Titanium catalysts tartrate catalyst

The synthetic utility of the oxirane technology was further extended by the development by Sharpless and Katsuki [33, 34] of the titanium(lV) tartrate catalyst for the asymmetric epoxidation of allylic alcohols with TBHP (eq. (16)). 

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. 

In light of the previous discussions, it would be instructive to compare the behavior of enantiomerically pure allylic alcohol 12 in epoxidation reactions without and with the asymmetric titanium-tartrate catalyst (see Scheme 2). When 12 is exposed to the combined action of titanium tetraisopropoxide and tert-butyl hydroperoxide in the absence of the enantiomerically pure tartrate ligand, a 2.3 1 mixture of a- and /(-epoxy alcohol diastereoisomers is produced in favor of a-13. This ratio reflects the inherent diasteieo-facial preference of 12 (substrate-control) for a-attack. In a different experiment, it was found that SAE of achiral allylic alcohol 15 with the (+)-diethyl tartrate [(+)-DET] ligand produces a 99 1 mixture of /(- and a-epoxy alcohol enantiomers in favor of / -16 (98% ee). 

The mechanism for such a process was explained in terms of a structure as depicted in Figure 6.5. The allylic alcohol and the alkyl hydroperoxide are incorporated into the vanadium coordination sphere and the oxygen transfer from the peroxide to the olefin takes place in an intramolecular fashion (as described above for titanium tartrate catalyst) [30, 32]. 

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

The mechanism by which the enantioselective oxidation occurs is generally similar to that for the vanadium-catalyzed oxidations. The allylic alcohol serves to coordinate the substrate to titanium. The tartrate esters are also coordinated at titanium, creating a chiral environment. The active catalyst is believed to be a dimeric species, and the mechanism involves rapid exchange of the allylic alcohol and /-butylhydroperoxide at the titanium ion. 

The original epoxidation with titanium-tartrate is homogeneous, but it can be carried out heterogeneously without diminishing enantioselectivity by using titanium-pillared montmorillonite catalyst (Ti-PILC) prepared from titanium isopropoxide, (+)-DAT, and Na+-montmorillonite.38 Due to the limited spacing of Ti-PILC, the epoxidation becomes slower as the allylic alcohol gets bulkier. 

Relative insensitivity to preexisting chiral centers In allylic alcohols with preexisting chiral centers, the diastereofacial preference of the chiral titanium-tartrate catalyst is often strong enough to override diastereofacial preferences inherent in the chiral olefinic substrate. 

Catalytic asymmetric epaxidation (13, 51-53). Complete experimental details are available for this reaction, carried out in the presence of heat-activated crushed 3A or powdered 4A molecular sieves. A further improvement, both in the rate and enantioselectivity, is use of anhydrous oxidant in isoctane rather than in CH2C12. The titanium-tartrate catalyst is not stable at 25°, and should be prepared prior to use at -20°. Either the oxidant or the substrate is then added and the mixture of three components should be allowed to stand at this temperature for 20-30 min. before addition of the fourth component. This aging period is essential for high enantioselectivity. Epoxidations with 5-10 mole % of Ti(0-/-Pr)4 and 6-12% of the tartrate generally proceed in high conversion and high enantioselectivity (90-95% ee). Some increase in the amount of catalyst can increase the enantioselectivity by 1-5%, but can complicate workup and lower the yield. Increase of Ti(0-i-Pr)4 to 50-100 mole % can even lower the enantioselectivity. 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

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. 

There has recently been much work in this area using Ru-based catalysts, particularly with porphyrin-based catalysts, following the work by Sharpless et al. on asynunetric epoxidation of allylic alcohols by a titanium-based tartrate system. There are reviews on asymmetric epoxidations catalysed by chiral Ru porphyrins [5, 18]. 

M. G. Finn, K. B, Sharpless, Epoxidation with Titanium-Tartrate Catalysts in Asymmetric Synthesis, J. D. Morrison, Ed.. Vol. 5, pp 269-271, Academic, New York 1985. 

Asymmetric epoxidation of ailylic alcohols.1 Epoxidation of allylic alcohols with r-bulyl hydroperoxide in the presence of titanium(lV) isopropoxide as the metal catalyst and either diethyl D- or diethyl L-tartrate as the chiral ligand proceeds in > 90% stereoselectivity, which is independent of the substitution pattern of the allylic alcohol but dependent on the chirality of the tartrate. Suggested standard conditions are 2 equivalents of anhydrous r-butyl hydroperoxide with 1 equivalent each of the alcohol, the tartrate, and the titanium catalyst. Lesser amounts of the last two components can be used for epoxidation of reactive allylic alcohols, but it is important to use equivalent amounts of these two components. Chemical yields are in the range of 70-85%. 

