Stereodivergent access to α- and β-azanucleosides via catalyst-free, achiral modulator-controlled iodocyclization: a concise synthesis of forodesine

Abstract

Stereoselective glycosidic bond formation remains a major challenge in nucleoside synthesis. Azanucleosides, a prominent class of nucleoside analogs wherein the sugar oxygen is replaced by nitrogen, exhibit unique biological activities but struggle to achieve anomeric selectivity in synthesis. We disclose a catalyst-free iodocyclization strategy that uses simple achiral molecules—NaI or 2-mercaptobenzimidazole—to stereodivergently access both α- and β-azanucleosides in high yields (up to 98%) with excellent stereocontrol (β : α up to β only and α : β up to 19 : 1). The utility of this method is demonstrated by a concise synthesis of forodesine in 8 steps with 20% overall yield and >20 : 1 β : α selectivity—the shortest route and highest stereoselectivity reported to date. DFT studies reveal that hydrogen bonding/Na–O coordination and π–π stacking interactions govern the stereochemical outcomes. This work provides an efficient, scalable platform for accessing diverse azanucleoside therapeutics.

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Introduction

Nucleoside analogues (NAs) are an important source of antiviral, antitumor and antibacterial drugs.^1–5 Among them, azanucleosides constitute a prominent group of structurally modified nucleosides, featuring a nitrogen-containing ring. Interestingly, β-azanucleosides usually exhibit unique physical, chemical, and biological properties.^6–8 For example, forodesine (BCX-1777, immucillin H) and galidesivir (BCX-4430, immucillin A), two well-known β-azanucleosides, are potent inhibitors of human purine nucleoside phosphorylase, protozoan nucleoside hydrolases, and purine phosphoribosyl transferases (Fig. 1).^9–12 Forodesine has been approved in Japan for the treatment of relapsed or refractory peripheral T-cell lymphoma. Galidesivir demonstrates broad-spectrum antiviral activity by disrupting viral RNA-dependent RNA polymerase.^13–20 Additionally, several other bioactive molecules structurally similar to forodesine also exhibit significant antiviral activity.^21–23 On the other hand, α-nucleosides usually have remarkable biological activities, high enzyme stabilities, and inhibitory activities against tumors, bacteria, and plasmodia.²⁴ However, investigations of α-azanucleosides are merely at the initial stage, due to limited synthetic methods. Given the importance of both β- and α-azanucleosides, it is essential to develop a stereocontrolled synthetic strategy applicable to both configurations.

Fig. 1 Structures of representative azanucleoside drugs and bioactive molecules.

C-Glycosylation is the most widely used method for synthesizing C-nucleosides, including eletrophillic addition,²⁵ nucleophilic addition,^26–29 the Friedel–Crafts reaction,^30,31 metal cross coupling,^32–35 and radical-mediated reactions.^36–40 Current strategies for synthesizing β-azanucleosides, as exemplified by the synthesis of forodesine, primarily involve constructing the key glycosidic bond through coupling reactions (Fig. 2A).^41–47 To achieve milder reaction conditions, improved stereoselectivity and higher yields, various sugar donors have been developed, such as imines, nitrones, and azalactams. Among all reported synthetic routes to forodesine, the highest β : α selectivity is 8 : 1, with a maximum yield of 38%.⁴⁷ The synthesis of galidesivir follows a similar strategy, focusing mainly on introducing the amine group at the C4 position of the purine ring.⁴⁵ Nevertheless, existing intermolecular cross-coupling methods for β-azanucleosides face two major challenges: (1) the synthesis of azasugar donors is often complex, typically requiring at least five steps from furanose with low efficiency; (2) control over glycosidic bond stereoselectivity remains unsatisfactory and is highly dependent on auxiliary groups at the C2′ position of the glycosyl donor.

Fig. 2 (A) Current strategies to synthesize forodesine. (B) This work: catalyst-free, achiral modulator-controlled iodocyclization for stereoselective synthesis of α- and β-azanucleosides.

