Diethyl tartrate allylic alcohol epoxidation

With optically active tartrate esters present in the reaction system, titanium alkoxides catalyze a very stereoselective oxidation of allylic alcohols. This method must depend on specific interactions in the transition state by which the hydroxyl group controls the relationship between the double bond and approaching reagent and the tartrate establishes a chiral environment at the metal atom. The (+) and (-) enantiomers of diethyl tartrate give enantiomeric epoxides, each in >90% yield." ... 

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 Sharpless-Katsuki asymmetric epoxidation reaction (most commonly referred by the discovering scientists as the AE reaction) is an efficient and highly selective method for the preparation of a wide variety of chiral epoxy alcohols. The AE reaction is comprised of four key components the substrate allylic alcohol, the titanium isopropoxide precatalyst, the chiral ligand diethyl tartrate, and the terminal oxidant tert-butyl hydroperoxide. The reaction protocol is straightforward and does not require any special handling techniques. The only requirement is that the reacting olefin contains an allylic alcohol. 

In 1980, Katsuki and Sharpless communicated that the epoxidation of a variety of allylic alcohols was achieved in exceptionally high enantioselectivity with a catalyst derived from titanium(IV) isopropoxide and chiral diethyl tartrate. This seminal contribution described an asymmetric catalytic system that not only provided the product epoxide in remarkable enantioselectivity, but showed the immediate generality of the reaction by examining 5 of the 8 possible substitution patterns of allylic alcohols all of which were epoxidized in >90% ee. Shortly thereafter. Sharpless and others began to illustrate the... 

A number of reaction variables or parameters have been examined. Catalyst solutions should not be prepared and stored since the resting catalyst is not stable to long term storage. However, the catalyst solution must be aged prior to the addition of allylic alcohol or TBHP. Diethyl tartrate and diisopropyl tartrate are the ligands of choice for most allylic alcohols. TBHP and cumene hydroperoxide are the most commonly used terminal oxidant and are both extremely effective. Methylene chloride is the solvent of choice and Ti(i-OPr)4 is the titanium precatalyst of choice. Titanium (IV) t-butoxide is recommended for those reactions in which the product epoxide is particularly sensitive to ring opening from alkoxide nucleophiles. ... 

The asymmetric epoxidation of an allylic alcohol 1 to yield a 2,3-epoxy alcohol 2 with high enantiomeric excess, has been developed by Sharpless and Katsuki. This enantioselective reaction is carried out in the presence of tetraisopropoxyti-tanium and an enantiomerically pure dialkyl tartrate—e.g. (-1-)- or (-)-diethyl tartrate (DET)—using tcrt-butyl hydroperoxide as the oxidizing agent. 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary ... 

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 transition-state model of this reaction has been proposed as (1), based on X-ray analyses of single crystals prepared from Ti(OPr )4, (R,R)-diethyl tartrate (DET), and PhCON(OH)Ph and from Ti(OPr )4, and (R,R) N,/V -dibenzyltartramide.30-32 The Z-substituent (R2), located close to the metal center, destabilizes the desired transition state and decreases enantioselectivity (vide supra). When the Z-substituent is chiral, face selection induced by the substituent strongly affects the stereochemistry of the epoxidation, and sometimes reversed face selectivity is observed.4 In contrast, the. E-substituent (R1) protrudes into an open space and E -allylic alcohols are generally good substrates for the epoxidation. 

Since its discovery in 1980,7 the Sharpless expoxidation of allylic alcohols has become a benchmark classic method in asymmetric synthesis. A wide variety of primary allylic alcohols have been epoxidized with over 90% optical yield and 70-90% chemical yield using TBHP (r-BuOOH) as the oxygen donor and titanium isopropoxide-diethyl tartrate (DET, the most frequently used dialkyl tartrate) as the catalyst. One factor that simplifies the standard epoxidation reaction is that the active chiral catalyst is generated in situ, which means that the pre-preparation of the active catalyst is not required. 

The asymmetric dihydroxylation protocol was the second massive contribution by Professor Barry Sharpless to synthetic organic chemistry. The first procedure, introduced with Katsuki, involves the catalytic asymmetric epoxida-tion of allylic alcohols. A typical example is shown in Scheme 17, wherein ( )-allylic alcohol (23) is epoxidized with tert-b utyl hyd roperox ide, in the presence of titanium tetra-isopropoxide and optically active diethyl tartrate to give the... 

