Diisopropyl tartrate , allylic alcohol epoxidation

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... 

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. ... 

Epoxidation of the simplest allylic alcohol, allyl alcohol 7, is achieved in 88-92% ee with yields of 50-60% using diisopropyl tartrate as ligand. In situ derivatization of the product glycidol 8 via esterification, sulfonylation, or ring opening with nucleophile is an attractive alternative to isolating glycidol. 

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. 

The Sharpless epoxidation of allylic alcohols with lert-butyl hydroperoxide/titanium tetraiso-propoxide/diisopropyl tartrate (DIPT) is a highly enantioface-selective reaction and follows the topicity shown51. 

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

Kinetic resolution of chiral aUylic alcohols.7 Partial (at least 60% conversion) asymmetric epoxidation can be used for kinetic resolution of chiral allylic alcohols, particularly of secondary allylic alcohols in which chirality resides at the carbinol carbon such as 1, drawn in accordance with the usual enantioface selection rule (Scheme I). (S)-l undergoes asymmetric epoxidation with L-diisopropyl tartrate (DIPT) 104 times faster than (R)-l. The optical purity of the recovered allylic alcohol after kinetic resolution carried to 60% conversion is often > 90%. In theory, any degree of enantiomeric purity is attainable by use of higher conversions. Secondary allylic alcohols generally conform to the reactivity pattern of 1 the (Z)-allylic alcohols are less satisfactory substrates, particularly those substituted at the /1-vinyl position by a bulky substituent. 

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. 

The procedure for catalytic asymmetric epoxidation of allyl alcohol coupled with in situ derivatization involves the same methodology detailed above for ( )-2-octenol. On a 1.0 mol scale using ( + )-diisopropyl L-tartrate the reaction was complete in 6 hours at — 5°C. 

In conclusion, a Sharpless asymmetric epoxidation reaction may be used to achieve regioselectivity in a complex molecule containing two allylic alcohol moieties with opposite topicity. Thus, 32 could be alternatively converted into laulimalide (1) and its C-20 regioisomer simply by switching the chiral additive from +)- R,R)- to -)- S,S)-diisopropyl tartrate (DIPT). Biological tests have shown that the natural compound 1 is by far the most active one compared to other derivatives such as the C-20 regioisomer. 

Among the reactions catalyzed by titanium complexes, the asymmetric epoxidation of allylic alcohols developed by Sharpless and coworkers [752, 807-810] has found numerous synthetic applications. Epoxidation of allylic alcohols 3.16 by ferf-BuOOH under anhydrous conditions takes place with an excellent enantioselectivity (ee > 95%) when promoted by titanium complexes generated in situ from Ti(0/ -Pr)4 and a slight excess of diethyl or diisopropyl (R,R)- or (iS, 5)-tartrates 2.69. The chiral complex formed in this way can be used in stoichiometric or in catalytic amounts. For catalytic use, molecular sieves must be added. Because both (RJ )- and (5,5)-tartrates are available, it is posable to obtain either enantiomeric epoxide from a single allylic alcohol. Cumene hydroperoxide (PhCMe20OH) can also be used in place of ferf-BuOOH. This method has been applied to industrial synthesis of enantiomeric glycidols [811, 812]. 

When racemic secondary allylic alcohols 3.17 are subjected to standard Sharpless epoxidation conditions, kinetic resolution takes place [127], By choosing (RJi)- or (5,5)-tartrate, either enantiomer of the epoxyalcohol can be obtained with a maximum yield of 50%, alongside the unreacted allylic alcohol. The ratio of epoxidation rates of the enantiomeric allylic alcohols is usually high enough to obtain both the epoxyalcohol and the unreacted allylic alcohols in high enantiomeric excesses. In some cases, the use of dicyclohexyl- instead of diisopropyl tartrate improves the enantioselectivity. Homoallylic alcohols are also epoxidized, but the selectivities are significantly lower [808]. 

The Sharpless epoxidation of allyl alcohols 3.16 by /erf-butyl hydroperoxide under catalysis with chiral titanium complexes is a very popular method that has frequently been used in industry [811, 812, 853], This epoxidation was initially developed with stoichiometric amounts of tartrate catalysts. Today, it is usually performed in the presence of catalytic amounts of Ti(0/ -Pr)4 and diethyl or diisopropyl tartrate (2R,3R)- or (25,35)-2.69 (R = Et or r-Pr). The reactions are conducted at or near room temperature in the presence of molecular sieves. Several... 

In general, the reaction accomplishes the efficient asymmetric synthesis of hydroxymethyl epoxides from allylic alcohols (Scheme 8.4). Operationally, the catalyst is prepared by dissolving titanium isopropoxide, diethyl or diisopropyl tartrate (DET or DIPT, respectively), and molecular sieves in CH2CI2 at -20 °C, followed by addition of the allylic alcohol or t-BuOOH. After a brief weiiting period (presumably to allow the ligand equilibration to occur on titanium), the final component of the reaction is added. 

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using fert-butylhydroperoxide in the presence of a chiral titanium-tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of a-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used . Thus treatment of racemic A-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [( )-74] with fert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-/)4], calcium hydride (CaHa), silica gel and L-(+)-diisopropyl tartrate [l-(+)-DIPT] gave (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [(S)-74] in high chemical yield and enantiomeric excess . Similarly prepared were the (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)-n-propylamine and other homologues of (S)-74 using l-(+)-D1PT. When D-(—)-DIPT was used, the enantiomers were formed . ... 

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. 

Catalytic Sharpless Epoxidation of allyl alcohol using (i )-diisopropyl tartrate as the source of asymmetry... 

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