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Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer Hydrogenation
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Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer Hydrogenation
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Organic Letters

Cite this: Org. Lett. 2025, 27, 3, 833–839
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https://doi.org/10.1021/acs.orglett.4c04501
Published January 13, 2025

Copyright © 2025 American Chemical Society. This publication is licensed under these Terms of Use.

Abstract

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We disclose a stereodivergent strategy to prepare vicinal difluorinated tetralins from γ-substituted tetralones via a combination of catalyst-controlled transfer hydrogenation and substrate-controlled fluorinations. This process is easily scalable and amenable to highly functionalized substrates, as demonstrated here in the late-stage synthesis of casdatifan, a clinical-stage inhibitor of hypoxia-inducible factor-2α. Analysis of the physicochemical properties of casdatifan, which features a cis-vicinal difluoride, revealed a higher level of facial polarization compared to its trans-vicinal difluoride isomers.

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Copyright © 2025 American Chemical Society

Note Added after ASAP Publication

Compound 9 was changed to 10 in the seventh paragraph line 4, Table 1 entry 1 dr column, and the first compound in Scheme 3 on January 14, 2025.

Carbocyclic structures with stereodefined fluorination patterns have been employed to tune the physicochemical and pharmacokinetic properties of a molecule without causing significant alteration to its steric signature. (1) Since fluorine is highly electronegative, it can significantly perturb a system’s electronic properties and often lead to an overall polarity reversal. Indeed, fluorine atoms are weak hydrogen bond acceptors and thus organofluorines are poorly solvated in water, possessing “polar hydrophobic” properties. (2) In constrained systems, vicinal difluorides are particularly remarkable, especially when the fluorine atoms are in a cis-relationship as this confers a large increase in polarity due to facial polarization. (3) This phenomenon is particularly evident with cis-hexafluorocyclohexane, which is exceptionally polarized and exhibit remarkable physicochemical properties (e.g., kinetic solubility, lipophilicity and permeability) and metabolic stabilities. (4)

In the context of life-saving medicines, this strategy has been implemented in the drug discovery efforts leading to a class of highly potent HIF-2α inhibitors (Figure 1A), including a series based on a [5,5]-cycloalkylpyrazole core, (i.e., compound 1) (5) and casdatifan (2). (6) The latter is currently in clinical development for treating adult patients with Von Hippel–Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) (8) and other advanced solid tumors, and was well-tolerated with an excellent PK profile in healthy volunteer studies. (7)

Figure 1

Figure 1. A. Cis-vicinal difluoride in drug discovery. B. Impact of difluorides on polarity in tetralins.

In constrained systems, cis-vicinal difluoride incorporation increases the molecule’s dipole moment due to increased alignment of the C(sp3)–F bonds’ polarity vectors (φ FCCF = 60°) compared to geminalFCCF = 108°) and trans-vicinalFCCF = 180°) difluorides (Figure 1B). (9) Along with the modulation of physicochemical and pharmacological properties, carbocycle fluorination leads to conformational preferences as a consequence of stabilizing hyperconjugative interactions (σC–H → σC–F* and π → σC–F*). (10) Fluorine also often improves metabolic stability, especially when incorporated at benzylic positions. (11)

Synthetically, the vicinal difluoride motif has often been prepared via the deoxyfluorination of chiral diols and derivatives obtained from asymmetric epoxidation or dihydroxylation. Strategies employing the catalytic stereoselective vicinal difluorination of alkenes using aryl iodide organocatalysts (12) and the asymmetric hydrogenation of vicinal difluoroalkenes have also been developed. (13) Alternatively, ruthenium-catalyzed asymmetric transfer hydrogenations (ATH) of prochiral α-halogenated cyclic ketones represents a straightforward pathway to chiral halohydrins via dynamic kinetic resolution (DKR). (14) Interestingly, in all cases starting from α-halogenated five- and six-membered ring ketones, (15) including tetralones, (16) chromanones, (17) tetrahydroquinolones, (18) and indanones, (19) cis-diastereoisomers are formed preferentially via a transition state wherein the catalyst approaches the ketone from the opposite face of the halogen atom. In the context of cis-fluorohydrins, subsequent deoxyfluorination affords the trans-vicinal difluoride motif (Figure 2A). (20)

Figure 2

Figure 2. A. Preparation of trans-vicinal difluoride via ATH/DKR. B. Preparation of cis-vicinal difluoride via stereocontrolled fluorination and ATH.

