Phosphate ester formation, general

SOME GENERAL METHODS FOR PHOSPHATE ESTER FORMATION REMOVAL OF PROTECTIVE GROUPS FROM PHOSPHORUS... 

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... 

Dihydroxy alcohols and amino alcohols in which the functional groups are not separated by more than four carbon atoms are effective acceptors. There is a general difference in the behavior of these compounds, however, in that hydroxyl alcohols decrease the rate of formation of p-nitro-phenol from p-nitrophenyl phosphate and amino alcohols increase the rate. Amino alcohols are relatively good nucleophiles in reaction with phosphate esters, perhaps because the amino group serves as a general base catalyst (143, 144)-... 

Structure of the substrate and the reaction conditions determine the transition state for reaction with a particular nucleophile 104, 105). The extreme cases are generally described as the dissociative and associative substitution mechanisms. The fully dissociative mechanism entails the formation of monomeric metaphosphate monoanion as a discrete intermediate and was first formulated by F. H. Westheimer, who pioneered the physical organic chemistry of the hydrolysis of phosphate esters 106, 107). This mechanism is depicted in Eq. (40) and is possible only for phosphomonoesters with good leaving groups, examples of which are shown. 

Since boldine and, to a lesser extent, bulbocapnine are the only two generally available naturally occurring aporphines, a useful series of chemical transformations has been worked out that leads from them to a variety of other aporphines. Thus reduction of the phosphate ester (23) of bulbocapnine with sodium in liquid ammonia resulted in the formation of 2-hydroxy-10-methoxy-aporphine (24), whose O-methylation generated (25). ... 

On the other hand, as seen in this chapter and in earlier chapters, the formation of phosphates of adenine (e.g., AMP, ADP, and ATP), guanidine (e.g., GTP), cytosine (e.g.,cytidine monophosphate [CMP]), uracil (e.g., uridine monophosphate [UMP]), and dTMP have all involved the carbohydrate scaffold as a building block for the formation of the finished heterocyclic base (purine or pyrimidine). It is also important to realize that, as part of nucleotide salvage pathways, it has been found that a family of enzymes collectively known as phosphorylases serves to catalyze reactions between free bases and phosphate esters of carbohydrates (and related compounds). For example, as shown in Scheme 14.13, the generalized enzyme, purine nucleoside phosphorylase (EC 2.4.2.1), catalyzes the conversion of a purine with... 

DNA ligase catalyzes the formation of a phosphodi-ester bond between a 3 hydroxyl at the end of one DNA strand and a 5 phosphate at the end of another strand. The phosphate must be activated by adenylyla-tion. DNA ligases isolated from viruses and eukaryotes use ATP for this purpose. DNA ligases from bacteria are unusual in that they generally use NAD+—a cofactor that normally functions in hydride transfer reactions... 

Recently the related cyclization of the phenyl ester of c/j-tetrahydrofuran-3,4-diol monophosphate to the corresponding five-membered phosphate with loss of phenol has been shown to be subject to general catalysis by imidazole132. This reaction serves as a model for the first step in the action of ribonuclease which leads to the formation of the nucleoside 2 ,3 -cyclic phosphate. The actual details of the transition state leading to the cyclic phosphate as catalyzed by the enzyme are presently the subject of some debate. One possibility is the in-line mechanism (53)... 

---