Oligonucleotide building blocks

Monaharan has developed a versatile synthetic route for the synthesis of 2 -0-[(N, iV-dimethylamino)-oxyethyl] modified purine and pyrimidine nucleoside phosphoramidites (63a-d) to be used as antisense oligonucleotide building blocks. In the syntheses of the purine-based analogues, the (iV, N-dimethylamino)-oxyethyl group was introduced via a 2 -allyloxy nucleoside intermediate, while the pyrimidine-based nucleosides were obtained from the TBDMS-protected 2,2 -anhydro-5-methyluridine via ring opening reaction in the presence of borane and ethylene glycol. The aminoxy derivatives were... 

Extensive work has been reported on the chemistry of polyphosphates, in particular that of dinucleoside and sugar nucleoside pyrophosphates. This reflects the reliability and flexibility of the phosphoramidate methods which have been developed over the past few years. Similarly, a wide range of oligonucleotide building blocks, incorporating extensive structural modifications when compared to the natural nucleoside structures, have been described. 

Clivio described the synthesis of an oligonucleotide building block containing a syn-cis thymine cyclobutane dimer photoproduct (216) and that of the phosphoramidite (217), and the thio analogue at the 5,6-dihydropyrimidine C5 position of the thymidyl(3 -5 )thymidine (6-4) photoproduct (218). ... 

This past year has been highlighted by the development of novel phosphate protecting groups and their use in nucleotide and chiral nucleoside thiophos-phate chemistry. Concise methodologies have been described for cost effective syntheses of oligonucleotide building blocks. Finally, the collection of unnatural nucleotides reported to have been synthesised has been expanded significantly. 

Further modifications to the nucleic base of oligonucleotide building blocks have been described. Spermine-containing oligodeoxynucleotides have been prepared from the trifluoroacetylated phosphoramidite derivative of 2-(4,9,13-triazatridecyl)-2 -deoxyguanosine (49). The stability of the hybridisation duplexes increased with the increased content of spermine residues and this stability was neither sequence nor position-dependent. ... 

Example 53 Engels and associates have synthesized monomeric phenylphosphonoamidites building blocks that serve as synthons for the introduction of phenylphosphono and phenylphosphonothioate linkages into oligonucleotides [87]. 

A supported sulfide source has been demonstrated by Zhang et al.16 to synthesize oligonucleotide phosphorothioates (entry 12). Aminodithiazole-thione attached to a methacrylate-ethyleneglycol copolymer is used to efficiently convert a nucleotide phosphite to a phosphorothioate. The product nucleotide possesses protecting groups suitable for solid-phase oligonucleotide synthesis and thus is a valuable building block for nucleic acid therapeutics. 

Figure 6.11 The use of oligonucleotides to encode a peptide combinatorial synthesis for a library based on two building blocks...

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