Enantiopure products

It is hoped that the hook will he of value to chemists and chemical engineers who are engaged in the manufacture of enantiopure products, and that they will sucess-fully apply some of the techniques described. In this way, an avenue will he provided for further progess to he made in this important field. 

Lipase Amano PS-C II was also found to be useful for a high-temperature reaction in the resolution of a bulky substrate, l,l-diphenyl-2-propanol, which showed no reactivity under usual conditions with lipase PS. An enantiopure product was obtained at 40-120°C, and the highest conversion (39%) was obtained at 80-90°C. It is very interesting that a single enzyme is usable in the reaction at a very wide range of temperatures from —80°C to 120°C. 

For the preparation of enantiopure products, chiral aldehydes, chiral 1,3-dicar-bonyl compounds as well as chiral Lewis acids [375, 376] can be used. 

Chiral 1,3-dicarbonyl compounds such as 2-765 and 2-766 have also been used for the preparation of enantiopure products [381, 382]. In addition, chiral mediators such as 2-767 have been employed with great success (Scheme 2.169) [375, 376]. 

Unlike kinetic resolution, catalytic desymmetrization and asymmetrization can afford enantiopure products in theoretical yields of 100 % and are more generally applicable than DKR or deracemization techniques. 

Other chiral oxetanes used to generate chiral y-oxido functionalized organolithium intermediates are 306-309, which gave the expected enantiopure products by reaction with non-prochiral electrophiles"" °. In all cases, when prochiral electrophilic reagents were used, a mixture of the corresponding diastereomers was obtained in variable proportions depending on the electrophile, which could be easily separated by column chromatography. 

However, as alcohol dehydrogenases can react stereo- as well as chemoselec-tively under very mild conditions, they should provide good access to enantiopure propargylic alcohols. This strategy would make it possible to start from a single substrate D which after enzymatic reduction affords either enantiomer of propargylic alcohol E and after further modifications a variety of different enantiopure products in only two to three steps (Scheme 2.2.7.12). 

An allylic halide has been used to give a better result than the corresponding allylic acetate (Scheme 8E.21) [134]. Notably, only 0.05 mol% of catalyst was sufficient to produce the enantiopure product in 96% yield. To achieve high enantioselectivity, the reactivity of the substrate had to be modulated by slow addition of the nucleophile, This deracemization strategy offers an efficient alternative method for the preparation of hydroxylactone, which has served as a synthetically useful building block for various natural product syntheses [135,136]. 

To obtain the enantiopure products, we explored an alternative procedure again by employing lipase-mediated resolution.5 It is well known that a furfuryl alcohol furnishes a 3-pyrone hemiacetal on oxidative treatment.6 Actually, the reaction of (2-furfuryl)ethylene glycol 13, obtained7 from furan 10, with mCPBA afforded isolevoglucosenone8,9 (+)-15 having the opposite enone disposition to 1 after acid-cyclization of the pyrone 14. For enzymatic resolution, ( )-15 was converted into the alcohol ( )-16 and the acetate ( )-17, diastereoselectively (Scheme 3). 

On stirring with vinyl acetate in THF in the presence of lipase PS, ( )-27 afforded enantiopure (-)-28, leaving enantiopure (+)-27. Interestingly, the attachment of an extra alkoxymethyl amplified the enantiodiscrimination in the enzymatic reaction.13 The amplification was also observed when ( )-28 was stirred in a phosphate buffer in the presence of the same lipase to afford enantiopure (-)-27 and enantiopure (+)-28. The enantiopure products were reverted to the enantiopure isolevoglucosenone13 26 under standard conditions15 (Scheme 8). 

Interestingly, again the alkoxymethyl attachment amplified the enantioselectivity in the AD reaction. Thus, 23, on reaction with AD-mix-a reagent, afforded the enantiopure (+)-24 while, with AD-mix-P reagent, it afforded the enantiopure (-)-24. Enantiopure products gave enantiopure 26 under standard conditions12 (Scheme 9). 

The a-oxidation of aldehydes was later further extended to the use of ketones as nucleophiles. In order to develop this reaction into a useful process, a considerable effort was made to optimize the reaction conditions as several different problems arose these included a lower reaction rate and yields because of the formation of the di-addition product at the two enolizable carbon atoms and lower 0/N-selectivity. Hayashi et al. [16a] and Cordova et al. [16c] partly solved these problems by using a relatively large excess of ketone and by applying the slow addition method leading to good chemical yields (44-91%), with near-enantiopure products being obtained (96-99% ee). 

