Oxygen chiral phosphate synthesis

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. 

Simultaneously and independently, Cullis and Lowe developed a second general methodology for the synthesis of, 0, 0-labeled chiral phosphate monoesters (76, 77). This synthesis relies upon the synthesis of a cyclic hydrobenzoin triester of the alcohol or phosphoric acid followed by hydrogenolysis to liberate the isotopically labeled monoester product (Fig. 2). Hydrobenzoin, chiral by virtue of stereospecific labeling with 0 and 0, is the source of the two specified oxygen isotopes, and O is derived from H2 0 via P OCL. The reader is referred to the articles by Cullis and Lowe for details of the synthesis. 

Lowe, Cullis, and co-workers have described general methods for the synthesis of oxygen chiral phosphorothioate monoesters (see Figs. 3 and 4). The synthesis by Cullis is strictly analogous to the synthesis of chiral phosphate monoesters by Knowles except that (- )-ephedrine is thiophosphorylated with PSCI3... 

Stec extended his work on P-chiral phosphorothioates and described the synthesis of P-chiral, isotopomeric deoxyribonucleoside-phosphorothioates and -phosphates (76a-p) labelled with an oxygen isotope. To obtain stereodefined PS 0-oligos, the 5 -0-DMT-nucleoside-3 -0-(2-thio- spiro -4,4-pentamethy-lene-l,3,2-[0 ]oxathiaphospholanes were synthesised by phosphitylation of the correct protected nucleoside with chirally pure [O ]oxathiaphospholane, with subsequent sulfurisation. The resulting oxadithiaphospholanes were separated by chromatography into diastereomerically pure forms and individually treated with Se02 to yield the oxathiaphospholanes. ... 

A. Synthesis of Phosphate Monoesters Chiral by Virtue of Oxygen Isotopes. 99... 

Although phosphate monoesters chiral by virtue of oxygen isotope substitutions cannot be used in stereochemical studies of phosphate monoester hydrolysis (since there are only three stable isotopes of oxygen), they have been used profitably in studies of phosphoryl transfer reactions relevant to the question of the intermediacy of monomeric metaphosphate anion in phosphoryl transfer reactions (see Section III,A). The laboratories of Knowles and Lowe have reported general methods for the synthesis of phosphate monoesters chiral by virtue of oxygen isotope substitution, and these syntheses are summarized in this section. 

C. Synthesis of Phosphate Diesters Chiral by Virtue OF Oxygen Isotopes and of Thiophosphate Diesters... 

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... 

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