Phosphoramidate analogs

Azhayev et al. (95) describes the synthesis of phosphoramidate analogs of ribonucleoside phosphates giving values for 5+ compounds using ready for use Silufol UV2S4 silica gel sheets and two solvents ... 

Furthermore, the GPO procedure can also be used for a preparative synthesis of the corresponding phosphorothioate (37), phosphoramidate (38), and methylene phosphonate (39) analogs of (25) (Figure 10.20) from suitable diol precursors [106] to be used as aldolase substrates [102]. In fact, such isosteric replacements of the phosphate ester oxygen were found to be tolerable by a number of class I and class II aldolases, and only some specific enzymes failed to accept the less polar phosphonate (39) [107]. Thus, sugar phosphonates (e.g. (71)/(72)) that mimic metabolic intermediates but are hydrolytically stable to phosphatase degradation can be rapidly synthesized (Figure 10.28). 

Spin-labeled phosphoramidates are synthesized analogously by the reaction of phosphoric imidazolides with primary or secondary amines[189] or amino acid esters.11883... 

Method B The procedure is analogous to 5.1.13.A, except that CBr4 (16.6 g, 0.05 mol) replaces CC14 and the reaction is conducted at room temperature. The phosphoramidate is isolated by the procedure described in 5.1.13.A. 

Fig. 9.14. Metabolic activation of phosphoramidic acid diester prodrugs 9.79 of stavudine (and analogous nucleosides). Carboxylesterase-mediated hydrolysis of the terminal carboxy-late is followed by spontaneous cyclization-elimination with formation of a pentacyclic mixed-anhydride species. The latter hydrolyzes rapidly to the corresponding phosphoramidic acid monoester, which can then be processed to stavudine 5 -monophosphate.

The synthetic protocols used for the preparation of oligonucleotides on supports can also be used to prepare oligomers from diols other than nucleosides. Symmetric or unsymmetric diols, such as N-acylated 4-hydroxyprolinol [268] or cyclopentane-derived diols (carbocyclic deoxyribose analogs [269]), can be selectively mono-trity-lated and then converted into a phosphoramidite that is suitable for the solid-phase synthesis of oligophosphates. An illustrative synthesis of protected //-phosphonates from diols, as well as their conversion on CPG into oligomeric phosphoramidates, are outlined in Figure 16.28. 

The phosphorus pentoxide-amine mixtures, which can readily be prepared in an exothermic reaction, were found to react analogously to phosphoramides. 

As a consequence of the different electronic interactions within the phosphoramidate group, P-N bond cleavage in phosphoric amides, contrary to the behavior of analogous carboxylic compounds, is accelerated by the electron - donation at the nitrogen atom. 

An analogous propargylation can be attained with allenyl tributyl stannane however, this reaction is catalyzed by SiCU that is activated by a bisphosphor-amide catalyst. Note that in this case, the role of the Lewis basic phosphoramide is to increase the Lewis acidity of SiCU rather than to increase the nucleophilicity of the stannane [51b]. A discussion of these effects is provided in Section 7.4. 

Introduction. [45-(4a,5p)]-1 -(1,3-Dimethyl-2-oxido-4,5-di-phenyl-l,3,2-diazaphospholidine-2-yl)piperidine (la) and its derivatives are an important class of phosphoramides which have seen much success as Lewis-basic catalysts for aldol additions, allylations, crotylations, and epoxide openings. The three nitrogen subunits of the phosphoramide provide the opportunity for a large number of structurally diverse analogs, allowing a wide spectrum of properties and shapes to be customized. ... 

Enantioselective Addition of Dialkylzincs to Imines. Enantioselective addition of dialkylzincs to N-diphenyl-phosphinoylimines in the presence of DBNE or its analog affords optically active phosphoramides. Subsequent hydrolysis affords optically active amines in up to 91% ee (eq 25). When the amount of DBNE is catalytic (10 mol %), the enantioselec-tivity is 75% ee. One of the advantages of this method over the alkyllithium method is the use of a lesser amount of chiral ligand. 

One of the two hydrogen atoms of phosphoramidates can be temporarily blocked with a trimethylsilyl group. The sodium salt of diethyl V-(trimethylsilyl)phosphoramidate (102) reacted with alkyl bromides in benzene in the presence of 10 mol % of tetra-n-butylammonium bromide to afford, after desilylation, the corresponding V-alkyl derivatives (103) in 79-95% yields for primary alkyl halides. Secondary alkyl halides gave poor results (Scheme 43). The addition of the quaternary ammonium salt is essential to promote the alkylation reaction. Hexamethyldisilazane and its cyclic analogs can also be utilized in the preparation of amines under moderate conditions (Scheme 43). ... 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Several nitroaryl phosphoramides were designed and synthesized, each with a strategically placed nitro group on the benzene ring in the para position to the benzylic carbon (Scheme 19). Compound 114 is a cyclophosphamide analog... 

The NagA enzyme from E. coli, unambiguously a member of CE 9, however, on isolation was found to contain one Zn " per active site and no Fe and was powerfully inhibited (K = 34 nM) by the methyl phosphoramidate analogue of the substrate, which accurately mimics the tetrahedral intermediate in both carboxypeptidase- and urease-like mechanisms. The metal dependence of CE 9 appears variable and both urease-like mechanisms and mechanisms analogous to that of CE 4 may operate. The crystal structure of the E. coli enzyme reveals only bound Zn, in a site equivalent to one of the two Fe sites of the B. subtilis enzyme and no potential histidine ligands for the other Fe the T. maritime enzyme appears to be intermediate, with one Fe bound. 

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