143791-12-2Relevant academic research and scientific papers
A 31P NMR stereochemical and kinetic study of the alkaline hydrolysis of cis-nucleoside 3′,5′-Cyclic Aryl [18O]Monophosphates and unlabeled analogs
Breeders, Niek L. H. L.,Van Der Heiden, Arthur P.,Peeters, Imre,Janssen, Henk M.,Koole, Leo H.
, p. 9624 - 9633 (2007/10/02)
The alkaline hydrolysis of the P-chiral cis-nucleoside 3′,5′-cyclic aryl [18O]monophosphates 4a-c and of the unlabeled analogs 3a-c was studied. Hydrolysis of the 18O-labeled phosphate triesters 4a-c yielded three products: 3′,5′-cyclic [18O]phosphate diester, 5′-acyclic aryl [18O]phosphate diester, and 3′-acyclic aryl [18O]phosphate diester. The stereochemistry of the formation of the 3′,5′-cyclic [18O]phosphate diester was determined by means of methylating the hydrolysis products with methyl iodide. The formation of the 3′,5′-cyclic [18O] phosphate diester during hydrolysis of compounds 4a and 4c proceeds with 17% inversion of configuration at phosphorus, whereas 40% inversion is found during hydrolysis of 4b. Inversion of configuration indicates the existence of a PV-TBP with a diequatorially located dioxaphosphorinane ring. Retention of configuration (83% for 4a and 4c, and 60% for 4b) can be explained in terms of Berry pseudorotation. The formation of the 5′-acyclic aryl [18O]phosphate diester during hydrolysis of compounds 4a and 4c proceeds with about 50% inversion of configuration at phosphorus, whereas formation of the 3′-acyclic aryl [18O]phosphate diester proceeds with an inversion/retention ratio of 88:12 or 12:88 for 4a and 79:21 or 21:79 for 4c. It is clear that Berry pseudorotation takes place during hydrolysis of the 3′,5′-cyclic phosphate triesters 4a-c. This is in contrast with earlier hydrolysis studies on 3′,5′-cyclic phosphate diesters proceeding without Berry pseudorotation, leading to complete inversion of configuration at phosphorus. Because of the very small amounts of 3′- and 5′-acyclic aryl [18O]phosphate diesters formed during the hydrolysis reaction of compound 4b, the stereochemistry could not be determined. The hydrolysis reactions, which have been studied on the unlabeled compounds 3a-c, obey second-order kinetics. Changing the ribose ring to a deoxyribose ring or changing the adenine base to thymine in the 3′,5′-cyclic phosphate triester does not dramatically influence the second-order reaction rate constant. However, the nature of the P-OR substituent significantly influences the reaction rate. The 3′,5′-cyclic phosphate triester with p-nitrophenoxy as substituent hydrolyzes approximately 18 times (T = 294 K) faster than the corresponding triester with phenoxy as substituent.
