H-phosphonates

Similarly, Pei and co-workers [66] explored the feasibility of using an H-phosphonate head group on a peptide cassette (4) to inhibit PDF activity. While inhibitor (4) was not highly potent (if,- = 76 pM versus E. coli... 

Zn -PDF, 37 pM versus E. coli Fe -PDF), it was successfully used to provide co-crystals bound in the active site of both Co - and Zn -E. coli PDF [58], These structures reveal that the H-phosphonate binds to the metal in a monodentate fashion, adopting a tetrahedral coordination state similar to that of the native resting state of the enzyme. This is in contrast to later co-crystal structures obtained with more potent hydroxamic acid or reverse hydroxamate inhibitors, which bind to the metal in a bidentate fashion vide infra). Presumably these bidentate inhibitors mimic the true transition state of the enzyme, in which the metal centre slips to a penta-coordinate geometry in order to activate the Wformyl carbonyl of the substrate [56, 67]. 

Incorporation of a flavin electron donor and a thymine dimer acceptor into DNA double strands was achieved as depicted in Scheme 5 using a complex phosphoramidite/H-phosphonate/phosphoramidite DNA synthesis protocol. For the preparation of a flavin-base, which fits well into a DNA double strand structure, riboflavin was reacted with benzaldehyde-dimethylacetale to rigidify the ribityl-chain as a part of a 1,3-dioxane substructure [49]. The benzacetal-protected flavin was finally converted into the 5 -dimethoxytri-tyl-protected-3 -H-phosphonate ready for the incorporation into DNA using machine assisted DNA synthesis (Scheme 5a). For the cyclobutane pyrimidine dimer acceptor, a formacetal-linked thymine dimer phosphoramidite was prepared, which was found to be accessible in large quantities [50]. Both the flavin base and the formacetal-linked thymidine dimer, were finally incorporated into DNA strands like 7-12 (Scheme 5c). As depicted in... 

Scheme 5 a Flavin-H-phosphonate and formacetal-linked thymine dimer phospho-ramidite used for the synthesis of the flavin and dimer containing DNA-strands 7-12. b Representation of a reduced flavin- and formacetal-linked cyclobutane pyrimidine dimer containing DNA strand, which upon irradiation (hv) and electron transfer (ET) performs a cycloreversion (CR) of the dimer unit, c Depiction of the investigated oligonucleotides... 

The thermal synthesis of nucleoside-5 -phosphite monoester using (NH HPCb was carried out under relatively mild conditions (60°C, reaction time about 24 h) by A. W. Schwartz s group in Nijmegen, Holland in the case of uridine, the yield was 20%. Ammonium phosphate, however, cannot be used it gave yields of only 0.15% after very long reaction times (46 days). This confirms earlier suggestions that nucleoside-H-phosphonates, and condensation products possibly derived from them, would have been formed more readily on the primeval Earth than nucleotides (de Graaf and Schwartz, 2005). 

H-phosphonates 20a-d were detected as the only side products (10-15%). They were produced by the competitive hydrolysis of the intermediate 18a-d which could be checked completely by carrying out sulfhydrolysis in the presence of trimethylsilyl chloride. 

In this context, it is interesting to note that the first synthesis of 2, 3 -0,0-cyclic phosphorothioate 22a was reported by Eckstein in 1968 [25], He also isolated pure Rp diastereomer by fractional crystallization of the triethylammonium salts [26] and used it as reference to determine the absolute configurations of the other phosphorothioate analogues [27], 2, 3 -0,0-Cyclic H-phosphonate 20a was used as a key substrate for the synthesis of uridine 2, 3 -0,0-cyclic boranophosphate 27. Silylation of H-phosphate 20a gave the phosphite triester 25 (two diastereomers). Its boronation, with simultaneous removal of the trimethylsilyl group, was achieved by its reaction with borane-A.A-diisopropylethylamine complex (DIPEA-BH3). 

Household waste, 25 864 House-of-cards glass-ceramic microstructure, 12 635 Housewares, LLDPE, 20 207-203 Housewrap, 17 482 Housings, for cartridge filters, 11 369 Hoveya-Grubbs catalysts, 26 934 H-phosphonate DNA synthesis method, 17 624-625... 

Application of H-phosphonate approach in the preparation of glycosyl 1-phosphates... 

The H-phosphonate approach entails phosphitylation of a hydroxylic component with an activated unprotected derivative of phosphonic acid to furnish H-phosphonate (a stable tetra-coordinate form of the unprotected monophosphite) followed by oxidation on phosphorus. The H-phosphonate approach is not generally used for the synthesis of monophosphates due to the difficulty of oxidation of the H-phosphonate monoesters and the necessity either to render the phosphorus atom of H-phosphonate into the three-coordinate form by silylation (to form disilylphosphite) or to introduce a protecting group (to form H-phosphonate diester) prior to oxidation. Nevertheless, in rare cases, the H-phosphonate procedure turns out to be a method of choice if, for instance, the simultaneous oxidation of functional groups other than H-phosphonate is required.51... 

Example 56 the Isis Pharmaceutical group in their extensive investigations of antisense oligonucleotides as therapeutics has described the synthesis of 3 -C-methylene nucleoside phosphonoamidites for the new backbone modification of oligonucleotides [90]. This paper gives good insight into tricoordinate phosphorus and related H-phosphonate chemistry in the service of nucleotide synthesis. 

Formation of the nucleoside phosphorodichloridite at -30 °C by PCI3 in CH2CI2 solution (step a) is followed by reaction with ethanol (step b). Subsequently dealkylation occurs with the assistance of hydrogen chloride formed in reaction (a) to give the desired 5 -nucleoside H-phosphonate (step c). It was found that a mixture of ethanol and tcrt-butanol (1 1) as alcoholysis agent prevented side reactions and gave a higher yield than when ethanol alone was used. 

The same refer to procedures based on H-phosphonate chemistry... 

Stawinski J (1992) Some aspects of H-phosphonate chemistry. In Engel R (ed) Handbook of organophosphorus chemistry. Marcel Dekker, New York, p 377 Stawinski J, Kraszewski A (2002) Acc Chem Res 35 952... 

A facile method for the oxidation of nucleoside H-phosphonates to phosphates has been developed with BTSP and N,0-bis(trhnethylsilyl)acetamide, MeC(NSiMe3)OSiMe3, in the presence of Me3Si0S02CF3 as a catalyst (equations 67 and 68) °. 

Scheme 9 is an example of a quinine-catalyzed reaction between an aldehyde and H-phosphonate (phosphite) to produce an optically active adduct (72). 

Phosphonates react with aldehydes or imines to yield a-hydroxy- or a-aminoalk-ylphosphonates, respectively. These reactions can also be conducted on cross-linked polystyrene. In Figure 11.2, a sequence is outlined in which polystyrene-bound H-phosphonates are treated with imines and aldehydes. The variant in which a support-bound imine is converted into an a-aminoalkylphosphonate has also been reported... 

Figure 16.28. Conversion of diols into protected H-phosphonates and the preparation of oligomeric...

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