Titanium isopropoxide - tartrate complex

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... 

Transition-metal-catalysed epoxidations work only on allylic alcohols, so there is one limitation to the method, but otherwise there are few restrictions on what can be epoxidized enantioselectively. When this reaction was discovered in 1981 it was by far the best asymmetric reaction known. Because of its importance, a lot of work went into discovering exactly how the reaction worked, and the scheme below shows what is believed to be the active complex, formed from two titanium atoms bridged by two tartrate ligands (shown in gold). Each titanium atom retains two of its isopropoxide ligands, and is coordinated to one of the carbonyl groups of the tartrate ligand. The reaction works best if the titanium and tartrate are left to stir for a while so that these dimers can form cleanly. 

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]. 

The epoxides (11) derived from 2-substituted allylic alcohols (10) are particularly susceptible to nucleophilic attack at C-3, a reaction that is promoted by titanium(IV) species. When stoichiometric amounts of titanium tartrate complex are used in these epoxidations considerable product is lost via opening of the epoxide before it can be isolated from the reaction. The primary nucleophilic culprit is the isopropoxide ligand of the Ti(OPr )4. The use of Ti(OBu )4 in place of Ti(OPr )4 has been prescribed as a means to reduce this problem (the t-butoxide being a poorer nucleophile). Fortunately, a better solution now exists in the form of the catalytic version of the reaction which uses only 5-10 mol % of titanium tartrate complex and greatly reduces the amount of epoxide ring opening. Some comparisons of results from reactions run under the two sets of conditions are possible tom the epoxidations summarized in Table 3. 

Titanium(IV) isopropoxide Chemical Abstracts nomenclature 2-propanol, titanium(4-f-) salt) is the titanium species of choice for preparation of the titanium tartrate complex in the asymmetric epoxidation process. The use of titanium(IV) t-butoxide has been recommended for those reactions in which the epoxy alcohol product is particularily sensitive to ring opening by the alkoxide. The 2-substituted epoxy alcohols (Section 3.2.5.2) are one such class of compounds. Ring opening by t-butoxide is much slower than by isopropoxide. With the reduced amount of catalyst that now is needed for all asymmetric epoxidations, the use of Ti(OBu )4 appears to be unnecessary in most cases, but the concept is worth noting. 

The precatalyst, however, is a chiral rather than a Mo complex. It is generated by the in situ treatment of titanium isopropoxide with optically pure diethyl or diisopropyl tartrate. As L-tartaric acid is a natural product, the optically pure ligand is easily made. As shown by reaction 8.5.3.1, at the optimum Ti tartarate ratio (1 1.2), complex 8.32 is the predominant species in solution. This gives the catalytic system of highest activity and enantioselectivity. 

Asymmetric Epoxidation Reactions. While Ti(0-i-Pr)4 clearly has the capacity to bring about the nucleophilic ring-cleavage of 2,3-epoxy alcohols (see above), it remains the preferred species for the preparation of the titanium tartrate complex central to the Sharpless asymmetric epoxidation process (see, for example, eq 7). Since f-butoxide-mediated ring-opening of 2-substituted 2,3-epoxy alcohols (a subclass of epoxy alcohols particularly sensitive to nucleophilic ring-cleavage) is much slower than by isopropoxide, the use of Ti(0-f-Bu)4 is sometimes recommended in place of Ti(0-i-Pr)4. However, with the reduced amount of catalyst that is now needed for all asymmetric epoxidations, this precaution appears unnecessary in most instances. 

Before leaving the area of oxene chemistry, there is one further system worthy of mention the manganese Schiff-base complexes. The Schiff-base complexes were prepared in response to the Katsuki-Sharpless system for stereospecific epoxidation (Figure 2.19).57 The Katsuki-Sharpless system consists of titanium(IV) isopropoxide and ( + )- or (—)-diethyl tartrate with... 

Of particular value in complex syntheses is a technique for epoxidation that can be applied to allylic alcohols and that directs the approach of the oxidizing group to one or the other of the two faces of the double bond. This results in the formation of one enantiomeric form in excess of the other and, thus, stands as an asymmetric synthesis. The technique is simple and consists of the formation of a chiral catalyst, a coordination complex, from titanium tetra-isopropoxide and one of the optically active forms of a dialkyl tartrate. The allylic alcohol associates with this complex in a specific way and then is epoxidized on one face by t-butyl hydroperoxide. The epoxide is produced in high enantiomeric excess, frequently more than 95%. This process has been used widely in organic synthesis since its discovery in 1980. It is now known as the Sharpless epoxidation. 

The stereoisomers of ethyl menthyl (methylthio)methylphosphonate 32 were obtained from commercially available diethyl (methylthio)methylphosphonate by subjecting them to a highly diastereoselective hydroperoxide oxidation in the presence of catalytic amounts of a titanium (/ )- or (5)-BlNOL complex. The prevailing phosphorus stereoisomer was oxidized with cumene hydroperoxide in the presence of a Sharpless complex between titanium tetra(isopropoxide) and diethyl (/ ,/ )- or (S,S)-tartrate, to yield the corresponding (methylsulfinyl) methylphosphonates 33 (76-82% de). The sulfoxide 33 was obtained in a diastereo-merically pure form (>98% de, upon recrystallisation) and was shown to have an (/ P,Ss)-configuration (Scheme 11) [32]. 

Scheme 8.20. A representation of the overall stereopecific conversion of allylic alcohol to oxirane as a function of the absolute stereochemistry of the diethyl tartrate used to form a complex with titanium(IV) isopropoxide.

The reaction is normally performed at low temperatures (-30 to 0°) in methylene chloride, and is catalytic in the chiral component diethyl or diisopropyl tartrate (DET or DIPT), and in titanium tetra-isopropoxide, provided water is rigorously excluded 4 A molecular sieves may be added to ensure this. Both enantiomers of tartaric acid are commercially available, allowing the synthesis of either enantiomer of the epoxylalcohol. The key to the remarkable enzyme-like enantioselectivity lies in the complex formed from the... 

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