L-amino add amide

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

Process economics dictate the recycling of the unwanted isomer. Path A in Figure A8.2 illustrates that racemisation of the D-N-benzylidene amino add amide is fadle and can be carried out under very mild reaction conditions. After removal of die benzaldehyde die D,L-amino add amide can be recyded 100% conversion to the L-amino add is theoretically possible. Another method for racemisation and recycling of the L-amino add (path B, Figure A8.2) comprises the conversion of the L-amino add into die ester in the presence of concentrated add, followed by addition of ammonia, resulting in the formation of the amide. Addition of benzaldehyde and racemisation by OH- (pH =13) gives the D,L-amino add amide. In this way 100% conversion to die D-amino add is possible. 

L-Amino adds could be produced from D,L-aminonitriles with 50% conversion using Pseudomonas putida and Brembacterium sp respectively, the remainder being the corresponding D-amino add amide. However, this does not prove the presence of a stereoselective nitrilase. It is more likely that the nitrile hydratase converts the D,L-nitrile into the D,L-amino add amide, where upon a L-spedfic amidase converts the amide further into 50% L-amino add and 50% D-amino add amide. In this respect the method has no real advantage over the process of using a stereospecific L-aminopeptidase (vide supra). 

A very simple and elegant alternative to the use of ion-exchange columns or extraction to separate the mixture of D-amino add amide and the L-amino add has been elaborated. Addition of one equivalent of benzaldehyde (with respect to die D-amino add amide) to the enzymic hydrolysate results in the formation of a Schiff base with die D-amino add amide, which is insoluble in water and, therefore, can be easily separated. Add hydrolysis (H2SQ4, HX, HNO3, etc.) results in the formation of die D-amino add (without racemizadon). Alternatively the D-amino add amide can be hydrolysed by cell-preparations of Rhodococcus erythropolis. This biocatalyst lacks stereoselectivity. This option is very useful for amino adds which are highly soluble in die neutralised reaction mixture obtained after acid hydrolysis of the amide. 

Recently a number of enzymatic systems have been developed at several chemical companies including Upases (synthesis of enantiotrope alcohols, R-amid, S-amin), nitrilases (R-mandehc acid), amidases (non-proteinogenic L-amino acids), aspartic acid ammonia lyase (L-aspartic add), penicilin acylase (6-Aminopenicilanic acid), acylases (semisynthetic penicillins), etc.( Koeller and Wong, 2001 and references therin). 

Type I CSPs have also been used with aqueous mobile phases. Pirkle et al. (32) have reported on the resolution of N-(3,5-dinitrobenzoyl) derivatives of M-amino adds and 2-aminophosphonic adds on an (l )-N-(2-naphthyl)-alanine-derived CSP using a mobile phase composed of methanol-aqueous phosphate buffer. The utility of achiral alkyltrimethylammoruum ion-pairing reagents was also investigated. Other examples include the following (1) The recently commercialized ot-Burke 1 CSP resolves the enantiomers of a number of underivatized p-blockers using an ethanol-dichlorornethane-ammonium acetate mobile phase (33) (2) an (R)-l-naphthylethylurea CSP was used to resolve N-(3,5-dinitrobenzoyI)-substituted amino adds and 3,5-dinitrobenzoyl amide derivatives of ibuprofen, naproxen, and fenoprofen with acetonitrile-sodium acetate mobile phases (34). 

Many chiral derivatization reactions were used and the compounds examined are mostly amphetamines, /3-blocking agents, amino adds, and anti-inflammatory drugs. Silica gel and, to a lesser extent, silanized silica were used as stationary phases. The Rf values obtained for the diastereomeric pairs were not usually very high (0.04 -0.07), with the exception of amino alcohol and amino acid diastereomers obtained with Marphey s reagent, a derivative of L-alanine amide (0.06 - 0.22). 

Figure 2.3. Representative peptides made up from L-a-amino adds, (a) The structural formula of a parallel (i-shcct showing H-bonds. (b) The structural formula of a right-handed a-helix showing H-bonds. (c) The standard tape depictions of the right-handed a-helix and antiparallel (i-shcct. All amide bonds are in the tram configuration.

Optically active magnesium amide can add to a, -unsaturated esters such as tert-butyl cinnamate to give /l-amino esters with excellent diastereoselectivity (>95% d.e.) and in good yield (90%) (Scheme 3.42). 

FIGURE 8.21 Chemical structure of the copoly(ester amide) based on L-lysine and L-leucine amino adds that has been developed to prepare microspheres for oral insulin delivery. 

C. Regaiio, A.M. De llarduya, J.I. Iribarren, S. Munoz-Guma, Polyfester amide)s derived from L-tartaric add and amino alcohols. II. Aregic polymers, J. Polym. Sd. A Polym. Chem. 38 (2000) 2687—... 

The antiparallel-chain rippled sheet and the parallel-chain rippled sheet are satisfactory stmctiues, in that they involve linear hydrogen bonds, the interatomic distances and bond angles have the accepted values, and the amide groups are planar. The orientations of the bonds around the a carbon atoms are such that there is room for a side chain, projecting out nearly perpendicularly to the sheet, if alternate chains are constructed of D amino-add residues and l amino-acid residues. These structures are accordingly satisfactory ones for equimolal mixtures of D polypeptides and L polypeptides. 

Natural poly(amino add)s, such as cyanophycin, poly( -L-lysine) and poly-y-glutamic acid, are biodegradable ionic polymers. These are polydispersed molecules that consist of a-amide linkages, P- and y-carboxylic groups and -amino groups. 

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