated picolinamide (IX) and (3-mercaptopropil)trimetoxisilane, using a catalytic quantity of 2,2′-azobisisobutyronitrile (AIBN) in chloroform (Tucker-Schwartz et al. 2011), these were found to be the optimized conditions. 
     
       
         
         
             
             
         
       
     
     The general strategy for immobilizing (IX) to the support is shown in the reaction: 
     
       
         
         
             
             
         
       
     
     In the case of the nanosilica, MCM-41 and silica-coated magnetic nanoparticle (SCMNP) supports, after the reaction was completed, the solids were filtered washed with CH 2 Cl 2  (3×20 mL) and dried under vacuum at a temperature of 60° C. for 4 hours. 
     The organocatalyst loading was determined by microanalysis. 
     With regard to the silica coated magnetic nanoparticles (SCMNPs), commercial magnetic iron oxide nanoparticles were used, and they were coated with a silica layer using literature methods (Lu et al. 2008, Schatz et al. 2009 and Zheng et al. 2009) ( FIG. 1 ). 
     In the case of the catalytic reactions, our three catalysts were screened for the hydrosilylation of N-phenyl 1-Phenylpropanimine (XII) using trichlorosilane (Table 1) 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Screening results with catalysts (X), (VIII) and 
               
               
                 (I) for the hydrosilylation of N-phenyl 1-Phenylpropanimine (XII). 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Entry  [a]   
                 Catalyst 
                 Yield(%)  [b]   
                 ee(%)  [c]   
               
               
                   
               
               
                 1 
                 (X) 
                 77 
                 81 
               
               
                 2 
                 (VIII) 
                 95 
                 75 
               
               
                 3 
                 (IX) 
                 83 
                 84 
               
               
                   
               
               
                   [a]  The reactions take-place at r.t. in the presence of 3 equivalents of HSiCl 3  in 1 mL de CH 2 Cl 2  for 18 h. 
               
               
                   [b]  Isolated yields. 
               
               
                   [c]  Determined by HPLC using a chiral stationary phase. 
               
            
           
         
       
     
     Some very good yields are obtained (up to 95%) and an enantioselectivity of up to 84% ee (Table 1). 
     A variety of ketimines were used giving good results (Table 2). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Screening results for the hydrosilylation of 
               
               
                 ketimines using the organocatalyst (IX) and a variety of ketimines 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Yield 
                 ee 
               
               
                 Entry  [a]   
                 Ketimine 
                 R 
                 R 1   
                 R 2   
                 (%)  [b]   
                 (%)  [c]   
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 (XII) 
                 Ph 
                 Et 
                 Ph 
                 86 
                 84 
               
               
                 2 
                 (XIII) 
                 Ph 
                 Et 
                 Tosyl 
                 73 
                 73 
               
               
                 3 
                 (XIV) 
                 4-MeO—C 6 H 4   
                 Met 
                 Tosyl 
                 30 
                 55 
               
               
                 4 
                 (XV) 
                 Ph 
                 Met 
                 Tosyl 
                 11 
                 50 
               
               
                 5 
                 (XVI) 
                 2-HO—C 6 H 4   
                 Met 
                 Ph 
                 38 
                 10 
               
               
                 6 
                 (XVII) 
                 4-MeO—C 6 H 4   
                 Met 
                 Ph 
                 58 
                 84 
               
               
                 7 
                 (XVIII) 
                 4-MeO—C 6 H 4   
                 Met 
                 4-BrC 6 H 4   
                 10 
                 69 
               
               
                 8 
                 (XIX) 
                 4-MeO—C 6 H 4   
                 Met 
                 4-BrC 6 H 4   
                 20 
                 69 
               
               
                 9 
                 (XX) 
                 4-NO 2 —C 6 H 4   
                 Met 
                 Ph 
                 68 
                 80 
               
               
                 10 
                 (XXI) 
                 4-NO 2 —C 6 H 4   
                 Met 
                 4-BrC 6 H 4   
                 9 
                 58 
               
               
                 11 
                 (XXII) 
                 4-NO 2 —C 6 H 4   
                 Met 
                 4-BrC 6 H 4   
                 75 
                 76 
               
               
                   
               
               
                   [a]  The reactions take-place at r.t. in the presence of 3 equivalents of HSiCl 3  in 1 mL de CH 2 Cl 2  for 18 h. 
               
