Titanium asymmetric hydrogenation

Asymmetric hydrogenation of nitrones in an iridium catalyst system, prepared from [IrCl(cod)]2, (S)-BINAP, NBu 4 BH4, gives with high enantioselectivity the corresponding A-hydroxylamines which are important biologically active compounds and precursors of amines (480). Further reduction of hydroxylamines to secondary amines or imines can be realized upon treatment with Fe/AcOH (479), or anhydrous titanium trichloride in tetrahydrofuran (THF) at room temperature (481). 

The enantioselectivity is not very sensitive to the nature of the allylic alcohol. By contrast, titanium and tartrates are essential to the success. This catalyst components combination is unique note the difference with the L-Dopa asymmetric hydrogenation, which can be carried out with hundreds of C2-chiral diphosphines, even monophosphines, but with a limited number of substrates only. 

Given the importance of chiral amines to synthetic chemistry as well as other fields asymmetric hydrogenation of imines has attracted wide interest but limited success compared to C=C and C=0 bond reduction. The first asymmetric hydrogenation of imines was carried out in the seventies with mthenium- and rhodium-based catalysts, followed later by titanium and zirconium systems [82]. Buchwald found that... 

In this chapter, we focus on the rhodium-catalyzed hydrogenation and the development of chiral phosphorous ligands for this process. Although there are other chiral phosphorous ligands, which are effective for ruthenium-, iridium-, platinum-, titanium-, zirconium-, and palladium-catalyzed hydrogenation, they are not discussed in this account. However, this does not preclude complexes of other transition metals as effective catalysts for asymmetric hydrogenation. Fortunately, there are numerous reviews and books that discuss this particular aspect of asymmetric hydrogenation [3]. 

Asymmetric Hydrogenation. Asymmetric hydrogenation with good enantio-selectivity of unfunctionalized prochiral alkenes is difficult to achieve.144 145 Chiral rhodium complexes, which are excellent catalysts in the hydrogenation of activated multiple bonds (first, in the synthesis of a-amino acids by the reduction of ol-N-acylamino-a-acrylic acids), give products only with low optical yields.144 146-149 The best results ( 60% ee) were achieved in the reduction of a-ethylstyrene by a rhodium catalyst with a diphosphinite ligand.150 Metallocene complexes of titanium,151-155 zirconium,155-157 and lanthanides158 were used in recent studies to reduce the disubstituted C—C double bond with medium enantioselectivity. 

Many other reports of ligand libraries for specific catalytic applications have been reported. Among them, Gilbertson and co-workers reported a chiral phosphine library, tested in the rhodium-catalyzed asymmetric hydrogenation of an enamide (158,159), and a similar library for the palladium-catalyzed allylation of malonates (160, 161) Hoveyda and co-workers (162, 163) reported a chiral Schiff base library, screened in the titanium-catalyzed opening of epoxides with (TMSCN) (trimethyl silyl cyanide) ... 

The 7 -symmetric complex ethylene bis(tetrahydroindenyl) titanium l,T-binaphth-2,2 -dithiolate has been used to catalyze the asymmetric hydrogenation of unfunctionalized trisubstituted olefins.1680 The kinetic resolution of racemic disubstituted 1-pyrrolidines via asymmetric reduction has been described.1681... 

Alkyl and aryl substituted imines have received the most attention as substrates for asymmetric hydrogenation, and the development of the field can therefore be outlined by examining their reductions. These are usually catalyzed by chiral complexes of titanium, ruthenium, rhodium, or iridium, though gold catalysts have also recently proven useful for this purpose [31]. New catalysts are generally tested for the reductions of substrates A-D (Scheme 6.1). 

A brief comparison of the advantages and disadvantages of titanium, ruthenium, rhodium, iridium, and gold catalysts for the asymmetric hydrogenation of alkyl and aryl substituted imines is given in Table 6.1. 

Table 6.13 Asymmetric, titanium catalyzed hydrogenation of imines...

As a final example not strictly within the bounds of this section, the work of Buchwald s group can be cited [109]. This demonstrates that asyrmnetric hydrogenations can be achieved with metals other than Rh or Ru (albeit rarely ). In this case, the reduction of simple enamines with high enantioselectivity is demonstrated with titanium catalysts. The genesis of the ligand lies in the cyclopen-tadienyl complexes developed for stereospecific polymerization, but its application here results in a useful transformation (cyclic enamines provide a difficult problem for the conventional asymmetric hydrogenation catalyst) illustrated in Fig. 32. 

Titanium complexes that are similar to Duthaler s ( 2.5.2) can be generated from TiCl4, Ti(Or-Pr)4 and diacetoneglucose 1.48. These complexes catalyze asymmetric hetero-Diels-Alder reactions, and give high enantiomeric excesses [827], Corey and coworkers [828] also prepared a chiral titanium catalyst derived from cis-/V-sulfonyl-2-amino-1 -indanol and used this to catalyze asymmetric Diels-Alder reactions. Buchwald and coworkers [829, 830] have proposed the use of titanocene-binaphthol catalysts for asymmetric hydrogenation of imines or trisubsti-tuted olefins. 

The basic compound of Brintzinger s ansa-titanocene complexes is ethylenebis-(tetrahydroindenyl)titanium dichloride, (EBTHI)TiCl2. Further analogues ((EBTHI)TiH, (EBTHI)Ti(Me)2, and (EBTHI)Ti(CO)2) have been wddely used for asymmetric hydrogenation, hydrosilylation, and Pauson-Khand reaction (121). Novel optically active titanium complexes containing a linked amido-cyclopentadienyl ligand have been developed and used for asymmetric hydrogenation (122). 

Titanium, Zirconium, Hafnium - The catalytic asymmetric hydrogenation of imines has been reported using a chiral titanocene catalyst. " An enantiopure titanocene catalyst has been used in the catalytic asymmetric hydrogaution of disubstituted enamines. Kinetic resolution of a racemic disubstituted pyrroline has been effected by asymmetric reduction with a chiral titanocene catalyst. Poly(methylhydrosiloxane) has been used as a stoichiometric... 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

More recently, an important chiral titanium catalyst for the asymmetric reduction with hydrogen of /V-substi luted dialkyl ketimines to enantioenriched amines has been... 

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