Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer HydrogenationClick to copy article linkArticle link copied!
- Guillaume Mata*Guillaume Mata*Email: [email protected]Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Guillaume Mata
- Artur K. MailyanArtur K. MailyanArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Artur K. Mailyan
- Jeremy FournierJeremy FournierArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Jeremy Fournier
- Joel W. BeattyJoel W. BeattyArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Joel W. Beatty
- Manmohan R. LeletiManmohan R. LeletiArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Manmohan R. Leleti
- Jay P. PowersJay P. PowersArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Jay P. Powers
- Kenneth V. LawsonKenneth V. LawsonArcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United StatesMore by Kenneth V. Lawson
Abstract
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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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 geminal (φ FCCF = 108°) and trans-vicinal (φ FCCF = 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
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.

Entry | Catalysta | Conditionsb | Yield (%)c | dr (Isomer)d |
---|---|---|---|---|
1 | None | NaBH4, THF, MeOH, 0 °C | 80 | 65(8)/35(10) |
2 | (R,R) | Et3N/HCO2H (2/3), CH2Cl2, 4 °C | 84 | 95(8)/5(9) |
3 | (R,R) | DBU/HCO2H (4/6), CH2Cl2, 23 °C | 41 | 52(8)/48(9) |
4 | (R,R) | DBU/HCO2H (8/6), CH2Cl2, 4 °C | 75 | 8(8)/92(9) |
5 | (R,R) | DBU/HCO2H (8/6), MeCN, 4 °C | 83 | 1(8)/99(9) |
6 | (R,R) | DBU/HCO2H (8/6), MeCN, 40 °C | 60 | 3(8)/97(9) |
7 | (S,S) | Et3N/HCO2H (2/3), CH2Cl2, 4 °C | 73 | 13(8)/87(10) |
8 | (S,S) | Et3N/HCO2H (4/6), MeCN, 4 °C | 78 | 8(8)/92(10) |
Catalysts used were RuCl(p-cymene)[(R,R)-Ts-DPEN] and RuCl(p-cymene)[(S,S)-Ts-DPEN] at 1.5 mol % loading.
Unless otherwise stated, reactions were performed on 0.15 mmol scale and run for 16 h.
Isolated yield of the major diastereoisomer.
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 RuII-η6-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)-RuII-η6-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)-RuII-η6-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
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
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
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
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
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information
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)
Deposition Numbers 2401479–2401481 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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Acknowledgments
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.
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However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.
- 2(a) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. The Polar Hydrophobicity of Fluorinated Compounds. ChemBioChem. 2004, 5, 622– 627, DOI: 10.1002/cbic.200300910Google Scholar2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtLs%253D&md5=bfe354a8ca8e095c2cdd6b79e964fc7cThe polar hydrophobicity of fluorinated compoundsBiffinger, Justin C.; Kim, Hong Woo; DiMagno, Stephen G.ChemBioChem (2004), 5 (5), 622-627CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review.(b) O’Hagan, D. Understanding Organofluorine Chemistry. An Introduction to the C–F Bond. Chem. Soc. Rev. 2008, 37, 308– 319, DOI: 10.1039/B711844AGoogle Scholar2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtVGnsw%253D%253D&md5=7d4111d3b05c22c8e6df282cf051fccbUnderstanding organofluorine chemistry. An introduction to the C-F bondO'Hagan, DavidChemical Society Reviews (2008), 37 (2), 308-319CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Fluorine is the most electroneg. element in the periodic table. When bound to carbon it forms the strongest bonds in org. chem. and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of specialty materials. Although highly polarized, the C-F bond gains stability from the resultant electrostatic attraction between the polarized Cδ+ and Fδ- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C-F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighboring bonds or lone pairs. In this tutorial review these fundamental aspects of the C-F bond are explored to rationalize the geometry, conformation and reactivity of individual organofluorine compds.
