Abstract
Competition from intramolecular folding is a major challenge in the design of synthetic oligomers that form intermolecular duplexes in a sequence-selective manner. One strategy is to use very rigid backbones that prevent folding, but this design can prejudice duplex formation if the geometry is not exactly right. The alternative approach found in nucleic acids is to use bases (or recognition units) that have different dimensions. A long-short base-pairing scheme makes folding geometrically difficult and is compatible with the flexible backbones that are required to guarantee duplex formation. A monomer building block equipped with a long hydrogen bond donor (phenol, D) recognition unit and a monomer building block equipped with a short hydrogen bond acceptor (phosphine oxide, A) recognition unit were prepared with differentially protected alcohol and carboxylic acid groups. These compounds were used to synthesise the homo and hetero-sequence 2-mers AA, DD and AD. 19F and 31P NMR experiments were used to characterize the assembly properties of these compounds in toluene solution. AA and DD form a stable doubly-hydrogen-bonded duplex with an effective molarity of 20 mM for formation of the second intramolecular hydrogen bond. AD forms a duplex of similar stability. There is no evidence of intramolecular folding in the monomeric state of this compound, which shows that the long-short base-pairing scheme is effective. The ester coupling chemistry used here is an attractive method for the synthesis of long oligomers, and the properties of the 2-mers indicate that this molecular architecture should give longer mixed sequence oligomers that show high fidelity sequence-selective duplex formation.
Highlights
1.1 BackgroundTwo sequence-complementary strands of nucleic acid will form a stable duplex due to hydrogen bonding interactions between the bases
A monomer building block equipped with a long hydrogen bond donor recognition unit and a monomer building block equipped with a short hydrogen bond acceptor recognition unit were prepared with differentially protected alcohol and carboxylic acid groups
A divergent approach to the synthesis of the monomer building blocks was employed, in which a common aromatic bromide intermediate was coupled with the hydrogen bond donor and acceptor recognition units, as shown in Scheme 1
Summary
Two sequence-complementary strands of nucleic acid will form a stable duplex due to hydrogen bonding interactions between the bases. Esters are sufficiently weak hydrogen bond acceptors (b z 5.5) not to compete signi cantly with the phosphine oxide recognition units (b z 10.5).[40] Ester coupling is sufficiently high-yielding to be used for the synthesis of polymers, and iterative coupling could be automated in a peptide synthesiser.[41,42,43] Orthogonal protecting groups have been developed for the preparation of oligoesters with sequences of different building blocks.[44,45,46,47,48,49,50,51] Here, we describe synthesis of the required monomer building blocks, demonstrate their use in the synthesis of different 2-mer sequences, and show that the long-short base-pairing scheme successfully prevents 1,2-folding for this oligomer architecture
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