P amino acids

Aminopropanoic acid known as 3 alanine It IS a p amino acid that makes up one of the stmctural units of coenzyme A... 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

P-amino acid products. Treatment of oxazoline 53 with 7V-lithiopiperidine followed by alkylation with iodomethane affords aniline derivative 54 in 94% yield and 99% de. Hydrolysis of the oxazoline group provided amino acid 55 in 92% yield and >99% ee. 

In the special case of 3-lactones, where small-angle strain is an important factor, alkyl-oxygen cleavage is observed (Bal2 mechanism, as in the similar case of hydrolysis of P-lactones, 10-10), and the product is not an amide but a P-amino acid ... 

Recent Stereoselective Synthetic Approaches to p-Amino Acids," Cole. D.C. Tetrahedron, 1994, 50, 9517... 

Some ligand-exchange CSPs have been used at preparative level [31, 32], In this case it must be taken into account that an extraction process, to remove the copper salts added to the mobile phase, must be performed following the chromatographic process [33], Teicoplanin, in contrast, resolves all ordinary a and P-amino acids with mobile phases consisting of alcohol/water mixtures. No buffer is needed in the... 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

Oxazolinyl-oxiranyllithiums (357) prepared from optically pure oxazolinyloxi-ranes react with nitrones diastereo and enantioselectively to give almost optically pure diazadispiroundecanes (358). These are appropriate candidates for the conversion to a-epoxy-P-amino acids (360) in view of the lability of the N-O bond of the isoxazolidinones (359) (Scheme 2.156) (590-596). 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

Figure 17.5 HTS hits and early P-amino acid acid derived DPP-4 inhibitors.

Incorporation of the P-amino acid amide from 25 into piperazine hit 26 improved DPP-4 inhibition by more than 80-fold and led to the discovery of 32 (Table 17.5) [46], The 2-fluorophenyl effect on DPP-4 potency was again observed with compound 33 however, this compound showed very high clearance and no oral bioavailability in the rat. More simplified truncated compounds 34 and 35 showed decreased DPP-4 potency by 10-fold compared to 33, and the removal of the benzyl group resulted in a more significant loss of DPP-4 activity (36). Unfortunately, while 34 showed good... 

Table 17.5 Off-target activities of early P-amino acid DPP-4 inhibitors (ICso s, nM).

Procedure 8.4 Gasoraetric assay of p-amino acid oxidase using a Gilson differential respirometer... 

Synthesis of Enantiomerically Pure p-Amino Acid from 2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1 H)-pyrimidinone (S)-p-Tyrosine-O-methyl Ether. 

A number of nonnatural amino acids were resolved into individual enantiomers on 0-9-(2,6-diisopropylphenylcarbamoyl)quinine-based CSPby Peter and coworkers [48,90,113,114] after derivatization with Sanger s reagent, chloroformates (DNZ-Cl, FMOC-Cl, Z-Cl), Boc-anhydride, or acyl chlorides (DNB-Cl, Ac-Cl, Bz-Cl). For example, the four stereoisomers of P-methylphenylalanine, P-methyltyrosine, P-methyltryptophan, and P-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid could be conveniently resolved as various A-derivatives [113]. The applicability spectrum of cinchonan carbamate CSPs comprises also P-amino carboxylic acid derivatives, which were, for example, investigated by Peter et al. [114]. A common trend in terms of elution order of DNP-derivatized P-amino acids was obeyed in the latter study On the utilized quinine carbamate-based CSP, the elution order was S before R for 2-aminobutyric acid, while it was R before S for the 3-amino acids having branched R substituents such as wo-butyl, iec-butyl, tert-butyl, cyclohexyl, or phenyl residues. 

Direct and indirect chromatographic methods were developed and compared in systematic examinations for the enantioseparation of P-amino acids direct separation of underivatized analytes involved the use of commercially available Crownpak CR(-I-), teicoplanin, and ristocetin A CSPs [148], while indirect separation was based on precolumn derivatization with 2,3,4,6-tetra-G-acetyl-f)-D-glucopyranosyl isothiocyanate (GITC) or A - a-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (EDAA, Marfey s reagent), with subsequent separation on a nonenantioselective column. 

A comparative and comprehensive study on the enantioseparation of several unnatural P-amino acids has onlyjust been published in 2006, testing six commercially... 

FIGURE 2.15 Separation of a P-amino acid on a A-40,926 CSP. (From D Acquarica, I. et al., Tetrahedron Asymmetry, 11, 2375, 2000. With permission from Elsevier, Copyright (2000).)... 

Another study focused on aryl-substituted P-lactams, using the same set of teicoplanin-based CSPs and variable-temperature conditions [99]. Tricyclic P-lactams were investigated by the same group of authors, together with some bicyclic P-amino acids, on five different commercially available glycopeptides CSPs, namely ristocetin A, TE, TAG, vancomycin, and VAG, and on a new dimethylphenyl carbamate-derivatized 5-cyclodextrin-based CSP. The chromatographic results, achieved with different methods, were compared in systematic examinations [170]. 

Arki, A. et al.. High-performance liquid chromatographic separation of stereoisomers of P-amino acids and a comparison of separation efficiencies on CHIROBIOTIC T and TAG columns, Chromatographia, 60, S43, 2004. 

Berkecz, R. et al., LC enantioseparation of -lactam and P-amino acid stereoisomers and a comparison of macrocyclic glycopeptide and P-cyclodextrin-based columns, Chromatographia, 63, S37, 2006. 

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