Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues

Abstract

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF2 and...

Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2′-Arabino Analogues and Ring Unsaturation

“…Previously, we reported the synthesis of 2′-deoxy 6′-fluorinated nucleoside analogues, 27 wherein a Barton-Mc-Combie deoxygenation 34 was used to effect 2′-deoxygenation via a C2′-thiocarbamate intermediate. Interestingly, upon repeating this synthesis (from 16), a major side-product was isolated in 39% yield, along with the desired product 17 in 55% yield (Scheme 4).…”

“…24 We also recently described a reliable and scalable synthesis of 6′-monofluoro and gem-difluoro carbauridines 1 and 2, respectively (Figure 1), incorporating late-stage modifications to create a small library of analogues. 27 Herein, we further expand on this capability and describe the introduction of unsaturation across the C1′-C2′ or C2′-C3′ bonds, as well as stereoinversion at C2′ (Figure 1).…”

Gilman reagent toward the synthesis of natural products

“…119,120 In 2022, Benckendorff et al presented a scalable and efficient synthesis of monouorinated and diuorinated carbocyclic nucleoside analogues 265-274 and evaluated their cellular viability against PANC-1 and cancer cell lines U87-MG (Scheme 31). 121 Their synthesis began with the readily available cyclopentenone 257, which was subjected to a conjugate addition reaction by employing the corresponding Gilman reagent. Thus, the treatment of cyclopentenone 257 with vinyl magnesium chloride and copper iodide in THF, with the adjustment of temperature at −78 °C furnished the compound 258 with a 78% yield.…”

Purine nucleoside antibiotics: recent synthetic advances harnessing chemistry and biology

“…These nucleosides consist of a sugar core (D-ribose) linked to the heterocyclic nucleobase via a b-N-glycosidic bond. When combined with either adenine (6-aminopurine) or guanine (2amino-6-hydroxypurine) the structures comprise adenosine (8) and guanosine (9), respectively. Modications to these scaffolds present the basis for structurally diverse nucleoside antibiotics, with examples incorporating C-glycosides (b-C-glycosidic linkage), ribose ring halogenation and the attachment of peptides, illustrated further in Fig.…”