The biosynthesis of phenazines: incorporation of [2H]shikimic acid

Etherington, Terence; Herbert, Richard B.; Holliman, F. G.; Sheridan, John B.

doi:10.1039/p19790002416

Cited by 7 publications

(4 citation statements)

References 11 publications

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“…As reported previously, the biosynthesis of the esmeraldins involves the same head-to-tail dimerization of an unknown metabolite of the shikimic acid pathway that has been demonstrated for the phenazines elaborated by Pseudomonas sp. − and by some other Streptomycetes. , The product, presumably phenazine-1,6-dicarboxylic acid ( 6 ), is then further converted into saphenic acid 2a or a derivative thereof by addition of a one-carbon unit, a methyl group derived from C-2 of acetate. Such one-carbon extensions of various structural backbones, particularly polyketides, have been encountered in the biosynthesis of a number of compounds, such as myxovirescin A 1 , virginiamycin, myxopyronin A, aurantinin, pseudomonic acid, , oncorhyncolide, cylindrophane, and pulvomycin…”

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confidence: 52%

“…Acetate as its coenzyme A thioester derivative is converted by acetyl-CoA carboxylase to malonyl-CoA, which then undergoes a decarboxylative Claisen condensation with the mono-CoA thioester of phenazine-1,6-dicarboxylic acid 6. Hydrolysis of the resulting thioester and decarboxylation of the β-keto acid produces 6-acetylphenazine-1-carboxylic acid (7), which is then reduced to saphenic acid 2a. Support for this pathway was ascertained by feeding stable isotope-labeled phenazine-1,6-dicarboxylic acid 6, 6-acetylphenazine-1-carboxylic acid 7, and saphenic acid 2a to Streptomyces antibioticus Tu ¨2706 and demonstrating their specific incorporation into esmeraldins 1b/1c and/or saphenyl esters 2b/2c.…”

Section: Resultsmentioning

confidence: 99%

“…4 As reported previously, 4 the biosynthesis of the esmeraldins involves the same head-to-tail dimerization of an unknown metabolite of the shikimic acid pathway that has been demonstrated for the phenazines elaborated by Pseudomonas sp. [5][6][7][8][9][10] and by some other Streptomycetes. 11,12 The product, presumably phenazine-1,6-dicarboxylic acid (6), 13 is then further converted into saphenic acid 2a or a derivative thereof by addition of a one-carbon unit, a methyl group derived from C-2 of acetate.…”

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Biosynthesis of Phenazine Antibiotics inStreptomyces antibioticus: Stereochemistry of Methyl Transfer from Carbon-2 of Acetate

et al. 1999

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Stable isotope labeling experiments have shown that the biosynthesis of the monomeric phenazines, the saphenyl esters, and their dimerization products, the esmeraldins, in Streptomyces antibioticus Tu ¨2706 proceeds from phenazine-1,6-dicarboxylic acid by chain extension with C-2 of acetate to 6-acetylphenazine-1-carboxylic acid, which is reduced to saphenic acid. The latter is incorporated into both halves of the esmeraldins, albeit differentially. By feeding of chiral acetate, degradation of the resulting saphenyl esters and esmeraldins, and configurational analysis of the acetic acid formed, the chain extension process was found to proceed with overall inversion of configuration at the methyl group. This suggests that the decarboxylation of a hypothetical intermediate β-keto acid proceeds in an inversion mode. This result is discussed with reference to analogous C-methylations of polyketide backbones by addition of C-2 of acetate.

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Biosynthesis of Phenazine Antibiotics inStreptomyces antibioticus: Stereochemistry of Methyl Transfer from Carbon-2 of Acetate

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“…Hydrolysis of the acetonide (aqueous acetic acid, 16 h, 20°C) and saponification produced (+) 5-epishikimic acid 9 in 39% overall yield from 1. This epimer of shikimic acid has not been previously synthesized but its methyl ester (6) and a related triacetate 10 are known (7). Hydrolysis of the acetonide 8, as before, and acetylation confirmed the identity ('Hmr) and stereochemistry of our product.…”

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Shikimic acids from furan; methods of stereocontrolled access to 3,4,5-trioxygenated cyclohexenes

Rajapaksa¹,

Keay²,

Rodrigo³

1984

Can. J. Chem.

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, 826 (1984). Oxabicycloheptenes 1 and 2 are converted to 3,4,5-oxygenated cyclohexenes by stereocontrolled hydroxylations and epoxidations coupled with reverse-Michael cleavage of the oxabicyclo system. Three epimers of shikimic acid are synthesized by these methods. In a current paper ( I ) we report the general occurrence of some 5-endo-trig reversals of 7-oxabicyclo[2.2. llheptenes and provide a stereoelectronic rationale for the violations of Baldwin's Rules (2) observed in these cases. The reverse-Michael reactions (1, 3) of such compounds, coupled with standard epoxidations and hydroxylations, offer significant opportunities for the generation of multi-oxygenated cyclohexenes with virtually complete control of stereochemistry. We illustrate herein the application of these procedures to the efficient synthesis of some shikimic acids (4).* Oxabicycloheptenes 1 and 2, easily obtained from furan (5), were employed as starting materials. Conversion (1) of cyanide 2 to cyclohexadiene 3 followed by osmylation (osmium tetroxide/pyridine) produced diol 4 with complete regio and stereoselectivity. There is little doubt that the bulky TBDMS group is responsible for directing hydroxylation from the lower face of the 3,4 double bond. The synthesis of (+) shikimic acid 5 was then completed by the standard procedures of desilylation (tetrabutylammonium fluoride/THF) and alkaline hydrolysis in 3 1% overall yield from 2.If the osmylation is conducted before the reverse-MichaeI fission, the stereochemistry of the cis-diol function thereby introduced is reversed and 5-epishikimic acid should result. Accordingly, bicyclo ester 1 was osmylated as before and the resulting exo-diols 6 converted to the acetonides 7. ReverseMichael cleavage of the latter (LDA, THF, 0°C) provided the expected cyclohexenol 8 (86%). Hydrolysis of the acetonide (aqueous acetic acid, 16 h, 20°C) and saponification produced (+) 5-epishikimic acid 9 in 39% overall yield from 1. This epimer of shikimic acid has not been previously synthesized but its methyl ester (6) and a related triacetate 10 are known (7). Hydrolysis of the acetonide 8, as before, and acetylation confirmed the identity ('Hmr) and stereochemistry of our product.Expoxidations of the double bond similarly timed can produce the other two isomers to shikimic acid. Thus exo-epoxides 11 obtained by MCPBA treatment of 1 reacted with LDA at -78°C to afford a 1 : 1 mixture of two products (86%). These were separated by distillation and identified as epoxycyclohexenol 12 (bp 1 10°C/0.05 Torr) and cyclopropane 13 (bp 92-100°C/0.05 Torr). The former has recently been con-H 0 , , , , , 3 q R 1 :ZmCO2Me' Author to whom correspondence may be addressed.

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