Phosphonomycin synthesis

C. Rearrangements.—The thermal rearrangement of di-t-butyl-2-propynyl phosphite (95) has been used in a new synthesis of phosphonomycin (96)." The half salt (97) was obtained optically pure after a single crystallization. 

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-... 

Dialkyl vinylphosphonates.13 Pd(0) catalyzes the reaction of vinyl bromides and dialkyl phosphites in the presence of trielhylamine (1 equivalent) to form dialkyl vinylphosphonates. The configuration of the starting material is retained. An example is the synthesis of phosphonomycin (1, equation I). 

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. 

Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis (Figure 43-5). An analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-V-acetylglucosamine. This reaction is the first step in the... 

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. 

Penz, G., and Zbiral, E., Synthesis of dialkyl ( )-cZ5-l,2-epoxy-3-oxoalkylphsphonates. Phosphonomycin analogues, Monatsh. Chem., 113, 1169, 1982. 

Phosphonomycin,—Yet another synthesis of phosphonomycin (22) has appeared (Scheme 6). The phosphonoaldehyde (23) was treated with pentan-3-one and cyclohexylamine to give (24), which was then converted into its oxime. Tosylation of this oxime followed by treatment with bicarbonate caused the molecule to fragment, liberating the dimethyl ester of (22). Disodium phosphonoacetic acid when administered orally or topically to mice infected with Herpes simplex virus will reduce significantly the mortality of mice caused by this virus. JV-Phosphonomethyl-glycine is a promising herbicide. Recent work has shown that it exerts its effect by inhibiting the biosynthesis of aromatic amino-acids. ... 

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 ... 

The halohydrin reaction has been used in the synthesis of (IR, 2S)-(l,2-epoxypropyl)-phosphonic acid (phosphonomycin)(370) and its derivatives. One such synthesis (Scheme 32) was deviscd soon after this substance was originally described. The treatment of (Z)-(prop-l-enyl)phosphonic acid with /erf-BuOCl or NaOCl affords (IRS, 2S R)-(1-chloro-2-hydroxypropyl)phosphonic acid (369), which was resolved by the use of (-)-PhCHMeNH2. When treated in turn with 10 m NaOH, the (+)-chlorohydrin afforded the desired compoimd 370. In a second and more recent synthesis, (Z)-(prop-l-enyl)-... 

The key reaction in the synthesis of biological organophosphates is the formation of a C-P linkage by the phosphoenolpyruvate phosphonopyruvate mutase reaction [Fig. 3(A)]. The enzyme has been purified from Tetrahymena pyriformis [35]. The equilibrium of the reaction is far on the side of phosphoenolpyruvate, and is shifted towards phosphonopyruvate formation by subsequent decarboxylation of phosphonopyruvate to phosphonoacetaldehyde [36]. Further phosphoenolpyruvate mutase enzymes have been characterized in Trypanosoma cruzi [37] and Mytilus edulis [38]. Phosphonoacetaldehyde is the key compound from which the synthesis of phosphonoethanolamine and phosphonomycin proceeds. Biosynthesis of phosphinothricin starts with an analogous reaction... 

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. 

SCHEME 47.14. Synthesis of phosphonomycin involving a diastereoselective Abramov reaction. 

Christensen BG, Leanza WJ, Beattie TR, Patchett A A, Arison BH, Ormond RE, Kuehl F, Albers-Schonberg G, Jar-detzky O. Phosphonomycin stmcture and synthesis. Science 1969 166 123-124. 

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