- 3(a) O’Hagan, D. Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene Motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044qGoogle Scholar3ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wltbg%253D&md5=fdc040b0921c21fe3c539031e2f6c624Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene MotifsO'Hagan, DavidJournal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.(b) Wu, D.; Tian, A.; Sun, H. Conformational Properties of 1,3-Difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164wGoogle Scholar3bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFKnt7Y%253D&md5=f44c4fc0316ebf223dc223162a793c04Conformational properties of 1,3-difluoropropaneWu, D.; Tian, A.; Sun, H.Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.(c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes. Angew. Chem. Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956Google Scholar3chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.(d) O’Hagan, D. Polar Organofluorine Substituents: Multivicinal Fluorines on Alkyl Chains and Alicyclic Rings. Chem.-Eur. J. 2020, 26, 7981– 7997, DOI: 10.1002/chem.202000178Google ScholarThere is no corresponding record for this reference.(e) Mondal, R.; Agbaria, M.; Nairoukh, Z. Fluorinated Rings: Conformation and Application. Chem.-Eur. J. 2021, 27 (25), 7193– 7213, DOI: 10.1002/chem.202005425Google ScholarThere is no corresponding record for this reference.
- 4(a) Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O'Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane is a Facially Polarized Cyclohexane. Nat. Chem. 2015, 7, 483– 488, DOI: 10.1038/nchem.2232Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtleisr8%253D&md5=811e1998f3076508664eebee80d4ecacAll-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexaneKeddie, Neil S.; Slawin, Alexandra M. Z.; Lebl, Tomas; Philp, Douglas; O'Hagan, DavidNature Chemistry (2015), 7 (6), 483-488CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are 'up', is prepd. in a 12-step protocol. The mol. adopts a classic chair conformation with alternate C-F bonds aligned triaxially, clustering three highly electroneg. fluorine atoms in close proximity. This generates a cyclohexane with a high mol. dipole (μ = 6.2 D), unusual in an otherwise aliph. compd. X-ray anal. indicates that the intramol. Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the mols. pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in org. chem. Derivs. have potential as new motifs for the design of functional org. mols. or for applications in supramol. chem. design.(b) Wang, Y.; Lee, W.; Chen, Y.-C.; Zhou, Y.; Plise, E.; Migliozzi, M.; Crawford, J. J. Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on Physicochemical and Metabolic Properties. ACS Med. Chem. Letters 2022, 13, 1517– 1523, DOI: 10.1021/acsmedchemlett.2c00312Google Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitFSmsr3L&md5=6a1b2e06bf5492e5ca8a9843a4205441Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on Physicochemical and Metabolic PropertiesWang, Yong; Lee, Wendy; Chen, Yi-Chen; Zhou, Yuhui; Plise, Emile; Migliozzi, Madyson; Crawford, James J.ACS Medicinal Chemistry Letters (2022), 13 (9), 1517-1523CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The targeted introduction of substituents in order to tailor a mol.'s pharmacol., physicochem., and metabolic properties has long been of interest to medicinal chemists. The all-cis tetrafluorocyclohexyl motif-dubbed Janus face, due to its electrostatically polarized cyclohexyl ring-represents one such example where chemists might incorporate a metabolically stable, polar, lipocompatible motif. To better understand its potential utility, we have synthesized three series of matched mol. pairs (MMPs) where each MMP differs only in the cyclohexane unit, i.e., with a tetrafluorocyclohexyl or a std. cyclohexyl motif. With the introduction of the facially polarized all-cis tetrafluorocyclohexyl ring, the resulting compds. have significantly modified physicochem. properties (e.g., kinetic soly., lipophilicity and permeability) and metabolic stabilities. These results further speak to the promise of this substituent as a tactic to improve the drug-like properties of mols.
- 5Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal, B.; Hardman, C.; Mailyan, A. K.; Lawson, K. V.; Leleti, M. R.; Liu, D.; Mata, G.; Podunavac, M.; Powers, J. P.; Rosen, B. R.; Yu, K. Arcus Biosciences, Inc., assignee. Inhibitors of HIF-2α and methods of use thereof. United States Patent No. US12071411B2, 2024.Google ScholarThere is no corresponding record for this reference.