               
                   [b]  Isolated yields. 
               
               
                   [c]  Determined by HPLC using a chiral stationary phase. 
               
            
           
         
       
     
     The loading of the catalyst can be reduced to 0.5 mol % without any significant decrease in the yield and the enantioselectivity (Table 3). The turnover frequencies (TOF) and Asymmetric Catalyst Efficiency (ACE) (Eq. 1) (El-Fayyoumy et al., 2009) were determined. 
     
       
         
           
             
               
                 
                   ACE 
                   = 
                   
                     
                       
                         MM 
                         product 
                       
                       × 
                       ee 
                       × 
                       Yield 
                     
                     
                       
                         MM 
                         cat 
                       
                       × 
                       mol 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       % 
                       × 
                       100 
                     
                   
                 
               
               
                 
                   ( 
                   
                     Equation 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     1 
                   
                   ) 
                 
               
             
           
         
       
     
     Significant was the enantioselectivity of 90% ee (Table 3, entry 7) using 1.5 equivalents of HSiCl 3 . 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Screening results for the hydrosilylation of 
               
               
                 ketimine (XII) using various loadings of organocatalyst (IX) 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 TOF 
                 TOF max   
                   
                   
               
               
                   
                 Cat. 
                   
                 Yield 
                 ee 
                 (mol · mol −1  · 
                 (mol · mol −1  · 
                   
                 ACES 
               
               
                 Entry  [a]   
                 (mol %) 
                 t rx  (h) 
                 (%)  [b]   
                 (%)  [c]   
                 h −1 ) 
                 h −1 ) 
                 ACE 
                 (h −1 ) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                  1 
                 20 
                 18 
                 85 
                 85 
                 0.24 
                 0.28 
                 1.53 
                 0.08 
               
               
                  2 
                 10 
                 18 
                 86 
                 84 
                 0.48 
                 0.56 
                 3.05 
                 0.17 
               
               
                  3 
                 5 
                 18 
                 88 
                 82 
                 0.98 
                 1.11 
                 6.09 
                 0.34 
               
               
                  4 
                 1 
                 18 
                 86 
                 80 
                 4.78 
                 5.56 
                 29.06 
                 1.61 
               
               
                  5 
                 0.5 
                 18 
                 78 
                 72 
                 8.67 
                 11.1 
                 47.43 
                 2.64 
               
               
                  6 
                 0.1 
                 18 
                 53 
                 18 
                 29.4 
                 55.6 
                 40.29 
                 2.24 
               
               
                  7  [d]   
                 10 
                 1 
                 81 
                 90 
                 8.1 
                 10 
                 3.08 
                 3.08 
               
               
                  8  [d]   
                 5 
                 1 
                 67 
                 88 
                 13.4 
                 20 
                 4.98 
                 4.98 
               
               
                  9  [d]   
                 10 
                 0.5 
                 77 
                 88 
                 15.4 
                 20 
                 2.86 
                 5.72 
               
               
                 10  [d]   
                 10 
                 0.25 
                 54 
                 87 
                 30.8 
                 40 
                 1.98 
                 7.94 
               
               
                   
               
               
                   [a]  The reactions take-place at r.t. in the presence of 3 equivalents of HSiCl 3  in 1 mL de CH 2 Cl 2  for 18 h. 
               
               
                   [b]  isolated yields. 
               
               
                   [c]  Determined by HPLC using a chiral stationary phase. 
               
               
                   [d]  The reactions take place with 1.5 equivs. of HSiCl 3 . 
               
