Racemic amides, enantioselective

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

Scientists at Shell began work onthe enantioselective hydrolysis of racemic amides in the early 1990s 5]. Enzyme mediated hydrolysis of racemic N 1 phenylethylace tamide 2 using whole cells of Arthrobacter sp. enabled the production of enantio merically pure (S) 1 and (f ) 2 (Figure 14.2). The use of whole cells was not optimal and long reaction times were required to obtain pure (R) 2, as the selectivity of the catalyst was not very high. 

Enzymatic hydrolysis of the racemic amides by the amino amidase from M, neoaurum affords the (5)-a,a-disubstituted amino acids and the (i )-a,a-disubstituted amino acid amides (15) in almost 100% e.e. at 50% conversion for most a-methyl-substituted compounds E > 200) [43] (see Scheme 7 and Table 7). Only for glycine amides wititi two small substituents the enantioselectivity is decreased for example, for isovaline amide die enantiomeric ratio E = 9 and for (a-Me)allylglycine amide = 40 [44]. Also a-H-amino acid amides are substrates and are hydrolyzed enantioselectively in contrast, however, dipeptides are not hydrolyzed [45]. For all a-methyl-substituted substrates the activity is high. Reactions performed at 5-10 w/w% substrate solutions in water (pH 8, 37 C) with 0.3-1.0 w/w% of freeze-dried biocatalyst are in general completed (i.e., 50% conversion) after 5-48 h. Increasing the size of the small substituent to ethyl, propyl, or allyl dramatically reduces the activity, especially if the large substituent contains no —CHj— spacer at the chiral center. Due to the longer reaction times the enantioselectivity is also reduced [44]. 

Racemic a-amino amides and a-hydroxy amides have been hydrolyzed enantio-selectively by amidases. Both L-selective and o-selective amidases are known. For example, a purified L-selective amidase from Ochrobactrum anthropi combines a very broad substrate specificity with a high enantioselectivity on a-hydrogen and a,a-disubstituted a-amino acid amides, a-hydroxyacid amides, and a-N-hydroxya-mino acid amides [102]. A racemase (a-amino-e-caprolactam racemase, EC 5.1.1.15) converts the o-aminopeptidase-catalyzed hydrolysis of a-amino acid amides into a DKR (Figure 6.38) [103]. 

Irimescu and Kato have recently described an interesting example of enzymatic KR in ionic liquids instead of organic solvents (Scheme 7.4) [12]. The resolution with CALB is based on the fact that the reaction equilibrium was shifted toward the amide synthesis by the removal of water under reduced pressure. Nonsolvent systems have been also employed in this enantioselective amidation processes, reacting racemic amines with aliphatic acids. The best reaction conditions for the conversion of acids to amides was observed using CALB at 90 °C under vacuum. Meanwhile, no... 

Kanegafuchi Chemical Industries produce D-p-hydroxyphenyl glycine, which is a key raw material for the semisynthetic penicillins ampicillin and amoxycillin. Here, an enantioselective hydantoinase is applied to convert the hydantoin to the D-p-hydroxyphenyl glycine. The quantitative conversion of the amide hydrolysis is achieved because of the in situ racemization of the unreacted hydantoins. Under the conditions of enzymatic hydrolysis, the starting material readily racemizes. Therefore, this process enables the stereospecific preparation of various amino acids at a conversion of 100% [38]. 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

A strain of Pseudomonas aeruginosa has been recently described, which shows the opposite enantioselectivity, converting racemic arylaminonitriles efficientiy into the D-amino acids. Again, whole-cell biocatalysis worked well, the cells being entrapped in alginate beads. It is unclear whether this biotransformation involves an amide intermediate. 

A resolution of racemic CHIRAPHOS ligand has been achieved using a chiral iridium amide complex (Scheme 8.3). The chiral iridium complex (- -)-l reacts selectively with (S.S -CHIRAPHOS to form the inactive iridium complex 2. The remaining (R,R)-CHIRAPHOS affords the catalytically active chiral rhodium complex 3. The system catalyzes asymmetric hydrogenation to give the (5)-product with 87% ee. The opposite enantiomer (—)-l gives the (R)-product with 89.5% ee, which is almost the same level of enantioselectivity obtained by using optically pure (5,5)-CHlRAPHOS. 

