Catalytic asymmetric synthesis of carbocyclic C-nucleosides

Nucleosides and their analogs are crucial antiviral and anticancer agents. Carbocyclic nucleoside analogs, exhibiting enhanced flexibility, lipophilicity, and metabolic stability, demonstrate broad antiviral activity. Clinically used examples include Entecavir (hepatitis B), Aristeromycin and Abacavir (HIV), and Galidesivir (Ebola and Zika viruses). Remdesivir and Molnupiravir are also notable for their activity against SARS-CoV-2. While N-nucleosides, C-nucleosides, and carbocyclic N-nucleosides are extensively studied, carbocyclic C-nucleosides (CC-Ns) remain rare due to synthetic challenges. Existing methods are often lengthy and lack modularity, exemplified by a 17-step synthesis of a potential Alzheimer's drug from D-Ribose. This research proposes a cross-coupling strategy as a more efficient and modular route to CC-Ns, aiming to address the current limitations in accessing this important chemical space.

The synthesis of nucleosides and their analogs is a well-established area of research, with numerous methods available for the production of N-nucleosides and C-nucleosides. Common strategies involve nucleophilic addition to carbohydrate-derived oxocarbeniums. Carbocyclic nucleoside synthesis focuses on carbocycle construction and nucleobase addition. Pd-catalyzed allylic amination followed by late-stage nucleobase construction is one such approach for carbocyclic N-nucleosides. However, the synthesis of CC-Ns lags significantly behind, hindered by the lack of general and efficient methods. Existing synthetic routes are often lengthy and non-modular, limiting the exploration of structural diversity and hindering the discovery of novel bioactive compounds. This scarcity of efficient synthetic methods underscores the need for innovative approaches to access this under-explored chemical space.

The proposed strategy centers on a catalytic asymmetric Suzuki-Miyaura coupling (SMC) reaction to form the key C-C bond. The reaction utilizes a suitably functionalized racemic bicyclic allyl chloride (1) and heteroaryl boronic acids (2) as coupling partners, aiming for a desymmetrizing reaction to establish the stereochemistry of the cyclopentene core. Three distinct strategies were explored: (A) using simpler boronic acids to access simpler CC-Ns, (B) directly employing complex heterocyclic boronic acids to achieve direct access to complex CC-Ns, and (C) using less complex boronic acids followed by late-stage modifications to build more elaborate nucleobases. The authors investigated various six-membered ring additions (benzene, pyridine, pyrimidine), finding that 2-halo-pyridyl boronic acids provided the best results, yielding products with high enantioselectivity. Subsequently, they explored five-membered O- and N-containing heterocyclic nucleophiles (furan, pyrrole), achieving high yields and enantioselectivities. The synthesis was scaled up to 5 mmol, demonstrating the scalability of the approach. The introduction of the 5'-hydroxymethyl group was achieved through a three-step hydroborylation-homologation-oxidation sequence, providing the desired cis stereochemistry. The final step involved acetonide deprotection to furnish the CC-Ns. The synthesis of more complex nucleobases was attempted through the use of complex boronic acids, but this proved challenging due to stability and reactivity issues. As an alternative approach, oxidative cleavage of a furan moiety was employed to create a carboxylic acid group allowing for late-stage construction of complex heterocycles, showcased in the synthesis of a benzoimidazole-derived CC-N. A carbocyclic analogue of Showdomycin was also synthesized to highlight the applicability of the approach to biologically active natural products.

The research successfully developed a catalytic asymmetric Suzuki-Miyaura-type coupling reaction for the synthesis of CC-Ns. High enantioselectivity (>90% ee) and good yields were achieved for a variety of heterocyclic boronic acids, including pyridines, furans, and pyrroles. The reaction was successfully scaled up to 5 mmol. A three-step hydroborylation-homologation-oxidation sequence allowed for the regio- and stereoselective introduction of the 5'-hydroxymethyl group. This method provided a series of CC-Ns bearing phenyl, pyridine, and furan moieties. Although attempts to directly incorporate complex heterocycles as boronic acids faced challenges due to stability issues, a late-stage modification strategy, using oxidative cleavage of a furan moiety followed by reaction with 1,2-diaminobenzene, was successfully employed to synthesize a more complex benzoimidazole-derived CC-N. This strategy was also applied to generate a carbocyclic analog of Showdomycin, demonstrating the synthetic utility of the approach towards biologically relevant compounds.

The reported methodology significantly advances the synthesis of CC-Ns, providing a more efficient and modular route compared to existing methods. The use of an asymmetric Suzuki-Miyaura coupling as the key step allows for high enantioselectivity and control over stereochemistry. The development of a three-step sequence for adding the 5'-hydroxymethyl group further enhances the utility of this approach. The successful synthesis of a Showdomycin analog showcases the potential to generate complex biologically active compounds. While the direct incorporation of highly complex boronic acids presents challenges, the alternative late-stage modification strategy proves effective in constructing more complex CC-Ns. This strategy offers flexibility and potential for broader application in creating a diverse range of CC-Ns.

This research presents novel and efficient strategies for synthesizing carbocyclic C-nucleosides. The key innovation is the use of an asymmetric Suzuki-Miyaura coupling, followed by a late-stage hydroxymethyl group addition. Two strategies were developed, one for simpler CC-Ns using readily available boronic acids, and a more complex approach involving late-stage modifications for more complex targets. The synthesis of a carbocyclic Showdomycin analogue demonstrates the potential of the methodology for producing biologically relevant molecules. Future research should focus on expanding the scope of late-stage modifications and exploring the biological activity of the synthesized CC-Ns.

The direct incorporation of complex heterocyclic boronic acids into the Suzuki-Miyaura coupling proved challenging due to stability issues. The hydroborylation-homologation-oxidation sequence, while effective for many substrates, was not universally compatible, leading to decomposition in some cases. While the late-stage modification approach was successful, it adds extra steps to the overall synthesis.