In 1980, Katsuki and Sharpless[1] reported that, with the combination of a titanium(IV) alkoxide, an enantiomerically pure tartrate ester [for example (+)-diethyl tartrate ((+)-DET) or (+) di-iso-propyltartrate ((+)-DIPT)] and tert-butyl hydroperoxide, they were able to carry out the epoxidation of a variety of allylic alcohols in good yield and with a good enantiomeric excess (Figure 5.1). 

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. 

Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-wo-propoxide, and optically pure diethyl tartrate. 

In 1980, Katsuki and Sharpless described the first really efficient asymmetric epoxidation of allylic alcohols with very high enantioselectivities (ee 90-95%), employing a combination of Ti(OPr-/)4-diethyl tartrate (DET) as chiral catalyst and TBHP as oxidant Stoichiometric conditions were originally described for this system, however the addition of molecular sieves (which trap water traces) to the reaction allows the epoxidation to proceed under catalytic conditions. The stereochemical course of the reaction may be predicted by the empirical rule shown in equations 40 and 41. With (—)-DET, the oxidant approaches the allylic alcohol from the top side of the plane, whereas the bottom side is open for the (-l-)-DET based reagent, giving rise to the opposite optically active epoxide. Various aspects of this reaction including the mechanism, theoretical investigations and synthetic applications of the epoxy alcohol products have been reviewed and details may be found in the specific literature . 

Earlier on in our work, we also used the other legendary Sharpless oxidation, the asymmetric epoxidation [22] for the transformation of the allylic alcohol 17 into the epoxide 18. In the presence of (+)-diethyl tartrate, 17 was converted... 

Both the ally lie alcohol and tert-hutyX hydroperoxide are achiral, but the product epoxide is formed in high optical purity. This is possible because the catalyst, titanium tetraiso-propoxide, forms a chiral (possibly dimeric [36]) complex with resolved diethyl tartrate [(+)-DET] which binds the two achiral reagents together in the reactive complex. The two enantiotopic faces of the allylic double bond become diastereotopic in the chiral complex and react at different rates with the tert-butyl hydroperoxide. Many other examples may be found in recent reviews [31, 37-39]. 

Asymmetric epoxidation of ailylic alcohols.1 Epoxidation of allylic alcohols with r-bulyl hydroperoxide in the presence of titanium(lV) isopropoxide as the metal catalyst and either diethyl D- or diethyl L-tartrate as the chiral ligand proceeds in > 90% stereoselectivity, which is independent of the substitution pattern of the allylic alcohol but dependent on the chirality of the tartrate. Suggested standard conditions are 2 equivalents of anhydrous r-butyl hydroperoxide with 1 equivalent each of the alcohol, the tartrate, and the titanium catalyst. Lesser amounts of the last two components can be used for epoxidation of reactive allylic alcohols, but it is important to use equivalent amounts of these two components. Chemical yields are in the range of 70-85%. 

DIBAH reduction of 4 at -78 °C provides the corresponding trans-allylic alcohol. Successive epoxidation with meto-chloroperbenzoic acid (MCPBA) yields a single syn epoxide 5. The stereochemical assignment is proven by a second experiment using the asymmetric Sharpless epoxidation protocol. Both MCPBA and the Sharpless protocol using (-)-diethyl D-tartrate provided 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. 

Thus, the reaction is very predictable. When a ( )-tartratc ligand such as (-)-DET (diethyl tartrate) or (-)-DIPT (diisopropyl tartrate) is used, the oxygen atom is delivered to the top face of the olefin when the allylic alcohol is depicted as in 31. The (+)-tartrate ligand, on the other hand, allows the bottom face to be epoxidized. 

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. 

Fig. 3.7. Definition of the enantiomeric excess ee using the Sharpless epoxidation of allylic alcohol as an example. The chiral auxiliary is tartaric acid diethyl ester (diethyl tartrate, DET).

Asymmetric epoxidation of homoallylic alcohols. Sharpless asymmetric epoxidation of primary homoallylic alcohols with l-( + )-diethyl tartrate proceeds with only moderate enantiomeric selectivity (23-55% ee) and opposite to that observed with allylic alcohols. Unfortunately, operation at low temperatures to improve the enantiomeric excess also retards the rate drastically. Even so, this epoxidation provides a useful synthesis of (-l-)--y-amino-P(R)-hydroxybutyric acid (1). 

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