Synthesis of 3-Aminonocardicinic Acid, the Basic Nucleus of Nocardicins

Hatanaka, Minoru; Noguchi, Noriyoshi; Ishimaru, Toshiyasu

doi:10.1246/bcsj.55.1234

Cited by 16 publications

(5 citation statements)

References 12 publications

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“…Ideally, a comparison to nocardicin A and the C-5 epimer of nocardicin A would provide a conclusive answer to the stereochemistry at this position. The C-5 epimer of nocardicin A is not readily available; however, the proton signals at C-5 for diastereomeric analogs at this position differ by as much as 0.30 ppm, which would be clearly discernible by 400 MHz 1 H nuclear magnetic resonance (4,14). A mixture of the nocK::apr nocardicin A and isonocardicin A with authentic nocardicin A resulted in a single, well-resolved signal at C-5.…”

Section: Resultsmentioning

confidence: 99%

Mutational Analysis of nocK and nocL in the Nocardicin A Producer Nocardia uniformis

Kelly

Townsend

2005

J Bacteriol

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The nocardicins are a family of monocyclic ␤-lactam antibiotics produced by the actinomycete Nocardia uniformis subsp. tsuyamanensis ATCC 21806. The most potent of this series is nocardicin A, containing a syn-configured oxime moiety, an uncommon feature in natural products. The nocardicin A biosynthetic gene cluster was recently identified and found to encode proteins in keeping with nocardicin A production, including the nocardicin N-oxygenase, NocL, in addition to genes of undetermined function, such as nocK, which bears similarities to a broad family of esterases. The latter was hypothesized to be involved in the formation of the critical ␤-lactam ring. While previously shown to effect oxidation of the 2-amine of nocardicin C to provide nocardicin A, it was uncertain whether NocL was the only N-oxidizing enzyme required for nocardicin A biosynthesis. To further detail the role of NocL in nocardicin production in N. uniformis, and to examine the function of nocK, a method for the transformation of N. uniformis protoplasts to inactivate both nocK and nocL was developed and applied. A reliable protocol is reported to achieve both insertional disruption and in trans complementation in this strain. While the nocK mutant still produced nocardicin A at levels near that seen for wild-type N. uniformis, and therefore has no obvious role in nocardicin biosynthesis, the nocL disruptant failed to generate the oxime-containing metabolite. Nocardicin A production was restored in the nocL mutant upon in trans expression of the gene. Furthermore, the nocL mutant accumulated the biosynthetic intermediate nocardicin C, confirming its role as the sole oxime-forming enzyme required for production of nocardicin A.

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Section: Resultsmentioning

confidence: 99%

Mutational Analysis of nocK and nocL in the Nocardicin A Producer Nocardia uniformis

Kelly

Townsend

2005

J Bacteriol

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“…Finally, colourless needles were collected, washed with cold ethanol (2 × 3 ml) followed by diethyl ether and dried in vacuo. Additional crystals separated from the filtrates (0.63 g, 59%, overall); [α] λ (λ/nm): 23 (589), 26 (578), 29.5 (546), 48.5 (436), 74.5 (364) and 110 (313), (0.5%, in 0.10  HCl) (Found: C, 28.1; H, 6.9; N, 13 The resulting mixture was aerated for 20 h before the charcoal was removed by filtration ("Hyflo" filter aid) and the diluted filtrate (4 l) adsorbed on a column of AG 50W-X2 resin (13 × 10 cm). After washing with water (1 l) and 0.5  HCl (0.5 l) a single orange band was eluted with 3  HCl and the eluate evaporated to dryness.…”

Section: (؉)-(S)-a 2 Pr(me 2 )ؒ2hclؒ05h 2 Omentioning

confidence: 99%

“…all members of the bleomycin 10, 11 and malonomicin 12 families. The S-A 2 pr unit constitutes the β-lactam element of the antibiotic nocardicin 13 and monobactam 14 structures. The serine protease (thrombin) inhibitor cyclotheonamide from the marine sponge Theonella sp.…”

mentioning

confidence: 99%

Novel metal complex synthons for chiral 4-azaleucine, 2,3-diaminopropanoic acid and its elaboration

