Nucleoside Analogues with a Seven-Membered Sugar Ring: Synthesis and Structural Compatibility in DNA–RNA Hybrids

Abstract

Herein we describe results on the pairing properties of synthetic DNA and RNA oligonucleotides that contain nucleotide analogues with a 7-membered sugar ring (oxepane nucleotides). Specifically, we describe the stereoselective synthesis of a set of three oxepane thymine nucleosides (OxT), their conversion to phosphoramidite derivatives, and their use in solid-phase synthesis to yield chimeric OxT-DNA and OxT-RNA strands. The different regioisomeric OxT phosphoramidites allowed for positional variations of the phosphate bridge and assessment of duplex stability when the oxepane nucleotides were incorporated in dsDNA, dsRNA, and DNA–RNA hybrids. Little to no destabilization was observed when two of the three regioisomeric OxT units were incorporated in the DNA strand of DNA–RNA hybrids, a remarkable result considering the dramatically different structure of oxepanes in comparison to 2′-deoxynucleosides. Extensive molecular modeling and dynamics studies further revealed the various structural features responsible for the tolerance of both OxT modifications in DNA–RNA duplexes, such as base–base stacking and sugar–phosphate H-bond interactions. These studies suggest that oxepane nucleotide analogues may find applications in synthetic biology, where synthetic oligonucleotides can be used to create new tools for biotechnology and medicine.

Acetal Substitution Reactions: Stereoelectronic Effects, Conformational Analysis, Reactivity vs Selectivity, and Neighboring-Group Participation

“…Reactions of other bicyclic acetals followed similar trends (Figure 12). 56,62 Considering the importance of seven-membered-ring compounds in the synthesis of biologically active compounds, [63][64][65] we addressed the issue of whether we could derive a model to explain the reactivities of such acetals. As…”

“…Considering the importance of seven-membered-ring compounds in the synthesis of biologically active compounds, 63 64 65 we addressed the issue of whether we could derive a model to explain the reactivities of such acetals. As for the model to explain reactions of five-membered-ring oxocarbenium ions, the critical constraint was to make the models consistent: torsional changes of the seven-membered-ring, not simply steric effects, would define the face of the carbocationic intermediate that would be attacked.…”

DFT Study on Mechanism of Ni–Al Bimetallic-Catalyzed C–H Cyclization to Construct Tricyclic Imidazoles: Roles of NHC Ligand and AlMe3

“…Tricyclic imidazoles and their 7-membered ring derivatives, as one of the most important classes of structural motifs, − are widely present in numerous biologically active material molecules. Owing to their significance, the synthesis of tricyclic imidazoles and their 7-membered ring derivatives − has attracted widespread attention, and extensive effort has been devoted to the development of new methodologies. − Among a large number of strategies, direct construction of a 7-membered ring via C7–H cyclization of benzimidazoles with alkenes would provide a more straightforward, atom- and step-economic access to tricyclic imidazoles from more easily accessible substrates. However, over the past few decades, transition metal-catalyzed C–H cyclization − for medium-ring synthesis has been a challenging goal.…”

Synthesis of Seven-Membered Ring Nucleosides and Serendipitous Simmons–Smith O-Glycosylation

“…We also systematically changed the location of phosphodiester linkage and reported on the synthesis and hybridization properties of DNA and RNA strands incorporating OxTs 3 , 4 and 5 (Figure ). Incorporation of any of these three OxT monomers in an RNA strand resulted in a substantial decrease in the melting temperature ( T m ) with either an RNA or DNA complement. In sharp contrast, OxT 2 and OxT 3 monomers were well tolerated when placed in the DNA strand of DNA–RNA hybrids (Δ T m ∼ 0 °C) .…”

“… Incorporation of any of these three OxT monomers in an RNA strand resulted in a substantial decrease in the melting temperature ( T m ) with either an RNA or DNA complement. In sharp contrast, OxT 2 and OxT 3 monomers were well tolerated when placed in the DNA strand of DNA–RNA hybrids (Δ T m ∼ 0 °C) . More recently, guide RNA strands incorporating OxTs 3 , 4 and 5 were evaluated to probe the role of the ribose 2′-OH in the RNA pseudoknot structure of AsCas12a …”