Nucleoside H-phosphonates

A new route to nucleoside 3 -H-phosphonate building blocks 21 involves the initial preparation of ammonium aryl H-phosphonates 22 by heating the appropriate phenol under reflux with phosphorus trichloride, followed by treatment with ammonia. The ammonium salt of 4-methylphenyl H-phosphonate is highly crystalline and its triethylammonium salt can be condensed with the nucleoside in the presence of pivaloyl chloride to give, after hydrolysis, 21 in essentially quantitative yield. 

The synthesis of the cyclic 2 -deoxyribodinucleotides 82 by a solution-phase H-phosphonate method has been described in which a 5 -protected nucleoside-3 -H-phosphonate (83) is first coupled to a nucleoside 3 -H-phosphonate diester (84). Removal of the cyanoethyl group from the 3 -phosphonate group reveals an H-phosphonate monoester function which remains intact during oxidation of the internucleoside H-phosphonate diester linkage. After further deprotection, this 3 -H-phosphonate is reacted to produce the cyclic derivative 82 in 15% overall yield. 

The only exception was an attempt at the 5 -to-3 solid-phase oligonucleotide synthesis using nucleoside 3 -H-phosphonate monoesters, polymer-bound through a trityl-type linker, and oxidative coupling conditions (HgCl2) [123], The H-phosphonates were produced by phosphitylation of the polymer-bound N-unpro-tected nucleoside with phosphorus trichloride followed by hydrolysis by aqueous pyridine [61c]. However, despite some advanced features [124] the stepwise yields were comparable with those in the contemporary phosphodiester method-that is they were too low for the method to be truly competitive. 

A new route to nucleoside 3 -H-phosphonates involves reacting a suitably protected nucleoside with phosphonic acid using 6is(trichloromethyl)carbonate (triphosgene) as the activating agent. The method allows reasonably good yields of H-pho phonates of both 2 -deoxy- and 2 -0-methylribonucleosides (31)... 

Triesters of type 182 (n = 2-5) have been prepared from the nucleoside 3 -H-phosphonate, via the cyclic phosphites. Methods were also developed for making H-phosphonates and phosphodiesters involving just one of the hydroxy-groups of the diols. ... 

Nucleoside 3 -H-phosphonates 1 (ribonucleosides) and 2 (deoxyribonucleosides) seem to be the most attractive as starting materials in the chemical synthesis of DNA and RNA fragments. They entirely dominate the field of oligonucleotide synthesis. Nucleoside... 

Nucleoside 3 -H-phosphonates were prepared by reacting 5 -dimethoxytrityl thymidine with PCl3/l,4,2-triazole [179]. 

Nucleoside 3 -H-phosphonates can be prepared by reacting deoxycytidine with PClj/imi-dazole mixture [180]. 

The nucleoside 3 -H-phosphonate monoester, when reacted in pyridine with phenol in the presence of pivaloyl chloride, produced the desired nucleoside phenyl H-phosphonate [182]. 

Todd et al. used nucleoside 3 -H phosphonates to prepare 3 -5 -intemucleotidic bonds for the first time [189], Diphenyl chlorophosphale was used to activate nucleoside H-phosphonate. 

A convenient method for the preparation of nucleoside 3 -H-phosphonothioate monoesters from suitably protected nucleoside 3 -H-phosphonates has been developed by Stawinski et al. [205]. It consists of the activation of nucleoside 3 -H-phosphonate monoesters with pivaloyl chloride followed by treatment with 1,1,1,3,3,3-hexamethyldisi-lanthiane (HMDTS). 

A further interesting development occurred soon afterward. Two groups of workers observed that a nucleoside 3 -H-phosphonate (22) could be activated and then coupled rapidly to give a diester H-phos-phonate in high yield, and the process automated for oligomer assembly (33,34). Such diester H-phosphonates (23) can, at will, be oxidized to the phosphate (24), thiated to the phosphorothioate, and aminated... 

The transesterification of aryl nncleoside 3 -H-phosphonate with alcohols or with suitably protected nucleosides under mild conditions furnished the corresponding ester or dinucleoside (3 -5 ) H-phosphonate diesters [182],... 

Coupling of di- or oligo-nucleosides having H-phosphonate at the 3 -position with a second mono- or oligo- nucleoside having a free 5 -hydroxyl group results in the formation of oligonucleosides (n > 2) [174],... 

A convenient preparation of deoxynucleoside 3 -H-phosphonates involves the reaction of a suitably-protected nucleoside with phosphonic acid in the presence of pivaloyl chloride. " Ribo- and deoxyribo-nucleoside 3 -phosphonothioates (131) can be obtained by reaction of the protected nucleoside with triethylammonium phosphinate and pivaloyl chloride to give the nucleoside phosphinate (132), followed by oxidation with sulphur. 9... 

The most reliable method for characterization of the product H-phosphonate IS H and P NMR. Hydrogen-phosphonates have a characteristic coupling constant of the P-H (Jp.n = 600-605 Hz) that can be seen in tire H-NMR spectrum as well as in the H-coupled P NMR spectrum. Furthermore, the P NMR spectrum of a nucleoside 3 -H-phos-phonate is split into another doublet due to the C-3 hydrogen (Jp.n = 8-12 Hz). 

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. 

Albrecht, H.P., Jones, G.H., and Moffatt. J.G.. Homonucleoside phosphonic acids. Part 1. A general synthesis of isosteric phosphonate analogs of nucleoside 3 -phosphates, Tetrahedron, 40, 79, 1984. 

Cook reported the syntheses of phosphonamidite and H-phosphonates derivatives of 3 -C-methylene modified thymidines (77a-e), 3 -C-methylene 5-methyl-iV-pyrrolidine-modified cytosine (78) and 3 -C-methylene 5-methyl modified uridine (79) having methoxy, fluoro, hydrogen and methoxyethoxy substituents at the 2 -positions. The H-phosphonates were synthesised from the corresponding key intermediate 3 -C-iodomethyl nucleosides through an... 

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