Phosphonic acid antibiotics

Kamiya, T., Hemmi, K., Takeno, H., and Hashimoto, M., Studies on phosphonic acid antibiotics. I. Structure and synthesis of 3-(N-acetyl-N-hydroxyami-nojpropylphosphonic acid (FR-900098) and its N-formyl analogue (FR-31564), Tetrahedron Lett., 95, 1980. 

A few other biologically interesting and naturally occurring peptides and amino acids of rather simple structure were synthesized using the Ugi four-component reaction (Figure 12.5) the phosphonic acid antibiotics plumbemycin A 249 and B 250 [126], both epimers of the polychlorinated antihypertensive peptide (+)-demethyldysidenin 251 [127], and the nucleoside antibiotic nikkomycin 252 [128]. 

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. 

Hashimoto, M., K. Hemmi, H.Takeno, and T. Kamiya Studies on Phosphonic Acid Antibiotics. II. Synthesis of 3-(N-Acetyl-N-hydroxyamino)-2(R)-hydroxypropyl-phosphonic Acid (FR-33289) and 3-(N-Formyl-N-hydroxyamino)-l-trans-propenyl-phosphonic Acid (FR-32863). Tetrahedron Letters 21, 99 (1980). 

C S-4-methyl-l,3-oxathietan-2-yl)phosphonic acid 5,5-dioxide is an intermediate in the preparation of ( )-cis(l,2-epoxypropyl)phosphonic acid. It is said to have antibiotic properties. Sulfur dioxide is lost from the intermediate either thermally or photochemically. 

Some epoxides carry functional groups. The compound (lR,2S)-(-)-(l,2)-cpox-ypropyl phosphonic acid (fosfomycin) is a clinically important drug with wide-spectrum antibiotic activity. It was isolated originally from a fermentation broth of Streptomyces fradiae and prepared mainly by epoxidation of cfs-l-propenylpho-sphonic acid (CPPA) [42] followed by optical resolution of the racemic epoxide with chiral amines. Recently, chiral W (salen) and Mo (salen) complexes have been used in the asymmetric epoxidation of CPPA [43]. 

Because of the commercial importance of fosfomycin, it is not surprising that several important and attractive synthetic methods are reported in patents. They include, for example, precursors such as dimethyl hydroxymethylphosphonate, dimethyl, dibenzyl, and diallyl formylphosphonate, trimethyl phosphite and 2-cyano-1-hydroxypropene, 9 trialkyl phosphite and 2-chloro-propionaldehyde or 2-acetoxypropionaldehydc, diethyl chloromethylphosphonate, dibenzyl phosphite, and 1-chloro-1,2-propylene oxide,2 propynylphosphonic acid, propenylphos-phonic acid,2 2-chloro-(czT-l,2-epoxypropyl)phosphonic acid, and extrusion reactions on thermolysis. The resolution of racemic acids has also been reported. In search of new effective antibiotics, a large variety of substituted epoxyethylphosphonic acids have been pre-pared.249... 

Firestone, R.A., Antibiotic phosphonic acid derivatives, Merck, German Patent Appl. DE 1924138, 1970 Chem. Abstr, 72, 111613h, 1970. 

Christensen, B.G., Beattie, T.R., and Graham, D.W., Antibiotic. substituted phosphonic acids and salts, Merck, French Patent Appl. FR 2034480, 1971 Chem. Abstr, 75, 88759, 1971. 

Ohler, E., and Kanzler, S., Synthesis of phosphonic acids related to the antibiotic fosmidomycin from allylic a- and y-hydroxyphosphonates. Phosphorus, Sulfur Silicon Relat. Elem., 112, 71, 1996. Ohler, E., and Zbiral, E., Valence isomerism between 2,4-dienones and 2//-pyrans with dialkoxyphos-phinyl substituents. First synthesis of dialkyl 2//-pyran-4-ylphosphonates, Chem. Ber, 118, 2917, 1985. 

The fiuorophosphoenolpyruvates also act as suicide substrates, alkylating Cysll5, also the target of the antibiotic phosphomycin [a simple exo-alfinity label, (li ,25)-epoxypropane-3-phosphonic acid]. It was suggested that an... 

Scheme 15 illustrates the asymmetric hydrogenation of 3-keto phosphonates catalyzed by a BINAP-Ru complex, giving P-hydroxy phosphonates in up to 99% ee [61]. The sense of enantioface differentiation is the same as that of hydrogenation of P-keto carboxylic esters (see table of Scheme 3). The reactivity of the phosphonates is much higher than that of the carboxylic esters so that the hydrogenation proceeds even at 1 to 4 atm of hydrogen and at room temperature. A Ru complex of BDPP also shows high enantioselectivity [46b]. Chiral P-hydroxy phosphonates thus obtained are useful intermediates for the syntheses of phosphonic acid-based antibiotics as well as haptens of catalytic antibodies. Similarly, P-keto thiophosphates are hydrogenated enantioselectively with a MeO-BIPHEP-Ru catalyst [61b].

Aminoethyl)phosphonic acid (5) occurs as various V-substituted derivatives in several lower organisms Compounds 6", 7 and 8, are all antibiotics. Further details of these compounds can be found in ref. 18. 

Miscellaneous Reactions.- A full report has appeared of the use of /er/-butyl 4-diethylphosphono-3-oxobutanthioates (232) in olefination reactions for the preparation of homologated 3-oxobutanthioates and hence of tetramic acid derivatives. The reaction of the phosphonate dianion (234) with the aldehyde (233) is a key step in a total synthesis of the tetramic acid antibiotic ( .)-tirandamycin B (235). Olefinations involving both ylides and phosphonates have been used to construct the triene (236) en route to the spirotetronate subunit of the aglycone of the antitumour antibiotic... 

CsHiiO P, Mr 198.11, syrup, [a] -4° (HjO) as the sodium salt. Natural P. has the (5) configuration. A her-bicidal antibiotic from cultures of Saccharothrix sp. P. is formed biosynthetically as an isoprenoid. A further herbicidal phosphonic acid is phosphinothricin (see bialaphos and ciliatine). 

The combination of a lipase and Shvo s catalyst has also been applied to the DKR of a- and jS-hydroxyphosphonates. Hydroxyphosphonates are an important class of substrates, with applications in medicinal chemistry (haptens of catalytic antibodies, phosphonic acid based antibiotics), biochemistry (enzyme inhibitors) and organic synthesis. Under typical conditions, Backvall s group has shown that the DKR of several dimethyl- and diethyl-a-hydr-oxyphosphonates proceeded with excellent enantioselectivities and moderate to good yields (Scheme 4.18). This was attributed to the coordination of the phosphonate moiety to the ruthenium catalyst at a low alcohol concentration. This DKR procedure was also applied to the de-racemisation of diethyl jS-hydroxyphosphonates. However, in contrast to the DKR results on the... 

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. ... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

The phosphonic amino acids are also an important class of compounds with applications as antibiotics, antiviral agents, and enzyme inhibitors. The first example of electrophilic amination of a-cuprophosphonates 14 was reported by Genet and co-workers [5a]. This route has opened new access to N-protected a-amino phosphonic derivates 15 from the corresponding phosphonates 13 (Scheme 5). 

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