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. 2022;5(1):154.
doi: 10.1038/s42004-022-00773-6. Epub 2022 Nov 19.

Catalytic asymmetric synthesis of carbocyclic C-nucleosides

Sourabh Mishra  1 , Florian C T Modicom  1 , Conor L Dean  1 , Stephen P Fletcher  1
Affiliations

Catalytic asymmetric synthesis of carbocyclic C-nucleosides

Sourabh Mishra et al. Commun Chem. 2022.

Abstract

Access to carbocyclic C-nucleosides (CC-Ns) is currently restricted. The few methods available to make CC-Ns suffer from long syntheses and poor modularity, hindering the examination of potentially important chemical space. Here we report an approach to CC-Ns which uses an asymmetric Suzuki-Miyaura type reaction as the key C-C bond forming step. After coupling the densely functionalized racemic bicyclic allyl chloride and heterocyclic boronic acids, the trisubstituted cyclopentenyl core is elaborated to RNA analogues via a hydroborylation-homologation-oxidation sequence. We demonstrate that the approach can be used to produce a variety of enantiomerically enriched CC-Ns, including a carbocyclic derivative of Showdomycin.

Keywords: Asymmetric catalysis; Asymmetric synthesis; Synthetic chemistry methodology.

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Conflict of interest statement

Competing interestsThe authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Antiviral nucleosides analogs.
Few examples of nucleoside analogs as commercially available antiviral drugs.
Fig. 2
Fig. 2. Classification and synthesis of carbocyclic C-nucleosides.
A Nucleoside analog synthesis. B Reported syntheses of carbocyclic C-Nucleosides. C Catalytic enantioselective approach to carbocyclic C-Nucleosides (this work).
Fig. 3
Fig. 3. Synthetic strategies toward CC-Ns.
A Cross-coupling with simpler boronic acids leads to simple CC-Ns. B Cross-coupling with complex boronic acids. C Cross-coupling with simpler boronic acids then elaborate to complex CC-Ns.
Fig. 4
Fig. 4. Asymmetric cross-coupling heterocyclic boronic acids with racemic 1.
A Heterocyclic boronic acid. B Relatively complex boronic acid (multiple heteroatoms). Reaction conditions: 1 (0.4 mmol, 1 equiv), 2a (0.8 mmol, 2 equiv), [Rh(COD)(OH)]2 (0.01 mmol, 2.5 mol%), (S)-SegPhos (0.024 mmol, 6 mol%), Aq. CsOH (0.4 mmol, 1 equiv), THF (2 mL), H2O (0.2 mL), 60 °C, 18 h. aReaction performed at 50 °C. bReaction performed at 21 °C.
Fig. 5
Fig. 5. Hydroborylation and homologation of cyclopentenes 3.
Elaboration of cyclopentenes 3 to RNA analogs. Reaction Conditions - Hydroborylation: 3 (1 equiv), pinacol borane (2 equiv), [Rh(PPh3)Cl] (2.5 mol%), CsCO3 (1 equiv), THF, 50 °C, 16 h. Homologation: 4 (1 equiv), iodochloromethane (3 equiv), nBuLi (2.5 equiv), THF, −78 °C to rt, 18 h.
Fig. 6
Fig. 6. Carbocyclic C-nucleosides bearing relatively simple ‘nucleobase’ moieties.
Access toward simpler CC-Ns featuring phenyl, halo-pyridines, and furan nucleobase.
Fig. 7
Fig. 7. Attempts toward complex CC-Ns.
Cross-coupling attempts with pyrrolo-trazine boronic acids.
Fig. 8
Fig. 8. Late-stage modification strategy.
Modification of furan to benzaimidazole derived CC-N.
Fig. 9
Fig. 9. Synthesis of carbocyclic Showdomycin.
Post-synthetic modification of Pyrrole to access carbocyclic analog of Showdomycin.
See this image and copyright information in PMC

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