Titanium tetraisopropoxide, and

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 best titanium mediator appears to be methyltitanium triisopropoxide, yet good yields are also obtained with titanium tetraisopropoxide and chlorotitanium triisopropoxide. The methyl group on titanium serves as a dummy alkyl ligand which is eliminated as methane after hydride transfer from the... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

The 4 A Molecular Sieves System. The initial procedure for the Sharpless reaction required a stoichiometric amount of the tartrate Ti complex promoter. In the presence of 4 A molecular sieves, the asymmetric reaction can be achieved with a catalytic amount of titanium tetraisopropoxide and DET (Table 4-2).15 This can be explained by the fact that the molecular sieves may remove the co-existing water in the reaction system and thus avoid catalyst deactivation. Similar results may be observed in kinetic resolution (Table 4-3).15... 

The first synthetically useful reaction of titanium complexes of type 4, leading to the formation of two new carbon—carbon bonds, was developed by Kulinkovich et al. [55]. They found that treatment of a carboxylic acid ester with a mixture of one equivalent of titanium tetraisopropoxide and an excess of ethylmagnesium bromide at —78 to —40 °C affords 1-alkylcyclopropanols 9 in good to excellent yields (Scheme 11.2) [55,56], This efficient transformation can also be carried out with sub-stoichiometric amounts of Ti(OiPr)4 (5—10 mol%) [57,58]. In this case, an ethereal solution of two equivalents of EtMgBr is added at room temperature to a solution containing the ester and Ti(OiPr)4. Selected examples of this transformation are presented in Table 11.1 (for more examples, see ref. [26a]). 

In the presence of titanium bis(TADDOLate)s such as 51 and 52 (25 mol%), generated from titanium tetraisopropoxide and the corresponding TADDOL, as well as chlorotri-... 

Engler and colleagues256 demonstrated that the way in which catalyst 406 is prepared has a strong effect on the regioselectivity and enantioselectivity of quinone Diels-Alder reactions. The most effective catalyst was prepared from a 1 1 1 mixture of titanium tetrachloride, titanium tetraisopropoxide and chiral diol 416. The cycloadditions of 2-methoxy-l,4-benzoquinones such as 414 with simple dienes to give adducts like 415 proceeded with high yields and enantioselectivities of up to 80% ee using this catalytic system (equation 123). 

Yamamoto and colleagues prepared chiral titanium catalyst 420 from titanium tetraisopropoxide and chiral binaphthol 419 (equation 126). This catalyst gave high asymmetric inductions in various Diels-Alder reactions of a,/J-unsaturated aldehydes with cyclopen-tadiene and 1,3-cyclohexadiene260. 

Although it was also Henbest who reported as early as 1965 the first asymmetric epoxidation by using a chiral peracid, without doubt, one of the methods of enantioselective synthesis most frequently used in the past few years has been the "asymmetric epoxidation" reported in 1980 by K.B. Sharpless [3] which meets almost all the requirements for being an "ideal" reaction. That is to say, complete stereofacial selectivities are achieved under catalytic conditions and working at the multigram scale. The method, which is summarised in Fig. 10.1, involves the titanium (IV)-catalysed epoxidation of allylic alcohols in the presence of tartaric esters as chiral ligands. The reagents for this asyimnetric epoxidation of primary allylic alcohols are L-(+)- or D-(-)-diethyl (DET) or diisopropyl (DIPT) tartrate,27 titanium tetraisopropoxide and water free solutions of fert-butyl hydroperoxide. The natural and unnatural diethyl tartrates, as well as titanium tetraisopropoxide are commercially available, and the required water-free solution of tert-bnty hydroperoxide is easily prepared from the commercially available isooctane solutions. 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

The real breakthrough in the field of enantioselective epoxidation was reached by Sharpless and Katsuki with the development of the catalytic system consisting of titanium tetraisopropoxide and optically active diethyl- or diisopropyl tartrate (DET or DIPT) and water-free TBHP as oxygen donor (Scheme This milestone in synthetic organic... 

Titanium nitride UFPs synthesized by a microwave plasma method from titanium tetraisopropoxide and NH, or N2 as reactants showed cubic (TiN) and tetragonal (Ti2N) structures, depending on the operational conditions, particularly on the relative nitrogen gas flow rates (62). 

