Dynamic chiral alcohol

Figure 10.17 Dynamic kinetic resolution of chiral alcohols.

Keto esters, 61, 63, 65, 357 dynamic resolution, 75 hydrogenation, 63, 357 Ketone hydrogenation, 56 chiral alcohols,... 

An excellent example of the successful combination of chemo- and biocatalysis in a two-step cascade process is provided by the dynamic kinetic resolutions (DKR) of chiral alcohols and amines. We first suggested [6], in 1993, that (de)-hydrogenation catalysts should be capable of catalyzing the racemization of chiral alcohols and amines via a dehydrogenation/hydrogenation mechanism as shown in Fig. 9.1. 

Figure 13 Dynamic kinetic resolution method to the ester of a chiral alcohol.

Dynamic kinetic resolution (DKR) is an important and useful method to generate enantiomerically pure compounds from racemic substrates [87]. In this case, an in situ racemization of slow reacting enantiomer of chiral alcohol has been successfully carried out by metal-enzyme catalyst where metal complex acts as a racem-izing catalyst (Scheme 10.6) [88]. The racemization was found to be more efficient... 

Scheme 10.6 Dynamic kinetic resolution of chiral alcohols (Reproduced from Ref. [88], with kind permission of The HO Royal Society of Chemistry)...

Catalysts constituting a C2-symmetric 1,2-diamine have been used to hydrogenate a-aryl aldehydes to yield chiral alcohols, under dynamic kinetic resolution conditions. Hydrogenation of the carbonyl group of acylsilanes with 3 (presence of f-AmOK or NaBHr as activator) is apphcable to acquisition of a-silyl aUylc alcohols from conjugated acylsilanes. ... 

Dynamic Kinetic Resolution. Another typical acid-catalysed reaction is the racemisation of chiral alcohols, due to inversion at the chiral carbon. This can actually be made use of in the formation of enantiopure compounds, by dynamic kinetic resolution using an enzyme, such as a lipase, that catalyses enantioseleetive esterification in an organic medium. By coupling zeolite Beta-catalysed intereonversion of benzylic alcohol enantiomers with enzyme-catalysed esterifieation of only one of the enantiomeric alcohols, almost complete eon version to enantiopure ester ean be achieved. ... 

For a long time, kinetic resolution of alcohols via enantioselective oxidation or via acyl transfer employing, for example, lipases along with dynamic kinetic resolution have been the biocatalytic methods of choice for the preparation of chiral alcohols. In recent years, however, impressive progress has been made in the use of alcohol dehydrogenases (ADHs) and ketor-eductases (KREDs) for the asymmetric synthesis of alcohols by stereoselective reduction of the corresponding ketones. Furthermore, recent remarkable multienzymatic systems have been successfully applied to the deracemisation of alcohols via stereoinversion based on an enantioselective oxidation followed by an asymmetric reduction. 

Dynamic Kinetic Resolution (DKR) under Hydrogenation Conditions Ruthenium-catalyzed asymmetric hydrogenation of racemic a-substituted ketones via-dynamic kinetic resolution (DKR) is one of the elegant and powerful methods for the synthesis of chiral alcohols that simultaneously control two adjacent stereogenic centers with high levels of selectivity in a single chemical operation. This method was first reported... 

Transfer hydrogenation is a mild and efficient means of reducing aldehydes, and can be advantageous over other reagents such as sodium borohydride. Clearly, the product is a primary alcohol and therefore not chiral, but a chiral center might be alpha to the aldehyde, in which case a resolution can be effected. Indeed, under the appropriate conditions the chiral center can be race-mized and a dynamic kinetic resolution effected [57]. 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

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... 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

Racemate resolution, 1, 2 Racemic compounds alcohols, 45 chirally labile, 75 computer simulation, 79 diphosphines, 26 dynamic resolution, 75 esters, 309... 

The combination of Ru complex-catalyzed stereomutation of secondary alcohols with enzyme-catalyzed enantioselective acylation is an efficient procedure to obtain chiral acyloxy compounds with excellent optical purity from a variety of racemic secondary alcohols via dynamic kinetic resolution [112]. 

Fu and co-workers have also applied their planar chiral catalyst 9 to dynamic kinetic resolution of racemic azalactones [50], Azalactones 54 racemize under the reaction conditions, allowing all material to be funneled to optically pure product. Protected (S)-amino acids 55 are formed in excellent yields with moderate enantioselectivities (83-98% yield, 44-61% ee, see Scheme 11). Use of more sterically encumbered alcohols as nucleophiles increases enantioselectivities but reaction rates become slower. 

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