Limonene epoxidation reactions

The two limonene epoxides (93) behave differently when treated with lithium in ethylamine. The trans-epoxide (93a) yields exclusively trons-) -terpineol (94a), excess lithium and long reaction periods reducing the double bond, whereas the c/s-epoxide (93b) yields not only cis-)8-terpineol (94b), but also neo- (95) and isodihydrocarveol (96). The menth-l-ene epoxides [e.g. (97)] behave similarly. ... 

Various chemical processes of limonene, which lead to the obtainment of useful chemicals and some analytical methods, are based on these reactions. Many flavor chemicals are synthesized from limonene by reaction with water, sulfur and halogens, or hydrolysis, hydrogenation, boration, oxidation and epoxide formation (Thomas and Bessiere, 1989). Hydroperoxides have also been studied and isolated because of their effect on off-flavor development in products containing citrus oil flavoring agents (Clark et al., 1981 Schieberle et al., 1987). Hydration of d-limonene produces alpha-terpineol, a compound that gives off an undesirable aroma in citrus-flavored products. It is also possible to produce alpha-terpineol and other useful value-added compounds... 

R. Barrera Zapata, A. L. Villa, C. Montes de Correa, Limonene epoxidation Diffusion and reaction over PW-amberlite in a triphasic system, Ind. Eng. Chem. Res. 45 (2006) 4589. 

Computational approaches to evaluate different mechanistic proposals for an enzyme have made great strides in the past 10 years. The chapter by Hopmann and Himo describe one such approach and its application to three different enzymatic reactions involving the transformation of an epoxide. The procedures and parameters to make a model of the active site are presented first and are followed by discussions of limonene epoxide hydrolase, soluble epoxide hydrolases, and haloalcohol dehalogenase. The results generally support the currently accepted mechanism for each enzyme but provide new insights into their regioselectivities. 

In this chapter, we will provide an overview of the employed methodology. To illustrate the various aspects of the methodology and to give the reader a feeling about the state of the art of the field, three very recent applications will be discussed in detail. All three enzymes are concerned with epoxide-transforming reactions, namely limonene epoxide hydrolase (LEH), soluble epoxide hydrolase (sEH), " and haloalcohol dehalo-genase C (HheC). First, however, a brief presentation of DFT and its accuracy will be given. 

Predict the products from opening of the two stereoisomeric epoxides derived from limonene by reaction with (a) acetic acid, (b) dimethylamine, and (c) lithium aluminum hydride. 

Costa et al. also tested their catalytic system based on complex 67, for the epoxidation (reaction 7.9) of cis-cyclooctene, 73, which yielded over 90% conversion within 2 hours at room temperature by TBHP in chloroform. Its chemoselectivity also is shown by the formation of only 1,2-epoxy limonene from limonene as the same condition as cyclooctene. 

Most EHs have a/ 3-hydrolase fold topology and consist of a core and a lid domain [65,66]. The lid domain is mainly a-helical and contains two tyrosine residues that point toward the catalytic triad and cover the core domain. Both tyrosine residues are involved in substrate binding, Uansition-state stabilization, and activation of the epoxide by protonation. The catalytic center is composed of two aspartate and one histidine residue. The first crystal structure of an epoxide hydrolase was solved for the enzyme from Agrobacterium radiobacter ADI (EchA) [67]. The reaction mechanism of EHs is depiaed in Scheme 9.9. First, a nucleophilic attack of the aspartic residue on the epoxide ring of the substrate 31 takes place and a covalently bound ester 32 is formed. This intermediate is subsequently hydrolyzed by a so-called charge relay system (general base catalysis) and the diol 33 is released from the active site. Key reaction parmers are a histidine residue and a water molecule. It is worth mentioning that a limonene epoxide hydrolase discovered by Arand et al. displayed a different crystal structure and catalytic cycle that is discussed elsewhere [68]. 

Two years later, in 2010, Aggarwal and coworkers reported the application of isothiocineole, which has a similar stmcture as 12 and 15 and was prepared via the reaction of limonene with elemental sulfur (Scheme 20.9). In the epoxidation reaction of aldehydes, good yields (56-97%) and high stereoselectivities (60-90% de, 70-98% ee) were obtained with stoichiometric amounts of the preformed benzyl and allyl sulfonium salts [24]. 

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

The alicyclic epoxide, limonene oxide, which is obtained from a renewable resource has shown modest activity compared to CHO for reaction with C02 to provide a copolymer. This significant decrease in reactivity is presumably due to the steric influence of a disubstitution at one of the ipso carbon centers. Of course, in either highly selective reaction, where complete formation of copolymer or cyclic carbonate occurs, the process displays 100% atom economy. The environmental attractiveness of this process is further enhanced by the fact that reactions are generally carried out in the absence of an organic cosolvent, that is, in C02-swollen epoxide solutions. 

These catalysts have been tested in the stereoselective epoxidation of R-(+)-limonene and (-)-a-pinene. Here only the epoxidation of (-)-a-pinene as depicted in Figure 4 is considered. The oxidant applied in the reaction is somewhat similar to the one introduced by Mukaiyama et al. and was favored over the system used by Jacobsen and coworkers14. 17. The major benefit of this system is that undesirable salt formation can be avoided by the use of environmentally benign molecular oxygen at RT instead of NaOCl as oxidant at 0°C. 

The selectivity pattern of d° transition metal catalyzed epoxidations is much less readily understood. In the molybdenum-catalyzed epoxidation of (S)-limonene (Table 2, entries 1 and 2) the cis selectivity could perhaps be explained by a directing effect due to -coordinating of the second double bond to molybdenum. Such a selectivity is completely missing in the analogous tungsten-catalyzed reaction of (S)-limonene (Table 2, entry 4) in the absence of a second double bond as, for example, in 3/(-acetoxy-5-cholestene (Table 4) reactions with both metals afford similar diastereomeric ratios. 

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