Finn, F M, Hofmann, K 1976, in Neurath, H, Hill, R L (eds), The Proteins, 3rd edn, Vol II, chapter 2(p 106—237), Academic Press New York London Finn, M G, Sharpless, fC. B 1985, On the Mechanism of Asymmetric Epoxidation with Titanium-Tartrate Catalysts, in Momson, J D (ed), Asymmetric Synthesis, Vol 5 Chiral Catalysis chapter 8, p 247, Academic Press New York Fischer, E 1914, Chem Ber 47,196 Fischer, H, Slangier G 1927, Liebigs, Ann Chem 459, 53 Fischer, H Neber, M 1932. Liebigs Ann Chem 496,1... 

With Tartrate-Derived Chiral 1,4-Diol/Ti Complexes A catalytic asymmetric Diels-Alder reaction is promoted by the use of a chiral titanium catalyst prepared in situ from (Pr O TiC and a tartrate-derived (2.R,3.R)-l,l>4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol. This chiral titanium catalyst, developed by Narasaka, has been successfully executed with oxazolidinone derivatives of 3-borylpropenoic acids as P-hydroxy acrylic acid equivalents [40] (Eq. 8A.21). The resulting chiral adduct can be utilized for the first asymmetric total synthesis of a highly oxygenated sesquiterpene, (-i-)-Paniculide. 

The asymmetric Diels-Alder reaction of diene and cyclopentenone derivatives can be promoted by a chiral titanium catalyst prepared in situ from (Pr 0)2TiCl2 and a tartrate-derived o.,a,a, a -tetraalkyl-l,3-dioxolane-4,5-dimethanol [54] (Eq. 8A.31). The resulting adducts can easily be tranformed to estrogens and progestogens. 

Narasaka s chiral titanium catalyst, prepared from (Pr 0)2TiCl2 and a tartrate-derived (2R,3R)-l,l,4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol, is utilized for the asymmetric [2+2] cycloaddition of A-acyl oxazolidinones to 1,2-propadienyl sulfides possessing a-substituents, which afford methylenecyclobutane derivatives with high enantiomeric purity. These chiral adducts are readily transformed to seven- and eight-membered carbocycles with chiral side chains by the ring-cleavage reaction and subsequent cationic cyclization of the chiral cyclobutane derivative [68] (Eq. 8A.44). 

B. E. Rossiter (1985). Synthetic aspects and application of asymmetric epoxidation , in Asymmetric Synthesis. Ed. J. Morrison. Orlando Academic Press, p. 194 M. G. Finn and K. B. Sharpless On the mechanism of asymmetric epoxidation with titanium-tartrate catalysts . Ibid., p. 247. 

Esomeprazole (Nexium, 13.45), a proton-pump inhibitor, is marketed as a singleenantiomer drug under the name Nexium (Scheme 13.7).17 The diethyl ester of (+) -tartaric acid (13.43, R = ethyl) serves as a chiral ligand for the titanium catalyst, and hydroperoxide is the stoichiometric oxidant. Because of the chiral environment created by the (+)-tartrate ligand, the catalyst selectively adds an oxygen atom to just one of the lone pairs to form a new stereocenter at the sulfur atom. 

Hie first of Sharpless s reactions is an oxidation of alkenes by asymmetric epoxidation. You met vanadium as a transition-metal catalyst for epoxidation with r-butyl hydroperoxide in Chapter 33, and this new reaction makes use of titanium, as titanium tetraisopropoxide, Ti(OiPr)4, to do the same thing. Sharpless surmised that, by adding a chiral ligand to the titanium catalyst, he might be able to make the reaction asymmetric. The ligand that works best is diethyl tartrate, and the reaction shown below is just one of many that demonstrate that this is a remarkably good reaction. 

Complexes based on titanium excess tartrate combination (the Padova system). In 1984, the same year the Orsay group developed their system, a group in Padova, Italy, headed by Modena,47 developed a different system, able to oxidize sulfides to sulfoxides with high selectivity, also based on a modification of the Sharpless catalyst. The Padova group used TBHP in the presence of 1 mol equiv of Ti(0-/-Pr)4/(/ ,/ )-DET, 1/4 combination. The reactions were performed at -20... 

