Phenylglycine, racemization

Even if there is some influence both from the protective group and the employed thiol, in essence it is only the a-carbon side chain that really makes the difference in the stabihzation of the corresponding enolate as expected. Indeed, only with stronger organic bases (e.g., l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)), it is possible to racemize the thioesters of N-protected alkyl amino adds in organic solvents. For instance, chiroptical measurements in isopropanol have shown that the ethylth-ioester of N-Boc-phenylglycine racemizes 60 times faster than the corresponding... 

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

Sheldon et al. have reported the DKR of phenylglycine esters via lipase-catalyzed ammonolysis [53]. Racemization was carried out by an aldehyde, such as salicyalde-hyde or pyridoxal, under basic conditions. The major problem they found was the racemization by these aldehydes of the final products. However, when performing the DKR at low temperatures (—20 °C) the substrate was racemized much faster than the product, and DKR was feasible yielding the product in good yield and high enantiomeric excess (Figure 4.27). 

Molecules having only a sulfoxide function and no other acidic or basic site have been resolved through the intermediacy of metal complex formation. In 1934 Backer and Keuning resolved the cobalt complex of sulfoxide 5 using d-camphorsulfonic acid. More recently Cope and Caress applied the same technique to the resolution of ethyl p-tolyl sulfoxide (6). Sulfoxide 6 and optically active 1-phenylethylamine were used to form diastereomeric complexes i.e., (-1-)- and ( —)-trans-dichloro(ethyl p-tolyl sulfoxide) (1-phenylethylamine) platinum(II). Both enantiomers of 6 were obtained in optically pure form. Diastereomeric platinum complexes formed from racemic methyl phenyl (and three para-substituted phenyl) sulfoxides and d-N, N-dimethyl phenylglycine have been separated chromatographically on an analytical column L A nonaromatic example, cyclohexyl methyl sulfoxide, did not resolve. 

Two other very interesting applications of proteases are firstly the use of a protease to convert porcine insulin into human insulin, and secondly the use of L-aminopeptidase to produce the pharmaceutically useful substance p-phenylglycine by selectively hydrolyzing L-phenylglycinamide in a racemic mixture. 

For the enantioselective synthesis of a-alkyl-a-phenylglycines the enolates 2, derived from (S)-3,6-dihydro-3-phenyl-2i/-l,4-oxazin-2-ones, 1, were alkylated91. (S)-l is available from an (S)-a-hydroxy acid (R1 = i-Pr, C6H5, Bn) and racemic phenylglycine in five steps. The yields of the alkylation step are around 90%, but the diastereoselectivity is strongly dependent on R1. 

No racemization occurs at the phenylglycine moiety throughout the entire sequence. With more complex arenetricarbonylmanganese complexes, such as that derived from the methyl ester of iV-acetyl-O-phenyltyrosine 5, two equivalents of the lithiated dialkoxydihydropyrazine 1 have to be used30. If not, no arylaled dialkoxydihydropyrazine is formed and the loss of tricarbonyl-manganese is observed. 

The hydantoinase process, consisting of a racemization reaction and hydrolyses of the hydantoin and the carbamoylic acid (Figure 7.14), has been enjoying much industrial success (> 1000 tpy) for almost 30 years in the production of D-amino acids such as D-phenylglycine and p-OH-phenylglycine which serve as side chains for /3-lactam antibiotics ampicillin and amoxicilin (Cecere, 1976). 

By using this method, both substance (A) and resolving agent (B) can be resolved using a resolving agent composed of optically active and racemic form with a b ratio. Experimental results of the resolution of ( )-phenylglycine (PG) with 10-camphorsulfonic acid (CSA) (a b = 2 1) are shown below (Table 8). 

Analytical Properties Higher selectivity for nitrogen-containing racemates than fl-/V-(3,5-dinitrobenzoyl) phenylglycine examples of nitrogen-containing racemates include succinimides, hydantoins, and mandelates Reference 41... 

Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycin derivatives [18]. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axial-chiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. 

As noted in a review, no economical chemical process has emerged for the asymmetric synthesis of amino acids.3 This presumably refers to large-scale production where the research costs associated with the development of a biological approach can be justified. Chemical methods can produce racemic substrates, as illustrated later in this chapter with L-methionine and D-phenylglycine. With methods in place, however, biological methods can be implemented rapidly.4... 

Such an example is formed by the resolution of 4-hydroxyphenylglycine (Hpg) (Figure 7.8). Hpg cannot be resolved by (+)-camphor-10-sulfonic acid [(+)-Csa] and is, therefore, resolved on industrial scale with the more expensive and difficult to recycle (lR)-(+)-(endo,anti)-3-bromo-camphor-8-sulfonic acid. However, if racemic or (R)-phenylglycine (Phg) is added to the resolution of Hpg with (+)-Csa, co-resolution of both phenylglycines is possible. (R)-(-)-Hpg is incorporated in the crystal lattice of the (R)-(-)-Phg—(+)-Csa salt by partial replacement of (R)-(-)-Phg.27... 

The high-yield synthesis of the racemate via a Strecker synthesis is elegantly combined with the asymmetric transformation process. Addition of the resolving agent (S)-mandelic acid results in the formation of both diastereoisomeric salts. In the presence of benzaldehyde these salts are in equilibrium with the Schiff base, which racemizes readily. The low solubility of the diastereoisomeric salts (in apolar solvents) eventually allows obtainment of a >95% yield of the (/f) (.S )-salt in more than 99% diastereoisomeric excess. After decomposition of this salt by hydrochloric acid, pure (Ah-phenylglycine amide is obtained, and the resolving agent can be recycled. 

Either (S)-specific aminopeptidase catalyzed hydrolysis of racemic PGA11 or crystallization-induced asymmetric transformation of racemic PGA with (.S l-mandelic acid as resolving agent12 can be used to prepare (R)-PGA. As a result of its ready availability on large scale within DSM, we envisaged the application of (R)-PGA for the production of enantiomerically pure amine functionalized compounds using the chirality transfer concept. Obviously, (S)-phenylglycine amide is also available and can be used for the preparation of the opposite enantiomer of the amines described. 

Catalytic hydrogenation of PGA-homoallylamines simultaneously reduced the double bond and removed the chiral auxiliary in one step. Some typical examples of enantiomerically pure (R)-aminobutanes 12 obtained are shown in Scheme 25.6. The nonoptimized yields varied between 49% and 88% with ee values of 94% to >98%. The high enantiomeric excesses of these chiral amines are in agreement with the equally high diastereoselectivity of the allylation reaction and lack of racemization of the phenylglycine amide moiety in any of the steps. Enantiomerically pure chiral (f )-a-propylpiperonylamine 12c is an important building block of the human leukocyte elastase inhibitor L-694,458 (13).28... 

Fig. 26 STM image (27 nm x 27 nm) showing two enantiomorphous domains of R- and S-phenylglycine on Cu(l 10) after adsorption of the racemate. Courtesy of N.V. Richardson...

System 1 was able to hydrolyze the 5-monosubstituted hydantoins faster than system 2 for the production of almost all the D-amino acids studied. System 1 was slightly slower than system 2 only for the production of the aromatic amino acids D-tyrosine and D-phenylglycine. This agrees with previously described results, finding that AtHyuAl enzyme (included in system 1) was more viable for industrial application than AtHyuA2 (included in system 2) due to its higher substrate affinity and racemization velocity [25]. 

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