Phosphate esters cleavage, general

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

A major advancement in the Fmoc-based solid-phase synthesis of Tyr(P)-peptides was realized with the Fmoc-Tyr[PO(OR1)2]-OH derivatives 7 (R1 = Bzl, tBu, Mdpse) [Mdpse = 2-(methyldiphenylsilyl)ethyl] in which the acid-labile phosphate esters offered simple cleavage by TFA treatment. While the initial difficult synthesis of derivatives 7 restricted general synthetic usage, the subsequent commercial availability of these derivatives and their compatibility with solid-phase synthesis has provided a simple and efficient procedure for the routine synthesis of large complex Tyr(P)-peptides. 

The excellent antitumor activity of ellipticine carbamate 153 led Archer and co-workers (84) to propose a new mechanism for the antitumor effects of ellipticine in general (Scheme 65). It is suggested that the C-5 methyl group is enzymatically hydroxylated and then converted either to the sulfate (402) or phosphate ester. This can now react with a cellular nucleophile (e.g., DNA, topoisomerase II), by an S l or 8 2 mechanism, to give the covalent adduct 403. This type of mechanism has been invoked to explain the antitumor activity of lucanthone (404) and hycanthone (405) (219,220). A study of the azaellip-ticines 204 and 406 showed that both compounds are active on topoisomerase II and initiate the cleavage of DNA (151,221). However, unlike ellipticine, these azaellipticines did not cleave DNA in isolated nuclei. 

Chemical transformations of a-hydroxyphosphonates Phosphonate-phosphate rearrangement. Dialkyl alkylphosphonates are, in general, more reactive than the corresponding phosphate esters because the carbon has no unpaired electrons to contribute to allow a pn-dm contribution to the P-C bond. This makes the phosphorus atom of phosphonates more electrophilic than the phosphorus atom of the corresponding phosphate ester. The P-C bond is usually stable to hydrolitic procedures. However, a-hydroxyalkylphosphonates, in the presence of alkali, rearrange to give phosphate with cleavage of the P-C bond [220]. 

Considerable study has been devoted to the reactions of dinucleotides and related molecules, like those in Fig. 10, because of the biological significance of RNA and interest in the mechanism of RNase, which catalyzes its cleavage. The /Jlg values were measured for the cyclization reaction of a series of aryl esters 10A (to yield a 2, 3 cyclic phosphate) under alkaline conditions. For the imidazole general... 

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