Titanium complexes allylic alcohols

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

The emergence of the powerful Sharpless asymmetric epoxida-tion (SAE) reaction in the 1980s has stimulated major advances in both academic and industrial organic synthesis.14 Through the action of an enantiomerically pure titanium/tartrate complex, a myriad of achiral and chiral allylic alcohols can be epoxidized with exceptional stereoselectivities (see Chapter 19 for a more detailed discussion). Interest in the SAE as a tool for industrial organic synthesis grew substantially after Sharpless et al. discovered that the asymmetric epoxidation process can be conducted with catalytic amounts of the enantiomerically pure titanium/tartrate complex simply by adding molecular sieves to the epoxidation reaction mix-... 

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. ... 

Allyltrialkylsilanes add to aldehydes in the presence of a Lewis acid." The mechanism of this reaction has been examined." " When chiral titanium complexes are used in the reaction, allylic alcohols are produced with good asymmetric... 

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. 

Following the success with the titanium-mediated asymmetric epoxidation reactions of allylic alcohols, work was intensified to seek a similar general method that does not rely on allylic alcohols for substrate recognition. A particularly interesting challenge was the development of catalysts for enantioselective oxidation of unfunctionalized olefins. These alkenes cannot form conformationally restricted chelate complexes, and consequently the differentiation of the enan-tiotropic sides of the substrate is considerably more difficult. 

It is also possible to carry out a substrate-controlled reaction with aldehydes in an asymmetric way by starting with an acetylene bearing an optically active ester group, as shown in Eq. 9.8 [22]. The titanium—acetylene complexes derived from silyl propiolates having a camphor-derived auxiliary react with aldehydes with excellent diastereoselectivity. The reaction thus offers a convenient entry to optically active Baylis—Hillman-type allyl alcohols bearing a substituent (3 to the acrylate group, which have hitherto proved difficult to prepare by the Baylis—Hillman reaction itself. 

The titanium reagent 1 reacts with allyl alcohol derivatives, such as halides, acetates, carbonates, phosphates, or sulfonates to afford allyltitanium complexes of the type (r 1-al-lyl)TiX(OiPr)2, as shown in Eq. 9.21 [42], As a variety of allylic alcohols are easily obtained,... 

Reactions of aldehydes with complexes 13—17 provide optically active homoallylic alcohols. The enantioselectivities proved to be modest for 13—16 (20—45% ee). In contrast, they are very high (> 94% ee) for the (ansa-bis(indenyl))(r]3-allyl)titanium complex 17 [32], irrespective of the aldehyde structure, but only for the major anti diastereomers, the syn diastereomers exhibiting a lower level of ee (13—46% ee). Complex 17 also gives high chiral induction (> 94% ee) in the reaction with C02 [32], in contrast to complex 12 (R = Me 11 % ee R = H 19% ee) [15]. Although the aforementioned studies of enan-... 

Figure 5.1 Allylic alcohol epoxidation using a chiral titanium(IV) 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... 

Other transition-metal oxidants can convert alkenes to epoxides. The most useful procedures involve /-butyl hydroperoxide as the stoichiometric oxidant in combination with vanadium, molybdenum, or titanium compounds. The most reliable substrates for oxidation are allylic alcohols. The hydroxyl group of the alcohol plays both an activating and a stereodirecting role in these reactions. /-Butyl hydroperoxide and a catalytic amount of VO(acac)2 convert allylic alcohols to the corresponding epoxides in good yields.44 The reaction proceeds through a complex in which the allylic alcohol is coordinated to... 

Indeed, several interesting procedures based on three families of active catalysts organometallic complexes, phase-transfer compounds and titanium silicalite (TS-1), and peroxides have been settled and used also in industrial processes in the last decades of the 20th century. The most impressive breakthrough in this field was achieved by Katsuki and Sharpless, who obtained the enantioselective oxidation of prochiral allylic alcohols with alkyl hydroperoxides catalyzed by titanium tetra-alkoxides in the presence of chiral nonracemic tartrates. In fact Sharpless was awarded the Nobel Prize in 2001. 

The oxygen that is transferred to the allylic alcohol to form epoxide is derived from tert-butyl hydroperoxide. The enantioselectivity of the reaction results from a titanium complex among the reagents that includes the enantiomerically pure tartrate ester as one of the ligands. The choice whether to use (+) or (-) tartrate ester for stereochemical control depends on which enantiomer of epoxide is desired. 

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. 

We were particularly interested to see whether a regio- and stereoselective hy-droxyalkylation and amrnoalkylation of 1 and 2 with aldehydes and imino esters, perhaps by choice of the substituent X at the Ti atom, with formation of the corresponding sulfonimidoyl-substituted homoallyl alcohols 4-7 and the homoallyl amines 8-11 (Fig. 1.3.3) could be achieved. Reggelin et al. had already demonstrated that the sulfonimidoyl-substituted mono(allyl)titanium complexes 3, the... 

Reaction of the bis (allyl) titanium complexes -16 with saturated and unsaturated aldehydes at -78 °C in the presence of 1.1 equiv of ClTi(OiPr)3 afforded the corresponding Z-anti-configured homoallyl alcohols 4 with >98% regioselectivity and >98% diastereoselectivity in good yields (Scheme 1.3.6) [14]. 

Reaction of the bis(allyl) titanium complexes 16 and 18 with aldehydes occurs in a step-wise fashion with intermediate formation of the corresponding mono (allyl) titanium complex containing the alcoholate derived from 4 and 5 as a ligand at the Ti atom. Then the mono(allyl)titanium complexes combine with a second molecule of the aldehyde. Both the bis (allyl) titanium complexes and the mixed mono(allyl)titanium complexes react with the aldehydes at low temperatures with high regio- and diastereoselectivities. Interestingly, control experiments revealed that for the reaction of the bis (allyl) titanium complexes with the aldehyde to occur the presence of Ti(OiPr)4 is required, and for that of the intermediate mono(allyl)titanium complexes the addition of ClTi(OiPr)3 is mandatory (vide infra). 

The treatment of the lithiated allyl sulfoximines E-15 with 1.1-1.2 equiv of ClTi(NEt2)3 at -78 to 0°C in THF or ether afforded the corresponding mono (allyl) titanium complexes E-19 in practically quantitative yields (Scheme 1.3.7) [14, 16]. Similarly the Z-configured complexes Z-19 were obtained from the Z-configured allyl sulfoximines Z-15. Reaction of the titanium complexes E-19 with aldehydes at -78 °C took place at the a-position and gave the corresponding homoallyl alcohols 6 with >98% diastereoselectivity in medium to good yields (Scheme 1.3.8) [14, 16]. 

However, a more detailed study of the reaction of the mono(allyl)titanium complexes -19 carrying different alkyl groups at the double bond with different aldehydes revealed in some cases the highly diastereoselective (>98%) formation of significant amounts of the isomeric homoallyl alcohols 4 besides 6 (Table 1.3.1). 

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