Catalytic asymmetric halocyclization of alkenes has proven to be a powerful strategy for accessing stereodefined heterocycles while installing halogen handles for further functionalization.^48–51 In our previous work, we established a chiral phosphoric acid-catalyzed intramolecular iodocyclization system for the synthesis of furanose nucleosides, in which achiral additives (NaI or S=PPh₃) were employed to modulate anomeric stereoselectivity.⁵² However, this system suffered from two critical limitations: it proved ineffective for synthesizing azanucleosides where the nucleophile is an NHR group, failing to deliver either α- or β-configured products with satisfactory stereocontrol (see SI Table S1); moreover, its reliance on a chiral phosphoric acid catalyst severely limited practicality and scalability. Indeed, industrial adoption of chiral phosphoric acid catalysts is often hampered by the high cost associated with the six-step synthesis from BINOL. The global environmental factor (E_G factor) highlights environmental drawbacks in synthetic systems by quantifying waste generation across the full lifecycle, including catalyst synthesis and reaction processes.^53,54 Reducing the use of expensive chiral catalysts represents a straightforward approach to minimize the E_G factor.

To address these challenges, we have developed a fundamentally distinct, catalyst-free iodocyclization strategy. Stereodivergent synthesis of azanucleosides is achieved in the absence of any chiral catalyst, using only simple achiral modulators: NaI for α-selectivity and 2-mercaptobenzimidazole for β-selectivity (Fig. 2B). This approach not only avoids the cost and environmental burden associated with chiral catalysts but also successfully addresses the long-standing challenge of stereoselective azanucleoside formation. The resulting C2-iodinated products serve as versatile intermediates for further functionalization, enabling efficient access to both α- and β-azanucleosides, including a concise synthesis of forodesine. We believe that this method provides a robust and scalable platform for diversifying azanucleosides, which remain underexplored in medicinal chemistry.

Results and discussion

Our synthesis commenced with the preparation of halocyclization substrate 5a (Scheme 1). Asymmetric α-alkylation of glycine Schiff base catalyzed by chiral phase-transfer catalysts (PTC) is a well-established method for accessing unnatural amino acids.^55–61 Quinuclidinium salts, derived from cinchonidine and cinchonine, are widely used to induce stereoselectivity.^62–65 To enhance the enantioselectivity, we chose glycine Schiff base 1 bearing a benzyl ester group instead of the conventional tert–butyl ester. The performance of cinchonidine-derived quinuclidinium salts (PTC-1 to 4) in the enantioselective allylation of 1 was evaluated (entries 1–4). The dimeric cinchonidine derivative linked by a benzophenone group (PTC-4) proved highly effective, affording product 2 with excellent enantioselectivity (entry 4, 92% yield, 95% ee). Lowering the reaction temperature improved both reactivity and enantioselectivity, giving 2 in 95% yield and 99% ee (entry 5). This condition performed well even on a 30 mmol scale (entry 6, 93% isolated yield, 99% ee). Acid deprotection afforded the free amine intermediate, which was subsequently protected with an Ns (nitrobenzenesulfonyl) group to yield compound 3 in 85% yield. A Heck reaction between aryl iodine 4 and alkene 3 in the presence of Pd[P(t-Bu)₃]₂ and Cs₂CO₃ furnished the C–C coupling product 5a, which served as the substrate for subsequent halocyclization.

Scheme 1 The synthesis of compound 5a. ^aReaction conditions: 1 (0.1 mmol), allyl bromide (0.12 mmol), PTC (0.0005 mmol), 50% aq. KOH (0.25 mL) in PhMe : CHCl₃ (v : v = 7 : 3, 0.75 mL), 0 °C, 8 h. ^bIsolated yield, ee values were determined by chiral HPLC.

In our previous work, NaI and S=PPh₃ were identified as key additives for controlling the stereoselectivity of catalytic halocyclization by directing the reaction along specific pathways.⁵² Therefore, we first investigated the effect of S=PPh₃ on stereochemical control (Table 1). Pleasingly, when S=PPh₃ was used as an achiral modulator with NIS as the halogen source, β-nucleoside 6a was obtained as the major product (entry 1; β : α = 5 : 1). In contrast, when NaI was used as the modulator, the configuration inverted, affording α-nucleoside 7a with a β : α ratio of 1 : 10 (entry 3). The absolute configuration of 7a was confirmed by single-crystal X-ray crystallography (CCDC No. 2378539). The configuration of 6a was then assigned by comparing its NMR NOE (Nuclear Overhauser Effect) data with those of 7a. In the absence of any modulator, no stereocontrol was observed (entry 2). These results suggested that the thiocarbonyl group might be crucial for β-selectivity. We then screened various thiocarbonyl-containing compounds as β-selective modulators (see SI Table S2). Among them, 2-mercaptobenzoheterocycles exhibited excellent reactivities and stereoselectivities (entries 4–6). Notably, 2-mercaptobenzimidazole 10 afforded product 6a in high yield (up to 95%) with excellent β-selectivity (β : α = 25 : 1; entry 6). To verify the necessity of the thiocarbonyl group, control experiments with compounds 11, 12, and 13 were conducted (entries 7–9). These compounds showed almost no stereocontrol. We further optimized the reaction conditions to improve α-selectivity (see SI Table S3). By fine-tuning the solvent, high α-selectivity was achieved (β : α = 1 : 19, entry 10). In the absence of NaI, the diastereomeric ratio was only β : α = 1 : 3 (entry 11). Loading studies revealed that both NaI and 10 could promote stereoselective iodocyclization catalytically. High α-selectivity was maintained (β : α = 1 : 19), while β-selectivity slightly decreased (β : α = 1 : 14) under reduced loading of 10 (see SI Table S4).

