Titanium tetraisopropoxide, allylic alcohol

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. 

Tamura et al. (170-172) discovered that, when reactions of ester-substituted nitrones with allylic alcohols are performed in the presence of an equimolar amount of titanium tetraisopropoxide under heating or at room temperature, transesterification takes place to form new nitrones bearing an inner alkene dipolarophile. The resulting nitrone substrates undergo regio- and stereoselective intramolecular cycloaddition reactions to give the ring-fused isoxazolidines (Scheme 11.52). This tandem transesterification/[3 + 2]-cycloaddition method leads to the selective... 

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). 

Enantiomerically pure carboxylic acids are routinely obtained from N-acylsultams by Hydrogen Peroxide assisted saponification with Lithium Hydroxide in aqueous THF. 4 Alternatively, transesterification can be effected under neutral conditions in allyl alcohol containing Titanium Tetraisopropoxide, giving the corresponding allyl esters which can be isomerized/hydrolyzed with Wilkinson s catalyst (Chlorotris(triphenylphosphine)rhodium(I)) in Et0H-H20. This provides a convenient route to carboxylic acids containing base-sensitive functionality. Primary alcohols are obtained by treatment with L-Selectride (Lithium Tri-s-butylborohydride) in THF at ambient temperature. ... 

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. 

Keck almost simultaneously reported two procedures using chiral titanium catalysts 6A and 6B for the enantioselective addition of allyltributyltin to aldehydes [11]. In the first procedure, the catalyst 6A is prepared from a 1 1 mixture of (R)-binaphthol and titanium tetraisopropoxide. The second procedure for the preparation of 6B, in contrast, requires a 2 1 mixture of BINOL, Ti(0 Pr)4, and a catalytic amount of CF3SO3H or CF3CO2H. Using 10 mol % of the catalyst 6A or 6B, a variety of aromatic, aliphatic, and a,P-unsaturated aldehydes are efficiently transformed into the corresponding optically active homoallylic alcohols with high enantioselectivity. An improved procedure was later published for the catalytic asymmetric allylation reactions using the 2 1 BINOL/Ti catalytic system [12]. 

Arylamines undergo A-allylation with allylic alcohols. The reaction system also contains titanium tetraisopropoxide and molecular sieves. Some dialkylation occurs when the amino group is unhindered. 

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... 

Throughout this section, allylic alcohols will be drawn in this way, such that it is clear how the stereochemistry can be related to the model. Thus, aUyl alcohol (4.01) is converted into (J )-glycidol (4.02) using the n-(-)-diethyl tartrate/titanium tetraisopropoxide combination. However, the use of L-(- -)-diethyltartrate as the ligand affords the opposite enantiomer, (S)-glycidol. 

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. 

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