Hydrohalogenation of racemic 4-rerr-butylcyclohexylideneacetic acid yields the tram-jg-ehloro-and / -bromocarboxylic acids 1 as single diastereomers which, on dehydrohalogenation with chiral lithium amides, yields 4 tcrt-butylcyclohexylideneacetic acid 2 b in high yield with modest to good enantioselectivity (Table 8)6,15,83b. 

Scheme 7.9 Resolution of racemic amines by lipase-catalyzed enantioselective amide formation (BASF).

The racemic compound bupivacaine, which was first synthesized by Ekenstam et al. in 1957, is an amide-type LA with a high lipophilicity, protein binding and pKa giving rise to an intermediate onset and a long duration of action. At the same time, bupivacaine has a high toxicity potential relatively often associated with convulsions and life-threatening cardivascular collapse (Moore et al., 1978). Levobupivacaine, the (S)-enantiomer of bupivacaine, has recently been developed for clinical use addressing the enantioselectivity of side-effects of bupivacaine (see below). 

Enantioselective enzymatic amide hydrolyses can also be applied for the preparation of optically active organosilicon compounds. The first example of this is the kinetic resolution of the racemic [l-(phenylacetamido)ethyl] silane rac-84 using immobilized penicillin G acylase (PGA E.C. 3.5.1.11) from Escherichia coli as the biocatalyst (Scheme 18)69. (R)-selective hydrolysis of rac-84 yielded the corresponding (l-aminoethyl)silane (R)-85 which was obtained on a preparative scale in 40% yield (relative to rac-84). The enantiomeric purity of the biotransformation product was 92% ee. This method has not yet been used for the synthesis of optically active silicon compounds with the silicon atom as the center of chirality. 

In contrast to acyl amino acids (pKa > 30) or amides, most 5-monosubstituted hydantoins racemize comparatively easily phenyl-substituted ones even racemize spontaneously at slightly alkaline conditions as their pK.d is around 8 (Kato, 1987). Under spontaneous or enzymatic racemization (Pietzsch, 1990), racemic hydantoins with the help of enantioselective d- or L-hydantoinases and the respective carb-... 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

Enantioselective acylation of amine and hydrolysis of amide are widely studied. These reactions are catalyzed by acylases, amidases and lipases. Some examples are shown in Figure 21.22 Aspartame, artificial sweetener, is synthesized by a protease, thermolysin (Figure 21(a)).22a In this reaction, the L-enantiomer of racemic phenylalanine methyl ester reacted specifically with the a-carboxyl group of N-protected L-aspartate. Both the separation of the enantiomers of the phenylalanine and the protection of the y-carboxyl group of the L-aspartate were unnecessary, which simplified the synthesis. 

There has been a study of the influence of ion-pairing reagents and solvents on the stability of the hydroxide adduct (11) of the diethylamide of 3,5-dinitrobenzoic acid e.g. (11) is stabilized by quaternary ammonium salts in benzene. The resulting methodology has been used to perform highly enantioselective biphasic kinetic resolutions of several racemic electron-deficient amides.50... 

Most of the product, i.e. iV-diphenylphosphoramides, are crystalline and their ees can often be improved to > 98% ee by the recrystallization.213 TV-diphenyl-phosphinyl group can be easily removed by acid hydrolysis (3 M HC1-THF,23 p-Ts0H-Me0H-H2021c) and the corresponding chiral amines are obtained without racemization. In addition, V-acylimines are utilized in the enantioselective addition of diethylzinc promoted by DBNE 1 affording chiral amides with up to 76% ee.24... 

The lithiation and silylation of the amide 71 is enantioselective for a very different reason. When the intermediate organolithium is made from the racemic stannane 72, it still gives the product 74 in good enantioselectivity provided the electrophile reacts in the presence of (-)-sparteine.72 The reaction must therefore be an enantioselective substitution. Furthermore, reaction of the deuterated analogue 75 gives a result which is not consistent with asymmetric deprotonation yield, deuterium incorporation and product ee are all high. 

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