Table 1 Optimization of reaction conditions^a

Entry	Variation from labeled conditions	Yield^b (%)	β : α (6a : 7a)^c
a Reaction conditions: 5a (0.05 mmol), NIS (0.10 mmol), S=PPh3 (0.05 mmol) in MeCN (2.5 mL), 0 °C for 1 h.b Isolated yield.c β : α values were determined by HPLC.
1	None	92	5 : 1
2	No S=PPh3	95	1 : 1
3	NaI instead of S=PPh3	85	1 : 10
4	8 instead of S=PPh3	93	11 : 1
5	9 instead of S=PPh3	95	10 : 1
6	10 instead of S=PPh3	95	25 : 1
7	11 instead of S=PPh3	80	2 : 1
8	12 instead of S=PPh3	82	5 : 1
9	13 instead of S=PPh3	79	2 : 1
10	NaI instead of S=PPh3, THF instead of MeCN	93	1 : 19
11	No S=PPh3, THF instead of MeCN	90	1 : 3

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We systematically evaluated the substrate scope under both β- and α-selective conditions, using a series of halocyclization substrates 5a–u bearing varied R¹ groups and nucleobase structures (Fig. 3). Starting from model substrate 5a, the effect of different ester groups (R¹=CO₂Me, CO₂t-Bu) was examined. Both β-azanucleosides 6b–c and α-azanucleosides 7b–c were obtained in high yields (>90%) with excellent stereoselectivity (β : α up to 24 : 1 and α : β up to 17 : 1). To closely mimic the azanucleoside structure, a hydroxymethyl group protected with various groups (TBS, TBDPS, MOM, and Bn) was introduced at the C4′ position. Substrates 5d–g performed well, affording β-azanucleosides 6d–g in high yields (>80%) with good stereocontrol (β : α up to 18 : 1) and α-azanucleosides 7d–g in high yields (>87%) with moderate stereocontrol (α : β up to 10 : 1). In the screening of nucleobase structures, we systematically examined the influence of substituents in 5H-pyrrolo[3,2-d]pyrimidine derivatives. Both mono-substituted derivatives at the C4-position (such as OEt, OtBu, Cl, H, NHBn, NHi-Pr, Ph, and 4-OMe-Ph) and disubstituted derivatives at the C2 and C4 positions generally exhibited good to excellent stereoselectivity under the optimized conditions. β-Azanucleosides 6h–r were formed with high selectivity (β : α up to β only) and high yields (>86%), except for 6k and 6o (β : α = 3 : 1). Similarly, α-azanucleosides 7h–r were mostly obtained with high selectivity (α : β up to 10 : 1), except for 7l (α : β = 2.5 : 1). Evaluation of N5-protecting groups (such as MOM and Bn) showed that they could direct the formation of the corresponding β-azanucleosides 6s–t and α-azanucleosides 7s–t with excellent stereoselectivities. Finally, preliminary evaluation of the 7H-pyrrolo[2,3-d]pyrimidine scaffold confirmed the good compatibility of the reaction system.

Fig. 3 Substrate scope of α- and β-azanucleoside synthesis.

To demonstrate scalability, β-nucleoside analogue 6a and α-nucleoside analogue 7a were synthesized on a gram scale from 5a (Fig. 4). Both yields and stereoselectivities were maintained: β-nucleoside 6a was obtained in 93% yield with β : α > 20 : 1, and α-nucleoside 7a in 90% yield with α : β > 15 : 1.

Fig. 4 Gram-scale synthesis of β-azanucleoside 6a and α-azanucleoside 7a via catalyst-free, achiral modulator-controlled iodocyclizations.