Katsuki and Sharpless reported the new process of asymmetric epoxidation8 using a complex of titanium tetraisopropoxide and diethyl tartrate (DET), and t-butyl hydroperoxide (equation 18). 

In order to prevent competing homoallylic asymmetric epoxidation (AE, which, it will be recalled, preferentially delivers the opposite enantiomer to that of the allylic alcohol AE), the primary alcohol in 12 was selectively blocked as a thexyldimethylsilyl ether. Conventional Sharpless AE7 with the oxidant derived from (—)-diethyl tartrate, titanium tetraisopropoxide, and f-butyl hydroperoxide next furnished the anticipated a, [3-epoxy alcohol 13 with excellent stereocontrol (for a more detailed discussion of the Sharpless AE see section 8.4). Selective O-desilylation was then effected with HF-triethylamine complex. The resulting diol was protected as a base-stable O-isopropylidene acetal using 2-methoxypropene and a catalytic quantity of p-toluenesulfonic acid in dimethylformamide (DMF). Note how this blocking protocol was fully compatible with the acid-labile epoxide. 

Sato S., Oimatsu S., Takanashi R., Sodesawa T., Nozaki F. (1997) Pore size regulation of Ti02 by use of a complex of titanium tetraisopropoxide and stearic acid, Chem. Comm., 2219-2220. 

Although many oxidizing reagents remove the chromium tricarbonyl group, benzylic alcohols can be oxidized to benzaldehydes using dimethyl sulfoxide with acetic anhydride, trifluoroacetic anhydride, or sulfurtrioxide with minimal decomplexation. Asymmetric oxidation of aUcylthio-substituted complexes can be achieved using titanium tetraisopropoxide and an optically active tartrate ester (Scheme 108). Dimethyloxirane can also be used to oxidize sulfides to sulfoxides. 

In the presence of a catalytic amount of the chiral titanium reagent (8) prepared from titanium tetraisopropoxide and the (/ )-1,4-diol, kinetic resolution of 5 -(2-pyridyl) thioesters of a-aryl carboxylic acids is achieved with high relative rate of both the enantiomers to give the (f )-isopropyl esters with high optical purity (eq 17). ... 

The same conversion is successfully catalyzed by using in-situ generated complexes of Ti(OPr )4 and tridentate Schiff bases (Stmcture 54), which are derived from substituted salicylaldehydes with chiral aminoalcohols [85]. Another similar chiral reagent is derived from reaction of titanium tetraisopropoxide and the Schiff base of 3,5-di-tert-butylsalicylaldehyde and (5)-valinol. The mechanism and stereoselectivity of these chiral Lewis acids are discussed by Corey and co-workers. Other chiral Ti Schiff base complexes have been employed in asymmetric TMSCN addition to benzaldehyde [85]. 

The recently launched Esomeprazole (97, AstraZeneca), which is the (5)-isomer of the anti-ulcer drug. Omeprazole (a typical racemic switch agent) is effectively synthesized by employing diethyl tartrate (DET), titanium tetraisopropoxide, and cumene hydroperoxide with > 90 % yield and > 90 % ee (Scheme 29) [89]. Under optimal conditions an amazing cost performance is realized to produce Esomeprazole cheaper than the racemic Omeprazole [89b]. 

Attention is drawn to the synthesis the oxygenated linalool oxide 896. This compound (and other stereoisomers) is not a naturally occurring monoterpenoid, but a fragment required in the synthesis of a calcium ion-selective ionophore, ionomycin, and was made from hydroxygeranyl acetate (113, R = Ac), then Sharpless conditions for introducing a chiral epoxide were used. The vital step is the cyclization of 897 by epoxidizing again under Sharpless conditions (titanium tetraisopropoxide and diethyl tartrate) when the product 896 is obtained. ... 

Brent et al. [32] produced gels from the hydrolysis of vanadyl triisopropoxide, titanium tetraisopropoxide, and silica tetraethoxide. 

An actual breakthrough in the field of asymmetric epoxidation was the discovery of a new method for the preparation of homochiral epoxy alcohols by Katsuki and Sharpless in 1980 [13]. The main idea was to change the catalytic system and to use titanium tetraisopropoxide and l-( + )- or d-( — )-diethyl tartrate (DET). With water-free solutions of TBHP various allylic alcohols can be epoxidized with high enantioselectivity. 

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