Synthesis of Phostone‐Constrained Nucleic Acid (P‐CNA) Dinucleotides Through Intramolecular Arbuzov's Reaction

Abstract

P‐CNAs are dinucleotide building blocks in which the torsional angles α and β of the sugar/phosphate backbone are constrained to non‐canonical values within a cyclic phosphonate structure (phostone) synthesised by diastereoselective intramolecular Arbuzov reaction. The reaction has been improved through the use of microwave activation and addition of lithium bromide.

Microwave‐Assisted Phosphitylation of DNA and RNA Nucleosides and Their Analogs

“…Since alternative phosphitylating reagents such as 2-cyanoethyl-N, N-diethylamino chlorophosphoramidite or 2cyanoethyl-N,N,N ,N -tetraethylamino phosphane were difficult to acquire and inherently more unstable, it was postulated that better results could be obtained through another strategy. Several examples in the literature suggested the reactions involving nucleic acids were facilitated through ball milling (Amigues et al, 2009;Hardcare et al, 2011) and microwave irradiation (Grünfeld and Richert, 2006;Meng et al, 2009;Catana et al, 2011). Once microwave-assisted phosphitylation was successfully applied to obtain ribuloside phosphoramidites (Fig.…”

Cover Picture: Catalytic Molecular Logic Devices by DNAzyme Displacement (ChemBioChem 7/2014)

“…The reaction mechanism is driven by the formation of the thermodynamically favored P=O bond, but this relies on reaction between the ester and a halide. Research into noncyclic reactions has shown that addition of excess halide59,60 and use of microwave conditions can increase yields and reduce the reaction time 61. This has increased the scope of reaction, especially for less stable compounds (e.g., nucleoside chemistry),59 in which the yields of products from intermolecular Arbuzov reactions are often difficult to match 62.…”

“…Research into noncyclic reactions has shown that addition of excess halide59,60 and use of microwave conditions can increase yields and reduce the reaction time 61. This has increased the scope of reaction, especially for less stable compounds (e.g., nucleoside chemistry),59 in which the yields of products from intermolecular Arbuzov reactions are often difficult to match 62. Additionally, microwave irradiation in the presence of excess LiBr at 90 °C gave the best yields of phostones 76 (Table 8).…”

Synthesis of Benzothiophene‐Containing 10‐ and 11‐Membered Cyclic Phostones

“…Examples of this type include C-glycoside mimics that block glioma stem cell proliferation (e.g., compound 3) [3] and conformationally rigidified nucleotides that are potentially useful in antisense technologies (e.g., phostone-based dinucleotide 4). [4] Six-membered ring phostones have also been explored as prodrugs of antiviral nucleosides, such as cidofovir (5), [5] and dioxaphosphinane 2oxide 6 has been identified as an inhibitor of γ-secretase, [6] an important target associated with the progression of Alzheimer's disease.…”

“…Six‐membered ring phosphinates (known as oxaphosphinanes or phostines) and phosphonates (known as phostones) have also been previously explored in drug discovery as bioisosteres of the furanose or pyranose ring, in which the anomeric carbon atom is replaced by the phosphinate or phosphonate moiety. Examples of this type include C‐glycoside mimics that block glioma stem cell proliferation (e.g., compound 3 ) and conformationally rigidified nucleotides that are potentially useful in antisense technologies (e.g., phostone‐based dinucleotide 4 ) . Six‐membered ring phostones have also been explored as prodrugs of antiviral nucleosides, such as cidofovir ( 5 ), and dioxaphosphinane 2‐oxide 6 has been identified as an inhibitor of γ‐secretase, an important target associated with the progression of Alzheimer's disease.…”