Phosphonamidate Phosphonate

Phosphonamidates, phosphonate esters, and oxo-methylene substrate analogs, which presumably mimic the geometry of the tetrahedral intermediate or transition state of the intermediate or transition state... 

Malachowski, W.P., and Coward, J.K., The chemistry of phosphapeptides. Investigations on the synthesis of phosphonamidate, phosphonate, and phosphinate analogues of glutamyl-y-glutamate, J. Org. Chem., 59, 7625, 1994. 

Blazis VJ, Koeller KJ, Spilling CD (1995) Reactions of chiral phosphorus acid diamides the asymmetric synthesis of chiral alpha-hydroxy phosphonamides, phosphonates, and phosphonic acids. J Org Chem 60 931-940... 

Phosphate diester Phosphorothioate diester Phosphonate monoester Phosphonamidate... 

Phosphonamidates are usually prepared by coupling an activated phosphonate monoester with the amine of interest. Since most phosphonate amino add analogues are prepared as their diesters, this procedure first requires selective cleavage to the monoester. Activation from the phosphonic acid oxidation level typically involves preparation of the phosphono-chloridate, but it can also be accomplished by chlorination of an H-phosphinic acid analogue. 

Scheme 17 Formation of Phosphonamidates from Phosphonic Acid Monoester 4-65-67-72-731...

In a detailed study on phosphonate diester and phosphonamidate synthesis, Hirschmann, Smith, and co-workers reported that pyrophosphonate anhydrides may be produced as side products during conversion of phosphonate monoesters into phosphonochloridates. 72 They recommended adding the phosphonate monoester to a solution of the chlorinating agent (thionyl chloride or oxalyl chloride) to minimize formation of the less reactive anhydrides. They also found that addition of tertiary amines (e.g., TEA) to the phosphonochloridates, prior to addition of the alcohol or amine component, results in formation of a phospho-nyltrialkylammonium salt that is more reactive than the corresponding phosphonochloridate and leads to better yields of the phosphonate esters and amides. 

After conversion of the phosphonate monoester into a phosphonochloridate, or subsequently to a phosphonamidate, a new chiral center at phosphorus is created. Thus, after coupling to a chiral amine, even optically pure aminoalkylphosphonate monoesters produce a mixture of two diastereomers (racemic aminoalkylphosphonates result in four diastereo-mers). It is often possible to separate these diastereomers chromatographically. Of course, this is not necessary if the phosphorus ester will eventually be hydrolyzed. 

Phosphonate peptides can be synthesized either by formation of the P—O bond or the O—C bond. The former coupling is typically carried out via reaction of an alcohol (e.g., an a-hydroxy acid) with an activated phosphonyl spedes in a manner similar to phosphonamidate synthesis (Section 10.10.2.1). The latter process employs the phosphonate anion as a nucleophile in a displacement reaction on an ester with a leaving group in the a-position. 

The Mitsunobu phosphonate coupling has been adapted to the solid-phase synthesis of peptidyl phosphonates as well.1 2 In this environment, with excess phosphonate, even the more hindered, p-branched esters are formed efficiently. A series of phosphonate tripeptides have been synthesized and used to identify novel thermolysin inhibitors from a small library. (A number of other solid-phase syntheses of phosphonamidate-, 831 phosphonate-, 79 84 and phosphinate-peptides185,86 have been described however, in these instances the phosphorus bond forming steps were performed in solution, prior to solid-phase coupling.)... 

Scheme 29 Cleavage of Phosphonate, Phosphonamidate, and Carboxylate Methyl Esters Using Lithium Propanethiolate 67 71 73 103 ...

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. 

Phosphonates and phosphonamidates were selected as transition-state analogs for carbonate and ester hydrolysis they are relatively stable molecules, they are known inhibitors of acyl transfer enzymes and they imitate the initial negative charge of the tetrahedral oxyanion of acyl transfer enzymes (such as serine proteases) in the dipole of the P=0 bond. 

The phosphonate g, prepared from L-B-phenyllactic acid and the phosphonochloridate gg, binds to CPA equally as tightly as does the more labile phosphonamidate 2. 

Phosphonates and phosphonamidates, which mimic the tetrahedral geometry and anionic character of the transition state for hydrolysis, have proven especially reliable as haptens. Antibodies generated against such compounds readily promote the cleavage of esters and, in a few cases, amides. High levels of stereospecificity are attainable even at chiral centers remote from the reaction site [11]. 

Bash et al. (1987) applied the thermodynamic perturbation method to complexes of thermolysin with a phosphonamidate [Cbz-Gly -(NH)-Leu-Leu] and the corresponding phosphonate inhibitor [Cbz-Gly -(0)-Leu-Leu]. The perturbation was carried out by using 20 windows, with 2-psec molecular dynamics simulations in each window. Computations were for the ligand in solution and bound to the enzyme. The solvation of the enzyme was represented by a spherical cap of 168 water molecules about the bound inhibitor. The difference in free energy of binding of the two inhibitors was calculated to be 4.38 kcal/mol, to be compared with the experimental value, 4.10 kcal/mol. These calculations point out the importance of solvation effects, which are seen in the 3.4 kcal/mol difference between the NH and O forms of the inhibitor. 

The asymmetric synthesis of chiral phosphonic acids has been accomplished starting from alkyl phosphonamides 5 derived from MiV -dimethyl-diaminocyclohexane, which are easily prepared by condensation with alkyl phosphonic dichlorides (eq 7). Upon... 

The BOP- or PyBOP-mediated SPPS of phosphinot or phosphono peptides can be carried out without protecting the phosphinic or phosphonic acid group. Indeed, phosphinic acids are activated, but the P—N bond is not formed. Phosphonic acids are also acti-vatedt and in fact an amide of methyl phenylphosphonic acid has been obtained, however, in the case of protected a-amino phosphonic acids, phosphonamides are only obtained by using AT-phthalyl protection. Side-chain unprotected phosphorylated tyrosine [Tyr(P03H2)] can be coupled by solid-phase synthesis using BOP (PyBOP), but pyrophosphate formation is also observed and some particular Tyr(P)-peptide syntheses are prone to total failure. ... 

---