Considering the unique properties of the cis-vicinal difluoride motif and our interest in developing a stereocontrolled synthesis of casdatifan and analogs, we sought to develop a strategy to access trans-fluorohydrins which could then be directly converted to cis-vicinal difluorides in a single stereoselective fluorination step (Figure 2B). In contrast to the ATH of racemic α-fluoro cyclic ketones under DKR conditions, we envisioned a stereoselective fluorination of a γ-substituted tetralone followed by a ruthenium-catalyzed asymmetric transfer hydrogenation under mild, nonepimerizing conditions. Herein, we report the stereodivergent synthesis of the cis-vicinal difluoride motif of casdatifan (2) and the other two trans-vicinal difluoride stereoisomers from a common stereodefined α-fluoro-γ-substituted tetralone intermediate 7 (Scheme 1).

Scheme 1

Scheme 1. Stereoselective Synthesis of α-(S)-Fluoro-Tetralone 7a

aThermal ellipsoids are shown at 30% probability. R = MOM.

Our study began with advanced intermediate 3, previously prepared via a Pd-catalyzed Suzuki cross-coupling to forge the C5–C6 bond (Scheme 1). (21) Substrate-controlled hydrogenation directed by the C14–OTBS group delivered 4 as a single detectable diastereoisomer (dr >20:1, 80% yield). Subsequent deprotection and oxidation afforded tetralone 5. Since direct α-fluorination conditions under strong acidic (SelectFluor, H2SO4, MeOH) or basic conditions (LiHMDS, NFSI, THF) were not compatible with the level of functionalization of 5 or our protecting group strategy, we opted for a milder two-step procedure involving the formation of a TBS enol ether─which was stable to chromatography─and subsequent treatment with SelectFluor at 40 °C in MeCN. Under these conditions, α-fluoro-ketone 7 was obtained as a single diastereoisomer (dr >20:1) in 84% yield, of which the absolute configuration was unambiguously assigned based on an X-ray single crystal structure. This stereoinduction could be rationalized by the steric hindrance from the indanol group shielding one face and forcing the reagent to approach the enol ether from the opposite face.

With α-(S)-fluoro-tetralone 7 in hand, the ATH reaction was evaluated. Initial attempts to reduce 7 using NaBH4 showed a noticeable substrate-controlled preference for trans-(1S,2S)-8 over cis-(1R,2S)-10 (dr = 2:1) with the hydride preferentially approaching the tetralone from the opposite side of the large γ-substituent (Table 1, entry 1). The reduction of 7 was then carried out at 4 °C in CH2Cl2 in the presence of RuCl(p-cymene)[(R,R)-Ts-DPEN] and a HCO2H/Et3N (3:2) mixture as the hydrogen source (entry 2). Under these conditions, trans-(1S,2S)-8 was obtained in high diastereoselectivity (dr = 95:5) in 84% yield, suggesting the ATH proceeds with retention of configuration at the α-C(sp3)–F position in a catalyst/substrate matched fashion. From a stereodivergent standpoint and for exploring structure–activity relationships (SAR) of this scaffold, we were also interested in obtaining the other diastereoisomers from the same common intermediate 7. To this end, reduction was carried out at 23 °C in the presence of DBU as a stronger base to induce racemization at the α-C(sp3)–F position. Indeed, using the HCO2H/DBU (6:4) system, a complete mixture of trans-(1S,2S)-8 and cis-(1S,2R)-9 isomers was obtained (entry 3). On the other hand, when the equivalents of DBU were increased (entry 4) and the solvent was changed to MeCN (entry 5), cis-(1S,2R)-9 was obtained almost exclusively (dr = 99:1, 83% yield), suggesting efficient dynamic kinetic resolution under a scenario with the best catalyst/substrate match.

