Titanium tetraisopropoxide, allylic alcohol epoxidation

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). 

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 epoxidation of allylic alcohols can also be effected by /-butyl hydroperoxide and titanium tetraisopropoxide. When enantiomerically pure tartrate ligands are included, the reaction is highly enantioselective. This reaction is called the Sharpless asymmetric epoxidation.55 Either the (+) or (—) tartrate ester can be used, so either enantiomer of the desired product can be obtained. 

Sharpless epoxidation involves treating an allylic alcohol with titanium(IV) tetraisopropoxide [Ti(0-/Pr)4], tert-butyl hydroperoxide [t-BuOOH], and a specific enantiomer of a tartrate ester. 

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 known allylic alcohol 9 derived from protected dimethyl tartrate is exposed to Sharpless asymmetric epoxidation conditions with (-)-diethyl D-tartrate. The reaction yields exclusively the anti epoxide 10 in 77 % yield. In contrast to the above mentioned epoxidation of the ribose derived allylic alcohol, in this case epoxidation of 9 with MCPBA at 0 °C resulted in a 65 35 mixture of syn/anti diastereomers. The Sharpless epoxidation of primary and secondary allylic alcohols discovered in 1980 is a powerful reagent-controlled reaction.12 The use of titanium(IV) tetraisopropoxide as catalyst, tert-butylhydro-peroxide as oxidant, and an enantiopure dialkyl tartrate as chiral auxiliary accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. If the reaction is kept absolutely dry, catalytic amounts of the dialkyl tartrate(titanium)(IV) complex are sufficient. 

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. 

Sharpless asymmetric epoxidation ° is an enantioselective epoxidation of an allylic alcohol with ferf-butyl hydroperoxide (f-BuOOH), titanium tetraisopropoxide [Ti(0-fPr)4] and (-b)- or (—)-diethyl tartrate [(-b)- or (—)-DET] to produce optically active epoxide from achiral allylic alcohol. The reaction is diastereoselective for a-substituted allylic alcohols. Formation of chiral epoxides is an important step in the synthesis of natural products because epoxides can be easily converted into diols and ethers. 

The SAE is arguably one of the most important reactions discovered in the last 30 years. The SAE converts the double bond of allyl alcohols into epoxides with high enantioselective purity using a titanium tetraisopropoxide catalyst, Ti(0-iPr)4, chiral additive, either L-(+)-diethyl tartrate [(+)-DET, 7.45] or D-(—)-diethyl tartrate [(—)-DET, 7.46], and tert-butyl peroxide (t-BuOOH, TBHP (f-butylhydroperoxide)) as the source of the oxidant in stoichiometric amounts (see section 1.5, references 28-30 of Chapter 1). 

The first practical asymmetric epoxidation of primary and secondary allylic alcohols was realized by Sharpless and Katsuki in 1980. They discovered that the use of titanium(IV) tetraisopropoxide, tert-butylhydroperoxide (TBHP), and an enantiopure chiral auxiliary (such as diethyl tartrate (6)) accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity ee > 90 %) to give chiral 2,3-epoxy alcohols, which represent valuable building blocks. In acknowledgement of the discovery and of his outstanding contributions to the development of this reaction. Sharpless was awarded one half of the Nobel Prize in Chemistry in 2001. ... 

Control of Chemoselectivity. The reaction of allylic alcohols with r-butyl hydroperoxide and vanadium acetylacetonate or titanium tetraisopropoxide provides a highly chemoselective method for the preparation of epoxides, as exemplified below. Catalysis by vanadium is envisioned to involve a complex of r-BuOOH, the OH group of the allylic alcohol, and the metal. 

Tartaric acid is the least expensive chiral starting material with twofold symmetry available from natural sources. The Sharpless Ti tartrate asymmetric epoxidation catalyst consists of titanium(IV) tetraisopropoxide (Ti(OiPr)4) in combination with a chiral tartrate diester to induce asymmetry in the reaction of allylic alcohols. It is used with an alkyl hydroperoxide such as TBHP in the presence of 3A or 4A molecular sieves (to remove water) for the epoxidation of allylic alcohols [75]. It was the first effective asymmetric epoxidation catalyst reported. 

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. 