- 6Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal, B.; Guney, T.; Haelsig, K. T.; Hardman, C.; Jacob, S. D.; Jeffrey, J. L.; Kalisiak, J.; Lawson, K. V.; Leleti, M. R.; Lindsey, E. A.; Mailyan, A. K.; Mandal, D.; Mata, G.; Moon, H.; Powers, J. P.; Rosen, B. R.; Su, Y.; Tran, A. T.; Wang, Z.; Yan, X.; Yu, K. Tetralin and Tetrahydroquinoline Compounds as Inhibitors of HIF-2α, WO-2021188769-A1, 2021Arcus Biosciences, Inc., assignee..Google ScholarThere is no corresponding record for this reference.
- 7(a) Lawson, K. V.; Sivick Gauthier, K. E.; Mailyan, A. K.; Fournier, J. T.; Beatty, J. W.; Drew, S. L.; Kalisiak, J.; Gal, B.; Mata, G.; Wang, Z. Abstract 1206: Discovery and characterization of AB521, a novel, potent, and selective hypoxia-inducible factor (HIF)-2α inhibitor. Cancer Res. 2021, 81, 1206, DOI: 10.1158/1538-7445.AM2021-1206Google ScholarThere is no corresponding record for this reference.(b) Lawson, K. V.; Sivick Gauthier, K. E.; Piovesan, D.; Mailyan, A.; Mata, G.; Fournier, J. T.; Yu, K.; Liu, S.; Soriano, F.; Jin, L. 46P AB521, a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor, for the treatment of renal cell carcinoma. Ann. Oncol. 2022, 33, S21, DOI: 10.1016/j.annonc.2022.01.055Google ScholarThere is no corresponding record for this reference.(c) Liao, K.; Foster, P.; Seitz, L.; Cheng, T.; Gauthier, K.; Lawson, K.; Jin, L.; Paterson, E. HIF-2α inhibitor AB521 modulates erythropoietin levels in healthy volunteers following a single oral dose. Eur. J. Cancer. 2022, 174, S20, DOI: 10.1016/S0959-8049(22)00856-5Google ScholarThere is no corresponding record for this reference.
- 8(a) Atkins, M. B.; Tannir, N. M. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat. Rev. 2018, 70, 127– 137, DOI: 10.1016/j.ctrv.2018.07.009Google Scholar8ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVWrt7bI&md5=d181337092e8b4b707c0644f76f99886Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinomaAtkins, Michael B.; Tannir, Nizar M.Cancer Treatment Reviews (2018), 70 (), 127-137CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)A review. There has been significant progress in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC), with improved knowledge of disease biol. and the introduction of targeted agents and immunotherapies. In this review, we discuss current and emerging first-line treatment options, including recent approvals of the tyrosine kinase inhibitor (TKI) cabozantinib and the immunotherapy combination of nivolumab (anti-programmed cell death 1 [PD-1])/ipilimumab (anti-cytotoxic T-lymphocyte-assocd. antigen 4 [CTLA-4]), and initial outcomes with the combination of atezolizumab (anti-PD-ligand 1 [PD-L1])/bevacizumab (anti-vascular endothelial growth factor [VEGF]). Key clin. data are reviewed, as these novel first-line treatments offer significant improvement, particularly for patients classified as intermediate/poor risk for whom previously available therapies have demonstrated limited efficacy. Treatment recommendations based on clin. evidence and expert opinion are discussed. We also review ongoing studies investigating combinations of checkpoint inhibitors with TKIs, including cabozantinib and axitinib, and with other novel immunomodulatory agents, and the potential role of single-agent immunotherapy for select patients. With a growing treatment armamentarium, identification and validation of biomarkers will be crucial for optimizing first-line selection and treatment sequences.(b) Nickerson, M. L.; Jaeger, E.; Shi, Y.; Durocher, J. A.; Mahurkar, S.; Zaridze, D.; Matveev, V.; Janout, V.; Kollarova, H.; Bencko, V.; Navratilova, M.; Szeszenia-Dabrowska, N.; Mates, D.; Mukeria, A.; Holcatova, I.; Schmidt, L. S.; Toro, J. R.; Karami, S.; Hung, R.; Gerard, G. F.; Linehan, W. M.; Merino, M.; Zbar, B.; Boffetta, P.; Brennan, P.; Rothman, N.; Chow, W.-H.; Waldman, F. M.; Moore, L. E. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 2008, 14, 4726– 4734, DOI: 10.1158/1078-0432.CCR-07-4921Google ScholarThere is no corresponding record for this reference.
