Abstract: Pyridoxal 5′-phosphate (PLP)-dependent enzymes catalyze a diverse range of chem. transformations. Despite their extraordinary functional diversity, no PLP-dependent enzyme is known to catalyze Mannich-type reactions, an important carbon-carbon bond-forming reaction in synthetic organic chem. Here we report the discovery of a biosynthetic enzyme LolT, a PLP-dependent enzyme catalyzing a stereoselective intramol. Mannich reaction to construct the pyrrolizidine core scaffold in loline alkaloids. Importantly, its versatile catalytic activity is harnessed for stereoselective synthesis of a variety of conformationally constrained α,α-disubstituted α-amino acids, which bear vicinal quaternary-tertiary stereocentres and various aza(bi)cyclic backbones, such as indolizidine, quinolizidine, pyrrolidine and piperidine. Furthermore, crystallog. and mutagenesis anal. and computational studies together provided mechanistic insights and structural basis for understanding LolT′s catalytic activity and stereoselectivity. Overall, this work expands the biocatalytic repertoire of carbon-carbon bond-forming enzymes and increases our knowledge of the catalytic versatility of PLP-dependent enzymes.
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] European Journal of Medicinal Chemistry, 1981, vol. 16, # 6, p. 515 - 524
[2] Russian Journal of Organic Chemistry, 2013, vol. 49, # 11, p. 1690 - 1702[3] Zh. Org. Khim., 2013, vol. 49, # 11, p. 1707 - 1718,12
[4] Polymer, 2015, vol. 65, p. 45 - 54
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[ 590-92-1 ]
[ 111-29-5 ]
[ 36840-85-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With triethylamine In toluene
a) 1,5-Pentamethylene diacrylate 1,5-Pentanediol (15.6 g) was heated in refluxing toluene (500 ml) with 3-bromopropionic acid (50.5 g) and a trace of p-toluenesulphonic acid for 4 hours. The cooled toluene solution was then washed with aqueous sodium acetate solution and treated with triethylamine (50 ml) at reflux. The cooled reaction mixture was washed well with water to remove triethylamine and triethylamine hydrobromide and then the toluene was removed under reduced pressure. The product, 1,5-pentamethylene diacrylate (24.0 g, 75percent yield) was obtained as a pale liquid by high vacuum distillation (b.p. 90°-95° C./0.1 mm Hg).
5-[2-(1-(S)-benzyl-2-hydroxy-ethylcarbamoyl)-2-phenyl-ethyl]-2-(4-trifluoromethylphenyl)-7-(4-trifluoromethylphenyl)ethynyl-benzofuran-3-carboxylic acid, 5-hydroxypentyl ester[ No CAS ]
5-[2-(1-(S)-benzyl-2-hydroxy-ethylcarbamoyl)-ethyl]-7-methoxy-2-(4-trifluoromethylphenyl)-benzo[b]furan-3-carboxylic acid, 5-hydroxy-pentyl ester[ No CAS ]
5-[2-(1-(S)-benzyl-2-hydroxy-ethylcarbamoyl)-2-phenyl-ethyl]-2-(4-methoxyphenyl)-7-(4-methoxyphenyl)ethynyl-benzofuran-3-carboxylic acid, 5-hydroxypentyl ester[ No CAS ]
5-[2-(1-(S)-benzyl-2-hydroxy-ethylcarbamoyl)-2-phenyl-ethyl]-2-(4-methylphenyl)-7-(4-methylphenyl)ethynyl-benzofuran-3-carboxylic acid, 5-hydroxypentyl ester[ No CAS ]
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