Epoxidation 2-substituted allyl alcohols

Substituted epoxides are attacked by organocopper reagents at the least hindered carbon atom and form alcohols (C.R. Johnson, 1973A). With a, 9-unsaturated epoxides tram-allylic alcohols are produced selectively by 1,4-addltion (W. Carruthers, 1973 G.H. Posner, 1972). 

In general, 2-substituted allylic alcohols are epoxidized in good enantioselectivity. Like glycidol, however, the product epoxides are susceptible to ring opening via nucleophilic attack at the C-3 position. Results of the AE reaction on 2-methyl-2-propene-l-ol followed by derivatization of the resulting epoxy alcohol are shown in Table 1.6.1. Other examples are shown below. 

This class of substrate is the only real problematic substrate for the AE reaction. The enantioseleetivity of the AE reaction with this class of substrate is often variable. In addition, rates of the catalytic reactions are often sluggish, thus requiring stoichiometric loadings of Ti/tartrate. Some representative product epoxides from AE reaction of 3Z-substituted allyl alcohols are shown below. 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Although the limited examples of AE reactions on 2,3Z-substituted allyl alcohols appear to give product epoxides in good enantioselectivity, the highly substituted nature of these olefins can have a deleterious effect on the reactivity. For example, Aiai has shown that the 2,3E-substituted allyl alcohol 30 can be epoxidized with either (-)-DET or (+)-DET in good yields and enantioselectivity. However, the configurational isomer 32 is completely unreactive using (-)-DET, even after a 34 h reaction time. 

The development of transition metal mediated asymmetric epoxidation started from the dioxomolybdcnum-/V-cthylcphcdrinc complex,4 progressed to a peroxomolybdenum complex,5 then vanadium complexes substituted with various hydroxamic acid ligands,6 and the most successful procedure may now prove to be the tetroisopropoxyltitanium-tartrate-mediated asymmetric epoxidation of allylic alcohols. 

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). 

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

Kinetic resolution through Sharpless epoxidation of the trimethylsilyl-substituted allyl alcohol, rac-( )-4-trimethylsilyl-3-buten-2-ol (rac-14), which provides the S-enantiomer [( )-14, see p 476 for chemical correlation]81. 

Chiral alkenyl and cycloalkenyl oxiranes are valuable intermediates in organic synthesis [38]. Their asymmetric synthesis has been accomplished by several methods, including the epoxidation of allyl alcohols in combination with an oxidation and olefination [39a], the epoxidation of dienes [39b,c], the chloroallylation of aldehydes in combination with a 1,2-elimination [39f-h], and the reaction of S-ylides with aldehydes [39i]. Although these methods are efficient for the synthesis of alkenyl oxiranes, they are not well suited for cycloalkenyl oxiranes of the 56 type (Scheme 1.3.21). Therefore we had developed an interest in the asymmetric synthesis of the cycloalkenyl oxiranes 56 from the sulfonimidoyl-substituted homoallyl alcohols 7. It was speculated that the allylic sulfoximine group of 7 could be stereoselectively replaced by a Cl atom with formation of corresponding chlorohydrins 55 which upon base treatment should give the cycloalkenyl oxiranes 56. The feasibility of a Cl substitution of the sulfoximine group had been shown previously in the case of S-alkyl sulfoximines [40]. 

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%. 

When the allylic alcohol needed for asymmetric epoxidation is unavailable from a commercial source, reasonably general synthetic routes have been developed to allylic alcohols of several different substitution patterns. Good methods are available for the preparation of 3-substituted allylic alcohols, whereas synthesis of 2-substituted allylic alcohols is more problematic. The substrates for kinetic resolution, 1-substituted allylic alcohols, frequently can be derived by addition of alkenyl or alkynyl organometallic reagents to aldehydes followed by modification of the resulting product as required. 

Before commencing, the attention of the reader is drawn to the terms enantiofacial selectivity and diastereoselectivity. The usage in this chapter does not conform to the strictest possible definitions of these terms. In particular, enantiofacial selectivity is used with reference to the selection and delivery of oxygen by the epoxidadon catalyst to one face of the olefin in preference to the other. This usage extends to chiral allylic alcohols (primarily the 1-substituted allylic alcohols) when the focus of the discussion is on face selection in the epoxidation process. Diastereoselectivity is used in the discussion of kinetic resolution when the generation of diastereomeric compounds is emphasized. 

The epoxides (11) derived from 2-substituted allylic alcohols (10) are particularly susceptible to nucleophilic attack at C-3, a reaction that is promoted by Ti(lV) species [18]. When stoichiometric amounts of Ti-tartrate complex are used in these epoxidations, considerable product is lost via opening of the epoxide before it can be isolated from the reaction. 

TABLE 6A.3. Epoxides from 2-Substituted Allylic Alcohols... 

