Oxygen chiral phosphate esters

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. 

III. Configurational Analyses of Oxygen Chiral Phosphate Esters... 

Stereochemical Studies Using Oxygen Chiral Phosphate Esters and P-NMR Methods of... 

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. 

As noted previously, the stereochemical course of the hydrolysis of a phosphate monoester can be studied only if an oxygen chiral phosphorothioate ester is used a substrate so that an enantiomer of 0-labeled chiral thiophos-... 

These comparative studies constituted the first example of an enzyme-catalyzed hydrolysis reaction whose stereochemical course was unaffected by sulfur substitution. At the time these experiments were performed, the stereochemical courses of the reactions catalyzed by glycerol kinase (83, 84) and by the bacterial adenylate cyclase (85, 86) had already been compared in the laboratories of Knowles and Gerlt, respectively, and these were also found to be unaffected by the sulfur substitution. A number of other comparisons of this type have been made, and in no case were the stereochemical consequences of the reactions studied with chiral phosphate esters and the chiral thiophosphate analogs found to differ. This agreement suggests that the necessary use of oxygen chiral thiophosphate monoesters to study the stereochemical course of phospho-monoesterases will provide pertinent results for ascertaining whether phosphory-lated intermediates are involved in the reaction mechanism. 

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... 

A -oxides) In sulfones, the sulfur bonds with a tetrahedral array, but since two of the groups are always oxygen, no chirality normally results. However, the preparation of an optically active sulfone (2) in which one oxygen is and the other illustrates the point that slight differences in groups are all that is necessary. This has been taken even further with the preparation of the ester 3, both enantiomers of which have been prepared. Optically active chiral phosphates 4 have similarly been made. ... 

Given the low natural abundance of O and 0, chemical methods for the synthesis of phosphate esters that are chiral by virtue of oxygen-isotope substitution must allow for the introduction of any oxygen isotope from (ideally) the commercially available forms of the heavy isotopes H2O, CO2, or O2. In addition, the substrates of the phosphoryl and nucleotidyl transfer reactions include three types of structurally and chemically different phosphates, almost all of which are polyhydroxylic phosphate monoesters, such as sugar phosphates and mononucleotides, phosphate diesters, such as 3, 5 -cyclic nucleotides and oligonucleotides, and phosphate anhydrides... 

In 2008, Gong and coworkers introduced a new chiral bisphosphoric acid 19 (Fig. 4) that consists of two BINOL phosphates linked by an oxygen atom for a three-component 1,3-dipolar cycloaddition (Scheme 42) [66]. Aldehydes 40 reacted with a-amino esters 105 and maleates 106 in the presence of Brpnsted acid 19 (10 mol%) to afford pyrrolidines 107 as endo-diastereomers in high yields (67-97%) and enantioselectivities (76-99% ee). This protocol tolerated aromatic, a,P-unsaturated, and aliphatic aldehydes. Aminomalonates as well as phenylglycine esters could be employed as dipolarophiles. 

The CHF and CF2 groups are superior to CH2 as isosteres of oxygen and this has led to extensive interest in their chemistry. The a-difluorophosphonate analogues of the phosphates of L-serine (219), L-threonine (220), and L-allothreonine (221) have been prepared by highly enantioselective reactions of difluoromethylpho-sphonate carbanion with chiral esters. Lipase PS catalysed acetylation of prochiral 1,3-propandiol alkylphosphonates 222 is reported to be highly enantioselective and the resulting monoacetate enantiomers 223 have been used to synthesise a series of (o-phosphono-a-amino acids, 224 and 225.Other routes to 225, one of... 

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