Phosphate Migration

Phosphate esters readily undergo intramolecular migration from one hydroxyl group to another under the influence of acid 171), (See Fig. 1, 172,) This migration probably proceeds through a cyclic compound similar to the orthoester structure proposed in acyl group migration (p. 147 and 433)  

Any procedure of isolation or preparation that involves treatment with hot m, H. W. Kosterlitz, Biochem, J. 33, 1087 (1939). 

Compounds possessing the cyclic phosphate structure may be prepared by the action of phosphorus oxychloride or phenyl phosphorodichloridate on a glycol, or by treating phosphate monoesters with trifluoroacetic anhydride (173) or a carbodiimide reagent (f74). The latter is the preferred reagent since it may be used in the presence of water and usually gives a good yield of a pure product. The reaction is formulated as follows  

The resulting cyclic phosphate diester is hydrolyzed readily in acid or alkali to the phosphate monoester. 

These cyclic phosphates are intermediates in the enzymic and alkaline degradation of ribonucleic acids, and may be the activated intermediates for the enzymic synthesis of ribonucleic acids from the nucleotides 175), Enzymes specific for the hydrolysis of nucleoside 2,3-cyclic phosphates to the monoesters have been prepared from snake venom, spleen, and intestinal mucosa. (See Chapter VIII.) 

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Apparently no phosphate migration was noticed by either group of authors, in spite of the acid conditions employed for the cleavage of the glycosidic bond. 

Whitted PO, Horner JH, Newcomb M, Huang X, Crich D (1999) Heterolytic cleavage of a p-phospha-toxyalkyl radical resulting in phosphate migration or radical cation formation as a function of solvent polarity. Org Lett 1 153-156... 

The possibility of a phosphate migration in phosphoserine from the N— to the O— position had already been suggested by Linderstr0m-Lang in 1933 (Linderstrdm-Lang, K. (1933). Ergeb. Physiol, u. Exptl. Pharmakol. SB, H5.)... 

Alkahne, hydrolytic deamination of cytidyhc acid h (under conditions which avoided phosphate migration) yielded midyhc acid h, proving that... 

It now appears that this is best interpreted in terms of a very rapid collapse of the initial contact ion pairs to the product radicals before any equilibration with solvent-separated ion pairs and free ions occurs. The more rapid collapse is of course in line with the more reactive nature of carboxylate ions as opposed to phosphate ions. The close similarities between the activation entropies of the carboxylate and phosphate migrations also point to reactions in which the rate-determining steps are closely related. 

Most important was the realization by D. M. Brown and Todd68,69 that the alkaline hydrolysis of RNA was analogous to the behavior of esters of glycerol phosphates described by E. Baer and M. Kates and involved the formation of 2, 3 -cyclic phosphates which wore further hydrolyzed irreversibly to give a mixture of the 2 - and 3 -monophosphates. The monoben-zyl esters of the 2 - and 3 -phosphates were prepared and related to the parent nucleotides by hydrogenolysis. conditions which did not cause phosphate migration. The action pattern of various diesterascs, particularly... 

Relatively fast phosphate migration has been observed in ribo-... 

Fig. 1. Acid catalyzed phosphate migration of D-glyceric acid 2-phosphate to the 3-phosphate.

In an effort to prove that phosphate migration takes place under conditions of acid hydrolysis (4N HQ, 4 h at 100 C) used in the determination of the structure of Lipid A, the 4- and 6-phosphates of 2-amino- and 2-acetamido-2-deo y-D-glucose as well as the Lipid A model (34) were synthesised. Migration of the phosphate from 0-4 to 0-6 was observed under the above conditions. Deacylation conditions were then found (IN HCl, 1 h at 100 C) which did not cause phosphate migration. ... 

Adenosine 2 - and 3 -monophosphate monomethyl and monoisopropyl esters undergo isomerization and hydrolytic cleavage to the 2, 3 -cyclic phosphate and the alcohol at comparable rates under acidic conditions, whilst at neutral pH, a pH-independent phosphate migration prevails.197 However the hydrolysis of the 2-chlorophenyl ester of uridine-3 -phosphate to 2-chlorophenol and uridine monophosphates is rapid compared with the phosphate migration under acidic conditions. 198 These studies have been extended to the interconversion and hydrolysis of 2 ,5 - and 3 ,5 -dinucleoside phosphates, where for adenosine systems, acid-catalysed depurination competed with phosphate migration and hydrolysis at pH<3.i99... 

Acid-catalyzed phosphate migration enables a-glycerophosphate to be converted to -glycerophosphate. Similarly ribose 4-phosphate may be obtained from ribose 2-phosphate or ribose 3-phosphate. 

See, for example, Newcomb, M., Homer, J. H., Whitted, P. O., Crich, D., Huang, X., Yao, Q., and Zipse, H., P-Phosphatoxyalkyl radical reactions competing phosphate migration and phosphoric acid elimination from a radical cation-phosphate anion pair formed by heterolytic fragmentation, /. Am. Chem. Soc. 121,10685, 1999 (and references cited). 

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