Using this β-selective iodocyclization as the key step, we developed an efficient asymmetric synthesis of forodesine and a formal synthesis of galidesivir. As shown in Scheme 2, forodesine was synthesized in 20% overall yield over eight steps from commercially available glycine Schiff base 1. Starting from the β-selective iodocyclization product 6a, one-pot reductive debenzylation and halide elimination smoothly afforded compound 14 in 75% yield. Stereospecific syn-dihydroxylation of 14 with OsO₄, followed by deprotection, gave compound 15. Treatment of 15 with HCl in methanol then furnished forodesine. Following literature procedures,⁴⁵ functional group modifications of the base moiety in forodesine, followed by deprotection, provided the bioactive compound galidesivir. To the best of our knowledge, this work provides the shortest route to forodesine (8 steps vs. 10 in prior reports) and the highest β : α selectivity (>20 : 1 vs. 8 : 1).

Scheme 2 Concise synthesis of forodesine and galidesivir.

To demonstrate the versatility of our method and its potential for constructing compound libraries in medicinal chemistry, we performed diverse derivatizations on both β- and α-azanucleosides (Scheme 3). Specifically, β-nucleoside 6a underwent reductive elimination with NaBH₄/DBU, affording alkene 14 in 75% yield. Removal of the Ns group under 1-mercaptooctane/t-BuOK conditions gave 17 in 87% yield. Subsequent reflux of 17 in concentrated HCl/MeOH furnished 18 in 72% yield. Alternatively, hydrogenation of 17 followed by deprotection afforded the C2′ and C3′-unsubstituted azanucleoside 20 in 60% yield over two steps. For the α-azanucleoside series, treatment of 7a with DIBAL-H and subsequent Ns deprotection provided 21 in 72% yield. Radical-mediated deiodination of 21 yielded 22, while DBU-promoted elimination afforded alkene 23 in 74% yield. Treatment of 23 with concentrated HCl gave 24. Furthermore, 23 served as a key intermediate for the stereoselective synthesis of target compound 25. This was achieved via Boc protection of the C4′ hydroxymethyl group, dihydroxylation of the C2′–C3′ alkene (occurring exclusively from the β-face to give the corresponding diol), and final Boc deprotection.

Scheme 3 Derivatization of β-azanucleoside 6a and α-azanucleoside 7a.

To gain a thorough understanding of the reaction mechanism, especially on the effect of two achiral molecules, NaI and 2-mercaptobenzimidazole 10, density functional theory (DFT) studies were performed at the PBE0 level,⁶⁶ using alkene 5a as a model substrate (Fig. 5). The α-selective iodocyclization starts from Int1 (−4.6 kcal mol⁻¹). We used the interaction region indicator (IRI)^67,68 to analyze the interactions between atoms of Int1 (IRI pic. of Int1). Interestingly, NaI in Int1 is identified as a centered role, cooperating with Ns and ester carbonyl oxygen through Na–O interactions. And Ns can stabilize NIS through π…π stacking, allowing NIS to attack substrates from the top face. These interactions provide a favorable spatial environment for α-selectivity. The electrophilic addition of I⁻ to 5a and meanwhile H⁺ being transferred to the N atom result in Int2 with a reaction barrier of 22.5 kcal mol⁻¹. The following nucleophilic cyclization occurs to generate PS, which is exergonic by 25.1 kcal mol⁻¹. In the β-selective iodocyclization pathway, the IRI result of Int3 reveals that due to the hydrogen bonding interaction, the thiol 10 consistently occupies the region above the C=C bond throughout the reaction. Due to the steric effect, the I⁻ from NIS attacks the alkene from the bottom face only, resulting in β-selectivity. Finally, nucleophilic cyclization is found to be exergonic by 16.9 kcal mol⁻¹, and the reaction barrier is 32.5 kcal mol⁻¹ (Int3 to PR).

Fig. 5 Calculated free energy profile for the formation of nucleosides with α- and β-configurations from substrate 5a and other reactants.

Conclusion

In summary, we developed a catalyst-free iodocyclization strategy using two simple achiral molecules, NaI and 2-mercaptobenzimidazole 10, for the stereoselective synthesis of α- and β-azanucleosides in high yields and stereoselectivities. DFT studies reveal that NaI directs α-selectivity through hydrogen bonding and Na–O coordination, while 2-mercaptobenzimidazole 10 controls β-selectivity via π–π stacking interactions. The resulting C2′-iodinated azanucleoside products serve as key intermediates for further functionalization into diverse azanucleoside analogues. The utility of this method is demonstrated by a concise synthesis of forodesine (β : α > 20 : 1, 8 steps, 20% overall yield). To our knowledge, few existing methods achieve such stereocontrol using solely achiral molecules in the absence of chiral catalysts, particularly in nucleoside synthesis. This work not only expands fundamental chemical understanding but also provides access to underexplored azanucleosides for therapeutic development.

