Synthesis and Properties of Oligodeoxynucleotide Analogs with Bis(methylene) Sulfone Bridges

A convergent, solution‐phase synthesis was developed for the bis(methylene) sulfone‐bridged oligodeoxynucleotide analogs (SNA) 5′‐d(HOCH₂‐Tso ₂Tso ₂Tso ₂Cso ₂Tso ₂Tso ₂Tso ₂T‐CH₂SO )‐3′ ( 35b ) and 5′‐d(HOCH₂‐Tso ₂Tso ₂Tso ₂Tso ₂Tso ₂Tso ₂Tso ₂T‐CH₂SO )‐3′ ( 34c ) (SO₂ corresponds to CH₂SO₂CH₂ instead of OP(?O)(O^?)(O). In these, the phosphodiester linkages are replaced by non‐ionic bis(methylene) sulfone linkers. The general strategy involved convergent coupling of 3′,5′‐bishomo‐β‐D ‐deoxyribonucleotide analogs functionalized at the 6′‐end (?CH₂? C(5′)) as bromides or mesylates and at the CH₂? C(3′) position as thiols, with the resulting thioether being oxidized to the corresponding sulfone. A single charge was introduced at the terminal CH₂? C(3′) position of the octamers to increase their solubility in water. During the synthesis, it became apparent that the key intermediates generated secondary structures through either folding or aggregation in a variety of solvents. This generated unusual reactivity and was unique for very similar structures. For example, although the dimeric thiol d(BzOCH₂‐Tso ₂C‐CH₂SH) ( 14b ) was a well‐behaved synthetic intermediate, the tetrameric thiol d(TrOCH₂‐Tso ₂Tso ₂Tso ₂^toC‐CH₂SH) derived from the corresponding thioacetate was rapidly converted to a disulfide by very small amounts of oxidant ( 28 → 29 , Scheme 6), while the analogous tetrameric thiol d(BzOCH₂‐Tso ₂Ts Tso ₂T‐CH₂SH) ( 26 ), differing only by a single heterocycle, was oxidized much more slowly (Bz=PhCO, Tr=Ph₃C, to=2‐MeC₆H₄CO (at N⁴ of dc)). The sequence‐dependent reactivity, well known in many classes of natural products (including polypeptides), is not prominent in natural oligonucleotides. These results are discussed in light of the proposal that the repeating negative charge in nucleic acids is key to their ability to serve as genetic molecules, in particular, their capability to support Darwinian evolution. The ability of 5′‐d(HOCH₂‐Tso ₂Tso ₂Tso ₂Cso ₂Tso ₂Tso ₂Tso ₂T‐CH₂SO )‐3′ ( 35b ) to bind as a third strand to duplex DNA was also examined. No triple‐helix‐forming propensity was detected in this molecule.