            
           
         
       
     
     The catalytic hydrosilylation of ketimine esters was also investigated giving very good yields and moderate to good enentioselectivities (Table 4). 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Screening results for the hydrosilylation of 
               
               
                 ketimine-esters (XXIII)-(XXVI) with HSiCl 3  and (IX). 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Ketimine 
                   
                   
                   
                 Yield 
                 ee 
               
               
                 Entry  [a]   
                 ester 
                 n 
                 R 
                 R 1   
                 (%)  [b]   
                 (%)  [c]   
               
               
                   
               
               
                 1 
                 (XXIII) 
                 1 
                 Meth 
                 Meth 
                 73 
                 23 
               
               
                 2 
                 (XXIV) 
                 1 
                 Meth 
                 Ethy 
                 82 
                 23 
               
               
                 3 
                 (XXV) 
                 1 
                 Ph 
                 Ethy 
                 72 
                 70 
               
               
                 4 
                 (XXVI) 
                 0 
                 Ph 
                 Ethy 
                 77 
                 51 
               
               
                   
               
               
                   [a]  The reactions take-place at r.t. in the presence of 3 equivalents of HSiCl 3  in 1 mL de CH 2 Cl 2  for 18 h. 
               
               
                   [b]  isolated yields. 
               
               
                   [c]  Determined by HPLC using a chiral stationary phase. 
               
               
                   [d]  The reactions ocurr with 1.5 equivs. of HSiCl 3 . 
               
            
           
         
       
     
     In the case of the immobilized catalysts the results are shown in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Screening results for the hydrosilylation of 
               
               
                 ketiminester (XII) with HSiCl 3  and immobilized 
               
               
                 organocatalyst (IX). 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 TOF 
                 TOF m {acute over ( a )} x   
                   
                   
               
               
                   
                 Immobi- 
                   
                 Yield 
                 ee 
                 (mol · mol −1  · 
                 (mol · mol −1  · 
                   
                 ACES 
               
               
                 Entry  [a]   
                 lized (IX) 
                 Cycle 
                 (%)  [b]   
                 (%)  [c]   
                 h −1 ) 
                 h −1 ) 
                 ACE 
                 (h −1 ) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 NSiO 2   
                 1 
                 47 
                 34 
                 0.26 
                 0.57 
                 0.37 
                 0.02 
               
               
                 2 
                 NSiO 2   
                 2 
                 50 
                 38 
                 0.28 
                   
                 0.45 
                 0.02 
               
               
                 3 
                 NSiO 2   
                 3 
                 17 
                 27 
                 0.09 
                   
                 0.11 
                 0.01 
               
               
                 4 
                 MCM 
                 1 
                 71 
                 37 
                 0.39 
                   
                 0.62 
                 0.03 
               
               
                 5 
                 MCM 
                 2 
                 36 
                 24 
                 0.20 
                   
                 0.20 
                 0.01 
               
               
                 6 
                 MCM 
                 3 
                 47 
                 8 
                 0.26 
                   
                 0.09 
                 0.00 
               
               
                 7 
                 MNP 
                 1 
                 97 
                 64 
                 0.54 
                   
                 1.46 
                 0.08 
               
               
                 8 
                 MNP 
                 2 
                 30 
                 50 
                 0.28 
                   
                 0.35 
                 0.02 
               
               
                 9 
                 MNP 
                 3 
                 30 
                 25 
                 0.14 
                   
                 0.18 
                 0.01 
               
               
                   
               
               
                   [a]  The reactions take-place at r.t. in the presence of 3 equivalents of HSiCl 3  in 1 mL de CH 2 Cl 2  for 18 h. 
               
               
                   [b]  isolated yields. 
               
               
                   [c]  Determined by HPLC using a chiral stationary phase. 
               
               
                   [d]  The reactions ocurr with 1.5 equivs. of HSiCl 3 . 
               
            
           
         
       
