Epoxides dynamic kinetic resolution

Scheme 9.20 Dynamic kinetic resolution of racemic epoxide...

Figure 18.22. Dynamic kinetic resolution of 2,2-disubstituted epoxides 63 by epoxide hydrolase.

Epoxides are a familiar sight in the world of kinetic resolutions. As well as being made by kinetic resolution, racemic epoxides can themselves be the substrates in a kinetic resolution. For example, the use of cobalt-salen complexes - something we shall see again in the dynamic kinetic resolution section - can be used to mediate the formation of enantiomerically pure oxazolidinones.20 Enzymes can be used to react with one enantiomer of epoxide.21 And enzymes are a good way to kinetically resolve compounds and can work under surprising conditions - supercritical C02 for example22... 

The HKR of epichlorhydrine (X = Cl, Scheme 141) and 4-hydroxy-l-butene oxide (X = OH, Scheme 141), the dynamic kinetic resolution of epibromhydrin and the enantioselective ring opening of epoxides by phenol were examined. In the first experiment, combination of the crude organic soluble products of the five recycle reactions and concentration led to the (5)-epichlorhydrine in 41% overall yield and > 99% ee and the (/ )-chlorodiol in 93% ee. In the second one, the sum of five experiments provided (iS)-triol in 36% overall yield and 94.4% ee while the enantioselectivity of the epoxide was only 59% ee. 

Despite the number of reports of the asymmetric synthesis of tertiary a-aryl cyclohexanones, there have only been three reports which describe the asymmetric synthesis of tertiary a-aryl cyclopentanones. The first of these was reported by Shi via asymmetric epoxidation of benzylidene cyclobutanes and epoxide rearrangement in a subsequent step [76]. Backvall used a dynamic kinetic resolution of aUyhc alcohols-aUylic substitution-oxidative cleavage sequence to access 2-phenylcyclopentanone [77]. The first direct catalytic asymmetric synthesis of tertiary a-aryl ketones was recently described by Kingsbury using a series of Sc-catalysed diazoalkane-carbonyl homologations with bis/tris oxazohne ligands [78]. 

Dynamic kinetic resolution of racemic P-haloalcohols direct access to enantioenriched epoxides. J. Am. Chem. Soc., 130 (41), 13508-13509. 

More recently, Jacobsen and coworkers have found that epoxides undergo a highly enantioselective ring-opening with TMS-azide when catalysed by (salen)Cr(III) complexes such as (5,5)-4. This asymmetric ring opening shows a second-order rate dependence on catalyst concentration . Applications of the process have included kinetic resolution of terminal epoxides , an efficient synthesis of (/ )-4-(trimethylsilyloxy)cyclopent-2-enone, the dynamic kinetic resolution (equation 11) of epichlorohydrin, an enantioselective route to carbocyclic nucleoside analogues and a formal synthesis (equation 12) of the protein kinase inhibitor 5. 

Silica bound chiral Co-salen complex (36) was synthesized and adapted to a continuous-flow reaction. The optical kinetic resolution of racemic epoxide (38) was successful to yield the desired triol (39) in good yield (36% conversion) and high enantiomeric excess (Scheme 7.31) [127]. A PASSflow microreactor consisting of Co-salen monolith (37) was used for the dynamic kinetic resolution of epibromohydrin (40). Three runs performed on the 1-mmol scale were completed and afforded (J )-(41) in 76-87% yield with constant enantiomeric purity of 91-93% ee [128]. 

Deracemization of a number of pharmaceutically valuable building blocks has been carried out by biocatalytic processes. They include epoxides, alcohols, amines, and acids [12,14,190-192]. Dynamic kinetic resolution (DKR) involves the combination of an enantioselective transformation with an in situ racemization process so that, in principle, both enantiomers of the starting material can be converted to the product with a high yield and ee. The racemization step can be catalyzed either enzymatically by racemases or nonenz3nnatically by transition metals. 

Pamies, O. and BackvaU, J.-E. (2002). Chemoenzymatic dynamic kinetic resolution of beta-halo alcohols. An efficient route to chiral epoxides. /. Org. Chem., 67,9006-9010. 

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

In the course of our earlier studies on terpenylboranes we developed a simple transformation of a- into 3-pinene," and a stereoselective synthesis of allylic alcohols by the reduction of vinylic epoxides.12 An extension of these studies to contrathermo-dynamic isomerization of a-thujene, 2- and 3-carene,13 and kinetic resolution of vinylic epoxides by the reduction with terpenylboranes,14 is described. 

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