Antibiotics phosphonomycin

An example of the synthetic use of allene hydrogenation is the preparation of the antibiotic phosphonomycin (equation 47)124. 

The first stage of cell wall synthesis formation of UDP-A-acetylmuramyl-pentapeptide (full structure shown at bottom). Point of inhibition by the antibiotic phosphonomycin are indicated. 

In addition to penicillin several other antibiotics (phosphonomycin, bacitracin, and vancomycin) block cell wall synthesis at different locations (see figs. 16.16 and 16.17). In addition to their biological and medical importance, these antibiotics have been very useful in elucidating the biosynthetic pathway. This is because they cause accumulation of the intermediate before the blocked step. This species can frequently be isolated and confirmed as a genuine intermediate in the pathway. 

Initially, /-menthyl 2-cyano-3-methyI-2-pentenoate, and /-menthyl and r/-bornyl cy-clopentylidenecyanoacetateswere epoxidized with hydrogen peroxide in the presence of sodium tungstate. Some asymmetric induction was achieved, but the degree of diastereoselectivity was not estimated26. In the final step of the synthesis of the antibiotic phosphonomycin, (Z)-propenylphosphonic acid was epoxidized under Weitz-Scheffer conditions and 92% optically pure phosphonomycin (+ )-x-phenethylammonium-c -epoxypropylphosphonate crystallized from the reaction mixture. It is unclear whether an asymmetric induction occurs during the epoxidation step and to what extent27. 

Allenes with a terminal double bond are selectively reduced in the terminal position, e.g., in the synthesis of the antibiotic phosphonomycin, 5. Here the catalyst is selective and is also highly stereospecific. The reduced product is pure phosphonomycin ... 

Finally, a diastereoselective addition of trimethylsilyl dibenzyl phosphite to (5)-lactaldehyde 56 was used in a synthesis of antibiotic phosphonomycin 59 (Scheme 47.14). An interesting feature of the reaction is that the observed stereochemical outcome could be explained by assuming a cyclic intermediate with a partial bonding between silicon and carbonyl oxygen 57, similarly as in the example shown in Scheme 47.10. 

B. Phosphonomycin.—Since the publication of the synthesis of (48), which was described in last year s Report, numerous patents have been filed of syntheses of this antibiotic. The isomerization of the trans-... 

Fosfomycin, the (IR,IS) (-)-l,2-cpoxy propylphosphonic acid, formerly called phosphonomycin, is a low-molecular-weight antibiotic of unusual structure that was originally isolated in 1969 from used culture medium of Streptomyces fradiae (Figure 4.l),i. 86-i88 yjjg structure was established by... 

Functionalized phosphonic and phosphinic acids and their derivatives are obviously of interest to the organophosphorus chemist, but the importance, both actual and potential, in other areas, particularly in the biological sphere, cannot be overemphasized. Prominent amongst the many important compounds are, for example,the insecticide dipterex (1) and the herbicide glyphosate (2), both synthetic compounds. Several phosphonic acid antibiotics have been isolated from Streptomyces species. (2 S)-2-Amino-4-(hydroxymethyl-phosphinoyl)butanoic acid (3), otherwise known as phosphinothricin, and a substance which also possesses herbicidal activity, is a component of the peptide y-(hydrox-ymethylphosphinoyl)-L-a-aminobutanoyl-L-alanyl-L-alanine, also present in the same organism. (1,2-Epoxypropyl)phosphonic acid, [(3-methyloxiranyl)phosphonic acid] as the (2R,3S)-diastereoisomer (4), also known as phosphonomycin, is important from the pharmaceutical standpoint as a broad spectrum bactericide, and it is produced commercially. 

Phosphonomycin (135n) and other phosphonates isolated from bacterial sources have been found to be valuable anti-bacterial antibiotics (Chapter 12.13). 

Originally called phosphonomycin, fosfomycin is a broad spectrum antibiotic produced by a... 

Hendlin D, Stapley EO, Jackson M, WaUick H, Miller AK, Wolf FJ, Miller T, Chaiet L, Kahan FM, Foltz EL, Woodruff HB, Mata JM, Hernandez S, Mochales S (1969) Phosphonomycin a new antibiotic produced by strains of Streptomyces. Science 166 122-123... 

In 1959, Horiguchi and Kandatsu discovered the first naturally occurring compound with the C—P bond, 2-aminoethylphosphonic acid. A decade later, a potent antibiotic produced by strains Streptomyces, phosphonomycin, was found, with a unique structural feature consisting of a phosphonic acid moiety attached to an oxirane system. Since that time, other alkylphosphonic acids, phospho-nolipids, and phosphinates have been detected as minor components in various living species." Interestingly, alkylphosphonic acid derivatives were also found in meteorites. ... 

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