     
     One of the principle advantages of our catalytic system (particularly in the homogeneous phase) is the high enantioselectivities that can be obtained—up to 90% with excellent TOFs up to 40 mol·mol −1 ·h −1  (Table 3), the best so far reported for ketimine hydrosilylation. 
     In the case of the described immobilized catalyst systems their principal advantage is that the covalent attachment via the vinyl group on the cinchona unit, forces the reaction site to be significantly removed from the support, thus not limiting the reactivity of the organocatalysts. 
     EXPERIMENTAL EXAMPLES 
     Example 1: 2-(N-methyl)pyridinium iodide (VI) 
     On the basis of literature precedent (Shah et al. 2009), ácido picolínico (4.9 g, 39.80 mmol) was dissolved in iPrOH (30 mL) and this was followed by the addition of iodomethane (4.96 mL, 79.60 mmol). The reaction mixture was warmed to a temperature of between 50-55° C. and maintained at this temperature for 3 days. The temperature was then lowered and the title compound obtained as a yellow solid (5.26 g, 48%) after being filtered and washed with cold iPrOH and drying under vacuum. 
       1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm)=8.97 (d, 1H, J=4 Hz), 8.58 (t, 1H, J=8 Hz), 8.21 (d, 1H, J=8 Hz), 8.08 (t, 1H, J=8 Hz), 4.39 (s, 3H). 
       13 C-NMR (100 MHz, DMSO-d 6 ): δ (ppm)=161.4, 149.9, 146.7, 145.9, 127.4, 127.4, 47.1. 
     Example 2: 2-(N-methyl)pyridium tetrafluoroborate (VII) 
     According to the literature procedure (Shah et al. 2009) 2-(N-methyl)-pyridium iodide (1.056 g, 3.98 mmol) was dissolved in MeOH (20 mL) and stirred under an inert atmosphere. During the dissolution process AgBF 4  (1.738 g) in dry metanol (20 mL) was added. The flask was covered in aluminium foil during the ion exchange process. Once the solubilization process was complete, AgBF 4  was added dropwise until there was formation of a AgI precipitate. The initial brown coloured solution gave rise to a biphasic mixture with a light yellow coloured liquid phase and a yellow precipitate. The AgI salt was filtered and the filtrate was concentrated by evaporation in vacuo. The title compound was obtained as an oily off-yellow solid (0.824 g, 92%). 
       1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm)=8.68 (d, 1H, J=8 Hz), 8.46 (t, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.91 (t, 1H, J=8 Hz), 4.27 (s, 3H). 
       13 C-NMR (100 MHz, DMSO-d 6 ): δ (ppm)=163.4, 147.0, 149.9, 128.2, 127.8, 47.9. 
       19 F-NMR (376 MHz, DMSO-d 6 ): δ (ppm)=−148.1. 
     Example 3: 9-O-mesylcinchonidine (III) 
     To a stirred solution of cinchonidine (10.032 g, 34.08 mmol) in anhydrous THF (350 mL) was added triethylamine (15 mL 107.6 mmol) and the solution was then cooled using an ice bath to aprox. 0° C. Methanesulphonyl chloride dissolved in a small quantity of THF was added dropwise to the mixture. Once this reagent was added, the reaction was stirred at room temperature for 2 h. The mixture was then quenched with 80 mL of a saturated solution of sodium bicarbonate and extracted with CH 2 Cl 2 . This was followed by column chromatography on silica gel using ethyl acetate as eluent to give the title compound as a with solid (11.760 g, 93%, mp 107.2-108° C.).  