Epoxides desymmetrization

Desymmetrization of meso-bis-allylic alcohols is an effective method for the preparation of chiral functionalized intermediates from meso-substrates. Schreiber et al has shown that divinyl carbonyl 58 is epoxidized in good enantioselectivity. However, because the product epoxy alcohols 59 and 60 also contain a reactive allylic alcohol that are diastereomeric in nature, a second epoxidation would occur at different rates and thus affect the observed ee for the first AE reaction and the overall de. Indeed, the major diastereomeric product epoxide 59 resulting from the first AE is less reactive in the second epoxidation. Thus, high de is easily obtainable since the second epoxidation removes the minor diastereomer. 

NOL-based systems for addition of (substituted) anilines to meso epoxides. Hou found that a ytterbium-BI NO L complex catalyzed desymmetrization of cyclohexene oxide in up to 80% ee [15], Shibasaki demonstrated that a praseodymium-BINOL complex could promote addition of p-anisidine to several epoxides in moderate yields with modest enantioselectivities (Scheme 7.7) [16]. 

Subsequent to the development of the (salen)Cr-catalyzed desymmetrization of meso-epoxides with azide (Scheme 7.3), Jacobsen discovered that the analogous (salen)Co(n) complex 6 promoted the enantioselective addition of benzoic acids to meso-epoxides to afford valuable monoprotected C2-symmetric diols (Scheme 7.15) [26], Under the reaction conditions, complex 6 served as a precatalyst for the (salen) Co(iii)-OBz complex, which was fonned in situ by aerobic oxidation. While the enantioselectivity was moderate for certain substrates, the high crystallinity of the products allowed access to enantiopure materials by simple recrystallization. 

The only notable success to date in the use of (salen)metal systems in catalysis of asymmetric cyanide addition to epoxides was achieved by Pietrusiewicz, who reported the aluminium-catalyzed desymmetrization of phospholene meso-epoxide (Scheme 7.23) in moderate ee [47]. Despite these significant efforts, a truly prac-... 

The principle cost determinant in typical hydrolytic or phenolic resolutions is the cobalt catalyst, despite the relatively low catalyst loadings used in most cases and the demonstrated recyclability with key substrates. From this standpoint, recently developed oligomeric (salen)Co complexes, discussed earlier in this chapter in the context of the hydrolytic desymmetrization of meso-epoxides (Scheme 7.16), offer significant advantages for kinetic resolutions of racemic terminal epoxides (Table 7.3) [29-31]. For the hydrolytic and phenolic kinetic resolutions, the oligo-... 

Andersson also showed that, in addition to meso-desymmetrization, kinetic resolution of some cyclic epoxides by use of the first-generation catalyst was also possible, giving both epoxides and allylic alcohols in good yields (Scheme 7.51) [108], Kozmin reported the effective use of the same catalyst in the desymmetrization of diphenylsilacyclopentene oxide. The resulting products could be used in the ster-eocontrolled syntheses of various acyclic polyols (Scheme 7.52) [109]. 

The epoxidation of divinyl carbinol constitutes a special case of a dienol epoxida-tion, as the starting diene is not conjugated (Scheme 9.10). Desymmetrization by SAE, followed by a Payne rearrangement, furnishes the vinylepoxide in high yield and with excellent enantioselectivity (compare Table 9.2, Entry 1) [43]. 

Figure 6.73 EH-catalyzed desymmetrization of cyclic meso-epoxides.

Other reactions not described here are formal [3 -i- 2] cycloadditions of a,p-unsaturated acyl-fluorides with allylsilanes [116], or the desymmetrization of meso epoxides [117]. For many of the reactions shown above, the planar chiral Fe-sandwich complexes are the first catalysts allowing for broad substrate scope in combination with high enantioselectivities and yields. Clearly, these milestones in asymmetric Lewis-base catalysis are stimulating the still ongoing design of improved catalysts. 

An elegant application of this protocol has recently been reported, which relied on the desymmetrization of a meso-epoxide to produce a key intermediate for the synthesis of merrilactone A (Equation (76)).275... 

Related catalytic enantioselective processes [115] Two catalytic procedures for asymmetric addition of cyanides to meso epoxides have been reported [116]. One is the result of work carried out in these laboratories, shown in Eq. 6.24, promoted by Ti-peptide chiral complexes, while the other, developed by Jacobsen and Schaus, is a Yb-catalyzed enantioselective reaction that is effected in the presence of pybox ligands (Eq. 6.25) [117]. Although the Shibasaki method (Eq. 6.21) is not as enantioselective as these latter methods, it has the advantage that it accomplishes both the epoxidation and subsequent desymmetrization in a single vessel. 

Scheme 6.37. Zr-catalyzed enantioselective desymmetrization of meso epoxides proceeds efficiently and with high levels of asymmetric induction.

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

Benzyloxy-2-methylpropane-l,2-diol, a desymmetrized form of 2-methylpropane-1,2,3-triol with its terminal hydroxy being protected as a benzyl ether, was prepared using the B. subtilis epoxide hydrolase-catalyzed enantioselective hydrolysis of the racemic benzyloxymethyl-l-methyloxirane readily available from methallyl chloride and benzyl alcohol. The preparation of the racemic epoxide, a key intermediate, was described in Procedures 1 and 2 (Sections 5.6.1 and 5.6.2), its overall yield being 78 %. The combined yield of enantiomerically pure (7 )-3-benzyloxy-2-methylpropane-l,2-diol was 74 % from ( )-benzyloxymethyl-l-methyloxirane, as described in Procedures 3-5 (Sections 5.6.3 and 5.6.5), with the overall procedures leading to the biocatalytic dihydroxylation of benzyl methallyl ether . 

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic di-methylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf)2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cydohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a y/a ratio of 98 2 (Scheme 8.28). The other substrates investigated produced sigmficantly lower ees of between 66% and 85%. 

Kassab, D. J. Ganem, B., (1999) An enantioselective synthesis of (-)-Allosamidin by asymmetric desymmetrization of a highly functionalized meso-epoxide. J. Org. Chem., 64 1782-1783. 

Pakulskia, Z. Pietrusiewicz, K. M. (2004) Enantioselective desymmetrization of phospholene meso-epoxide by nucleophilic opening of the epoxide.. Tetrahedron ... 

Nugent, W. A. (1998) Desymmetrization of meso-epoxides with halides A new catalytic reaction based on mechanistic insight, J. Am. Chem. Soc., 120 7139-7140. Bruns, S. Haufe, G. (1999) Catalytic asymmetric ring opening of epoxides to chlorohydrins with mild chloride donors and enantiopure titanium complexes.. 

Shibasaki and coworkers have applied heterobimetalhc gallium complexes to the desymmetrization of meso epoxides using phenolic nucleophiles. Complex 35 is... 

Inaba and coworkers reported that a Ti-BINOL complex is an effective catalyst for the desymmetrization of epoxide 44 using primary amines as nucleophiles. Of significant note is the efficiency of this reaction, with only 1 mol% catalyst necessary to attain high yields and selectivities [Eq. (10.11)]. Unfortunately, this epoxide is uniquely effective in this reaction. Cycloheptene oxide, dihydrofuran oxide, and an acyclic version of 44 each provided negligible yields under these reaction conditions ... 

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