Enantiospecific synthesis of (s)-4-amino-4,5-dihydro-2-furancarboxylic acid, a new suicide inhibitor of gaba-transaminase.

Burkhart, Joseph P.; Holbert, Gene W.; Metcalf, Brian W.

doi:10.1016/s0040-4039(01)81580-x

Cited by 26 publications

(10 citation statements)

References 11 publications

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“…MoOPH under a variety of conditions resulted in complete recovery of unchanged starting material, as was recently observed in a related case (21). However, when the oxaziridine was used as oxidant, hydroxylation took place to give the (4s)-hydroxy analog as the major (9: 1) isomer, when LiHMDS was used as the base.…”

supporting

confidence: 67%

“…Although there are ample precedents for the hydroxylation of ester (l8),' lactone (19), and lactam (20) enolates, there are few practical examples in the amino acid series (21), one, to the best of our knowledge, in the case of acidic amino acids (22), and none with amino lactones. Our choice of L-aspartic and L-glutamic acids as substrates was instigated by the fact that the corresponding p-and y-hydroxy acids, respectively, are found in nature.…”

mentioning

confidence: 99%

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Novel access to (3R)- and (3S)-3-hydroxy-L-aspartic acids, (4S)-4-hydroxy- L-glutamic acid, and related amino acids

Hanessian¹,

Vanasse²

1993

Can. J. Chem.

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. Derivatives of L-aspartic and L-glutamic acids can be converted into a-hydroxy acids via oxygenation of the corresponding enolates. :There is at present much interest in the asymmetric synthesis of non-proteinogenic as well as unusual amino acids 2). In this regard, the p-and y-hydroxy a-amino acid motif, which can / be found in a number of natural products (e.g., cyclosporin 1 (3a) and lysobactin (3b); see also ref. 4), presents a chal-I lenging area for studies in stereocontrolled synthesis. Most of the synthetic routes to p-and y-hydroxy a-amino acids and , their derivatives have been developed only recently and they ) rely basically on chemical (1, 2), or enzymatic methods (4, , 5). In connection with other ongoing projects in our labo-1 ratory, we became interested in the synthesis of (3R)-and 1 (3s)-3-hydroxy-L-aspartic acids. Although the four optical isomers have been obtained by resolution (6) and by individual synthesis (7), recent reports have described alternative methods relying on asymmetric processes using amino acids (8, 9), on utilizing (R, R)-(+)-tartaric acid as a chiral template (1 0-16), and on other methodology.We wish to disclose a novel access to (3R)-and (3s)-3-hydroxy-L-aspartic acids and (4s)-4-hydroxy-L-glutamic acid, as well as to a,?-dihydroxy amino acids (17), by the stereocontrolled hydroxylation of the dianions derived from appropriate amino acids or their functional equivalents. Although there are ample precedents for the hydroxylation of ester (l8),' lactone (19), and lactam (20) enolates, there are few practical examples in the amino acid series (21), one, to the best of our knowledge, in the case of acidic amino acids (22), and none with amino lactones. Our choice of L-aspartic and L-glutamic acids as substrates was instigated by the fact that the corresponding p-and y-hydroxy acids, respectively, are found in nature. In planning our strategy for the stereocontrolled hydroxylation of dianions we wished to control the process by capitalizing on internal asymmetric induction resulting from the inherent chirality and functional disposition of a resident N-substituted amino group. We reasoned that by the judicious choice of oxidation reagent, we could alter the stereochemical course of the hydroxylation by taking advantage of the steric bulk in the substrate on the one hand, and chelation of proximal N-substituted groups on the other, as illustred by paths A and B for the enolate resulting from L-aspartic acid in Scheme 1.'~u t h o r to whom correspondence may be addressed.or some examples using molecular oxygen and lead tetra- To test our plan, we chose the readily available (23) lactone 1 as a model in which the geometry of the dianion is fixed. 'Thus, lactone 1 was treated with a variety of bases, and the resulting enolate was treated with the Davis oxaziridine reagent (24) on the one hand, and the Mimoun-Vedejs, oxodiperoxymolybdenum pyridine hexamethylphosphoric triamide (MoOPH) reagent (25) on the other (Scheme 2).As can be appreciated from the results in Table 1, regard...