1 H-NMR (400 MHz, CDCl 3 ): δ 8.94 (d, 1H, J=4 Hz, H2′), 8.28 (d, 1H, J=8 Hz, H5′), 8.15 (d, 1H, J=8 Hz, H8′), 7.75 (t, 1H, J=8 Hz, H7′), 7.66 (t, 1H, J=8 Hz, H6′), 7.52 (bs, 1H, H3′), 6.59 (bs, 1H, H9), 5.73 (m, 1H, J=12 Hz, H10), 5.00 (pseudot, 2H, H11), 3.45-3.32 (m, 2H, H6, H8), 3.11 (bs, 1H, H2), 2.76 (bs, 5H, H6, H2, CH 3  mesyl), 2.38 (bs, 1H, H3), 1.96-1.65 (m, 5H, H7, H5, H4).  13 C-NMR (100 MHz, CDCl 3 ): δ 150.0 (C-2′), 148.8 (C-10′), 142.4 (C-10 endo), 140.1 (C-4′), 130.8 (C-8′), 129.9 (C-7′), 128.0 (C-9′), 125.1 (C-6′, C-5′), 123.0 (C-3′), 115.6 (C-11 exo), 59.9 (C-9), 56.0 (C-8, C-2), 39.3 (C-6, C-3, mesyl), 27.2 (C-7, C-4, C-5), [α] D   21 −67.8 (c 1.03, CH 2 Cl 2 ). 
     Example 4: (8S,9S)-9-azido-9-epicinchonidine (CDAZ) 
     9-O-Mesylcinchonidine (2.06 g, 5.53 mmol) was dissolved in anhydrous dimethylformamide (DMF) (40 mL) at room temperature, and this was followed by the addition of 2 equivalents of NaN 3  (0.719 g; 11.06 mmol) and the mixture was heated to 80° C. and stirred for 24 h. The solvent was then removed by distillation and the residue was re suspended in H 2 O (15 mL) and extracted with CH 2 Cl 2  (3×10 mL), then purified by column chromatography on silica gel with ethyl acetate to furnish the title compound as a yellowish dense oil (1.701 g; 96%).  1 H-NMR (400 MHz, CDCl 3 ): δ 8.95 (d, 1H, J=4 Hz, H2′), 8.23 (d, 1H, J=8 Hz, H5′), 8.18 (d, 1H, J=8 Hz, H8′), 7.77 (t, 1H, J=8 Hz, H7′), 7.65 (t, 1H, J=8 Hz, H6′), 7.41 (d, 1H, J=4 Hz, H3′), 5.76 (m, 1H, J=12 Hz, H10), 5.15 (d, 1H, J=10 Hz, H9), 4.99 (pseudot, 2H, J=13.2 Hz, H11), 3.35-3.21 (m, 3H, H6, H2, H8), 2.95-2.83 (m, 2H, H6, H2), 2.30 (bs, 1H, H3), 1.71-1.58 (m, 4H, H4, H7, H5), 0.77-0.72 (pseudoq, 1H, H7).  13 C-NMR (100 MHz, CDCl 3 ): δ 150.0 (C-2″), 148.7 (C-10′), 142.2 (C-10 endo), 141.3 (C-4′), 130.6 (C-8′), 129.4 (C-7′), 127.2 (C-6′), 126.6 (C-9′), 123.0 (C-5′), 120.2 (C-3′), 114.4 (C-11 exo), 59.5 (C-9), 55.9 (C-8), 53.4 (C-2), 40.9 (C-6), 39.3 (C-3), 27.8 (C-7), 27.1 (C-4), 26.0 (C-5), [α] D   21 +42.1 (c 1.27, CH 2 Cl 2 ). 
     Example 5: (8S,9S)-9-amino-9-epicinchonidine (VI) 
     9-azido-9-epicinchonidine (8.37 g, 26.2 mmol) was dissolved in 120 mL of anhydrous THF at room temperature, and this was followed by the slow addition of 1.5 equivalents of triphenylphosphine (10.18 g, 39.3 mmol) and was heated to 50° C. with stirring for 4 h. After complete consumption of the azide (CDAZ)), the mixture was allowed to cool to room temperature and then 3 mL of distilled water was added. The hydrolysis occurred overnight. After this, the excess of water was removed by the addition of anhydrous MgSO 4 , followed by filtration and concentration of the organic phase. The product was purified by column chromatography on silica gel with AcOEt/MeOH/NEt 3  (100:2:3) to furnish the title compound as a yellowish dense oil (7.07 g, 92%).  