Author contributions

F. C. and H. W. conceived the idea and guided the project. H. W. wrote the manuscript with feedback from the other authors. Y. Z. made the initial observations and analyzed the results. Y. Z., M. L., K. Z., J. M., S. G. and P. T. explored substrate scope and performed derivatizations. J. Z. and Y. L. performed the density functional theory calculations on the reaction mechanism.

Conflicts of interest

A patent application (grant no. 202411109085.7, China) dealing with the synthesis of forodesine has been applied, and Huijing Wang and Fener Chen may benefit from royalty payments.

Data availability

CCDC 2378539 contains the supplementary crystallographic data for this paper.⁶⁹

Additional data supporting the findings described in this paper are available in the supplementary information (SI) and available from the corresponding author upon reasonable request. Supplementary information: detailed experimental procedures, compound characterization data (including NMR spectra and HPLC chromatograms), and additional computational results. Supplementary information is available. See DOI: https://doi.org/10.1039/d5sc08431h.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (Grant No. 22201192, U24A20482, and 22301228).

Notes and references

1. M. Guinan, C. Benckendorff, M. Smith and G. J. Miller, Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analogues, Molecules, 2020, 25, 2050.
2. G. Li, T. Yue, P. Zhang, W. Gu, L. J. Gao and L. Tan, Drug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthday, Molecules, 2021, 26, 923.
3. M. I. Elzagheid, Nucleosides and nucleoside analogues as emerging antiviral drugs, Mini-Rev. Org. Chem., 2021, 18, 672–679.
4. S. Man, Y. Lu, L. Yin, X. Cheng and L. Ma, Potential and promising anticancer drugs from adenosine and its analogs, Drug Discov. Today, 2021, 26, 1490–1500.
5. Q. Wang, K. Chen, Y. Wang, Z. Rao and X. Zhang, Biotechnological synthesis of nucleoside analogs: recent progress and perspectives, Green Synth. Catal., 2025 DOI:10.1016/j.gresc.2025.05.002.
6. P. Merino, T. Tejero and I. Delso, Current developments in the synthesis and biological activity of aza-C-nucleosides: immucillins and related compounds, Curr. Med. Chem., 2008, 15, 954–967.
7. G. B. Evans, P. C. Tyler and V. L. Schramm, Immucillins in infectious diseases, ACS Infect. Dis., 2018, 4, 107–117.
8. G. B. Evans, V. L. Schramm and P. C. Tyler, The immucillins: design, synthesis and application of transition- state analogues, Curr. Med. Chem., 2015, 22, 3897–3909.
9. R. W. Miles, P. C. Tyler, R. H. Furneaux, C. K. Bagdassarian and V. L. Schramm, One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase, Biochemistry, 1998, 37, 8615–8621.
10. G. A. Kicska, L. Long, H. Hörig, C. Fairchild, P. C. Tyler, R. H. Furneaux, V. L. Schramm, H. L. Kaufman and H. Immucillin, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes, Proc. Natl. Acad. Sci. U. S. A., 2001, 98, 4593–4598.
11. S. Bantia, P. J. Miller, C. D. Parker, S. L. Ananth, L. L. Horn, J. M. Kilpatrick, P. E. Morris, T. L. Hutchison, J. A. Montgomery and J. S. Sandhu, Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H) a novel potent and orally active immunosuppressive agent, Int. Immunopharmacol., 2001, 1, 1199–1210.
12. A. Korycka, J. Z. Błoński and T. Robak, Forodesine (BCX-1777, Immucillin H) – a new purine nucleoside analogue: mechanism of action and potential clinical application, Mini Rev. Med. Chem., 2007, 7, 976–983.
13. T. K. Warren, J. Wells, R. G. Panchal, K. S. Stuthman, N. L. Garza, S. A. V. Tongeren, L. Dong, C. J. Retterer, B. P. Eaton, G. Pegoraro, S. Honnold, S. Bantia, P. Kotian, X. Chen, B. R. Taubenheim, L. S. Welch, D. M. Minning, Y. S. Babu, W. P. Sheridan and S. Bavari, Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430, Nature, 2014, 508, 402–405.
