Enantiopure epoxide

Lithiation/electrophile trapping of enantiopure epoxide 209 stereoselectively gave epoxide 211 further elaboration via a metalated epoxide gave spirocydic epoxide 212, which after treatment with acid gave epoxylactone 213 as a single dia-stereomer (Scheme 5.49) [74]. 

Figure 6.72 An enantioconvergent process leading to an enantiopure epoxide.

Archelas A, R Furstoss (1997) Synthesis of enantiopure epoxides through biocatalytic approaches. Annu Rev Microbiol 51 491-525. 

Heating of a racemic mixture of2-820 in xylene at 140 °C led to the diastereomeri-cally pure cycloadduct 2-822 via 2-821 in two intramolecular processes in a yield of 90% (Scheme 2.183). Clearly, enantiopure isoxazolidines can also be obtained starting from enantiopure epoxides [412a]. 

Another very recent development in the field of enzymatic domino reactions is a biocatalytic hydrogen-transfer reduction of halo ketones into enantiopure epoxides, which has been developed by Faber, Bornscheuer and Kroutil. Interestingly, the reaction was carried out with whole lyophilized microbial cells at pH ca. 13. Investigations using isolated enzymes were not successful, as they lost their activity under these conditions [26]. 

Poessl, T.M., Kosjek, B., Ellmer, U. et al. (2005) Non-racemic halohydrins via biocatalytic hydrogen-transfer reduction of halo-ketones and one-pot cascade reaction to enantiopure epoxides. Advanced Synthesis and Catalysis, 347 (14), 1827-1834. 

Boyd, D.R., Sharma, N.D., Boyle, R., Evans, T.A., Malone, J.E., McCombe, K.M., Dalton, H. and Chima, J., Chemical and enz3mie-catalysed syntheses of enantiopure epoxide and diol derivatives of chromene, 2,2-dimethylchromene, and 7-methoxy-2,2-dimethylchromene (pre-cocene-1). J. Chem. Soc. Perkin Trans. 1,1996, 1757. 

Asymmetrie ring opening (ARO) reaction of enantiopure epoxide... 

An example of a whole-cell process is the two-step synthesis of an enantiopure epoxide by asymmetric reduction of an a-chloro ketone (Scheme 6.4), catalyzed by recombinant whole cells of an Escherichia coli sp. overexpressing an (R)-KRED from Lactobacillus kefir and GDH from Thermoplasma acidophilum, to the corresponding chlorohydrin, followed by non-enzymatic base-catalyzed ring closure to the epoxide [17]. 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

In the metal-free epoxidation of enones and enoates, practically useful yields and enantioselectivity have been achieved by using catalysts based on chiral electrophilic ketones, peptides, and chiral phase-transfer agents. (E)-configured acyclic enones are comparatively easy substrates that can be converted to enantiomeri-cally highly enriched epoxides by all three methods. Currently, chiral ketones/ dioxiranes constitute the only catalyst system that enables asymmetric and metal-free epoxidation of (E)-enoates. There seems to be no metal-free method for efficient asymmetric epoxidation of achiral (Z)-enones. Exocyclic (E)-enones have been epoxidized with excellent ee using either phase-transfer catalysis or polyamino acids. In contrast, generation of enantiopure epoxides from normal endocyclic... 

The chiral lithium amide 18 has also been used for catalytic kinetic resolution of epoxides117. Epoxide 104 was subjected for kinetic resolutions under the conditions shown in Scheme 75, which resulted in roughly enantiopure epoxide and allylic alcohol. 

Enantiopure epoxides (3/ ,4Y)-dibenz[ 7, ]anthracene 3,4-oxide and (3iJ,4Y)-phenanthrene 3,4-oxide were synthesized via involved routes and were observed to spontaneously racemize. This racemization of arene oxides is in accordance with perturbation molecular orbital predictions based on resonance energy considerations, and presumably occurs via an electrocyclic rearrangement to the corresponding (undetected) oxepine tautomer (Scheme 17) <2001J(P1)1091>. 

The synthesis of enantiopure epoxides through biocatalytic approaches (including enzymatic approaches to oxirane precursors in addition to direct olefin oxidation) has been reviewed <1997ARM491>. 

Keywords Enantiopure epoxides. Oxidative enzymes. Cytochrome P-450, co-hydroxylases. Methane monooxygenases. Lipases, Microbial oxidations. Epoxide hydrolases. Biotransformations. 

Biocatalytic Approaches forthe Synthesis of Enantiopure Epoxides... 

Similar results were described by Mamouhdian and Michael, who isolated 18 bacterial strains able to produce optically enriched epoxides with excellent ee s (up to 98%) [104, 105]. However, in the case of trflns-(2J ,3J )-epoxybutane, it was shown that the enantiomeric enrichment is in fact due to a second-step enantioselective hydrolysis of the epoxide, which is first produced in racemic form. This, interestingly, is an unexpected example of the possible use of microbial epoxide hydrolases for the synthesis of enantiopure epoxides (see below). 

Numerous other examples have been described indicating the ability of various different microbial strains [108,109] and several patents have been filed in this context [see for example 110,111 ]. However, although interesting, it is not clear whether some of these processes are used indeed for the production of enantiopure epoxides. (See Table 2 for a summary of bacterial epoxidations). 

In addition to the above described procedures implying either direct oxidation of an olefinic double bond or stereoselective reduction of a ketone precursor, which, as discussed above, do not really provide very efficient ways for the large scale synthesis of enantiopure epoxides, some indirect strategies have also been explored. These are essentially based on the resolution of epoxide-ring bearing substrates as exemplified below. As will be seen, these approaches imply the use of cofactor-independent enzymes, which are in practice much easier to work with, and lead to very interesting results. As a matter fact, some of these processes are already used on an industrial scale, and it can be predicted that future industrial applications will continue to be essentially based on the use of these very promising easy-to-use biocatalysts. 

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