Stereochemical studies of reactions of phosphate and thiophosphate esters.
thesisposted on 19.11.2015, 08:45 by Anna. Iagrossi
Nucleophilic substitution reactions involving phosphate monoesters have been investigated. Two general syntheses of O-alkyl or O-aryl [16O,18O] thiophosphate monoesters are reported. An independent and general method for the determination of the enantiomeric excess of isotopically chiral thiophosphate monoesters has been developed and the absolute configurations of the diastereoisomers of (2R)-O-(O-ethyl thiophosphoryl)-3, 4S-dimethyl-5S-phenyl-l,3,2-oxazaphos- pholidin-2-one have been assigned. The solvolysis of p-nitrophenyl [R-16O,18O] thiophosphate in ethanol gives rise to ethyl [16O, 18O] thiophosphate with a large degree of racemisation of configuration (~80%). This observation is consistent with the formation of a thiometaphosphate intermediate of finite life-time which is then trapped by ethanol with accompanying loss of stereochemical integrity. This study provides the first direct evidence for a monomeric thiometaphosphate in protic solvent. During the course of developing the stereochemical analysis, it was noted that O-ethyl thiophosphate reacts with cis-2-chloro-3, 4-dimethyl- 5-phenyl-l, 3, 2-oxazaphospholidin-2-one with ca. 10% inversion and 90% retention of configuration. This system also reacts with fluoride ion with complete loss of stereochemistry. Cis-2-chloro-3, 4-dimethyl-5- phenyl-l, 3, 2-oxazaphospholidin-2-one and the corresponding 2-thione are epimerised to the more stable trans isomers by pyridine and other nucleophilic catalysts. These reactions require an in-line exocyclic displacement at a phosphorus centre held in a five-membered ring. Nucleophilic substitution at di- and tri-esters have also been studied. The stereochemical course of the hydrolysis of the 1, 3, 2-dioxaphosphor- inan-2-one system involving good leaving groups such as chloride and fluoride occur with inversion of configuration via an in-line mechanism, whereas hydrolysis of this system involving poor leaving groups occurs with retention of configuration via a pseudorotation mechanism.