14. J. G. Julander, S. Bantia, B. R. Taubenheim, D. M. Minning, P. Kotian, J. D. Morrey, D. F. Smee, W. P. Sheridan and Y. S. Babu, BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model, Antimicrob. Agents Chemother., 2014, 53, 6607–6614.
15. E. De Clercq, C-nucleosides to be revisited, J. Med. Chem., 2016, 59, 2301–2311.
16. R. Taylor, P. Kotian, T. Warren, R. Panchal, S. Bavari, J. Julander, S. Dobo, A. Rose, Y. El-Kattan, B. Taubenheim, Y. Babu and W. P. Sheridan, BCX4430 – a broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease, J. Infect. Public Health, 2016, 9, 220–226.
17. J. G. Julander, V. Siddharthan, J. Evans, R. Taylor, K. Tolbert, C. Apuli, J. Stewart, P. Collins, M. Gebre, S. Neilson, A. Van Wettere, Y. M. Lee, W. P. Sheridan, J. D. Morrey and Y. S. Babu, Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model, Antiviral Res., 2017, 137, 14–22.
18. J. B. Westover, A. Mathis, R. Taylor, L. Wandersee, K. W. Bailey, E. J. Sefing, B. T. Hickerson, K. H. Jung, W. P. Sheridan and B. B. Gowen, Antiviral Res., 2018, 156, 38–45.
19. J. G. Julander, J. F. Demarest, R. Taylor, B. B. Gowen, D. M. Walling, A. Mathis and Y. S. Babu, An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral, Antiviral Res., 2021, 195, 105180.
20. Y. Xie, L. Y. Chi, S. Q. Liu and W. Y. Zhu, BCX4430 inhibits the replication of rabies virus by suppressing mTOR-dependent autophagy in vitro, Virology, 2023, 585, 21–31.
21. K. J. Sparrow, R. Shrestha, J. M. Wood, K. Clinch, B. L. Hurst, H. Wang, B. B. Gowen, J. G. Julander, E. B. Tarbet, A. M. McSweeney, V. K. Ward, G. B. Evans and L. D. Harris, An Isomer of galidesivir that potently inhibits influenza viruses and members of the bunyavirales order, ACS Med. Chem. Lett., 2023, 14, 506–513.
22. Y. S. Babu, P. L. Kotian, S. Bantia, M. Wu, V. S. Kumar, Preparation of antiviral aza-sugar-containing nucleosides, WO 2014078778, 2014.
23. Y. S. Babu, P. L. Kotian, S. Bantia, M. Wu and V. S. Kumar, Antiviral azasugar-containing nucleosides, US Pat., US20150291596, 2015.
24. G. Ni, Y. Du, F. Tang, J. Liu, H. Zhao and Q. Chen, Review of α-nucleosides: from discovery, synthesis to properties and potential applications, RSC Adv., 2019, 9, 14302–14320.
25. J. Bouton, S. Van Calenbergh and J. Hullaert, Sydnone ribosides as a platform for the synthesis of pyrazole C-nucleosides: a unified synthesis of Formycin B and Pyrazofurin, Org. Lett., 2020, 22, 9287–9291.
26. Q. Li, E. Lescrinier, E. Groaz, L. Persoons, D. Daelemans, P. Herdewijn and S. De Jonghe, Synthesis and biological evaluation of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides with a ribose, 2’-deoxyribose, and 2’,3’-dideoxyribose sugar moiety, ChemMedChem, 2018, 13, 97–104.
27. T. Liu, Z. Zhu, H. Ren, Y. Chen, G. Chen, M. Cheng, D. Zhao, J. Shen, W. Zhu, B. Xiong and Y. L. Chen, Efficient syntheses of alpha- and beta-C-nucleosides and the origin of anomeric selectivity, Org. Chem. Front., 2018, 5, 1992–1999.
28. P. Nie, E. Groaz, D. Daelemans and P. Herdewijn, Xylo-C-Nucleosides with a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base: synthesis and antiproliferative properties, Bioorg. Med. Chem. Lett., 2019, 29, 1450–1453.
29. P. Nie, E. Groaz and P. Herdewijn, Synthesis of a threosyl-C-nucleoside phosphonate, Eur. J. Org Chem., 2019, 2019, 6666–6672.
30. H. Marzag, M. Zerhouni, H. Tachallait, L. Demange, G. Robert, K. Bougrin, P. Auberger and R. Benhida, Modular synthesis of new C-aryl-nucleosides and their anti-CML activity, Bioorg. Med. Chem. Lett., 2018, 28, 1931–1936.