Using titanium(IV) tetraisopropoxide, fcrf-butyl hydroperoxide, and an enantiomerically pure dialkyl tartrate, the Sharpless reaction (Figure 2.7) accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. 

The asymmetric epoxidation of allylic alcohols using titanium tetraisopropoxide/ tartrate ester/terf-butylhydroperoxide was developed by Sharpless during the 1980s to become one of the most important methods of asymmetric catalysis. Whilst there... 

Sharpless epoxidation of allyl alcohols (Sharpless, 1985, 1988 Pfenninger, 1986 Rossiter, 1985 Woodard et al., 1991 Finn and Sharpless, 1991 Corey, I990a,b), an example of which is included in Table 9.6, is perhaps the most recent and one of the most remarkable applications of asymmetric catalysis. The reaction is normally performed at low temperatures (-30 to 0°C) in methylene chloride with a titanium complex consisting of a chiral component [diethyl tartrate (DET) or diisopropyl tartrate (DIPT)] and a titanium salt (titanium tetraisopropoxide) as the catalyst. The beauty of the synthesis is that both enantiomers of the tartrate are available so that either form of the product can be prepared in more than 90% ee. 

The Sharpless asymmetric epoxidation of allylic alcohols (one of the reactions that helped K. Barry Sharpless earn his part of the 2001 Nobel Prize) offers a good example of an enantioselective technique that can be used to create either enantiomer of an epoxide product. This reaction uses a diester of tartaric acid, such as diethyl tartrate (DET) or diisopropyl tartrate (DIPT), as the source of chirality. The dialkyl tartrate coordinates with the titanium tetraisopropoxide [Ti(Oi-Pr)4] catalyst and t-butyl hydroperoxide (r-BuOOH) to make a chiral oxidizing agent. Since both enantiomers of tartaric acid are commercially available, and each enantiomer will direct the reaction to a different prochiral face of the alkene, both enantiomers of an epoxide can be synthesized. 

Sharpless Asymmetric Epoxidation (Section 11.8D) Oxidation of the carbon-carbon double bond of a 1° allylic alcohol by tert-butyl hydroperoxide in the presence of a chiral catalyst consisting of either (+)- or (-)-diethyl tartrate and titanium tetraisopropoxide gives an enantiomerically pure epoxide. The enantiomer formed depends on which enantiomer of diethyl tartrate is used in the catalyst. 

In 1980, K. B. Sharpless (then at the Massachusetts Institute of Technology, presently at The Scripps Research Institute) and co-workers reported a method that has since become one of the most valuable tools for chiral synthesis. The Sharpless asymmetric epoxidation is a method for converting allylic alcohols (Section 11.1) to chiral epoxy alcohols with very high enan-tioselectivity (i.e., with preference for one enantiomer rather than formation of a racemic mixture). In recognition of this and other work in asymmetric oxidation methods (see Section 8.16A), Sharpless received half of the 2001 Nobel Prize in Chemistry (the other half was awarded to W. S. Knowles and R. Noyori see Section 7.14). The Sharpless asymmetric epoxidation involves treating the allylic alcohol with tert-butyl hydroperoxide, titanium(IV) tetraisopropoxide [Ti(0—/-POJ, and a specific stereoisomer of a tartrate ester. (The tartrate stereoisomer that is chosen depends on the specific enantiomer of the epoxide desired). The following is an example ... 

Sharpless epoxidation (Chapter 14 Lagniappe) A method for enantioselective synthesis of a chiral epoxide by treatment of an allylic alcohol with ferf-butyl hydroperoxide, (CHa)3C—OOH, in the presence of titanium tetraisopropoxide and diethyl tartrate. 

The poorer enantioselectivities observed in the Sharpless epoxid-ation of allylic alcohols following the use of 1 1 complexes of various sugar diols compared with diisopropyl tartrate has been ascribed to the observed formation of tricyclic dimers between the former and titanium tetraisopropoxide, whereas the latter gives a monocyclic 2 1 complex. 

One of the most significant discoveries published during 1980 was the first practical method for achieving asynmietric epoxidation in very high enantiomeric excess. The reaction involves oxidation of allylic alcohols by t-butyl hydroperoxide in the presence of titanium tetraisopropoxide using either (+)- or (-)-diethyl tartrate as the chiral component. In Scheme 3 the use of (+)-diethyl... 

---