Several factors contribute to the frequent use of (3 )-substituted allylic alcohols (13) for asymmetric epoxidation (a) The allylic alcohols are easily prepared (b) conversion to epoxy alcohol normally proceeds with good chemical yield and with better than 95% ee (c) a large variety of functionality in the (3E) position is tolerated by the epoxidation catalyst. Representative epoxy alcohols (14) are summarized in Table 6A.4 [2,4,18,41-53] and Figure 6A.3 (4,54-61], with results divided arbitrarily according to whether the (3E) substituent is a hydrocarbon (Table 6A.4) or otherwise (Fig. 6A.3). The versatility of these and other 3-substi-tuted epoxy alcohols for organic synthesis is illustrated with several examples in the following discussion. 

If values are known for two of the three variables, the third can be predicted by use of this graph. Inspection of the graph reveals that relative rates of 25 or more are very effective for achieving kinetic resolution of 1-substituted allylic alcohols. With a relative rate of 25, the epoxidation need be carried to <60% conversion to achieve essentially 100% ee for the unreacted alcohol. A convenient method for limiting the extent of epoxidation to 60% is simply by controlling the amount of oxidant used in the reaction. However, for some substrates (see Table 6A.8, entries 1, 9, or 10) even fcfast is extremely slow and the epoxidation takes several days [2,13,104-106]. To shorten the time needed for such reactions, an alternate practice is to use an... 

Figure 6AJ5. Dependence of enantiomeric excess on relative rate in the epoxidation of 1 -substituted allylic alcohols.

Relative rate data for the kinetic resolution/epoxidation of 1-substituted allylic alcohols of varying structure are summarized in Table 6A.8. The j values at -20°C for all entries in Table 6A.8 were determined using DIPT as the chiral ligand. Additionally, for several entries (1-3, 10, 11) the dependence of rel on temperature, 0 versus -20°C, and on steric bulk of the tartrate ester (DIPT vs. DET vs. DMT) has been measured. Lower reaction temperature and larger tartrate ester groups are factors that clearly increase the magnitude of kre] and, therefore, improve the efficiency of the kinetic resolution process. Although the results summarized in Table 6A.8... 

At the end of 1989, the number of 1-substituted allylic alcohols that had been used in kinetic resolution/asymmetric epoxidation experiments exceeded 75. In slightly more than half of these experiments, the desired product was the kinetically resolved allylic alcohol, whereas in the remainder the epoxy alcohol was desired. In addition to the compounds in Table 6A.8, experimental results for other kinetically resolved alcohols are summarized in Table 6A. 10 [38,77,110-115a-d]. From these results, it appears that kinetic resolution is successful regardless of the nature of the (3E) substituent and is successful with any except the most bulky substituents at C-2. 

Three different principles of selectivity are required to achieve this result. First, the difference in rate of epoxidation by the catalyst of a disubstituted versus a monosubstituted olefin must be such that the propenyl group is epoxidized in complete preference to the vinyl group. The effect of this selectivity is to reduce the choice of olefinic faces to four of the two propenyl groups. Second, the inherent enantiofacial selectivity of the catalyst as represented in Figure 6A.1 will narrow the choice of propenyl faces from four to two. Finally, the steric factor responsible for kinetic resolution of 1-substituted allylic alcohols (Fig. 6A.2) will determine the final choice between the propenyl groups in the enantiomers of 80. The net result is the formation of epoxy alcohol 81 and enrichment of the unreacted allylic alcohol in the (35)-enantiomer. 

A number of derivatives of the tartaric acid structure have been examined as substitutes for the tartrate ester in the asymmetric epoxidation catalyst. These derivatives have included a variety of tartramides, some of which are effective in catalyzing asymmetric epoxidation (although none display the broad consistency of results typical of the esters). One notable example is the dibenzyltartramide, which in a 1 1 ratio (in reality, a 2 2 complex as shown by an X-ray crystallographic structure determination [138]) with Ti(0-i-Pr)4 catalyzes the epoxidation of allylic alcohols with the same enantiofacial selectivity as does the Ti-tartrate ester complex [18], It is remarkable that, when the ratio of dibenzyltartramide to Ti is changed to 1 2, epoxidation is catalyzed with reversed enantiofacial selectivity. These results are illustrated for the epoxidation of a-phenylcinnamyl alcohol (Eq. 6A.12a). 

Epoxidation of / - or y-trimethylsilyloxy allylic alcohols. The stereoselectivity of cpoxidation of these allylic alcohols (followed by desilylation) can be controlled by substitution with a trimethylsilyl group. A /i-silyl substituted allylic alcohol is converted mainly into an erythro-epoxy alcohol, whereas a y-silyl substituent favors formation of a threo-epoxy alcohol. The stereoselectivity is usually the opposite to that obtained with m-chloroperbenzoic acid.1 Example ... 

The epoxy-Ramberg-Backlund reaction (ERBR) has been used for the conversion of a,/3-epoxy sulfones into a range of mono-, di-, and tri-substituted allylic alcohols.34 Modification of this method has permitted the preparation of enantio-enriched allylic alcohols following the diastereoselective epoxidation of enantio-enriched vinyl sulfones that were accessed efficiently from the chiral pool. 

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