1 H-NMR (400 MHz, CDCl 3 ): δ (ppm)=8.92 (d, 1H, J=4 Hz, H2′), 8.36 (bs, 1H, H5′), 8.15 (d, 1H, J=8 Hz, H8′), 7.73 (t, 1H, J=8 Hz, H7′), 7.60 (t, 1H, J=8 Hz, H6′), 7.54 (bs, 1H, H3′), 5.82 (m, 1H, H10), 5.03-4.72 (m, 2H, H11), 4.72 (bs, 1H, H9), 3.33-3.22 (m, 2H, H6, H2), 3.10 (bs, 1H, H8), 2.85-2.82 (m, 2H, H6, H2), 2.42 (s, 2H, NH2), 2.30 (bs, 1H, H3), 1.64-1.58 (m, 3H, H4, H7, H5), 1.43-1.41 (m, 1H, H5), 0.79-0.74 (m, 1H, H7).  13 C-NMR (100 MHz, CDCl 3 ): δ (ppm)=150.5 (C2′), 148.8 (C10′), 141.8 (C10, C4′), 130.6 (C8′), 129.2 (C7′), 128.0 (C6′), 126.7 (C9′), 123.4 (C5′), 119.7 (C3′), 114.6 (C11), 62.1 (C9), 56.4 (C8), 41.1 (C6), 39.9 (C2), 29.8 (C3), 28.2 (C7), 27.7 (C4), 26.2 (C5). 
     Example 6: (8S,9S)-9-picolinamide(9-desoxy)-epi-cinchonidine (X) 
     (8S,9S)-9-Amino-9-epicinchonidine (1.064 g, 3.63 mmol) was dissolved in dry toluene (30 mL) to which was added commercial acid picolinic (0.446 g, 3.63 mmol) at room temperature giving a white suspension, the reaction was then subjected to a Dean-Stark distillation at a temperature of between 120-130° C. After 19 h the reaction became intensely orange in colour but transparent. The reaction was then cooled, and then concentrated on a rotary evaporator to give an orange spongy solid. This was then purified by silica gel column chromatography (AcOEt/MeOH (4:1)) affording the title compound as a white solid (1.08 g, 75%). 
       1 H-NMR (400 MHz, CDCl 3 ): δ (ppm)=9.04 (bs, 1H, HN), 8.88 (d, 1H, J=4 Hz, H2′), 8.57 (d, 1H, CH pyridine), 8.50 (d, 1H, CH pyridine), 8.12 (d, 1H, J=8 Hz, H5′), 8.02 (d, 1H, J=8 Hz, H8′), 7.75-7.68 (m, 2H, H7′, CH pyridine), 7.62 (t, 1H, J=8 Hz, H6′), 7.51 (d, 1H, J=4 Hz, H3′), 5.78-5.64 (m, 2H, H10, H9), 5.00-4.93 (m, 2H, H11), 3.37-3.27 (m, 2H, H6, H2), 3.21 (bs, 1H, H8), 2.83-2.72 (m, 2H, H6, H2), 2.29 (bs, 1H, H3), 1.66-1.58 (m, 3H, H4, H7, H5), 1.42-1.29 (m, 1H, H5), 0.96-0.91 (m, 1H, H7). 
       13 C-NMR (100 MHz, CDCl 3 ): δ (ppm)=164.3 (C═O), 150.2 (pyridine), 149.8 (C2″), 148.7 (C10′), 148.3 (pyridine), 146.9 (C4′), 141.4 (pyridine), 137.3 (C10 endo), 130.5 (C8′), 129.2 (C7′), 127.5 (C6′), 126.9 (C9′), 126.2 (pyridina), 123.5 (pyridine), 122.3 (C5′), 119.6 (C3′), 1114.1 (C11 exo), 60.1 (C9), 56.0 (C8, C2), 41.1 (C6), 39.6 (C3), 27.9 (C7), 27.5 (C4), 26.2 (C5). 
     Example 7: (8S,9S)-9-[2-(N-methyl)pyridinium]-(9-desoxy)-epi-cinchonidine iodide (VIII) 
     This compound was prepared according to the method described in 6 using (8S,9S)-9-amino-9-epicinchonidine (1.128 g, 3.84 mmol) and 1.5 equivalents of 2-(N-methyl)pyridinium iodide (1.528 g, 5.76 mmol). The reaction mixture was purified by column chromatography on silica gel (AcOEt/MeOH (4:1)) giving the title compound as an oily orange solid (0.853 g, 43%). 
       1 H-NMR (400 MHz, CDCl 3 +DMDO-d6): δ (ppm)=9.20 (bs, 1H, HN), 8.82 (d, 1H, J=4 Hz, H2′), 8.56 (d, 1H, CH pyridine), 8.48 (d, 1H, CH pyridine), 8.00 (d, 1H, J=8 Hz, H5′), 7.92 (d, 1H, J=8 Hz, H8′), 7.80 (t, 1H, J=8 Hz, H7′), 7.68 (t, 1H, J=8 Hz, H6′), 7.63-7.59 (m, 2H, H3′, CH pyridine), 7.45-7.42 (m, 1H, CH pyridine), 5.79-5.71 (m, 2H, H10, H9), 5.02-4.92 (m, 2H, H11), 3.33 (m, 6H, H6, H2, H8,  + N—CH 3 ), 2.89-2.81 (m, 2H, H6, H2), 2.35 (bs, 1H, H3), 1.66 (bs, 3H, H4, H7, H5), 1.42 (bs, 1H, H5), 0.91 (bs, 1H, H7).  13 C-NMR (100 MHz, CDCl 3 +DMDO-d6): δ (ppm)=162.4 (C═O), 148.8, 148.2, 147.0, 146.9, 135.1, 135.2, 128.7, 128.6, 127.7, 125.7, 125.4, 125.1, 122.3, 122.2, 120.6, 113.5, 57.9, 53.7, 48.7, 39.7, 25.7, 24.2. 
