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. 

Asymmetric Synthesis of Allylic Thioesters and Kinetic Resolution of Allylic Esters... 

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. 

Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer. This is not quite the same as the methods of resolution previously mentioned, though an outside optically active substance is required. For example, the racemic thioester 46 was placed in contact with a certain optically active amide. After 28 days the solution contained 89% of one enantiomer and 11% of the other.137 To effect the deracem-... 

Narasaka et al. demonstrated the utility of titanium-ligand complexes in the resolution of chiral a-aryl esters [52]. Ti(Oi-Pr)4-ligand 56 complex resolves 2-pyridine thioesters with high selectivities (fcrei=26-42, see Scheme 13). Seebach and co-workers have examined titanium-TADDOLate complexes as reagents for the ring opening of meso anhydrides, dioxolanones, and azalactones [53]. Addition of an achiral isopropoxide source renders the desymmetrization of meso... 

The DKR hydrolysis of thioesters described previously has also been extended to transesterifications in toluene, using triethylamine and Candida antartica lipase.28 This general approach can therefore be applied to the resolution of a wide range of both water-soluble and water-insoluble thioesters by selecting an appropriate solvent, base, and enzyme system. 

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... 

Scheme 13.16 Enzymatic kinetic resolution of N-Boc-amino acid thioesters coupled with base-catalyzed racemization.

Enzymatic Kinetic Resolution of N-Boc-Amino Add-Thioesters Coupled with Base-catalyzed Racemization Recently, a new method leading to the preparation of a number of aryl-glycines of the L-configuration has been published. The method is based on the hydrolysis of N-Boc-amino acid thioesters 15 catalyzed by an industrial preparation of the protease subtilisin (Scheme 13.16) [43]. 

In the presence of a catalytic amount of the chiral titanium reagent (8) prepared from titanium tetraisopropoxide and the (/ )-1,4-diol, kinetic resolution of 5 -(2-pyridyl) thioesters of a-aryl carboxylic acids is achieved with high relative rate of both the enantiomers to give the (f )-isopropyl esters with high optical purity (eq 17). ... 

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. 

Drueckhammer and his associates supplied the answer we sought when they reported the first example of the enzymatic dynamic resolution of substrates containing thioesters [26]. For certain propionates, the presence of a thio substituent next to a thioester sufficiently lowered the pKa of the a-proton to permit racemization to occur under enzyme-friendly reaction conditions (Fig. 5). 

They later discovered it was possible to forego the second thio function (the thiophenol) by careful selection of the thioester, the enzyme, and reaction conditions [27]. This considerably broadened the scope of the new reaction, but their first communication suggested a new path for our process. The use of thioesters as substrates in enzymatic resolution is not frequent but it is still well prece-dented [26-28]. In particular, an example of its use in large-scale pharmaceutical manufacture is our company s preparation of the antihypertensive Captopril [29]. 

Fig. 5 First example of thioester dynamic enzymatic resolution.

Process Development of the Dynamic Enzymatic Resolution of the Thioester of 10b... 

Another factor to consider is that the site of enzyme-catalyzed hydrolysis would not be adjacent to the stereocenter but rather /> to it. While there are many examples where reaction enantioselectivity is attenuated by the distance of the stereo-genic carbon from the enzymatic action site [31], resolution of centers up to five bonds distant from the site of enzymatic action is still possible [32]. We hoped that we would be able to reproduce the example of the enzymatic kinetic resolution of 9 but with a thioester, inasmuch as the resolution of 9 had been excellent and the resolved center was located two bonds from the ester. 

Finally, it would be necessary to develop an excellent preparation of the thioester substrate since it appeared likely that any route to it would be longer than the analogous preparation of 9. While it might be possible to establish a dynamic resolution, the advantage would evaporate if the preparation of the thioester was not highly efficient. 

Fig. 7 First successful isoxazoline thioester dynamic resolution.

With this validation, we now embarked on a third phase of experimentation. We sought to combine the established choices of enzyme (Amano PS-30) and class of thioesters with proper racemization conditions to optimize the resolution. Key experiments are listed in Tab. 4. 

There are remarkably few transformations of esters to thioesters. The use of bis(dimethylaluminum) thiolates produced an unoptimized 50% yield of 10b but was unattractive since the reagent required a separate preparation and it partially reacted with the aryl nitrile [53], Nor did simply mixing propyl mercaptan with 9 under enzymatic resolution conditions provide any equilibrium between 9 and 10b that might have allowed a dynamic resolution. The problem was ultimately solved by the use of silylated thiols and aluminum chloride (Fig. 9). 

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