Kinetic resolution of racemic epoxides

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well 

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One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

Scheme 9.20 Dynamic kinetic resolution of racemic epoxide...

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Aminolytic Kinetic Resolution of Racemic Epoxides with... 

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... 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

It should finally be mentioned that chiral base methodology is not limited to the desymmetrization of meso-epoxides but also enables kinetic resolution of racemic epoxides [57, 63, 65], This (organocatalytic) type of reaction seems, however, to be less prominent than the desymmetrization of meso-epoxides. Some examples of kinetic resolution of chiral epoxides are summarized in Scheme 13.35. 

Jacobsen s cobalt and chromium salen complexes 69 and 70 have proven extremely successful in the enantioselective ring opening of meso-epoxides (and kinetic resolution of racemic epoxides). Recent accounts of these most efficient and practical catalysts can be found elsewhere [71-73]. 

A review of the metal-catalysed ring opening of achiral epoxides by achiral carbon-, sulfur-, nitrogen- and halogen-containing nucleophiles and kinetic resolution of racemic epoxides has been published.24 The review also discusses the reactions of chiral bases with epoxides that give allylic alcohols. 

The chiral amide approach has also been applied to the catalytic kinetic resolution of racemic epoxides. For example, exposure of the tricyclic epoxide 90 with 10 mo % 86 and stoichiometric LDA at 0°C led to the recovery of the chiral spiro[4.5]decenol 91 with 90% ee and in 45% isolated yield, compared to the theoretical 50% maximum <02OL3777>. This halfway barrier... 

Beller et al. [85] recently described the aerobic dihydroxylation of olefins catalyzed by osmium at basic pH, as mentioned above. When using the hydroquini-dine and hydroquinine bases, they were able to obtain reasonable enantioselectivities (54% ee to 96% ee) for a range of substrates. An alternative route towards enantiopure diols, is the kinetic resolution of racemic epoxides via enantioselec-tive hydrolysis catalyzed by a Co(III)salen acetate complex, developed by Jacob-... 

A so far still unsolved problem is the direct enantioselective epoxidation of simple terminal olefins. For example the epoxidation of propylene that was achieved with a 41% ee almost twenty years ago by Strukul and his coworkers using Pt/diphosphine complexes is still unsurpassed. Unfortunately such low ee s are of no practical interest. The problem was circumvented by Jacobsen using hydrolytic kinetic resolution of racemic epoxides (Equation 26) and is practised on a multi 100 kg scale at Chirex. The strategy used is to stereose-lectively open the oxirane ring of a racemic chiral epoxide leaving the other enantiomer intact. Reactions are carried out to a 50% maximum conversion. The catalyst belongs to the metal-salen class described above and can be recycled. The products are separated by fractional distillation. 

A less common strategy for asymmetric synthesis, but one with considerable merit, is the enantioselective opening of meso epoxides (Fig. la) by achiral nucleophiles in the presence of a chiral catalyst. [5] Similarly, the kinetic resolution of racemic epoxides (Fig. lb), in the best cases, can deliver high enantiomeric excesses in the unreacted epoxide and ring-opened product. 

Despite the phenomenal success of these homogeneous catalysts, further developments of new asymmetric catalysts, bio-catalysts and heterogeneous catalysts will benefit from a greater understanding of the mechanistic pathways involved in the catalytic reactions [7]. A good illustration of this process is the hydrolytic kinetic resolution of racemic epoxides using a Co-based Salen catalyst... 

Scheme 5.2-126 The kinetic resolution of racemic epoxides in [BMiM][PF6] or [BMiM][Tf2N] [276],...

The chiral (salen)Co catalysts have also been applied to cyclization reaction and preparation of intermediates for natural product synthesis [85]. In addition, chiral (salen)Ru catalysts proved to be effective for kinetic resolution of racemic epoxides [86]. Tridentate Schiff base Cr(III) complex (201) derived l-amino-2-indanol acts as a potent catalyst for asymmetric ring-opening reaction of meso-aziridines with trimethylsilyl azide (Scheme 16.60) [87]. The aziridine (200) was readily converted at —30 °C to the corresponding amino-azide in 95% yield with 94% ee. 

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]. 

Scheme 7.31 Hydrolytic kinetic resolution of racemic epoxides.

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