     Example 8: (8S,9S)-9-[2-(N-methyl)pyridinium]-(9-desoxy)-epi-cinchonidine tetrafluorobate (IX) 
     This compound was prepared according to the method described in 6 using (8S,9S)-9-amino-9-epicinchonidine, (1.030 g, 3.51 mmol) and 1.5 equivalents of 2-(N-methyl)pyridinium tetrafluoroborate (1.184 g, 5.26 mmol). The reaction mixture was purified by column chromatography on silica gel (AcOEt/MeOH (4:1)) giving the title compound as an orange solid (0.828 g, 47%). 
       1 H-NMR (400 MHz, CDCl 3 ): δ (ppm)=9.03 (bs, 1H, HN), 8.85 (d, 1H, J=4 Hz, H2′), 8.46 (d, 1H, CH pyridine), 8.42 (d, 1H, CH pyridine), 8.12 (d, 1H, J=8 Hz, H5′), 8.01 (d, 1H, J=8 Hz, H8′), 7.76-7.71 (m, 2H, J=8 Hz, CH pyridine, H7′), 7.67-7.64 (m, 2H, J=8 Hz, CH pyridine, H6′), 7.32-7.29 (m, 1H, CH pyridine), 6.00 (bs, 1H, H9), 5.84-5.75 (m, 1H, H10), 5.13-5.07 (m, 2H, H11), 4.44 (bs, 3H,  + N—CH 3 ), 3.97 (m, 1H, H6), 3.67 (bs, 1H, H8), 3.51 (bs, 1H, H2), 3.19-3.15 (m, 1H, H6), 3.07-2.99 (m, 1H, H2), 2.51 (bs, 1H, H3), 1.83 (m, 3H, H4, H7, H5), 1.68 (m, 1H, H5), 1.08-1.03 (m, 1H, H7). 
       13 C-NMR (100 MHz, CDCl 3 ): δ (ppm)=164.9 (C═O), 150.6, 149.3, 148.8, 148.4, 144.6, 139.2, 137.4, 130.6, 129.6, 127.6, 127.1, 126.5, 123.3, 122.6, 119.9, 116.3, 59.8, 54.9, 41.7, 38.2, 29.8, 27.2, 26.2, 25.5. 
       19 F-NMR (376 MHz, CDCl 3 ): δ (ppm)=−145.5. 
     Example 9: (8S,9S)-9-[2-(N-methyl)pyridinium]-(9-desoxy)-(11-(3-(trimethoxysilylpropylthio)-epi-10,11-dihydrocinchonidine tetrafluoroborate (XI) 
     (8S,9S)-9-[2-(N-methyl)pyridinium]-(9-desoxy)-epi-cinchonidine tetrafluoroborate (IX) (0.4 g, 0.76 mmol) was dissolved in CHCl 3  (4 mL), to which was added (3-mercaptopropil)trimetoxisilane (0.142 mL, 0.76 mmol) and the stirred mixture was irradiated with uv light from a mercury vapor lamp for 24 h. The solvent and other volatile compounds were removed in vacuo, giving the title compound as a viscous orange oil (0.509 g, 96%) that was immobilized to the solid support. 
     MS (ESI): calculated for C 32 H 45 N 4 O 4 SSi +  611.30, observed value 611.27. 
     Example 10: Grafting of (8S,9S)-9-[2-(N-methyl)pyridium]-(9-desoxy)-epi-cinchonidine tetrafluoroborate (IX) to Nanosilica Gel Particles, MCM-41 and Magnetic Nanoparticles 
     (8S,9S)-9-[2-(N-methyl)pyridinium]-(9-desoxy)-epi-cinchonidine tetrafluoroborate (IX) (0.180 g, 0.25 mmol) was placed in a 50 mL round bottom flask and dissolved in dry toluene. The support was then added [0.280 g (1.6% m/m)] and the mixture was refluxed under an inert atmosphere for 24 h. 
     (Nanosilica and MCM-41): 
     At the end of the reaction period the mixture was cooled and the solids were filtered and washed with CH 2 Cl 2  (3×20 mL) followed by drying under reduced pressure with heating at 60° C. for 4 h. 
