Asymmetric hydrolysis step

An alternative to extraction crystallization is used to obtain a desired enantiomer after asymmetric hydrolysis by Evonik Industries. In such a way, L-amino acids for infusion solutions or as intermediates for pharmaceuticals are prepared [35,36]. For example, non-proteinogenic amino acids like L-norvaline or L-norleucine are possible products. The racemic A-acteyl-amino acid is converted by acylase 1 from Aspergillus oryzae to yield the enantiopure L-amino acid, acetic acid and the unconverted substrate (Figure 4.7). The product recovery is achieved by crystallization, benefiting from the low solubility of the product. The product mixture is filtrated by an ultrafiltration membrane and the unconverted acetyl-amino acid is reracemized in a subsequent step. The product yield is 80% and the enantiomeric excess 99.5%. 

The key-step of Mori s synthesis of 12 was pig pancreatic lipase (PPL)-cat-alyzed asymmetric hydrolysis of raeso-diacetate A to give B (Scheme 22) [32]. Purification of B (90.8% ee) afforded pure C, which was converted to 12. 

Although the asymmetric isomerization of allylamines has been successfully accomplished by the use of a cationic rhodium(l)/BINAP complex, the corresponding reaction starting from allylic alcohols has had a limited success. In principle, the enantioselective isomerization of allylic alcohols to optically active aldehydes is more advantageous because of its high atom economy, which can eliminate the hydrolysis step of the corresponding enamines obtained by the isomerization of allylamines (Scheme 26). 

An interesting asymmetric transformation is the asymmetric conjugate addition to a-acetamidoacryhc ester 30 giving phenylalanine derivative 31, which has been reported by Reetz (Scheme 3.10) [10]. The addition of phenylboronic acid 2m in the presence of a rhodium complex of l,T-binaphthol-based diphosphinite ligand 32 gave a quantitative yield of 31 with up to 11% enantiomeric excess. In this asymmetric reaction the stereochemical outcome is determined at the hydrolysis step of an oxa-7r-aUylrhodium intermediate, not at the insertion step (compare Scheme 3.7). 

One of the first fluorescence-based ee assays uses umbelliferone (14) as the built-in fluorophore and works for several different types of enzymatic reactions 70,86). In an initial investigation, the system was used to monitor the hydrolytic kinetic resolution of chiral acetates (e.g., rac-11) (Fig. 8). It is based on a sequence of two coupled enzymatic steps that converts a pair of enantiomeric alcohols formed by the asymmetric hydrolysis under study (e.g., R - and (5)-12) into a fluorescent product (e.g., 14). In the first step, (R)- and (5)-ll are subjected separately to hydrolysis in reactions catalyzed by a mutant enzyme (lipase or esterase). The goal of the assay is to measure the enantioselectivity of this kinetic resolution. The relative amount of R)- and ( S)-12 produced after a given reaction time is a measure of the enantioselectivity and can be ascertained rapidly, but not directly. 

The overall process for this enzymatic resolution is compared with the conventional chemical process in Fig. 14. The enzymatic process can skip several tedious steps which are necessary in chemical resolution and this is a considerable practical advantage. There have been several reports on the application of enzymatic asymmetric hydrolysis to the optical resolution of pantolactone [141, 142], In these cases, esterified substrates, such as O-acetyl or O-formyl pantolactone, and lipases were used as the starting materials and catalysts, respectively. Since the lactonase of F. oxysporum hydrolyzes the intramolecular ester bond of pantolactone, it is not necessary to modify the substrate, pantolactone. This is one of the practical advantages of this enzyme. 

