Naturally Occurring Phosphonic Acids

Few papers have appeared during the past year which have dealt with naturally occurring phosphonates. A diacylglyceryl ester of 2-aminoethylphosphonic acid (17)... 

Hildebrand, R.L., The Role of Phosphonates in Living Systems, CRC Press, Boca Raton, 1983. Hildebrand, R.L., Curley-Joseph, J, Lubansky, H.J., and Henderson, T.O., Biology of alkylphosphonic acids. A review of the distribution, metabolism, and structure of naturally occurring alkylphosphonic acids, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 297-338. Hudson, H.R., Quasi-phosphonium intermediates and compounds, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 339-436. 

Aminoethylphosphonate.—n.m.r. measurements indicate that 78% of the phosphorus present in a water-soluble glycoprotein from the sea anemone Metridium dianthus is in the phosphonate form and includes 2-aminoethyl-phosphonic acid (20). N.m.r. for the identification of naturally occurring phosphonates appears to be a technique superior to chromatography, which has been used hitherto. ... 

Aminoethyl phosphonic acid most common naturally occurring phosphonate, found in a variety of organisms. 

The identification of a naturally occurring phosphonate was by Horiguchi and Kandatsu [134], who identified 2-aminoethylphosphonic acid in an amino acid extract from a hydrolysate of rumen protozoal lipid. Subsequently, it has been shown that phosphonates occur naturally in a variety of organisms. Consequently, there is a growing need to develop new and efficient synthetic methods for preparation of organophosphorus compounds bearing a P-C bond. 

Naturally occurring phosphonates were first discovered in 1959 when Horiguchi and Landatsu [10] isolated 2-aminoethylphosphonic acid (AEP) from the anemone (Chapter 6.5). Since that date other alkylphosphonic acids, a few phosphinates and some phosphonolipids and phosphonopeptides have been detected as minor components of various living species (11.135). Synthetic phosphonate DNA was reported in 1996 (Chapter 10.4) [11]. 

The synthesis of chiral w-amino phosphonic acids (analogues of natural amino acids) may be accomplished from imines. The key step in this synthesis is the formation of an aziridine by reaction of a phosphonamide with an imine (equation 153)555. The reaction occurs in very good yield in THF, at —78 °C with BuLi. 

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]. 

The early literature describes examples of elimination reactions of a rather forcing nature which have not been explored further. For example, the elimination of HCl from (2-chloroethyl)phosphonic dichloride occurs over BaCl2 at 330 and dechlorination of (l,2-dichloroethyl)phosphonic diesters occurs on heating with zinc dust. Dehydrochlorination of a (2-chloroalkyl)phosphonic acid occurs on simple pyrolysis but the preferred procedure consists in the treatment of the acid diester with Et3N in warm benzene, a procedure also used for analogous (2-chloroethyl)phosphinic esters ". The dehydro-halogenation of isopropyl (2-haloethyl)phenylphosphinate by a chiral tertiary amine, such as quinine, quinidine, 1 -phenylethylamine or A-methylephedrine, in a less than equivalent quantity, affords an enrichment of one enantiomer of the ethenylphenylphosphinic... 

Monoalkyl esters of the same acid likewise decompose under acidic conditions to give benzonitrile and monoalkyl metaphosphates. The nature of the solvent in which degradation occurs can have a profound effect on the course of such degradation the predominantly ( )-oximes from the mono-2,2,2-trihaloethyl esters 121 and 122 of [a-(hydroxyimino)benzyl]phosphonic acid, as their anions, lose benzonitrile in boiling ethanol or propan-2-ol and yield mixed phosphodiesters 124 (R = Et or Pr ) ( )-(121) does... 

The scarcity of unnatural D-amino acids makes these compounds attractive synthetic targets, especially when one considers the disparity of price relative to their naturally occurring partners. If the hydroxyl group of an L-lactate could be displaced by a nitrogen nucleophile with inversion of configuration, this would allow easy access to D-alanine derivatives. Such a transformation can be realized by the reaction of 2 with diphenyl phosphorylazide and DBU to produce the (R)-azidoester 96 (98% ee) [33]. The initial step of the reaction is the formation of phosphonate 95. The resulting liberated azide then completely displaces the phosphonate group, with nearly total inversion of the stereo center. 

Bisphosphonates were prepared and from naturally occurring 1-amino acids [141], In this case, initial protection of the amino acid-amine moiety was required. Insertion of a phosphorus atom was divided into two steps initial reaction with a suitable phosphorus reagent to produce the acylphosphonate, and a second phosphorus attack to form the bis-phosphonate. Since conversion to acid chloride served as the acid activation process, the amine-protecting group had to be either Fmoc or phtaUmide, both of which are stable in acidic conditions. Prolonged reaction times always resulted in partial rearrangement and formation of by-products. 

Derivatives of phosphonic N-hydroxyamino acid analogues (22-25) (Scheme 38, page 236) are also known as naturally occurring compounds. 

Figure 3.2 Schematic representation of the reactions between sarin and AChE. (a) Sarin and the active site of AChE combine to form an inhibitor-enzyme intermediate, (b) The fluoride has been lost, leaving a complex of sarin and AChE. From this state, either (c) spontaneous hydrolysis and restoration of function or (d) dealkylation can occur, (c) The ester link in the phosphonylated AChE has been hydrolysed, the enzyme has reactivated and alkyl methyl phosphonic acid has been formed, (d) The link between the alkyl group and the phosphorus has been cleaved. This produces a conformational change that results in the formation of a very stable agent-enzyme complex that is then resistant to spontaneous hydrolysis and reactivation by oximes. This is known as ageing . The rate of ageing is dependent on the nature of the alkyl group and is fairly slow (hours) in the case of sarin and VX, but is very rapid (minutes) in the case of soman. Figure adapted from Vale et aL ...

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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