Epoxidation 3.3- disubstituted allyl alcohols

Ten years after Sharpless s discovery of the asymmetric epoxidation of allylic alcohols, Jacobsen and Katsuki independently reported asymmetric epoxidations of unfunctionalized olefins by use of chiral Mn-salen catalysts such as 9 (Scheme 9.3) [14, 15]. The reaction works best on (Z)-disubstituted alkenes, although several tri-and tetrasubstituted olefins have been successfully epoxidized [16]. The reaction often requires ligand optimization for each substrate for high enantioselectivity to be achieved. 

Rearrangement of 1,2-disubstituted compounds Diethoxytriphenylphosphorane, 109 epoxides to allylic alcohols Methylmagnesium N-cyclohexylisopro-pylamide, 189... 

Extensive use in synthesis has been made of the asymmetric epoxidation of (2,3 )-disubstituted allylic alcohols. With few exceptions enantiofacial selectivity is excellent (90-95% ee). The results for a number of epoxidations of allylic alcohols with smaller substituents are collected in Table 6A.6 [2,4,41,61b,79-84], while a variety of other compounds with larger groups are illustrated by structures 47-60. 

TABLE 6A.6. Epoxides from (2,3 )-Disubstituted Allylic Alcohols... 

Epoxidation of (Z)-2-methyl-2-hepten-l-ol gave epoxy alcohol 61 (80% yield, 89% ee) [2], of (Z)-2-methyl-4-phenyl-2-buten-l-ol gave 62 (90%, 91% ee) 177], and of (2T)-1 -hydroxy squalene gave 63 (93%, 78% ee) [85]. The epoxy alcohol 64 had >95% ee after recrystallization [91], In the epoxidation of (Z)-2-r-butyl-2-buten-l-ol, the allylic alcohol with a C-2 r-butyl group, the epoxy alcohol was obtained in 43% yield and with 60% ee [38], These results lead one to expect that other 2,3Z-disubstituted allylic alcohols will be epoxidized in good yield and with enantioselectivity similar to that observed for the 3Z-monosubstituted allylic alcohols (i.e., 80-95% ee). 

The 3,3-disubstituted allyl alcohols are substrates that combine a 3 -substituent with a 3Z-sub-stituent in the same molecule. Allylic alcohols with only a 3 substituent generally are epoxidized with excellent enantioselectivity, whereas those with only a 3Z-substituent are epoxidized with enantioselectivity in the range of 80-95% ee. In combination, many of the reported examples have a methyl substituent at the 3Z-position, and all are epoxidized with 90-95% ee (see Table 6A.7, entries 1-4, 6) [2,4,92-97]. Only a limited number of examples... 

The rationale that explains the kinetic resolution of the 1-monosubstituted allylic alcohols predicts that a 1,1-disubstituted allylic alcohol will be difficult to epoxidize with the Ti-tartrate catalyst. In practice, the epoxidation of 1,1-dimethylallyl alcohol (88) with a stoichiometric quantity of the Ti-tartrate complex is very slow, and no epoxy alcohol is isolated... 

Table 7 Epoxides from 3,3-Disubstituted Allylic Alcohols R R R v. R2...

Substrate structure has a dramatic influence on the rate of the Sharpless asymmetric epoxidation. -Disubstituted and trisubstituted allylic alcohols react the most rapidly whereas Z-disubstituted and unsyininetrical disubstituted analogs react much more slowly32. Chemical yields for these substitution patterns are all in the range of 77-87% and enantioselection is in the range of 95% ee except for the slow-reacting Z-disubstituted allylic alcohols that exhibit enantioselectivities in the range of 90 % ee. 