Table 1. Stereodivergent Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation
EntryCatalystaConditionsbYield (%)cdr (Isomer)d
1NoneNaBH4, THF, MeOH, 0 °C8065(8)/35(10)
2(R,R)Et3N/HCO2H (2/3), CH2Cl2, 4 °C8495(8)/5(9)
3(R,R)DBU/HCO2H (4/6), CH2Cl2, 23 °C4152(8)/48(9)
4(R,R)DBU/HCO2H (8/6), CH2Cl2, 4 °C758(8)/92(9)
5(R,R)DBU/HCO2H (8/6), MeCN, 4 °C831(8)/99(9)
6(R,R)DBU/HCO2H (8/6), MeCN, 40 °C603(8)/97(9)
7(S,S)Et3N/HCO2H (2/3), CH2Cl2, 4 °C7313(8)/87(10)
8(S,S)Et3N/HCO2H (4/6), MeCN, 4 °C788(8)/92(10)
a

Catalysts used were RuCl(p-cymene)[(R,R)-Ts-DPEN] and RuCl(p-cymene)[(S,S)-Ts-DPEN] at 1.5 mol % loading.

b

Unless otherwise stated, reactions were performed on 0.15 mmol scale and run for 16 h.

c

Isolated yield of the major diastereoisomer.

d

Ratio between the major and one of the minor diastereoisomers was determined using a combination of analytical HPLC and 19F NMR spectroscopy of the crude reaction mixture. R = MOM.

Complementary to the above results, reduction in the presence of RuCl(p-cymene)[(S,S)-Ts-DPEN] and a HCO2H/Et3N (3:2) mixture afforded cis-(1R,2S)-10 preferentially over trans-(1S,2S)-8, albeit with reduced diastereoselectivity (dr = 87:13), a consequence of a catalyst/substrate mismatch (entry 7). Gratifyingly, running the reduction in MeCN instead of CH2Cl2 (entry 8) improved the diastereoselectivity (dr = 92:8). (22) The synthesis of the remaining diastereoisomer, trans-(1R,2R)-11, from 7 was not investigated due to high catalyst/substrate mismatch arising from the undesirable configurations of both α-C(sp3)–F and γ-substituents.

Stereoselectivity of the ATH with RuII6-p-cymene complexes arises from of the multiple stabilizing C–H−π attractions between the C(sp2)–H or benzylic C(sp3)–H in the p-cymene ring and the aromatic carbons on the tetralone (Scheme 2). (23) In addition to edge-to-face interactions, a hydrogen bonding interaction from the N–H bond of the catalyst to the C═O bond of the substrate stabilizes the transition state and assists the hydridic Ru–H and protic N–H transfer to the tetralone. In the catalyst/substrate matched case, the (R,R)-RuII6-p-cymene complex approaches the tetralone on the opposite side of the large γ-substituent and on the same side of the small α-fluoro substituent leading to a high level of diastereoselectivity for the trans-fluorohydrin 8. The opposite occurs in the catalyst/substrate mismatched case, where the (S,S)-RuII6-p-cymene complex approaches the tetralone on the same side of the large γ-substituent (a destabilizing interaction) and on the opposite side of the small α-fluoro substituent, leading to a lower level of diastereoselectivity for the cis-fluorohydrin 10.

