Dynamic kinetic resolution thioesters

Lin, C.N. and Tsai, S.W., Dynamic kinetic resolution of suprofen thioester via coupled triocty-lamine and lipase catalysis. Biotechnol. Bioeng., 2000, 69, 31-38. 

Chen, C.Y, Cheng, Y.C. and Tsai, S.W., Lipase-catalyzed dynamic kinetic resolution of (R,S)-fenoprofen thioester in isooctane. J. Chem. Technol. Biotechnol., 2002, 77, 699-705. 

In this section, dynamic kinetic resolution of substrates having a proton with low pKa is discussed. Racemization occurs by performing the DKR in the presence of a weak base. Enzyme- and base-catalyzed DKRs are categorized, according to the nature of the substrates, as being thioesters, -activated esters, oxazolones, hydan-toins or acyloins. 

When the esters of chiral acids are submitted to a kinetic resolution, the wrong enantiomer cannot be racemised easily. However, if the chiral center of the acid can be racemised via the enol of the acid, this can be utilized. Esters do not en-olize easily, but thioester and other activated esters [27] do so much more readily. This was exploited to convert kinetic resolutions into dynamic kinetic resolutions, thus increasing the yield from a maximum of 50% to a maximum of... 

The ability to achieve dynamic kinetic resolution using thioester substrates has been recognized by other workers, and reports of dynamic resolution strategies... 

Isoxazoline 41 was obtained from racemic thioesters 40 in yields up to 89% and >90% ee by means of a dynamic kinetic resolution catalysed by lipase PS-30 in the presence of phosphate buffer (pH = 9.2), an amine, and a surfactant <01JA11075>. 

Wang, L, Cheng, Y., and Tsai, S.-W. (2004) Process modeling of the lipase-catalyzed dynamic kinetic resolution of (R, S)-suprofen 2, 2, 2-trifluoroethyl thioester in a hollow-fiher membrane. Bioprocess. Biosyst. Eng., 27 (1), 39-49. 

D. (2007) Chemo-enzymatic dynamic kinetic resolution of amino acid thioesters. Adv. Synth. Catal, 349 (8-9), 1345-1348. 

Moreover, the same authors employed a closely related organocatalyst and the corresponding urea derivative to promote the enantioselective dynamic kinetic resolution of azalactones with allylic alcohol. In this case of substrates, the urea derivatives proved to be superior to their thiourea analogues and, most usefully, these catalysts were insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine- and phenylalanine-derived azalactones to undergo dynamic kinetic resolution with unprecedented levels of enantioselectivity, as shown in Scheme 9.4. Furthermore, the compatibility of these catalysts with thiol nucleophiles was exploited in the first enantioselective catalytic dynamic kinetic resolution of azalactones by thiolysis to furnish enantioenriched amino acid thioesters of potential use with moderate enantioselectivities (<64% ee). 

We describe the process development for the preparation of (R)-XU305, a key intermediate of roxifiban. This process evolved from a small-scale enzymatic kinetic resolution into a pilot plant-scale preparation. The combination of an unusual method of racemization of (S)-XU305 as a thioester permitted a dynamic enzymatic resolution to proceed, removing the need to recycle the less-reactive isomer in order to obtain acceptable overall yields. 

A kinetic resolution of an ester requiring separate steps to recover and recycle the less reactive enantiomer has been transformed into a dynamic resolution of the corresponding thioester. While the thioester route requires an additional synthetic step, the efficiency of this step renders the dynamic resolution route to (R)-l shorter. The development of an alternative route provides our company with additional options for commercial-scale roxifiban preparation. 

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