Methylcyclohexene oxide

G. Bellucci, C. Chiappe, F. Marioni, Enantioselectivity of the Enzymatic Hydrolysis of Cyclohexene Oxide and ( )-l-Methylcyclohexene Oxide A Comparison between Microsomal and Cytosolic Epoxide Hydrolases , J. Chem. Soc., Perkin Trans. 1 1989, 2369 -2373. 

Hydrogenolysis of epoxides to alcohols by catalytic hydrogenation over platinum requires acid catalysis. 1-Methylcyclohexene oxide was reduced to a mixture of cis- and /ranj-2-methylcyclohexanol [652]. Steroidal epoxides usually gave axial alcohols stereospecifically 4,5-epoxycoprostan-3a-ol afforded cholestan-3a,4/J-diol [652 ]. 

Since the pioneering report of Curci in 1984 that a chiral ketone can catalyze asymmetric epoxidation reactions (methylcyclohexene oxide produced with up to 12% ee using (- -)-isopinocamphone/KHSOs) <1984CC155>, this area has attracted considerable interest with particular advances being achieved in the past decade by numerous research groups. 

Epoxides may undergo rearrangement in the presence of protic or Lewis acids to give carbonyl compounds. However, the nature of the products may depend quite subtly on the reaction conditions. For example, 1-methylcyclohexene oxide has been reported to give the ring-contracted aldehyde as the major product with lithium bromide, but with lithium perchlorate, 2-methylcyclohexanone is the major product (Scheme 2.22a). In the presence of a strong base such as lithium diethylamide, an allylic alcohol may be formed from an epoxide (Scheme 2.22b). 

Japanese authors have made comprehensive investigations of the rearrangements of oxiranes in the presence of solid acids, bases, and salts.The model compounds employed were cyclohexene oxide and 1-methylcyclohexene oxide. The effects of the acidic and basic properties of the catalysts on the selectivity were interpreted on the basis of the products obtained. The main products are carbonyl compounds and allyl alcohol isomers. Rearrangements of limonene oxide over acids and bases were studied on five different types of Al203 similar research has been carried out on 2- and 3-carene oxides, cis- and trans-carvomenthene oxides and a-pinene oxide. ... 

Although infrequently used, sodium cyanotrihydroborate in the presence of BF3 has been shown to reduce epoxides with interesting regio- and stereo-chemical results. For example, 1-methylcyclohexene oxide is converted in high yield to c/s-2-methylcyclohexanol contaminated with only small amounts of the n ans and 1-methylcyclohexanol isomers. 

Enhanced reactivity associated with a tertiary center appears to be a factor in the observations made by Naqvi et on treatment of 1-methylcyclohexene oxide (229 equation 97) with MgBr . At 0 C, conditions which give only halohydrin with cyclohexene oxide, (229) was converted into the aldehyde (230). Conversely, when (229) was added to a solution of MgBr2 at 60 C, only ketone rearrangement products were isolated. The modest yields prevent mechanistic conclusions. 

Only products which can be attributed to bromohydrin (salt) intermediates are formed when epoxides are treated with LiBr (solubilizer) in refluxing benzene. Any apparent exceptions to this generalization are believed to be due to interconversion of halohydrin stereoisomers, as discussed below. The bromohydrin is formed by traditional anti opening (antiperiplanar, probably nearly exclusively trans diaxial). It has been established that a model epoxide (1-methylcyclohexene oxide) reacts by a process that is kinetically first order in a 1 1 complex of LiBr-HMPA, but the state of aggregation [n in the formula (LiBr HMPA)n] is not known.The nature of the epoxide-(LiBr-HMPA)n interaction that allows bromide to attack (exclusively) in the anti mode is not known, but must require fairly extensive ion pair (aggregate) reorganization. 

Methylcyclohexene oxide (equation 118) provides a useful model system for mechanistic discussion. It is important that no 2-methylcyclohexanone is formed, since this rules out carbenium ion pathways. The major product is derived from the bromohydrin (276), formed by bromide attack at the tertiary center (followed by chair-chair interconversion), but care must be taken to avoid overinterpretation of this observation. Thus, if the bromohydrins are rapidly interconverting via the epoxide, the product distribution would be determined not only by the equilibrium ratio of (276) and (277), but also by the respective rate constants for rearrangement to (230) and (215). Although cyclohexene bromohydrin is immediately converted to the epoxide by treatment with Bu"Li in benzene," the possible effect of HMPA on the bro-mohydrin(salt)/epoxide equilibrium is not known. The rearrangement rates would be Br (276) > Br ... 

Reduction of epoxides. The reaction of diborane alone with epoxides is complicated. Thus 1,2-butylene oxide requires 48 hrs. and gives a mixture of butanols (96% 2-butanol and 4% 1-butanol) in only 48% yield. The reaction with trisub-stituted epoxides is even more complicated and only trace amounts of simple alcohols are formed. Brown and Yoon1 found that the presence of trace amounts of sodium or lithium borohydride greatly enhances the rate of reaction and modifies the course to give predominantly anti-Markownikov opening of the epoxide ring. Thus 1-methylcyclohexene oxide is reduced mainly to m-2-methylcydohexanol ... 

