H-phosphonate chemistry

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. 

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 new one-pot method has been developed by Kraszewski for the synthesis of aryl nucleoside phosphate (3a-p) and phosphorothioate (4a-p) diesters. This method, based on H-phosphonate chemistry, employed diphenyl phosphoroch-loridate and a series of phenols. Depending on the substituents present on the phenols, oxidation conditions were optimized to avoid competing hydrolysis. A versatile procedure that permits easy access to H-phosphonoselenoate monoesters (5) has been developed by Stawinski. These monoesters, obtained by selenisation of a phosphinate using triphenylphosphine selenide in combination with trimethylsilyl chloride, reacted with a suitable nucleoside in pyridine/acetonitrile in the presence of diphenyl phosphorochloridate to yield... 

Guzaev et al. report that the synthesis of ODNs without phosphate protection of the growing ODN may be carried out, with few side reactions, by converting the phosphate (or phosphorothioate) into its 4-(N,iV-dimethylamino)pyridinium salts. The advantage of this system is that it allows ODN synthesis using both phosphoramidite and H-phosphonate chemistries. 

Recently, a polymer-bound DMTr group has been applied by Mihaichuk et al. [124c] for the 5 -to-3 synthesis on PS using either phosphoramidite or H-phosphonate chemistry. 

C) or 20% piperidine in DMF (3 h, ambient temperature) the 3 -phosphate can be liberated from NPE support by standard ammonia treatment. The NPE linker has been used primarily for the preparation of the oligonucleotides containing sensitive nucleobases [234], with DBU-mediated deprotection and phosphoramidite or H-phosphonate chemistry, [235] as well as for the synthesis of peptide-oligonucleotide conjugates [236]. 

Kraszewski et al. [208] have developed a new, efficient method for the synthesis of phosphorothioate diester, based on the H-phosphonate chemistry. The reaction of aryl nucleoside H-phosphonate with elemental sulfur furnished the corresponding aryl nucleoside phosphorothioate. The synthesis of phosphorothioates can be carried out as a four-components-one-pot reaction, by allowing nucleoside H-phosphonate to react with phenols in the presence of diphenyl phosphorochloridate to furnish aryl nucleoside H-phosphonates, which react with elemental sulfur. 

All ribooligonucleotides described in the following were chemically synthesized using the H phosphonate method [34, 35]. It was demonstrated that this method allows the preparation of the relatively large amounts (> 10 mg) of RNA being necessary for 2D NMR studies at reasonable costs and with the required purity. In addition, as compared to phosphora-midite chemistry, the H phosphonate chemistry offers the advantage of recovery and reusing of synthons. This is particularly important for expensive modified or isotopically labelled nucleotides. 

One of the advantages of H-phosphonate chemistry is the ease with which phosphate analogs are prepared (Fig. 3). Phosphorothioates are readily prepared by oxidation with Sg in pyridine/CS2. This is a very clean reaction leading to virtually 100% substitution by sulfur on phosphate. This reaction has been extended to the synthesis of oligo-phosphorothioates (7,12,13), as well as uniformly labeled phosphorothioates (29,30). The synthesis of phosphorothioates has been discussed in greater detail in Chapter 8. 

Scheme 2. Steps involved in DNA synthesis following H-phosphonate chemistry.

Configuration of Reagent Solvent Rearrangement for H-Phosphonate Chemistry... 

Aimer H, Stawinski J, Strdmberg R (1994) Synthesis of stereochemically homogeneous oligoribonucleoside all-/fp-phosphorothioates by combining H-phosphonate chemistry and enzymatic digestion. J Chem Soc Chem Commun 1994 1459-1460... 

---