Nucleoside Analogues: Synthesis from Strained Rings

Abstract

Nucleoside analogues are widely employed as bioactive compounds against cancer and viral infections. Consequently, it is important to develop efficient synthetic methods to access them with high efficiency and structural diversity. Herein, we present a full account of our work on the synthesis of nucleoside analogues via annulations of donor acceptor aminocyclopropanes and aminocyclobutanes. Thymine-and uracil-derived diester cyclopropanes were accessed from the corresponding nucleobases via vinylation and rhodium-catalyzed cyclopropanation, and were then used in (3+2) annulations with aldehydes, ketones and enol ethers.The obtained analogues could be transformed into important hydroxymethyl derivatives. Thymine and fluoro-uracil derived diester cyclobutanes obtained from the nucleobases via vinylation and (2+2) cycloaddition could also be used in a (4+2) annulation with aldehydes. Finally, purine-derived diester cyclopropanes could be accessed using the condensation of nucleobases with chloromethyl ethylidene malonates, but annulation reactions with this class of substrates was not successful.

Selective Carbon–Carbon Bond Cleavage of Cyclopropylamine Derivatives

“…Nucleobase-substituted diester cyclopropanes containing thymine, uracil, or 5-fluorouracil also undergo cycloaddition with aldehydes, ketones, and enol ethers to give cyclic products such as 76 and 77 (Scheme A) . However, when purine was used as nucleobase, no C–C-bond cleavage was observed (Scheme B) . The low reactivity was rationalized by the modified electronics of the cyclopropane ring.…”

“…68 However, when purine was used as nucleobase, no C−C-bond cleavage was observed (Scheme 22B). 69 The low reactivity was rationalized by the modified electronics of the cyclopropane ring.…”

Dearomatization of electron poor six-membered N-heterocycles through [3 + 2] annulation with aminocyclopropanes

“…6 In particular, these reactions are highly successful with enol-ethers, 7 nitrosoarenes, 8 imines, 9 heteroatom substituted alkynes, 10 carbonyl compounds 11 and nitrones. 12 However, dearomative [3 + 2] annulation reactions were only intensively studied with indoles 13 and a single example was reported for benzothiazoles (Scheme 2).…”

Ring Expansion of Donor–Acceptor Cyclopropane via Substituent Controlled Selective N-Transfer of Oxaziridine: Synthetic and Mechanistic Insights

“…We paid particular attention to establishing the N -transfer ability of oxaziridines to the carbon nucleophile, which can give direct access to different valuable acyclic or cyclic N -containing molecular entities. Our work imparts a novel N -transfer reactivity of oxaziridine to donor–acceptor cyclopropane , (DAC) for the synthesis of azetidine derivatives. MgI 2 catalyzes this transformation with good yield (Scheme B).…”