Phosphates, oxygen chiral, configurational

II. Methods for Syntheses and Configurational Analyses of Oxygen Chiral Phosphate and... 

Methods based on the effects of the quadrupolar O nucleus (/ = f) and the 0 nucleus (7 = 0) on the P NMR spectral properties of the isotopically labeled P nucleus are now the only methods used to ascertain the configurations of tetrahedral phosphorus atoms in oxygen chiral phosphate esters. The chemical... 

The first application of this 0 effect for determining the configuration of an oxygen chiral phosphate ester was the author s determination of the configuration of diastereomeric samples of cyclic [, 0]dAMP, the chiral substrate for studying the stereochemical consequences of the reverse reaction catalyzed by adenylate cyclase (formation of cyclic AMP from ATP), and of the hydrolysis reaction catalyzed by 3, 5 -cyclic nucleotide phosphodiesterase (25) (see Fig. 

Whereas the 0 effect on P NMR chemical shifts is sufficient for determining the configurations of chirally labeled samples of prochiral phosphorus atoms in a diastereomeric environment, additional use of the quadrupolar effect of O on P NMR resonances is required for configurational analyses of oxygen chiral phosphate monoesters. The basic strategy for the configurational analyses of phosphate monoesters is the same, i.e., the enantiomeric center in the monoester must be converted to a diastereomeric center in a cyclic phosphodiester so that... 

Given the inability to implicate free metaphosphate anion in these studies, Cullis and Rous examined the stereochemical consequence of an alcoholysis reaction (55). When [ 0, 0, 0]P -0-ethyl-P -thiopyrophosphate is treated with methyl iodide in ethanol, the S-methyl derivative rapidly decomposes to form 0-ethyl-S-methyl thiophosphate and ethyl [ 0, 0, 0]phosphate this reaction is thought to proceed via a mechanism involving metaphosphate anion, but, as would be expected on the basis of the observations by Knowles, the stereochemical consequence is nearly quantitative inversion of configuration. In dichloromethane solution, the decomposition of the oxygen chiral substrate yields ethyl [ 0, 0, 0]phosphate that has suffered extensive racemization (approximately 70%). This stereochemical result can be rationalized by the intermediacy of free metaphosphate anion in the absence of nucleophile acceptors. 

The first account of the synthesis of an oxygen chiral phosphate monoester was reported in 1978 by Knowles and co-workers (Abbott et ai, 1978, 1979). This ester, a diastereomer of l-phospho-(5)-1,2-propanediol, was selected as the synthetic target because the general method of configurational analysis that Knowles devised for monoesters was based on the ability to assign the configuration of the diastereomers at phosphorus of this particular phosphate monoester. The chemical steps in this synthesis are shown in Fig. 1. Briefly, [ OJPOCls, prepared in hi yield from and... 

Methods have been developed for the synthesis of essentially any oxygen chiral phosphate ester of biological importance, and the P-NMR methods described and illustrated in this chapter provide a convenient method for determining their configurations and elucidating the stereochemical consequences of enzyme-catalyzed phosphoryl and nucleotidyl transfer reactions. 

The first chiral phosphates to be used for stereochemical analyses were chiral phosphorothioates, which were used to determine the stereochemical courses of ribonuclease, UDP-glucose pyrophosphorylase, adenylate kinase and several other kinases and synthetases. The chiral phosphorothioates either had sulfur in place of an oxygen at an otherwise prochiral center of a phosphodiester or phosphoanhydride or stereospecifically placed sulfur and 180 (or nO) in a terminal phosphoryl group. The syntheses and configurational analyses of the most important of these compounds are outlined in the following. 

The absolute configuration of the amine 7 may be explained by a stereochemical model based on the X-ray crystal structure of the chiral BINOL-phosphate (Fig. 4). In the transition state the ketimine is activated by the Brpnsted acid in such a way, that the nucleophile has to approach from the less hindered si face as the re face is effectively shielded by the large aryl substituent of the catalyst (Fig. 4, left). Furthermore, a bifunctional activation seems to be plausible, where next to the ketimine protonation, the dihydropyridine is activated through a hydrogen bond from the Lewis basic oxygen of the phosphoryl group. 

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