31. H. Tachallait, M. Safir Filho, H. Marzag, K. Bougrin, L. Demange, A. R. Martin and R. Benhida, A Straightforward and versatile FeCl₃ catalyzed Friedel-Crafts C -glycosylation process. Application to the synthesis of new functionalized C -nucleosides, New J. Chem., 2019, 43, 5551–5558.
32. H. Gong and M. R. Gagné, Diastereoselective Ni-catalyzed Negishi cross-coupling approach to saturated, fully oxygenated C-alkyl and C-aryl glycosides, J. Am. Chem. Soc., 2008, 130, 12177–12183.
33. Q. Wang, S. An, Z. Deng, W. Zhu, Z. Huang, G. He and G. Chen, Palladium-catalysed C–H glycosylation for synthesis of C-aryl glycosides, Nat. Catal., 2019, 2, 793–800.
34. Y. Li, Z. Wang, L. Li, X. Tian, F. Shao and C. Li, Chemoselective and diastereoselective synthesis of C-Aryl nucleoside analogues by Nickel-catalyzed cross-coupling of furanosyl acetates with aryl iodides, Angew. Chem., Int. Ed., 2022, 61, e202110391.
35. R. Xie, J. Xu, H. Shi, C. Xiao, N. Wang, N. Huang and H. Yao, Stereocontrolled Synthesis of aryl C-nucleosides under ambient conditions, Org. Lett., 2024, 26, 5162–5166.
36. S. O. Badir, A. Dumoulin, J. K. Matsui and G. A. Molander, Synthesis of reversed C-acyl glycosides through Ni/photoredoxdual catalysis, Angew. Chem., Int. Ed., 2018, 57, 6610–6613.
37. A. Dumoulin, J. K. Matsui, Á. Gutiérrez-Bonet and G. A. Molander, Synthesis of non-classical arylated C-saccharides through Nickel/photoredox dual catalysis, Angew. Chem., Int. Ed., 2018, 57, 6614–6618.
38. Y. Ma, S. Liu, Y. Xi, H. Li, K. Yang, Z. Cheng, W. Wang and Y. Zhang, Highly stereoselective synthesis of aryl/heteroaryl-C-nucleosides via the merger of photoredox and Nickel catalysis, Chem. Commun., 2019, 55, 14657–14660.
39. Q. Wang, J. Duan, P. Tang, G. Chen and G. He, Synthesis of non-classical heteroaryl C-glycosides via Minisci-type alkylation of N-heteroarenes with 4-glycosyl-dihydropyridines, Sci. China Chem., 2020, 63, 1613–1618.
40. Y. Wei, B. Ben-zvi and T. Diao, Diastereoselective synthesis of aryl C-glycosides from glycosyl esters via C–O bond homolysis, Angew. Chem., Int. Ed., 2021, 6, 9433–9438.
41. G. B. Evans, R. H. Furneaux, G. J. Gainsford, V. L. Schramm and P. C. Tyler, Synthesis of transition state analogue inhibitors for purine nucleoside phosphorylase and N-riboside hydrolases, Tetrahedron Lett., 2000, 56, 3053–3062.
42. G. B. Evans, R. H. Furneaux, T. L. Hutchison, H. S. Kezar, P. E. Morris, V. L. Schramm and P. C. Tyler, Addition of lithiated 9-deazapurine derivatives to a carbohydrate cyclic imine: convergent synthesis of the aza- C -nucleoside immucillins, J. Org. Chem., 2001, 66, 5723–5730.
43. V. P. Kamath, J. Xue, J. J. Juarez-Brambila and P. E. Morris, Alternative route towards the convergent synthesis of a human purine nucleoside phosphorylase inhibitor – forodesine HCl, Tetrahedron Lett., 2009, 50, 5198–5200.
44. V. P. Kamath, J. Xue and J. J. Juarez-Brambila, Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor – Part II, Bioorg. Med. Chem. Lett., 2009, 19, 2627–2629.
45. M. Zhang, F. Xue, J. Ou, Y. Huang, F. Lu, B. Zhou, Z. Zheng, X. Y. Liu, W. Zhong and Y. Qin, Practical synthesis of immucillins BCX-1777 and BCX-4430, Org. Chem. Front., 2020, 7, 3675–3680.
46. J. Ou, M. Zhang, P. Li, F. Xue and Y. Qin, Synthesis of purine nucleoside phosphorylase inhibitor Forodesine, West China J. Pharm. Sci., 2021, 36, 495–500.
47. K. A. Krishnakumar and R. S. Lankalapalli, Synthesis of immucillins BCX-1777 and BCX-4430 from a common precursor, Eur. J. Org Chem., 2022, e202200428.
48. S. E. Denmark, W. E. Kuester and M. T. Burk, Catalytic, asymmetric halofunctionalization of alkenes-a critical perspective, Angew. Chem., Int. Ed., 2012, 51, 10938–10953.