Barfod¹,

Bendahl²,

Hammershøi³

et al. 1999

J. Chem. Soc., Dalton Trans.

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Efficient syntheses of chiral Co() complexes with 2,3-diaminopropanoic acid (A 2 pr) have been developed. In these complexes, the amino acid zwitterion [A 2 pr(H ϩ )O Ϫ ] is bound didentate through the carboxylate and N 2 -amine groups while the N 3 -ammonio group [pK a = 7.19(2)] is unprotected. Syntheses of Λ(ϩ) 578 -and ∆(Ϫ) 578 -[(en) 2 Co-(S-A 2 pr(H ϩ )O)]Cl 3 ؒH 2 O were effected stereoretentively from the similarly didentate aspartato complexes Λand ∆-[(en) 2 Co(S-Asp(OH)O)]Cl 2 in reaction sequences transforming the unbound β-carboxyl group into an amine by Curtius rearrangement. The absolute configuration of the Λ(ϩ) 578 -[(en) 2 Co(S-Asp(OH)O)](ClO 4 ) 2 complex was determined by X-ray crystallographic analysis and defined the absolute stereochemistry of diastereoisomers and derived products. Methylation of the N 3 -amine group of Λ(ϩ) 578 -[(en) 2 Co(S-A 2 pr(H ϩ )O)]Cl 3 ؒH 2 O gave the (S)-4azaleucine complex Λ(ϩ) 578 -[(en) 2 Co(S-A 2 pr(Me 2 H ϩ )O)](C 4 F 9 SO 3 ) 3 from which enantiopure (ϩ)-(S)-2-amino-3-(dimethylamino)propanoic acid dihydrochloride hemihydrate [=(ϩ)-(S)-A 2 pr(Me 2 )ؒ2HClؒ0.5H 2 O] was obtained upon reductive removal of the protecting Co(III) centre. Racemic 4-azaleucine was easily produced by an alternative, but also metal-dependent method and the intermediate rac-(p)-[(tren)Co(A 2 pr(Me 2 H ϩ )O)]Zn 2 Cl 7 ؒ3H 2 O obtained in a simple solid-phase synthesis by selective reduction of achiral (p)-[(tren)Co(2-amino-3-(dimethylamino)acrylyl chloride)] 3ϩ ion adsorbed on AG 50W-X2 cation exchange resin. The epimerization rate of the Λ-[(en) 2 Co(S-A 2 prO)] 2ϩ complex ion was first-order in [HO Ϫ ] [k E = 3.8 × 10 Ϫ2 dm 3 mol Ϫ1 s Ϫ1 , I = 1.00 M (NaClO 4 ), 25 ЊC] with the diastereoisomer ratio K C (=[Λ-R]/[Λ-S]) = 0.77(2) at equilibrium in 10 mM NaOH. However, no epimerization was observed after at least 3 hours in 6 M HCl at 45 ЊC.

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“…In another application of these methods we have synthesized a 3-oxo azetidinone 87 by a short and highly efficient route from isoprene . This compound had previously been used as a precursor for the synthesis of 3-aminonocardicinic acid ( 88 ), which was the starting point for the preparation of the nocardicin antibiotics . The pathway to the azetidinone 87 , which is outlined in Scheme , begins with the tricarbonyliron lactone complex 89 , derived from isoprene monoepoxide.…”

Section: B Natural Product Synthesismentioning

confidence: 99%

(π-Allyl)tricarbonyliron Lactone Complexes in Organic Synthesis: A Useful and Conceptually Unusual Route to Lactones and Lactams

1996

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Synthesis of 3-Aminonocardicinic Acid, the Basic Nucleus of Nocardicins

Cited by 16 publications

References 12 publications

Mutational Analysis of nocK and nocL in the Nocardicin A Producer Nocardia uniformis

Mutational Analysis of nocK and nocL in the Nocardicin A Producer Nocardia uniformis

Novel metal complex synthons for chiral 4-azaleucine, 2,3-diaminopropanoic acid and its elaboration

(π-Allyl)tricarbonyliron Lactone Complexes in Organic Synthesis: A Useful and Conceptually Unusual Route to Lactones and Lactams

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