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Mimicking the Reaction of Phenylalanine Ammonia Lyase by a Synthetic Model
Author(s) -
Rettig Martin,
Sigrist Andreas,
Rétey János
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20000906)83:9<2246::aid-hlca2246>3.0.co;2-x
Subject(s) - chemistry , electrophile , moiety , nucleophile , stereochemistry , elimination reaction , intramolecular force , phenylalanine , medicinal chemistry , amino acid , organic chemistry , catalysis , biochemistry
Abstract Phenylalanine and histidine ammonia lyases (PAL and HAL) catalyze the reversible conversion of α ‐amino acids to the corresponding acrylic acids by elimination of ammonia. The prosthetic group 3,5‐dihydro‐5‐methylidene‐4 H ‐imidazol‐4‐one (MIO) at the active site of both enzymes supposedly undergoes an electrophilic attack at the aromatic nucleus in the first step of the mechanism of action. Since no chemical analogy existed for such an electrophile‐assisted elimination, we synthesized model compounds, some portion of which mimicked the essentials of the substrate phenylalanine and another portion the electrophilic Michael acceptor in a sterically appropriate distance. The first model, (±)‐ rel ‐(1 R ,2 S ,3 S )‐3‐[1‐methylidene‐2‐oxo‐2‐(pyrrolidin‐1‐yl)ethyl]‐2‐phenylcyclohexanamine ( 7 ) did not react under Friedel‐Crafts conditions in the expected way ( Scheme 2 ). The second model compound (±)‐2‐ rel ‐(1 R ,2 S ,3 S )‐3‐(dimethylamino)‐2‐(3‐methoxyphenyl)cyclohexyl]prop‐2‐enal ( 12 ) with a more nucleophilic methoxyphenyl and a more electrophilic α , β ‐unsaturated carbonyl moiety, underwent an intramolecular Friedel‐Crafts‐ type substitution, but no elimination of the dimethylamino group ( Scheme 4 ). The third model compound, (±)‐ γ ‐[(dimethylamino)methyl]‐3‐methoxy‐2,4,6‐trimethyl‐ α ‐methylidenebenzenebutanal ( 25 ) eliminated dimethylamine upon treatment with Lewis acids and subsequent hydrolysis of the intermediate ( Scheme 6 ). When the 3‐methoxy‐2,4,6‐trimethylphenyl moiety of 25 was replaced by the 2,4,6‐trimethyl‐3‐nitrophenyl group, no elimination product could be observed ( Scheme 7 ).