49. R. Kristianslund, J. E. Tungen and T. V. Hansen, Catalytic enantioselective iodolactonization reactions, Org. Biomol. Chem., 2019, 17, 3079–3092.
50. S. Liu, B. Zhang, W. Xiao, Y. Li and J. Deng, Recent advances in catalytic asymmetric syntheses of functionalized heterocycles via halogenation/chalcogenation of carbon-carbon unsaturated bonds, Adv. Synth. Catal., 2022, 364, 3974–4005.
51. J. Yan, Z. Zhou, Q. He, G. Chen, H. Wei and W. Xie, The applications of catalytic asymmetric halocyclization in natural product synthesis, Org. Chem. Front., 2022, 9, 499–516.
52. Q. Wang, J. Mu, J. Zeng, L. Wan, Y. Zhong, Q. Li, Y. Li, H. Wang and F. Chen, Additive-controlled asymmetric iodocyclization enables enantioselective access to both α- and β-nucleosides, Nat. Commun., 2023, 14, 138.
53. R. A. Sheldon, The E factor 25 years on: the rise of green chemistry and sustainability, Green Chem., 2017, 19, 18–43.
54. A. Antenucci and S. Dughera, Usefulness of the global E factor as a tool to compare different catalytic strategies: four case studies, Catalysts, 2023, 13, 102.
55. K. Maruoka and T. Ooi, Enantioselective amino acid synthesis by chiral phase-transfer catalysis, Chem. Rev., 2003, 103, 3013–3028.
56. T. Ooi and K. Maruoka, Recent advances in asymmetric phase-transfer catalysis, Angew. Chem., Int. Ed., 2007, 46, 4222–4266.
57. S. Jew and H. Park, Cinchona-based phase-transfer catalysts for asymmetric synthesis, Chem. Commun., 2009, 46, 7090–7103.
58. S. Shirakawa and K. Maruoka, Recent developments in asymmetric phase-transfer reactions, Angew. Chem., Int. Ed., 2013, 52, 4312–4348.
59. H. J. Lee and K. Maruoka, Recent asymmetric phase-transfer catalysis with chiral binaphthyl-modified and related phase-transfer catalysts over the last 10 years, Chem. Rec., 2023, 23, e202200286.
60. H. J. Lee and K. Maruoka, Asymmetric phase-transfer catalysis, Nat. Rev. Chem., 2024, 8, 851–869.
61. P. Pecchini, M. Fochi, F. Bartoccini, G. Piersanti and L. Bernardi, Enantioselective organocatalytic strategies to access noncanonical α-amino acids, Chem. Sci., 2024, 15, 5832–5868.
62. E. J. Corey, F. Xu and M. C. Noe, Rational approach to catalytic enantioselective enolate alkylation using a structurally rigidified and defined chiral quaternary ammonium salt under phase transfer conditions, J. Am. Chem. Soc., 1997, 119, 12414–12415.
63. S. Woo, Y. G. Kim, B. Lim, J. Oh, Y. Lee, H. Gwon and K. Nahm, An unusual electronic effect of an aromatic-F in phase-transfer catalysts derived from cinchona-alkaloid, Org. Lett., 2002, 4, 4245–4248.
64. S. Woo, Y. G. Kim, B. Lim, J. Oh, Y. Lee, H. Gwon and K. Nahm, Dimeric cinchona ammonium salts with benzophenone linkers: enantioselective phase transfer catalysts for the synthesis of α-amino acids, RSC Adv., 2018, 8, 2157–2160.
65. J. Oh, J. Park and K. Nahm, Counter-rotatable dual cinchona quinuclidinium salts and their phase transfer catalysis in enantioselective alkylation of glycine imines, Chem. Commun., 2021, 57, 6816–6819.
66. J. P. Perdew, K. Burke and M. Ernzerhof, Generalized Gradient Approximation Made Simple, Phys. Rev. Lett., 1997, 78, 1396.
67. T. Lu and Q. Chen, Interaction region indicator: a simple real space function clearly revealing both chemical bonds and weak interactions, Chem.: Methods, 2021, 1, 231–239.
68. T. Lu and F. Chen, Multiwfn: a multifunctional wavefunction analyzer, J. Comput. Chem., 2012, 33, 580–585.
69. CCDC 2378539: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2kv22l.

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Footnote

† These authors contributed equally to this work.

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