Chiral epoxides are important intermediates in organic synthesis. A benchmark classic in the area of asymmetric catalytic oxidation is the Sharpless epoxidation of allylic alcohols in which a complex of titanium and tartrate salt is the active catalyst [273]. Its success is due to its ease of execution and the ready availability of reagents. A wide variety of primary allylic alcohols are epoxidized in >90% optical yield and 70-90% chemical yield using tert-butyl hydroperoxide as the oxygen donor and titanium-isopropoxide-diethyltartrate (DET) as the catalyst (Fig. 4.97). In order for this reaction to be catalytic, the exclusion of water is absolutely essential. This is achieved by adding 3 A or 4 A molecular sieves. The catalytic cycle is identical to that for titanium epoxidations discussed above (see Fig. 4.20) and the actual catalytic species is believed to be a 2 2 titanium(IV) tartrate dimer (see Fig. 4.98). The key step is the preferential transfer of oxygen from a coordinated alkylperoxo moiety to one enantioface of a coordinated allylic alcohol. For further information the reader is referred to the many reviews that have been written on this reaction [274, 275]. 

This section presents a summary of the currently preferred conditions fw perfrmning titanium-catalyzed asymmetric epoxidations and is derived primarily from the detailed account of Gao et al We wish to draw the reader s attention to several aspects of the terminology used here and throughout this chapter. The terms titanium tartrate complex and titanium tartrate catalyst are used interchangeably. The term stoichiometric reaction refers to the use of the titanium tartrate complex in a stoichiometric ratio (100 mol %) relative to the substrate (allylic alcohol). The term catalytic reaction (or quantity) refers to the use of the titanium tartrate complex in a catalytic ratio (usually S-10 mol %) relative to the substrate. 

Two aspects of stoichiometry are important in an asymmetric epoxidation one is the ratio of titanium to tartrate used for the catalyst and the other is the ratio of catalyst to substrate. With regard to the catalyst, it is crucial to obtaining the highest possible enantiomeric excess that at least a 10% excess of tartrate ester to titanium(IV) alkoxide be used in all asynunetric epoxidations. This is important when the reaction is being done with either a stoichiometric or a catalytic quantity of the complex. There appears to be no need to increase the excess of tartrate ester beyond 10-20% and, in fact, a larger excess has been shown to slow the epoxidation reaction unnecessarily. ... 

The addition of activated molecular sieves (zeolites) to the asymmetric epoxidation milieu has the beneficial effect that virtually all reactions can be carried out with only 5-10 mol % of the titanium tartrate catalyst. Without molecular sieves, only a few of the more reactive allylic alcohols are epox-idized efficiently with less than an equivalent of the catalyst. The role of the molecular sieves is thought to be protection of the catalyst from adventitious water and water that may be generated in sn l amounts by side reactions during the epoxidation process. 

In this case, the optically active allylic alcohol (12) was subjected to epoxidation with both antipodes of the titanium tartrate catalyst. With (-h)-DIPT enantiofacial selectivity was 96 4 ( matched pair ), but with (-)-DIPT selectivity fell to only 1 3 ( mismatched pair ), a further indication that a sec-ondaiy C-2 substituent can perturb the fit of the substrate to the active catalyst species. In the epoxidation of the allylic alcohol shown in elation (4), the epoxy alcohol is obtained in 96% yield and with a 14 1 ratio of enantiofacial selectivity. An interesting alternate route to the epoxide of entry 12 (Table 3) has been described, in which 2-r-butylpropene is first converted to an allylic hydroperoxide via photooxyge-nation and then, in the presence of the titanium tartrate catalyst, undergoes asymmetric epoxidation (79%... 

Fortunately, a wide variety of functionality is compatible with the titanium tartrate catalyst (see Table 1), but the judicious placement of functional groups relative to the allylic alcohol can lead to further desirable reactions following epoxidation. For example, in (40), asymmetric epoxidation of the allylic alcohol is followed by intramolecular cyclization un r the reaction conditions to give the tetrahydrofuran... 

The rationale that explains the Icinetic resolution of the l-monosubstituted allylic alct ols predicts that a 1,1-disubstituted allylic alct ol will be difficult to epoxidize with the titanium tartrate catalyst In practice, the epoxidation of 1,1-dimethylallyl alcohd (88) with a stoichiometric quantity of the titanium tartrate complex is veiy slow and no epoxy alcohol is isolated. Qearly, the rate of qmxidadon of this substrate is slower than the subsequent reacdon(s) of the epoxide. 

Tertiary alkylamines can be converted into the corresponding N-oxides with hydrogen peroxide or with peroxy acids." r-Butyl hydroperoxide has also been used in the presence of a catalyst such as VO(acac)2. Sharpless and coworkers have carried out the oxidative kinetic resolution of several p-hy-droxy tertiary amines such as (41) with r-butyl hydroperoxide, titanium(rv) isoprcqtoxide and (-i-)-diiso-propyl tartrate, the titanium(rv) tartrate ratio being ateut 2 1." After 60% conversion, one enantiomer was selectively oxidized, and the other enantiomer could be recovered in good optical purity (Scheme... 

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