P -Hydroxy-aspartate

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

The key step of the approach to 45 is the ring opening of /V-Boc p-lactam 43 with ammonia, Scheme 17. The synthesis starts from the 4-carboxy azetidin-2-one 41, which is a p-hydroxy aspartic acid form possessing the p-carboxyl group and the a-amino moiety simultaneously protected. The dipeptide unit 42 is obtained in 95% overall yield after activation of the a-carboxy group with cyanuric fluoride and... 

Femlund P, Stenflo J. (3-Hydroxy-aspartic acid in vitamin -dependent proteins. J Biol Chem 1983 258 12509-12512. 

The microbial biotechnology of amino acids production which was developed and industrialized in Japan have been summarized. The amino acids include L-glutamic acid, L-lysine, L-threonine, L-aspartic acid, L-alanine, L-cysteine, L-dihydroxyphenylalanine, D-p-hydroxy-phenyl-glycine, and hydroxy-L-proline. 

Resolutions. The following types of substrates have been resolved via lipase-mediated enantioselective esterification malic and aspartic esters, 3-hydroxyalken-l-yl p-tolyl sulfoxides, P-hydroxy sulfoxides." A practical method involves sequential transacetylation and sulfation, followed by extraction and treatment of the aqueous layer with methanolic HCl to recover the alcohol (the organic layer yields the acetate). The use of 1-ethoxyvinyl acetate as acetyl donor in these reactions has been proposed."... 

Dehydration of the P-hydroxy acyl chain is achieved by the DH domain, yielding an a, P-unsaturated moiety from an ElcB-elimination mechanism (Fig. 1.25). The proposed mechanism for dehydration proceeds via donation of a proton from an aspartic acid residue in the HPALLD motif, followed by removal of an a-proton by a catalytic histidine, generating the unsaturated product [87, 88], The monomeric DH unit is -280 residues in length, and forms a dimeric unit across the centre of type 1 PKSs (see Sect. 1.2.4). 

Ring-opening of aziridinecarboxylic acids has been used in the conversion of threonine into /Areo-3-methylcysteine and in the synthesis of p-alkoxy-a-amino-acids. Improved methods have appeared for the synthesis of iV-(phosphono-acetyl)-amino-acids and for the preparation of y-esters of glutamic acid and (3-esters of aspartic acid. The protected P-hydroxy-a-amino-acids (278) are converted into a-fluoro-P-amino-acids (279) with DAST (Scheme 137). ... 

Lu C., Chan S. L., Haughey N., Lee W. T., and Mattson M. P. (2001). Selective and biphasic effect of the membrane lipid peroxidation product 4-hydroxy-2,3-nonenal on V-methyl-D-aspartate channels. J. Neurochem. 78 577-589. 

Varga V., Jenei Z., Janaky R., Saransaari P., and Oja S. S. (1997). Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-ainino-3-hydroxy-5-metliyl-4-isoxazolepropionate (AMPA) receptors. Neurochem. Res. 22 1165-1171. 

The cyclization of aspartic acid residues to form aspartimide is the most likely side-reaction observed in routine SPPS (Fig. 10). This is a sequence-dependent side-reaction that occurs either during chain elongation or during final TFA cleavage when Asp(OtBu)-AA sequence (AA = Ala, Gly, Ser, Asn(Trt)) is present in the peptide. Hydrolysis of the aspartimide ring leads to a mixture of both a- and P-peptides. Its reaction with piperidine used for Fmoc removal also leads to the formation of a- and p-piperidides. Normally, in Fmoc-based SPPS, Asp (OtBu) provides sufficient protection. However, for particular sequences such as Asp(OtBu)-Asn(Trt) particularly sensitive to aspartimide formation, addition of HOBt to the piperidine solution or protection of the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group should be considered (36). 

Cyclization of aspartic acid and asparagine to form aspartimides, and to a lesser extent of glutamic acid and glutamine to form glutarimide is an acid- and base-catalyzed common side reaction in peptide synthesis (see also Section 2.2.2). In SPPS it is particularly troublesome when Asp-Gly, Asp-Ala, and Asp-Ser sequences are present,but also with Asp-Asn.P P Piperidine-catalyzed aspartimide formation can be very rapid,and in this context DBU is even worse than piperidine.P The formation of aspartimide is reduced by the addition of HOBt or 2,4-dinitrophenol, but more efficiently it is reduced by protecting the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group (see Section 2.3.2).P 1... 

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