Scheme 2

Scheme 2. Proposed Model for Asymmetric Induction

Installation of the benzylic C(sp3)–F bond via deoxyfluorination in the presence of a nucleophilic fluorinating reagent was then explored (Scheme 3). Interestingly, when the reaction was run in the presence of (diethylamino)sulfur trifluoride (DAST) at −40 °C with warming to 23 °C, both cis-diastereoisomers, cis-(1S,2R)-9 and cis-(1R,2S)-10, afforded the trans-vicinal difluorides in excellent stereoselectivities (dr >20:1). One the other hand, trans-(1S,2S)-8 generated the desired cis-vicinal difluoride as a 12:1 diastereomeric ratio. As this result implied competition between a stereospecific SN2 benzylic deoxyfluorination and a dissociative SN1 process, addition of N-(trimethylsilyl)morpholine in combination with Deoxo-Fluor instead of DAST was investigated. (24) Under these conditions, the diastereoselective deoxyfluorination of 8 was substantially improved (85% yield, dr >20:1). Final deprotection of the MOM group under acidic conditions afforded the three vicinal difluorinated stereoisomers 12, 13, and casdatifan (2).

Scheme 3

Scheme 3. Synthesis of Vicinal Difluorides

To assess the impact on polarity of the cis-vicinal difluoro motif of casdatifan (2) compared to its trans-vicinal siblings, chromatographic retention times (tR) were directly compared on a reversed-phase HPLC (MeCN in water). (25) While the two trans-vicinal stereoisomers showed very similar retention times (tR = 31.76 for 12 and 31.80 min for 13), the cis-vicinal stereoisomer eluted noticeably earlier (tR = 31.27 min for 2), which suggests reduced lipophilicity in line with our working hypothesis. Considering the level of functionalization of casdatifan, the impact the cis-vicinal difluoro motif alone has on polarity is quite remarkable and highlights the importance of stereocontrolled methods for the synthesis of vicinal difluorinated motifs as a unique tool to modulate the physicochemical profiles of drug candidates.

To validate the robustness of the stereoselective four-step process, the sequence was performed on multigram scale (Scheme 4). A single batch of >200 g of tetralone 5 was submitted to enolization to give intermediate 6 in 90% yield after column chromatography. Fluorination of this material provided α-(S)-fluoro-tetralone 7 (98% yield, dr >20:1). Without chromatography, a 50 g batch of 7 was subjected to transfer hydrogenation to provide trans-fluorohydrin 8 (85% yield, dr >20:1). Finally, deoxyfluorination and deprotection of a 20 g batch of 8 afforded >15 g of casdatifan (2, 83% yield over 2 steps, dr >20:1).

Scheme 4

Scheme 4. Scaleup and Single-Crystal X-ray Structuresa

aThermal ellipsoids are shown at 30% probability. R = MOM.

Single crystal X-ray diffraction analysis of casdatifan (2) and its intermediate (8) unambiguously confirmed the configuration of the newly created stereocenters. A pertinent feature of the solid-state structure of casdatifan is the relative pseudo-axial orientations of the C10–C12 and C7–F bonds in the half-chair. In this conformation, the C11–C10–C12 and C6–C7–F angles of 114° and 108° satisfy the stereoelectronic requirements for antiperiplanarity while minimizing 1,3-allylic strain with the proximal C2–CN and C5–H bonds. The relationship of the pseudo-axial benzylic C7–F bond to neighboring donor orbitals potentially suggests the presence of stabilizing hyperconjugative interactions, while its relationship to the pseudo-equatorial C8–F suggests a particularly favorable alignment of polarity vectors (φ FCCF = 54.9°).

To further highlight the utility and scope of this process, the advanced compound 19 was prepared on gram-scale (Scheme 5). Such an intermediate is particularly useful for SAR exploration in a drug discovery campaign since it is amenable to late-stage derivatization and cross-coupling at the C(sp2)–Cl bond. To this end, substrate-controlled hydrogenation of alkene 14, which features several sensitive functional groups, was achieved in the presence of Et3N in MeOH/EtOAc to yield the reduced product 15 as a single diastereomer. After deprotection, oxidation and preparation of the TBS enol ether, treatment with SelectFluor delivered α-fluoro-ketone 17 (dr > 20:1). Subsequent transfer hydrogenation generated 18 in 89% yield in high diastereoselectivity (dr = 93:7); final fluorination using the combination of N-(trimethylsilyl)morpholine and Deoxo-Fluor then delivered 19 (dr >20:1).