The most straightforward hydrolase-catalysed preparation of an enantiopure product from a racemic starting material is a kinetic resolution. In a kinetic resolution a racemic ester or amide is hydrolysed enantioselectively (Scheme 6.5 A). At the end of the reaction an enantiopure alcohol or amine is obtained. The unreactive enantiomer of the starting material should ideally also be enantiopure. Consequently the maximum yield for either compound in a kinetic resolution is only 50%. The enantiopurity of the products is dependent on the enantioselectivity of the enzyme this is expressed as the enantiomeric ratio, E, of the enzyme [28]. If the E value for the enzyme is low (<25) neither the unreacted ester nor the obtained product are really pure at 50% conversion. Consequently kinetic re-... 

Scheme 6.6 A Dynamic kinetic resolution of a racemic starting material yields 100% enantiopure product B in a synthetic dynamic kinetic resolution a new bond is formed enantioselectively with 100% yield.

Another possibility to obtain 100% yield of the enantiopure product is to combine the kinetic resolution with an inversion reaction [25, 35, 36]. In this case an enzymatic hydrolysis is followed by a Mitsunobu inversion. It is, however, in fact a three-step reaction with solvent changes between the reactions. Similarly the sulfatase-catalysed enantios elective inversion of a racemic sulfate yields a homo-chiral mixture of alcohol and sulfate. This yields 100% enantiopure product after a second, acid-catalysed hydrolysis step, which is performed in organic solvent/water mixtures [26]. 

Instead of starting with racemic starting material it is also possible to use symmetric substrates [25]. The hydrolase selectively catalyses the hydrolysis of just one of the two esters, amides or nitriles, generating an enantiopure product in 100% yield (Scheme 6.7). No recycling is necessary, nor need catalysts be combined, as in the dynamic kinetic resolutions, and no follow-up steps are required, as in the kinetic resolutions plus inversion sequences. Consequently this approach is popular in organic synthesis. Moreover, symmetric diols, diamines and (activated) diacids can be converted selectively into chiral mono-esters and mono-amides if the reaction is performed in dry organic solvents. This application of the reversed hydrolysis reaction expands the scope of this approach even further [22, 24, 27]. 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

Do you need a chiral starting material which can be converted into a number of enantiopure products Or a chiral auxiliary to perform an asymmetric transformation at a certain point of a complex molecule Would you like to have a protecting group for an acid, which activates the ortho-position of an aromatic ring Or do you need an easy-to-synthesize chiral catalyst For all these problems oxazolines can be the solution. 

The desired bicycle 58 was obtained but oddly the enantiopuiity of the previous intermediate was lost, and the bicycle was a completely racemic mixture. It was an unexpected result in view of the previous work by Somfai describing the same reaction leading to enantiopure product from the Af-tosyl analogue (with a methoxy instead ethoxy group in the a-position) (Skrinjar et al. 1992 Somfai and Ahman 1992). Although there was no logical explanation for these discrepancies, they proposed that the racemization could go via hydride abstraction by the iminium ion. As a result, a different ( )-anatoxin-a synthesis was completed by deprotection (TMSI) (Manfre et al. 1992) in 65% yield (9% overall for nine steps). 

Note should also be made that in some cases recrystallization reduces the enantiomeric excess, which can lead to crystallization of the racemate (94). In these cases the mother liquors contain moderately to highly enriched material. It is therefore important to plan the strategy at which point the enantiomer is recrystallized to optical purity. This may be from an enzymic resolution, or in the event that an asymmetric synthesis has failed, to deliver enantiopure product. As discussed in Section 3, the liquors from the diastereomeric resolution with DTTA of 88%de can be cleaved to the free base, and crystallization of the hydrochloride salt gives >98% ee. This is because of the fact that methylphenidate hydrochloride has a eutectic point of 30% ee. Davieset al. (95) and Winkler et al. (96) have prepared single enantiomer methylphenidate (29), Their approaches use an enantioselective synthesis the enantiomeric excesses are 86% and 69%, respectively, thus requiring recrystallization... 

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