Reaction times with the catalytic method are comparable to those obtained with the stoichiometric method and Z-disubstituted allylic alcohols can be efficiently epoxidized at —20 JC in 1 -4 hours using just 5% titanium(IV) isopropoxide and 6-7.5% tartrate (Table 4). The method is especially useful for epoxidation of alcohols that react only very slowly under normal conditions. In particular, Z-disubstituted allylic alcohols (Table 4) react at useful rates only if the reaction is warmed to —10 °C. In the catalytic procedure the absence of large quantities of titanium salts and tartrate minimize epoxide opening that would be a problem in the stoichiometric procedure at this temperature. A similar situation exists for unsymmetrical disubstituted allylic alcohols (Table 4) which are also prone to opening under the conditions of the stoichiometric method. 

Epoxidation of allylic alcohols with peracids or hydroperoxide such as f-BuOaH in the presence of a transition metal catalyst is a useful procedure for the synthesis of epoxides, particularly stereoselective synthesis [587-590]. As the transition metal catalyst, molybdenum and vanadium complexes are well studied and, accordingly, are the most popular [587-590], (Achiral) titanium compounds are also known to effect this transformation, and result in stereoselectivity different from that of the aforementioned Mo- and V-derived catalysts. The stereochemistry of epoxidation by these methods has been compared for representative examples, including simple [591] and more complex trcMs-disubstituted, rrans-trisubstituted, and cis-trisubstituted allyl alcohols (Eqs (253) [592], (254) [592-594], and (255) [593]). In particular the epoxidation of trisubstituted allyl alcohols shown in Eqs (254) and (255) highlights the complementary use of the titanium-based method and other methods. More results from titanium-catalyzed diastereoselective epoxidation are summarized in Table 25. 

Oxiranes are transformed by tris(ethylthio)borane to sulfur-containing derivatives.With selenoboranes, terminal or a,)3-disubstituted epoxides yield 3-hydroxyse enides trisubstituted epoxides give allyl alcohols. 

Enolisable aldehydes such as 101 or 103 do not give quite such good yields but the ees are still good and the diastereoselectivity in favour of the trans epoxides 102 and 104 is excellent. The secret of this method is the simple preparation of the reagent 96. In the next chapters you will see that superior catalytic methods are available for asymmetric epoxidation of allylic alcohols and of m-alkenes but they are less good for the trans disubstituted alkenes that would give 97, 102, or 104. You will also see catalytic versions of sulfur ylid epoxidation. 

The isomerization shows high regiospecificity. Thus the Z-epoxide (5) is converted in high yield into the disubstituted allylic alcohol (6), whereas the E-epoxide (7) is converted mainly into the trisubstituted allylic alcohol (8). The bulk of the base may contribute to the selectivity of isomerization. 

The radical-induced epoxide ring-opening of a,/3-epoxy-0-thiocarbonyl-imidazolides (23) [equation (3)] has been reported to be a convenient alternative to the Wharton rearrangement (action of hydrazine on epoxides of a,/3-unsaturated ketones) for production of allylic alcohols. /3,y-Disubstituted allylic alcohols with Z-conhguration are the major products formed on addition of alkyl-lithiums to the vinyl epoxide (24) [equation (4)]. ... 

Sharpless early investigations of epoxidation reactions of secondary allylic alcohols were accompanied by an intriguing observation the enantiomeric alcohols display substantial rate differences in the epoxidation event. This allowed a kinetic resolution process to be considered [78, 79]. As showcased in Equation 12, the racemic substrate 56 features four diastereotopic olefin faces and its epoxidation represents a particularly interesting case [79]. As anticipated, the more nucleophilic, disubstituted olefin displays greater reactivity in the epoxidation to give 58 in > 95 % ee. As is generally the trend for metal-catalyzed epoxidation of allylic alcohols, the anti epoxy alcohol 58 is preferentially formed. Kinetic studies have shown that the use of bulkier tartrate esters, such as diisopropyl tartrate (57), generally further enhances the rate differences between two enantiomeric allylic alcohols [19]. 

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. 

We will describe representative procedures for the epoxidation of a disub-stituted aromatic allylic alcohol (A), a trisubstituted aromatic allylic alcohol (B) and a disubstituted aliphatic allylic alcohol (C). 

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