Scheme 5

Scheme 5. Preparation of Intermediate 19 for Derivatization

The incorporation of “polar hydrophobic” vicinal difluorides in our novel series of HIF-2α inhibitors proved to be a powerful tool for modulating the compounds’ physicochemical and pharmacological properties. To enable this tactic, a stereodivergent platform was developed to access cis- and trans-vicinal difluorinated tetralins via asymmetric catalyst-controlled transfer hydrogenation and highly stereoselective substrate-controlled electrophilic and nucleophilic fluorinations. Among the three vicinal difluorinated tetralin isomers prepared, the cis-vicinal stereoisomer exhibited higher polarity than the two trans-vicinal stereoisomers. Ultimately, this stereodivergent strategy contributed to the discovery and development of casdatifan, a highly potent HIF-2α inhibitor, currently under evaluation in patients with ccRCC and other advanced solid tumors.

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c04501.

  • Experimental procedures and characterizations, 1H, 13C and 19F NMR spectra for all compounds, HPLC traces, and crystallographic data (PDF)

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Deposition Numbers 24014792401481 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

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Author Information

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  • Corresponding Author
  • Authors
    • Artur K. Mailyan - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United States
    • Jeremy Fournier - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesOrcidhttps://orcid.org/0000-0003-3162-3588
    • Joel W. Beatty - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United States
    • Manmohan R. Leleti - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United States
    • Jay P. Powers - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United States
    • Kenneth V. Lawson - Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesOrcidhttps://orcid.org/0000-0001-5094-6337
  • Author Contributions

    All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We acknowledge Jake B. Bailey (University California San Diego) for carrying out X-ray diffraction measurements and analysis and Tiffany Huang (Arcus Biosciences) for recording HR-MS data.

References

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    Structural confirmation of cis-diastereomers 10 was established after Mitsunobu reaction with 4-nitro benzoic acid and subsequent saponification to generate trans-diastereoisomer 8.

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  1. Clayton Hardman, Artur K. Mailyan, Guillaume Mata, Joel W. Beatty, Samuel L. Drew, Jeremy Fournier, Jaroslaw Kalisiak, Brandon R. Rosen, Matthew Epplin, Balint Gal, Kai Yu, Zhang Wang, Karl Haelsig, Anh Tran, Manmohan R. Leleti, Jay P. Powers, Kenneth V. Lawson. Development of a Scalable Synthesis of Casdatifan (AB521), a Potent, Selective, Clinical-Stage Inhibitor of HIF-2α. Organic Process Research & Development 2025, Article ASAP.

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  • Abstract

    Figure 1

    Figure 1. A. Cis-vicinal difluoride in drug discovery. B. Impact of difluorides on polarity in tetralins.

    Figure 2

    Figure 2. A. Preparation of trans-vicinal difluoride via ATH/DKR. B. Preparation of cis-vicinal difluoride via stereocontrolled fluorination and ATH.

    Scheme 1

    Scheme 1. Stereoselective Synthesis of α-(S)-Fluoro-Tetralone 7a

    aThermal ellipsoids are shown at 30% probability. R = MOM.

    Scheme 2

    Scheme 2. Proposed Model for Asymmetric Induction

    Scheme 3

    Scheme 3. Synthesis of Vicinal Difluorides

    Scheme 4

    Scheme 4. Scaleup and Single-Crystal X-ray Structuresa

    aThermal ellipsoids are shown at 30% probability. R = MOM.

    Scheme 5

    Scheme 5. Preparation of Intermediate 19 for Derivatization
  • References


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  • Supporting Information

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