Enantioselective hydrogenation titanium complexes

A full account5 describes the enantioselective carbonyl-ene reaction of glyoxylate esters catalyzed by a binaphthol-derived chiral titanium complex that is potentially useful for the asymmetric synthesis of a-hydroxy esters of biological and synthetic importance.6 The present procedure is applicable to a variety of 1,1-disubstituted olefins to provide ene products in extremely high enantiomeric purity by the judicious choice of the dichloro or dibromo chiral catalyst (see Table). In certain glyoxylate-ene reactions involving removal of a methyl hydrogen, the dichloro catalyst... 

Transformations involving chiral catalysts most efficiently lead to optically active products. The degree of enantioselectivity rather than the efficiency of the catalytic cycle has up to now been in the center of interest. Compared to hydrogenations, catalytic oxidations or C-C bond formations are much more complex processes and still under development. In the case of catalytic additions of dialkyl zinc compounds[l], allylstan-nanes [2], allyl silanes [3], and silyl enolethers [4] to aldehydes, the degree of asymmetric induction is less of a problem than the turnover number and substrate tolerance. Chiral Lewis acids for the enantioselective Mukaiyama reaction have been known for some time [4a - 4c], and recently the binaphthol-titanium complexes 1 [2c - 2e, 2jl and 2 [2b, 2i] have been found to catalyze the addition of allyl stannanes to aldehydes quite efficiently. It has been reported recently that a more active catalyst results upon addition of Me SiSfi-Pr) [2k] or Et2BS( -Pr) [21, 2m] to bi-naphthol-Ti(IV) preparations. 

The most widely studied approach for the enantioselective hydrogenation of non-functionalized alkenes has been the use of reduced chiral titanocene complexes. The initial promising demonstration utilized bis(menthylcyclopentadi-enyl)titanium dichloride (12) in the presence of Red-Al to catalyze the hydrogenation of 2-phenylbutene in 23% ee (determined by optical rotation) [13,14, 15]. Two mechanisms have been postulated for hydrogenations involving reduced titanocene catalysts a Ti(II)/Ti(IV) cycle and the more commonly invoked Ti(III) cycle shown in Scheme 2. 

All effective catalysts for the asymmetric reduction of prochiral C=N groups are based on complexes of rhodium, iridium, ruthenium, and titanium. Whereas in early investigations (before 1984) emphasis was on Rh and Ru catalysts, most recent efforts were devoted to Ir and Ti catalysts. In contrast to the noble metal catalysts which are classical coordination complexes, Buchwald s a sa-titanocene catalyst for the enantioselective hydrogenation of ketimines represents a new type of hydrogenation catalyst [6]. In this chapter important results and characteristics of effective enantioselective catalysts and are summarized. 

High enantioselectivities in the hydrogenation of 2-phenyl-l-butene have been achieved using chiral samarium complexes such as 55 (96% ee at — 80°C, 64-80% cc at 25°C)129. The reaction was carried out in heptane at 1 bar of H2 using a substrate/catalyst ratio of 200 1, and quantitative conversion and high turnover frequencies were observed under these conditions. The same catalyst gave 72% ee in the deuteration of styrene with D2 at 25 "C. Substantial enantiomeric excesses in the hydrogenation of 1,1-disubstituted olefins have also been obtained with the chiral bis(cyclopentadienyl)titanium complex 5690. 

Enantioselective epoxidation of allylic alcohols using hydrogen peroxide and chiral catalysts was first reported for molybdenum 7B) and vanadium 79) complexe. In 1980, Sharpless 80) reported a titanium system. Using a tartaric acid derivative as chiral auxiliary it achieves almost total stereoselection in this reaction. 

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. 

In this context it is worth noting that neither the titanium(IV) tartrate catalyst nor other metal catalyst-alkyl hydroperoxide reagents are effective for the asymmetric epoxidation of unfunctionalized olefins. The only system that affords high enantioselectivities with unfunctionalized olefins is the manganese(III) chiral Schiff s base complex/NaOCl combination developed by Jacobsen [42]. There is still a definite need, therefore, for the development of an efficient chiral catalyst for asymmetric epoxidation of unfunctionalized olefins with alkyl hydroperoxides or hydrogen peroxide. 

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. 

Examination of the enantioselectivities in Table 7.5 indicates a striking difference in selectivity achieved in the reduction of cyclic (entries 1-8) vs. acyclic imines (entries 9-11). The former is very nearly 100% stereoselective. The simple reason for this is that the acyclic imines are mixtures of E and Z stereoisomers, which reduce to enantiomeric amines vide infra). The mechanism proposed for this reduction is shown in Scheme 7.11 [86]. The putative titanium(III) hydride catalyst is formed in situ by sequential treatment of the titanocene BINOL complex with butyllithium and phenylsilane. The latter reagent serves to stabilize the catalyst. Kinetic studies show that the reduction of cyclic imines is first order in hydrogen and first order in titanium but zero order in imine. This (and other evidence) is consistent with a fast 1,2-insertion followed by a slow hydrogenolysis (a-bond metathesis), as indicated [86]. Although P-hydride elimination of the titanium amide intermediate is possible, it appears to be slow relative to the hydrogenolysis. 

Epoxidation of oleic and linoleic acid was readily achieved by treatment with the acetonitrile complex of hypofluorous acid (55). Phase-transfer-catalyzed biphasic epoxidation of unsaturated triglycerides was accomplished with ethylmethyldioxirane in 2-butanone (56). The enantioselective formation of an a,P-epoxy alcohol by reaction of methyl 13()S)-hydroperoxy-18 2(9Z,llfi) with titanium isopropoxide has been reported (57). An immobilized form of Candida antartica on acrylic resin (Novozyme 435) was used to catalyze the perhydrolysis and the interesterification of esters. Unsaturated alcohols were converted with an ester in the presence of hydrogen peroxide to esters of epoxidized alcohols (e.g., epoxystearylbutyrate) directly (58). Homoallyl ethers were obtained from olefinic fatty esters by the ethylaluminium-in-duced reactions with dimethyl acetals of formaldehyde, acetaldehyde, isobutyralde-hyde, and pivaldehyde (59). Reaction of 18 2(9Z, 12Z) with 50% BF3-methanol gave monomethoxy and dimethoxy derivatives (60). A bulky phosphite-modified rhodium catalyst was developed for the hydroformylation of methyl 18 1 (9Z)and 18 1(9 ), which furnished mixtures of formylstearate and diformylstearate (61). 

The most practical method that is used in the industrial synthesis of esomeprazole involves titanium-catalyzed oxidation with an alkyl hydroperoxide, and a dialkyltartrate as chiral ligand, in an organic solvent such as dichloromethane. A variety of oxidoreductases are known to catalyze the enantioselective oxidation of prochiral sulfides, usually as whole-cell biotransformations in aqueous media, but no simple metal complexes have been shown to be effective in water and the development of practical systems employing aqueous hydrogen peroxide as the primary oxidant is still an important challenge. In this context it is worth mentioning the enantioselective sulfoxidation of prochiral sulfoxides catalyzed by the semisynthetic peroxidase, vanadium-phytase, in an aqueous medium. 

---