Phosphonamides

Six categories of 7V-hetero atom derivatives are considered N-M (M = boron, copper), N-N (e.g., N-nitro, A-nitroso), N-oxides (used to protect teriary amines), N-P (e.g., phosphinamides, phosphonamides), N-SiR3 (R = CH3), and N-S (e.g., sulfonamides, sulfenamides). 

Organomagnesium derivatives have not so far been isolated [80JA994 80JOM(193)C13]. Bis[bis(trimethylsilyl)phosphonamide] with diphenylbutadi-yne and calcium or strontium in THE yields the TiyP)-coordinated species 129. Reaction of (THE)4Ba[P(SiMc3)2]2 with diphenylbutadiyne gives an ri -coordinated species 130 (98JA6722). 1-Chloro-and l-cyclopentadienyl-3,4-dimethyl-2,5-bis-(trimethylsilyl)-l-phosphacyclopenta-2,4-dienes both react with calcium to give... 

Alkyl halides, reaction of sugar phosphorodiamide and phosphonamide derivatives with 178... 

Phosphonamide-stabilized allylic anions react y-selectively and serve as homocnolate reagents86 in the reaction with aldehydes only moderate simple diastereoselectivity is observed. 

Semirigid phosphonamide ligands have been synthesized from the corand precursors by the reaction of 1,3-propanediol ditosylate or 1,2-dichloroethane <96JOC8904>. 

In their work concerning the anions derived from chiral phosphonamidates, Denmark and Chen [68] obtain a high diasteromeric excess of 88% for the compound 108 resulting from the addition of the carbanion of phenylsulfenyl phos-phonamidate 107 to 4-terf-butylcyclohexanone (Scheme 31). 

Irradiation of 1-azidophosphetan-l-oxide (112) in methanol leads to the phosphonamide esters (113) and (114), although the stereochemistry of these products is not yet fully settled. Their formation is reasonably consistent with the intervention of a nitrene intermediate which inserts into the P—C and C—H bonds. 

Corey s phosphonamide olefin synthesis has been extended to the synthesis of vinyl ethers using the phosphonamides (Me2N)2P( O)- CHjOR. 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

In an anionic approach, the sodium salt of the chiral chloroallyl phosphonamide 132 engages in nucleophilic addition onto oximes and gives the optically pure A-alkoxy aziridines... 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

Phosphate diester Phosphorothioate diester Phosphonate monoester Phosphonamidate... 

Fig. 18 Antibody NPN43C9, raised against the phosphonamidate hapten [49], was capable of accelerating the hydrolysis of the anilide [50].

The structures of the salts (131)168 and (132),159 a chelated ylide,160 and the insecticide coroxon161 have been determined. The structures of the cis- and trans-isomers of the cyclic phosphonamide (133) differed in that the cw-isomer has a half-chair conformation whereas the trans-isomer has an envelope conformation. Both compounds had hydrogen bonds of approximately 269 pm.162 The phosphadiazane (134)... 

Figure 3 Amide hydrolysis catalyzed by the antibody 43C9 raised against phosphonamidate 1.

Phosphonamidate peptide analogues mimicking the P1...F3 substrate residues have been prepared and evaluated against a CHC mixture Table 8.5). Inhibitors with an aromatic side-chain in subsite P] are some 20-fold more effective than are those with an aliphatic one (compare (31) to (29) or (30), Table 8.S). An opposite, albeit less pronounced, preference at this site appears to exist for the ketone inhibitors for fi-CYlC ((17) vs. (25) and (21) vs. (26), Table 8.4). However, this difference could be attributable to a predominance of class II CHC in the mixture assayed in Table 8.5. Thus, comparisons of this sort must be made with caution. Introduction of a double bond into the Pi side-chain decreases the potency of the phosphonamidate by more than a factor of 10 ((41) vs. (42), Table 8.5), perhaps because of... 

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