A short de novo synthesis of nucleoside analogs

Abstract

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism

“…For the synthesis of 2 ,3 -dideoxy-2 ,3 -difluoro nucleosides, the potential for hydroxyl elimination rather than substitution, due to the poor nucleophilicity yet considerable basicity of fluoride, adds to the synthetic challenge. A recent four-step sequence [28] giving access to series of nucleoside analogues, though notably no ribose-fluorinated analogues, was reported using a "ribose-last" approach whilst we were preparing this manuscript for publication; in a complementary study, we set out to explore a direct approach to ribose-fluorinated 5 -O-protected uridine analogues to gain greater insight into their conformations and thereby the mechanisms by which they might be formed.…”

Recent progress in non-native nucleic acid modifications

“…In this regard, inspired by a "ribose-last approach", Britton and colleagues recently demonstrated an efficient synthesis of a modified ribose core bearing nucleobases with the correct stereochemistry. 37 This approach takes advantage of a tandem α-fluorination followed by proline catalyzed aldol addition of an aldehyde and a dioxanone; then an annulative fluoride displacement yields modified ribose α-or βnucleosides in good yields and enantioselectivity. This strategy also allows for easy access to C4′ modified nucleosides including bicyclic and certain C-nucleosides via treatment with Grignard reagents (Fig 2b).…”

Chemical synthesis of 4′-thio and 4′-sulfinyl pyrimidine nucleoside analogues

“…2 Consequently, research activity in this field continues to develop syntheses for next generations of nucleoside analogues that can overcome these limitations and provide new therapeutic options. [3][4][5] Within this context, 4'-thionucleosides, where the furanose ring oxygen is substituted with sulfur, have received attention from several academic and industrial groups since a first disclosure of 4'-thioadenosine in the early 1960's; 6,7 Figure 1 highlights some key achievements in this area. Bioisosteric replacement of furanose oxygen with larger sulfur seeks to explore the biological effect, imparted through changes to furanose ring conformation and the hydrolytic stability of a thiohemiaminal glycosidic linkage.…”