Enantiospecific process

Another advantage of biocatalysis is that chemo-, regio-, and stereoselectivities are attainable that are difficult or impossible to achieve by chemical means. A pertinent example is the production of the artificial sweetener, aspartame, which has become somewhat of an industrial commodity. The enzymatic process (Fig. 2.31), operated by the Holland Sweetener Company (a joint venture of DSM and Tosoh), is completely regio- and enantiospecific (Oyama, 1992). 

Tocopherol can be produced as the pure 2R,4 R,8 R stereoisomer from natural vegetable oils. This is the most biologically active of the stereoisomers. The correct side-chain stereochemistry can be obtained using a process that involves two successive enantioselective hydrogenations.28 The optimum catalyst contains a 6, 6 -dimethoxybiphenyl phosphine ligand. This reaction has not yet been applied to the enantioselective synthesis of a-tocopherol because the cyclization step with the phenol is not enantiospecific. 

Johnson and co-workers (92) have recently reported the cyclization of the D-allylic alcohol 242 (optical purity of 91%). When the substrate 242 was treated with trifluoroacetic acid in 1,1-difluoroethane containing ethylene carbonate, a 65% yield of a- -5b-pregnen-20-one (243) was obtained with an optical purity of 91%. In a similar fashion, the enantiomer of 242 gave the enantiomer of 243 with an optical purity of 92%. Very little racemiza-tion has occurred and the cyclization step is essentially enantiospecific. Again, the A/B ring junction is cis and the process involves essentially total asymmetric synthesis due to the C-6 chiral center in 242. 

There are three possible approaches to the separation of chiral species by CE (1) addition of chiral selectors to the buffer, (2) use of a chiral stationary phase, and (3) precolumn derivatization. These correspond to the approaches in HPLC, and the separation mechanisms are described in Section 2.8. In the first approach, additives are added to CZE, CGE, or MECC buffers to effect the separation. In the second approach, chiral selectors can be immobilized on the capillary wall, although that is a difficult process. Alternatively, capillaries filled with enantiospecific packings can be employed for CEC. In the third approach, enantiomers are derivatized with chirally specific reagents prior to CZE or MECC. Addition of chiral selectors to the buffer is the most common approach. 

In order to observe the chiral amplification given in Fig. 3, two considerations have to be regarded for the choice of the rate parameters (i) the rate constant ko has to be adequately small. For instance, chiral amplification does not occur if ko > 0.2 M 1 s It is apparent that if the chirally unspecific process A + Z R or S proceeds too fast it generates a high amount of racemic matter that can overwhelm the enantiospecific amplification process. (ii) The mutual inhibition rate constant k2 (R + S->-RS) must be higher than k, (R + RR, or it must occur faster than the homodimerization. Moreover, taking into account the equilibrium constants Ahetero = fe/fa and Ana,via = h/ks, it is vital that Ahetero > Aromo. i.e., the heterochiral dimer has to be thermodynamically more stable than its homochiral coun-... 

R,5,S)-l-Allyl-2,5-dimethylpiperazine has been prepared by direct enantiospecific synthesis [29,39] and via classical resolution of the racemic piperazine [23,29]. Kilo-scale batches of (-)-(2R,55)-l-allyl-2,5-dimethylpi-perazine have been prepared from tra s-2,5-dimethylpiperazine by the three-step monoallylation shown in Scheme 5, followed by a resolution using di-p-toluoyl-D-tartaric acid. This resolution has also been achieved in a two-stage process using (—)-camphoric acid followed by di-p-toluoyl-D-tartaric acid, giving (—)-(22 ,5S)-l-allyl-2,5-dimethylpiperazine in >99% optical purity. 

It is often very useful to be able to alkylate a readily available chiral a-hetero-substitut-ed carboxylic acid in an enantiospecific manner, as a means of using the chiral center and at the same time building-up the rest of the target carbon skeleton. Such a reaction has been devised by Seebach and coworkers524. In this process a-hydroxy- and a-mercaptocar-boxylic acids were first reacted with pivaldehyde, to produce a 1,3-dioxolanone or 1,3-oxathiolanone. This was followed by reaction with base and alkylation by an alkyl halide and subsequent hydrolysis to regenerate the hydroxyl or mercapto group (equation 70). The product was obtained in greater than 95% ee. Similar reactions with other electrophiles were also successful. 

Several synthetic targets have been attacked by exploitation of this methodology examples include an enantiospecific synthesis of acromelic acid A and a formal synthesis of physovenine (equations 186 and 187)362. Recent work has focused on rendering the radical generation and addition processes catalytic in cobalt successes have been achieved by using more readily reduced cobaloxime complexes and carefully controlled conditions363. 

As early as 1984 the porcine pancreas lipase-catalysed enantioselective synthesis of (R)-glycidol was described. At pH 7.8 and ambient temperatures the reaction was allowed to proceed to 60% conversion (Scheme 6.9). This means that the enzyme was not extremely enantioselective, otherwise it would have stopped at 50% conversion. Nonetheless, after workup the (R)-glycidol was obtained in a yield of 45% with an ee of 92% [42]. This was a remarkable achievement and the process was developed into an industrial multi-ton synthesis by Andeno-DSM [34, 43]. While on the one hand a success story, it also demonstrated the shortcomings of a kinetic resolution. Most enzymes are not enantiospecific but enantioselective and thus conversions do not always stop at 50%, reactions need to be fine-tuned to get optimal ees for the desired product [28]. As mentioned above kinetic resolutions only yield 50% of the product, the other enantiomer needs to be recycled. As a result of all these considerations this reaction is a big step forward but many steps remain to be done. 

In this crystal lattice system, all surfaces with Miller indices, (hkl), satisfying the conditions h x k x 1 and h k l h are chiral [11]. Although such high Miller index surfaces have been studied for decades, it was not until recently that McFadden et al. specifically pointed out and demonstrated that their low synunetry structures render them chiral and, therefore, that they might have enantiospecific interactions with chiral adsorbates [12]. There has been a growing interest in the enantiospecific properties of naturally chiral metal surfaces and in the possibility of using such surfaces for enantioselective chemical processes. 

For some years Foray s enzymatic process for L-lysine (L-Lys, 41) was competitive compared with fermentation. This chemoenzymatic L-Lys production was established with a capacity of 5000-10000 t/y. The key intermediate is a-amino-e-caprolactam (ACL), produced from cyclohexanone in a modified Beckmann rearrangement. The enantiospecific hydrolysis forming L-Lys is based on two enzymes L-ACL-hydrolase opens the ring of ACL to L-Lys and in the presence of the ACL-racemase the d-ACL is racemized. Incubating d,l-ACL with cells of Cryptococcus laurentii having l-ACL lactamase activity together with cells of Achromobacter obae with ACL-racemase activity, L-Lys could be obtained in a yield of nearly 100% (Scheme 24) [102]. 

TIP Any reaction that is not enantiospecific or stereospecific should be positioned at the beginning of a synthetic sequence in order to minimize wasted processing downstream. 

The first enantiospecific total synthesis of (+)-ajmaline [(+)-17] was developed by Cook et al. 161). D-(+)-Tiyptophan methyl ester (126) was converted enantiospecifically, via intermediate 127, to the optically active )-N -benayltetracyclic ketone (-) 107, which was then transformed into the ot,P-unsaturated aldehyde (-)-128. When compound (-)-128 was stirred with 3-bromo-4-hq>tene in die Barbier Grignard process conditions the 1,4-addition products 129a,b... 

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