     Loadings (microanalysis) (Nanosilica)—0.340 mmol g −1  (MCM-41)—0.405 mmol g −1    
     Silica Coated MNPs: 
     The magnetic nanoparticles were prepared according by a literature method (Zeng et al. 2011). At the end of the reaction period the mixture was cooled and the solids were filtered and washed with CH 2 Cl 2  (3×20 mL) followed by drying under reduced pressure with heating at 60° C. for 4 h. 
     Loading (microanalysis)—0.470 mmol g −1    
     Example 11: Catalytic Homogeneous Asymmetric Hydrosilylation of N-phenyl 1-Phenylpropanimine (XII) 
     N-phenyl 1-Phenylpropanimine (XII) (100 mg, 0.42 mmol) was dissolved in CH 2 Cl 2  (2 mL) to which was added the organocatalyst (IX) (10 mol %). The reaction mixture was then cooled on an ice-bath and after 15 minutes the HSiCl 3  (3 equivs) was added drop-wise. Once the addition was complete the reaction mixture was stirred at room temperature for 21 h. The reaction was quenched by the addition of a saturated solution NaHCO 3  (2 mL). The organic phase was extracted with CH 2 Cl 2  (3×10 mL) dried with anhydrous MgSO 4 , filtered and evaporated to dryness in vacuo. The resulting residue was purified by column chromatography with silica gel (CH 2 Cl 2 ) affording (R)—N-phenyl-1-phenylpropyl-1-amine (86 mg, 86%) as a colourless oil. 
       1 H-NMR (400 MHz, CDCl 3 ) δ 7.39 (m, 4H), 7.28 (m, 1H), 7.14 (t, 2H), 6.69 (t, 1H), 6.59 (d, 2H), 4.29 (t, 1H), 4.13 (bs, 1H), 1.89 (m, 2H), 1.02 (t, 3H). 
       13 C NMR (101 MHz, CDCl 3 ) 147.63, 144.04, 129.20, 128.61, 127.00, 126.60, 117.24, 113.36, 59.84, 31.78, 10.95. 
     HPLC (Daicel Chirapak OD-H, hexane/isopropanol=80:20, fluxo 1 mL/min), λ=254 nm: t R =4.91 min (minor enantiomer), t S =5.46 min (major enantiomer). 
     Example 12: Catalytic Heterogenous Asymmetric Hydrosilylation of N-phenyl 1-Phenylpropanimine (XII) 
     According to the procedure described in Example 11, the immobilized catalysts were added at a loading of 10 mol % to the 1-Phenylpropanimine (XII) substrate in CH 2 Cl 2 , and this was followed by the dropwise addition of HSiCl 3 . At the end of 18 h at room temperature, the reaction was worked up by filtering off the supported catalyst (which was dried under vacuum at 60° C. for 1 h, so that it is available to be reused in subsequent cycles) and subjecting the crude product to a work-up as described in Example 11. The resulting residue was purified by column chromatography with silica gel (CH 2 Cl 2 ) affording (R)—N-phenyl-1-phenylpropyl-1-amine (97 mg, 97%) as a colourless oil. 
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     Naturally, the present application is by no means restricted to the embodiments described in this document, and a person with average skills in the art might predict many possibilities of altering the same without departing from the general idea, as defined in the claims. 
     All the embodiments described above may obviously be combined with each other. The following claims additionally define preferred embodiments.