Sharpless epoxidation selectivity

In the Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

The Sharpless epoxidation is a popular laboratory process that is both enantioselective and catalytic in nature. Not only does it employ inexpensive reagents and involve various important substrates (allylic alcohols) and products (epoxides) in organic synthesis, but it also demonstrates unusually wide applicability because of its insensitivity to many aspects of substrate structure. Selection of the proper chirality in the starting tartrate esters and proper geometry of the allylic alcohols allows one to establish both the chirality and relative configuration of the product (Fig. 4-1). 

In Sharpless epoxidation reactions, (Z)-substituted allylic alcohols react much more slowly than the corresponding (E )-substituted substrates, and sometimes the reaction is sensitive to the position of preexisting chirality in the selected substrate. For instance, in the presence of (+)-DET, chiral (E)-allylic alcohol 10 undergoes epoxidation in 15 hours to give product 11 as the major product with a diastereomeric ratio of >20 1. As for reaction with ( )-DET, 12 is then obtained, also with a diastereoselectivity of >20 1 (Scheme 4-4). 

In 1990, Choudary [139] reported that titanium-pillared montmorillonites modified with tartrates are very selective solid catalysts for the Sharpless epoxidation, as well as for the oxidation of aromatic sulfides [140], Unfortunately, this research has not been reproduced by other authors. Therefore, a more classical strategy to modify different metal oxides with histidine was used by Moriguchi et al. [141], The catalyst showed a modest e.s. for the solvolysis of activated amino acid esters. Starting from these discoveries, Morihara et al. [142] created in 1993 the so-called molecular footprints on the surface of an Al-doped silica gel using an amino acid derivative as chiral template molecule. After removal of the template, the catalyst showed low but significant e.s. for the hydrolysis of a structurally related anhydride. On the same fines, Cativiela and coworkers [143] treated silica or alumina with diethylaluminum chloride and menthol. The resulting modified material catalyzed Diels-Alder reaction between cyclopentadiene and methacrolein with modest e.s. (30% e.e.). As mentioned in the Introduction, all these catalysts are not yet practically important but rather they demonstrate that amorphous metal oxides can be modified successfully. 

Diastereofacial selectivity in Sharpless epoxidation of 1-substituted allylic alcohols... 

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. 

The Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

Selective polymerization, enantiomers, 185 Semico rrin-copper complexes, 199 Sharpless epoxidation, racemic alcohols, 45 Side-chain units, prostaglandins, 310 Sigmatropic reactions, 222 Silanes, oxidative addition, 126 Silica gel, 285, 352... 

The absolute configurations of the new stereogenic centers in 15, introduced through the Sharpless epoxidation and crotylation, can be predicted with the aid of the rules cited above. It is worth notice, however, that crotylation in the present case was carried out at 10 kbar. This is a frequently used modification of standard reaction conditions (with other synthetic methods as well) designed to improve selectivity and/or yield. 

Consider the reactions A-F. Assume that the Sharpless epoxidations proceed with complete a-facial selectivity regardless of substrate. Select the best answer among the following choices regarding the stereochemical outcome of each of the reactions. 

Reactions B, C, E and F lead to mixtures of diastereomers. Reaction D affords a single enantiomer since the Sharpless epoxidation proceeds with complete n-facial selectivity. 

FIGURE 9.1 Face selectivity for the Sharpless epoxidation of allyl alcohols. 

Fig. 3.41. Mechanistic details of Sharpless epoxidations, part III epoxidations of chiral racemic secondary allylic alcohols in the presence of l-(+)-DET and their diastereo-selectivities. Transition state of the matched pair (top), transition states of the mismatched pair (bottom).

Similar results were obtained for -benzyl /j-hydroxyenones 4 which were epoxidized selectively under Sharpless conditions (no reaction was observed for compounds with a protected hydroxy group) and with moderate selectivity with peroxides in alkaline environment77. 

Schreiber and co-workers48 have developed a mathematical model that allows calculation of the enantiomeric purity of products of reactions exhibiting enantiocontrol and diastereoselection. Application of this model to the Sharpless epoxidation of 10 using the relative facial selectivities obtained34 for 9 leads to the expectation that the enantiomeric excess of the epoxide products 11 should increase with the progress of the reaction. Within the limits of detection, this was experimentally observed (Table 6)48. 

Sharpless epoxidation of symmetrical diols can be expected, on purely mathematical grounds, to produce diepoxide products whose enantiomeric purities are dramatically increased over those obtained for formation of a single epoxide56. Hoyle56 recently exploited the double Sharpless epoxidation of a symmetrical diol 12 to produce epoxides 13, 14 and 15 that were required for subsequent conversion to chiral 2,5-linked bistetrahydrofurans. Although the diastereomeric ratios and enantiomeric purities could not be determined, it was possible to calculate that if the enantiofacial selectivity was 19 1 (90% ee) for a single epoxidation, the ratios of isomers would be 361 38 1 for 13/14/15. Thus, in this double enantioselective epoxidation the diastereomeric excess of the chiral diepoxide (13, 15) is expected to be 99.45%. 

The asymmetric Sharpless epoxidation allowed us to obtain the epoxide of desired stereochemistry by use of the proper catalyst, however, the selectivity was not high. Much more selective was the epoxidation process of a precursor of higher sugar p)ranosidic nucleosides 79, which provided only epoxide 80 with (-)-DET, while (+)-DET afforded exclusively the opposite stereoisomer 81 (O Scheme 24) [1]. 

Optically active a ,/3-epoxyaldehydes are readily available via Sharpless epoxidation of allyl alcohols followed by oxidation. Studies by Heydari on the addition of fran -substituted a,/3-epoxyaldehydes to tri-n-butylallylstannane provide a general method for the synthesis of the corresponding yn-alcohols (9) with high selectivity (Scheme 6.3.5). 

Asymmetric oxidations have followed the usual development pathway in which face selectivity was observed through the use of chiral auxiliaries and templates. The breakthrough came with the Sharpless asymmetric epoxidation method, which, although stoichiometric, allowed for a wide range of substrates and the stereochemistry of the product to be controlled in a predictable manner [1]. The need for a catalytic reaction was very apparent, but this was developed and now the Sharpless epoxidation is a viable process al scale, although subject to the usual economic problems of a cost-effective route to the substrate (see later) [2]. The Sharpless epoxidation has now been joined by other methods and a wide range of products are now available. The pow er of these oxidations is augmented by the synthetic utility of the resultant epoxides or diols that can be used for further transformations, especially those that use a substitution reaction (see Chapter 7) [1]. 

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