The synthesis of 6,6′‐cyclo‐6′‐deoxyhexofuranosyluracils via a diazomethane‐promoted ring‐enlargement reaction

Abstract

The protected 5′‐oxo‐6,5′‐cyclouridine 13 reacts with diazomethane to afford mostly the spiro‐epoxide 18 (79%), but it also undergoes ring‐expansion to give the corresponding 5′‐oxo‐6,6′‐cyclonucleoside 16. Under the conditions of the reaction, ketone 16 reacts further with diazomethane to give the enol ether 20 (12% overall), the isomeric 4‐methoxy nucleoside 15 (2%), and the spiro‐epoxide 19 (4.4%). Acid hydrolysis of the enol ether 20, followed by reduction of the resulting ketone with sodium borohydride, affords a separable mixture of the 5′S (L‐talo) and 5′R (D‐allo) methylene‐bridged cyclonucleosides 7 and 8, respectively. From proton nmr measurements, it appears that the 6′‐methylene groups of these cyclonucleosides project towards the 2′,3′‐edge of the furanose ring.

Homologation Reaction of Ketones with Diazo Compounds

“…The use of Lewis acids as promoters failed to attenuate the epoxide formation, and the yields of ring-expanded products remained the same (Scheme ). , …”

Synthesis of 6,6′-(S)-cyclo-2′-deoxyuridine featuring a unique Barbier-style cyclization

“…[10][11][12][13] Otter et al were able to produce a modified, ribose variant of 6,69-cyclouridine with a 59 OH, but the work relies on the use of diazomethane, which results in methylation of the N3 position, making studies related to duplex formation impossible. [10][11][12][14][15][16] Eventually they were able to make the 6,69-cyclouridine, but the synthesis was long and suffered from low yields. 16 Our synthesis of 6,69-(S)-cyclo-29-deoxyuridine takes only seven steps, highlighted by a cyclization, yielding the newly formed 7-membered ring.…”

“…[10][11][12][14][15][16] Eventually they were able to make the 6,69-cyclouridine, but the synthesis was long and suffered from low yields. 16 Our synthesis of 6,69-(S)-cyclo-29-deoxyuridine takes only seven steps, highlighted by a cyclization, yielding the newly formed 7-membered ring. Due to synthetic limitations the uracil base was utilized instead of the naturally occurring thymidine base, which prevents access to the cyclo bridge.…”