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confidence: 67%

mentioning

confidence: 99%

Novel access to (3R)- and (3S)-3-hydroxy-L-aspartic acids, (4S)-4-hydroxy- L-glutamic acid, and related amino acids

Hanessian¹,

Vanasse²

1993

Can. J. Chem.

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“…Last year, however, we showed that the antibiotic l -cycloserine ( 5 ) also inactivates GABA-AT via an aromatization mechanism . With gabaculine as the lead compound, two other dihydroaromatic GABA analogues, ( S )-4-amino-4,5-dihydro-2-thiophenecarboxylic acid (SADTA, ( S )- 6 ) and ( S )-4-amino-4,5-dihydro-2-furancarboxylic acid ( 7 ), were synthesized by Metcalf and co-workers and shown to be irreversible inactivators of GABA-AT, but no mechanistic studies were carried out. The mechanism of inactivation for both of these compounds was proposed to be identical to that of gabaculine on the basis of structure analogy (Scheme shows the mechanism for 6 ), although no experimental support was provided.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic Acid

Nikolić

Breemen

et al. 1999

J. Am. Chem. Soc.

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(S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic acid ((S)-6) was previously synthesized (Adams, J. L.; Chen, T. M.; Metcalf, B. W. J. Org. Chem. 1985, 50, 2730−2736.) as a heterocyclic mimic of the natural product gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid), a mechanism-based inactivator of γ-aminobutyric acid aminotransferase (GABA-AT) (Rando, R. R. Biochemistry 1977, 16, 4604). Inactivation of GABA-AT by (S)-6 is time-dependent and protected by substrate. Two methods were utilized to demonstrate that, in addition to inactivation, about 0.7 equiv per inactivation event undergoes transamination. Inactivation results from the reaction of (S)-6 with the pyridoxal 5‘-phosphate (PLP) cofactor. The adduct was isolated and characterized by ultraviolet−visible spectroscopy, electrospray mass spectrometry, and tandem mass spectrometry. All of the results support a structure (11) that derives from the predicted aromatization inactivation mechanism (Scheme ) originally proposed by Metcalf and co-workers for this compound. This is only the third example, besides gabaculine and l-cycloserine, of an inactivator of a PLP-dependent enzyme that acts via an aromatization mechanism.

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“…Two of these compounds are ( S )-4-amino-4,5-dihydro-2-thiophenecarboxylic acid (S-ADTA)(12) and ( S )-4-amino-4,5-dihydro-2-furancarboxylic acid (S-ADFA)(13). Both have been investigated for their potential to undergo an aromatization mechanism(7, 14).…”

mentioning

confidence: 99%

Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid,

Liu

Pozharski

et al. 2010

Biochemistry

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As a potential drug to treat neurological diseases, the mechanism-based inhibitor (S)-4-amino-4,5-dihydro-2-furancarboxylic acid (S-ADFA) has been found to inhibit the γaminobutyric acid aminotransferase (GABA-AT) reaction. To circumvent the difficulties in structural studies of a S-ADFA-enzyme complex using GABA-AT, L-aspartate aminotransferase (L-AspAT) from E. coli was used as a model PLP-dependent enzyme. Crystal structures of the E. coli aspartate aminotransferase with S-ADFA bound to the active site were obtained via co-crystallization at pH 7.5 and 8. The complex structures suggest that S-ADFA inhibits the transamination reaction by forming adducts with the catalytic lysine 246 via a covalent bond while producing one equivalent of pyridoxamine 5′-phosphate (PMP). Based on the structures, formation of the K246-S-ADFA adducts requires a specific initial binding configuration of S-ADFA in the L-AspAT active site, as well as deprotonation of the ε-amino group of lysine 246 after the formation of the quinonoid and/or ketimine intermediate in the overall inactivation reaction.

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Enantiospecific synthesis of (s)-4-amino-4,5-dihydro-2-furancarboxylic acid, a new suicide inhibitor of gaba-transaminase.

Cited by 26 publications

References 11 publications

Novel access to (3R)- and (3S)-3-hydroxy-L-aspartic acids, (4S)-4-hydroxy- L-glutamic acid, and related amino acids

Novel access to (3R)- and (3S)-3-hydroxy-L-aspartic acids, (4S)-4-hydroxy- L-glutamic acid, and related amino acids

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic Acid

Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid,

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