One of the first enantiofacially selective processes catalyzed by an antibody involved the hydrolysis of enol esters [15]. Hapten 4 was used to elicit antibodies for the hydrolysis of enol ester 5 (Scheme 2). This reaction proceeds via a putative enolate intermediate 6 and the key asymmetric induction step involves antibody-catalyzed enantiofacial protonation of one of the prochiral faces of 6. Antibody 27B5 catalyzes the hydrolysis of the enol ester 5 with a turnover number k apO.Ol min corresponding to an enhancement ratio (ER), k j/non-cata-lyzed rate (kuncat) provides an optically enriched mixture of the R-ke-tone product 7 (42% ee). Although the asymmetric induction is lower than that achievable by natural enzymes for certain substrates [ 16], it was a successful demonstration, at entry level, for catalytic antibodies and asymmetric induction. 

An enzymatic production process for Diltiazem (54), a coronary vasodilator and calcium channel blocker, was started in 1993 by Tanabe Seiyaku, Japan [7, 77]. The epoxide (2i, 3S)-52 is a key intermediate in this synthesis (Scheme 17) and can be produced via asymmetric hydrolysis of rac-52 catalyzed by Serratia marescens lipase immobilized on spongy layers. The whole process takes place in a polyacrylonitrile hollow fiber membrane reactor and produces (2i, 3S)-52 in yields of 40-45%. The hydrolyzed product (2S,3i )-53 is not stable under the prevailing reaction conditions and decarboxylates to aldehyde 55, a strong enzyme deactivator. The aldehyde needs therefore to be removed, which is achieved by continuous filtration of its bisulfite adduct 56. Using this enzymatic process it was possible to bring down the number of required steps en route to 54 from nine to five. This process is also carried out by other companies (e.g., DSM) with a worldwide annual production of 1001. 

Tokunaga and coworkers reported the enantioselective hydrolysis of enol esters (111) in the presence of catalyst 8b under phase-transfer conditions with aqueous KOH. The proposed mechanism of this reaction has the protonation of the ammonium-enolate ionic complex as the enantioselective step. Their achievement of the first nonbiomimetic asymmetric hydrolysis of esters catalysed by organocatalysts with high catalytic efficiency in buffer-free conditions has considerable potential to replace enzymatic resolutions in industrial processes (Scheme 16.41). ... 

Many of the most useful applications of enzymes in asymmetric synthesis involve kinetic resolution and an example is the hydrolysis of ( )-A -acetylphenylalanine methyl ester (43) with a-chymotrypsin to give the (S)-acid (44) and the unchanged (/ )-ester (45). Very often, as in this case, we can make use of either of the two products once they have been resolved by a further simple non-asymmetric chemical step (here hydrolysis of (45) to give the (/ )-acid). 

However, this is a good example of the dangers which face the unwary in asymmetric synthesis, since it was later discovered that the hydrolysis step is actually accompanied by efficient inversion of absolute configuration at the stereogenic centre. Thus it is the (5)-product from quinine which gives the (/ )-malic acid and vice versa as shown. Regardless of this complication, the method allows convenient access to either enantiomer of the synthetically useful malic acid on a commercial scale. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

Scheme 4-38. Proposed mechanism for asymmetric aminohydroxylation. Sequence of steps in the first catalysis cycle (left) (1) addition (a1), (2) reoxidation (O), (3) hydrolysis (h1) in the second catalysis cycle (right) (1) addition (a2), (2) hydrolysis (h2), (3) reoxidation (O). The first cycle proceeds with high ee, the second with low ee. L = chiral ligand X = CH3SO2. ... 

In the asymmetric total synthesis of the marine natural product, methyl sarcoate, the key step for the introduction of the chirality, was achieved by using an asymmetric Michael addition. Asymmetric addition of /-PrMgCl to aminal ester 93 in the presence of a catalytic amount of Cul, followed by acidic hydrolysis of the aminal function, afforded the chiral aldehyde 94 in 60% yield (Equation 10) <2005TL1263>. 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

An asymmetric cyanosilylation followed by hydrolysis and cyclization has been used by Curran and co-workers as the key step in the asymmetric synthesis of camptothecin <2001JA9908, 2003F1(59)369>. 

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