Efficient chemoenzymatic synthesis of enantiomerically pure β-heterocyclic amino acid derivatives

Synthesis of Unnatural/Nonproteinogenic α‐Amino Acids

“…In addition, the racemization can be performed with an enzyme or by imine formation. This approach has been used to provide L-a-methyl-DOPA [104,105], as well as a variety of b-heterocyclic a-amino acids [106]. The methodology provides a general, industrial-scale process for the production of either L-or D-amino acids through the hydrolysis of the amide [107][108][109][110].…”

Enzymatic resolution for the preparation of enantiomerically enriched D‐β‐heterocyclic alanine derivatives using Escherichia coli aromatic L‐amino acid transaminase

“…Racemic pyrazolylalanine, triazolylalanine, and imidazolylalanine were synthesized according to the general procedure described elsewhere (Ferreira et al, 1999;Rolland-Fulcrand et al, 2000). All potassium salts of Nacetyl-h-heterocyclic alanine derivatives could be obtained from the reaction of an excess of 1,2-pyrazole, 1,2,4triazole, or imidazole on methyl-2-acetamidoacrylate in the presence of acetonitrile and K 2 CO 3 .…”

“…For the preparation of enantiomerically pure D-h-heterocyclic alanine derivatives, a chemo-enzymatic synthesis method comprising AroATEc is illustrated in Figure 4. Addition of excess (i) pyrazole, (ii) imidazole, or (iii) 1,2,4triazole to methyl-2-acetamidoacrylate in acetonitrile in the presence of potassium carbonate at 60jC until the completion of the reaction was able to directly lead to the potassium salts of N-acetyl-h-pyrazolylalanine, N-acetyl-htriazolylalanine, and N-acetyl-h-imidazolylalanine, respectively (Rolland-Fulcrand et al, 2000). NMR data for the three racemic h-heterocyclic alanine derivatives were as follows: .…”

“…Unnatural amino acids which show rare and special pharmacological effects and low degradation rates in living organism are drawing great attention as they become im-portant chiral building blocks for the synthesis of various pharmaceuticals (Bommarius et al, 1998;Fotheringham et al, 1997;Taylor et al, 1998). As an example of the unnatural amino acids, h-heterocyclic alanine derivatives such as pyrazolylalanine, triazolylalanine, and imidazolylalanine are known as important drugs for treatment of diabetes (Ferreira et al, 1999;Ikegami and Murakoshi, 1994;Rolland-Fulcrand et al, 2000). Several attempts for the synthesis of h-heterocyclic alanine derivatives have been described (Arnold et al, 1988;Barbaste et al, 1998;Farthing et al, 1996;Ferreira et al, 1999;Rolland-Fulcrand et al, 2000).…”

“…As an example of the unnatural amino acids, h-heterocyclic alanine derivatives such as pyrazolylalanine, triazolylalanine, and imidazolylalanine are known as important drugs for treatment of diabetes (Ferreira et al, 1999;Ikegami and Murakoshi, 1994;Rolland-Fulcrand et al, 2000). Several attempts for the synthesis of h-heterocyclic alanine derivatives have been described (Arnold et al, 1988;Barbaste et al, 1998;Farthing et al, 1996;Ferreira et al, 1999;Rolland-Fulcrand et al, 2000). Among them, a few notable attempts are as follows: (1) efficient synthesis of racemic h-heterocyclic alanine derivatives using Michael addition of nucleophilic heterocycles to N-di-tert-butyloxycarbonyl dehydroalanine methylester and subsequent total deprotection of the Ndi-tert-butyloxycarbonyl group (Ferreira et al, 1999); (2) chemo-enzymatic synthesis of enantiomerically pure hheterocyclic alanine derivatives using Aspergillus genus acylase (Rolland-Fulcrand et al, 2000); (3) direct condensation of 7-azaindole with L-serine catalyzed by tryptophan synthase allowing the preparation of enantiomerically pure 7-azatryptophan (Sloan and Phillips, 1996).…”