Chemoenzymatic Dynamic Kinetic Resolution of Acyloins

Abstract

[Reaction: see text]. Acyloins (alpha-hydroxy ketones) are important building blocks in organic synthesis, e.g., for the total synthesis of epothilones. Optically pure acyloins can be obtained by lipase-catalyzed kinetic resolution (KR) of the racemate with, for example, Burkholderia cepacia lipase, but this process suffers from a yield limitation of 50%. To devise a dynamic kinetic resolution (DKR), we studied the racemization of two different acyloins and corresponding esters with various amine bases and ion exchangers. No combination of base and solvent was found that could selectively racemize the acyloin or corresponding ester under the conditions needed for a DKR. In contrast to bases, acidic resins (ARs) were found to racemize the acyloins selectively in n-hexane and in water. Unfortunately, the AR deactivated the lipase, preventing a one-pot DKR. Minor side reactions involving the AR, the substrate acyloin, and the vinyl ester acyl donor were also observed. However, an efficient DKR was made possible by the spatial separation of lipase and ion exchanger, with enzymatic transesterification and AR-catalyzed racemization taking place simultaneously in two compartments connected by a pump loop. The conversion of substrate alcohol was 91%, the selectivity toward the product butyrate ester 90%, and the enantiomeric excess of the (S)-product 93% ee.

Dynamic Kinetic Resolution of Secondary Alcohols Combining Enzyme‐Catalyzed Transesterification and Zeolite‐Catalyzed Racemization

“…Acidic ion exchangers have been used for the racemization of optically active arylethanolamines, [8] benzylic acids, [9] and acyloins. [10] Wuyts et al [11] reported on a heterogeneous catalyst based on Ru 3 + exchanged into a hydroxyapatite for the racemization of secondary alcohols under relatively mild conditions. However, this catalyst was not compatible with chelating groups.…”

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

“…The stereogenic center C13 constitutes an α-acyloxy ketone moiety and deacylation catalyzed by a base may result in the loss of chirality because of epimerization [12]. To circumvent this problem, we initially attempted to protect the ketone group prior to chemical conversion (Scheme 1).…”

Chemoenzymatic dynamic kinetic resolution of rac-1-phenylethanol in ionic liquids and ionic liquids/supercritical carbon dioxide systems

“…It should be noted that, if vinyl propionate was present in the media, undesirable esterification reactions catalyzed by SCX led to the full esterification of both (R) and (S) isomeric alcohols after 24 h. Experiments carried out by increasing the amount of SCX or the temperature of the reaction aggravated these undesirable side reaction. Several authors (Wuyts et al 2003(Wuyts et al , 2005Ö dman et al 2005) have described the DKR of rac-1-phenylethanol using a combination of solidacids and immobilized enzymes in water:organic solvent biphasic systems, the racemization step occurring in the aqueous phase, while the enzymatic reaction occurs in the organic phase. In such cases, the loss of the alcohol and the hydrolysis of the acyl donor substrates catalyzed by acidic resins represent as a significant problem that must be minimized.…”

“…As ILs coating biocatalyst particles enhanced mass-transfer limitations for all substrates and products in scCO 2 reaction media (Garcia et al 2004;Lozano et al 2004), this could be related with the observed low level of SCX-catalyzed undesirable side reactions. In the context of DKR catalyzed by a combination of acidic resins and immobilized lipases, the use of water: organic solvent biphasic reaction media represent the usual strategy for physically separating both the chemical and enzymatic steps of the processes (Ö dman et al 2005;Wuyts et al 2003Wuyts et al , 2005.…”

“…Ru 2+ ) complexes (Pamies and Backvall 2004) and, more recently, acid on solid supports (e.g. acid zeolites, Amberlyst) (Ö dman et al 2005;Wuyts et al 2003Wuyts et al , 2005 have been described as suitable catalysts for the racemization of sec-alcohols via a hydrogen transfer process. DKR based on lipase combined with metal catalysis is the most widely reported strategy, which has been assayed in anhydrous organic solvents (e.g.…”