Synthesis of D‐Altritol Nucleosides with a 3′‐O‐Tert‐Butyldimethylsilyl Protecting Group

Abstract

Four D-altritol nucleosides with a 3'-O-tert-butyldimethylsilyl protecting group are synthesized (base moieties are adenine, guanine, thymine and 5-methylcytosine). The nucleosides are obtained by ring opening reaction of 1,5:2,3-dianhydro-4,6-O-benzylidene-D-allitol. Optimal reaction circumstances (NaH, LiH, DBU, phase transfer, microwave irridation) for the introduction of the heterocycles are base-specific. For the introduction of the 3'-O-silyl protecting group, long reaction times and several equivalents of tert-butyldimethylsilyl chloride are needed.

Fmoc‐Protected Altritol Phosphoramidite Building Blocks and Their Application in the Synthesis of Altritol Nucleic Acids (ANAs)

“…Seven phosphoramidites of D ‐altritol nucleosides incorporating a 3′‐ O ‐(9‐fluorenylmethoxycarbonyl) protecting group – compounds 1a – 7a (base moieties are adenine, guanine, uracil, cytosine, thymine and 5‐methylcytosine) – were synthesized by a new strategy. The nucleosides were obtained by ring opening of 1,5:2,3‐dianhydro‐4,6‐ O ‐benzylidene‐ D ‐allitol,3 which was in turn prepared in five steps from commercially available tetraacetyl α‐ D ‐bromoglucose (54 % overall yield), basically by the procedure described by Brockway et al (Figure 1). 9…”

“…Different conditions were tested for the nucleophilic opening of the epoxide by the salts of nucleobases. As well as the classical sodium and lithium salts,1 a softer base (DBU) or a phase‐transfer catalyst such as tetrabutylammonium chloride/potassium carbonate could be applied 3. The preferred reaction conditions proved to be base‐dependent.…”

“…The problems in ANA oligonucleotide synthesis have usually been overcome by the use of the benzoyl protecting group for the 3′‐hydroxy group, in combination with the phosphoramidite method 1. However, the problem of 3′→4′ benzoyl migration during the synthesis of the protected building blocks2 results in difficulties for the large‐scale preparation of isomerically pure phosphoramidites, and so we investigated the use of the 3′‐ O ‐TBDMS protecting group in ANA oligonucleotide synthesis 3. Although RNA could be produced by this process, the deprotection steps for the preparation of ANA sequences were much more difficult than those for RNA sequences.…”

Nucleic Acids with a Six‐Membered ‘Carbohydrate’ Mimic in the Backbone

“…The cytosine nucleoside was obtained from the uracil congener. Initially, the main problems were encountered for the introduction of the guanine base [66] [67]. These problems were solved by synthesizing the guanine analogue from the 2-amino-6-chloropurine precursor.…”

“…For the introduction of a 3'-O-TBS group, long reaction times and several equiv. of t BuMe 2 SiCl (TBSCl) are needed [66]. Although RNA can be produced using this protecting group, the deprotection step for the preparation of ANA sequences is much more difficult than those for RNA sequences [68].…”