LEH displays relatively narrow substrate specificity and accepts only few substrates. These include both enantiomers of 1-methylcyclohexene oxide (1 and 2, Scheme 2) and all four stereoisomers of the natural substrate limonene-1,2-epoxide (3-6, Scheme 2). The substrates are converted with different enantioselec-tivities and regioselectivities. The four stereoisomers of limonene-1,2-epoxide are hydrolyzed in an enantioconvergent fashion. Conversion of the diastereomeric mixture of 3 and 4 leads to enantioconvergent formation of (li ,2i ,4i)-limonene-l,2-diol, whereas conversion of 5 and 6 leads to enantioconvergent... 

Scheme 2 Conversion of the two enantiomers of 1 -methylcyclohexene oxide and the four stereoisomers of limonene-1,2-epoxide by LEH. Adapted from K. H. Hopmann B. M. Hallberg F. Himo, J. Am. Chem. Soc. 2005, 127, 14339-14347.

The regioselectivity of LEH has been studied experimentally with different substrates. Studies with the enantiomers of 1-methylcyclohexene oxide (1 and 2, Scheme 2) revealed preferred attack at the methyl-substituted oxirane carbon, Cl, with a regioselectivity of 85(C1) 15(C2). This indicated an acid-catalyzed mechanism, which would result in preferred attack at the more substituted carbon. However, conversion of limonene-1,2-epoxide did not support this conclusion and showed somewhat intriguing results. Exclusive attack at the more substituted carbon (Cl) is seen for the stereoisomers 4 and 5, while exclusive attack at the less substituted carbon (C2) is observed for stereoisomers 3 and 6 (Scheme 2). Interestingly, the two limonene-1,2-epoxide stereoisomers with the same stereochemistry at the oxirane ring, (IR,2S) for 3 and 5 and IS,2R) for 4 and 6, exhibit attack at opposite carbons (Scheme 2). A suggested explanation for the differences was differential binding of the substrates in the active site, which would lead to attack at different carbons. ... 

Regioselectivity of 1-methylcyclohexene oxide hydrolysis Of the two stereoisomers of 1-methylcyclohexene oxide, 1 is the preferred substrate of LEH. The two helicity conformers of 1 have almost the same energy and can be assumed to exist in equal amounts. For each conformer, attack is preferred at the carbon that will lead to a chair transition state, for 1 in the Tf-helicity this is C2 and for 1 in the P-helicity this is Cl. The two helicity forms of 1 are competing substrates of LEH, but because attack at the more substituted carbon Cl of the P-helicity has a lower barrier (14.9 kcalmol. Table 2) than attack at C2 of the Af-helicity (15.9 kcal mol . Table 2), attack occurs preferentially, but not exclusively, at Cl of the P-helicity. A mixture of products is thus expected, with preferred attack at Cl (of the P-helicity) and minor attack at C2 (of the Af-helicity). The difference in barrier of 1 kcal mol corresponds well to the experimentally observed regioselectivity of 85(Cl) 15(C2) for 1-methylcyclohexene oxide. ... 

Table 2 Calculated barriers and reaction energies (kcal mol ) for LEH-mediated conversion of 1 -methylcyclohexene oxide to 1 -methylcyclohexane-1,2-diol...

H) Regioselectivity of limonene-1,2-epoxide hydrolysis For limonene-1,2-epoxide, the natural substrate of LEH, the situation is less complex than for 1-methylcyclohexene oxide. The isopropyl substituent at C4 of limonene-1,2-epoxide determines the preferred helicity of the half-chair, and for each stereoisomer, only the helicity with the substituent in an equatorial position will be observed (Scheme 4). For this helicity, attack is preferred at the carbon that leads to a chair-like transition state. The transition states for attack at either Cl or C2 of 5 are shown in Figure 3. Attack at Cl of 5 leads to a chair-like transition state and exhibits a barrier of 14.9 kcal mol. Attack at C2 of 5 results in a twist-boat transition state and exhibits a barrier of... 

Pre-cooled 1-methylcyclohexene oxide added to a stirred 0.76 M soln. of KBHPh3 in THF containing 0.76 Af Ph3B-THF at 0°, the mixture stirred for 0.5 h, and hydrolyzed with HjO at room temp, for 0.5 h c/5-2-methylcyclohexanol. Y 90%. Ph3B as Lewis acid dramatically accelerates the rate of reduction and directs attack of hydride exclusively at the most congested C-atom of trisubst. epoxides tetra-subst. epoxides failed to react. F.e.s. N.M. Yoon, K.E. Kim, J. Org. Chem. 52, 5564-70 (1987). 

A number of interesting cyclizations not directly involving the sulphur function have been described. 1-Methylcyclohexene oxide with sodium 2-chIoroallylthiolate gave (21), which underwent add-catalysed cyclization to (22), whilst 2,4-diphenylthiepan-6-one was formed from benzalaceto-phenone on sequential treatment with 2-chloroallylthiolate ions, lithium... 

Epoxide rings can he cleaved by metal hydrides, which serve as a source of hydride ion. Write the product of the reaction of l-methylcyclohexene oxide and LiAID4. 

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