- 9(a) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455Google Scholar9ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsrzM&md5=20d7a36b75501c02570744857c82f325Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug DiscoveryHuchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, KlausJournal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.(b) Aufiero, M.; Gilmour, R. Informing Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis. Acc. Chem. Res. 2018, 51, 1701– 1710, DOI: 10.1021/acs.accounts.8b00192Google Scholar9bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSltL%252FJ&md5=cdfe3b6d51933baa54b098102d7d54ccInforming Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in CatalysisAufiero, Marialuisa; Gilmour, RyanAccounts of Chemical Research (2018), 51 (7), 1701-1710CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)The axioms of stereoelectronic theory constitute an atlas to navigate the contours of mol. space. All too rarely lauded, the advent and development of stereoelectronic theory has been one of org. chem.'s greatest triumphs. Inevitably, however, in the absence of a comprehensive treatise, many of the field's pioneers do not receive the veneration that they merit. Rather their legacies are the stereoelectronic pillars that persist in teaching and research. This ubiquity continues to afford practitioners of org. chem. with an abundance of opportunities for creative endeavor in reaction design, in conceiving novel activation modes, in preorganizing intermediates, or in stabilizing productive transition states and products. Antipodal to steric governance, which mitigates destabilizing nonbonding interactions, stereoelectronic control allows well-defined, often complementary, conformations to be populated. Indeed, the prevalence of stabilizing hyperconjugative interactions in biosynthetic processes renders this approach to mol. preorganization decidedly biomimetic and, by extension, expansive. In this Account, the evolution and application of a simple donor-acceptor model based on the fluorine gauche effect is delineated. Founded on reinforcing hyperconjugative interactions involving C(sp3)-H bonding orbitals and C(sp3)-X antibonding orbitals [σC-H → σC-X*], this general stratagem has been used in conjunction with an array of secondary noncovalent interactions to achieve acyclic conformational control (ACC) in structures of interest. These secondary effects range from 1,3-allylic strain (A1,3) through to electrostatic charge-dipole and cation-π interactions. Synergy between these interactions ensures that rotation about strategic C(sp3)-C(sp3) bonds is subject to the stereoelectronic requirement for antiperiplanarity (180°). Logically, in a generic [X-CH2-CH2-Y] system (X, Y = electron withdrawing groups) conformations in which the two C(sp3)-X bonds are synclinal (i.e., gauche) are significantly populated. As such, simple donor-acceptor models are didactically and predictively powerful in achieving topol. preorganization. In the case of the gauche effect, the low steric demand of fluorine ensures that the remaining substituents at the C(sp3) hybridized center are placed in a predictable area of mol. space: An exit vector analogy is thus appropriate. Furthermore, the intrinsic chem. stability of the C-F bond is advantageous, thus it may be considered as an inert conformational steering group: This juxtaposition of size and electronegativity renders fluorinated org. mols. unique among the organo-halogen series. Cognizant that the replacement of one fluorine atom in the difluoroethylene motif by another electron withdrawing group preserves the gauche conformation, it was reasoned that β-fluoroamines would be intriguing candidates for investigation. The burgeoning field of Lewis base catalysis, particularly via iminium ion activation, provided a timely platform from which to explore a postulated fluorine-iminium ion gauche effect. Necessarily, activation of this stereoelectronic effect requires a process of intramolecularization to generate the electron deficient neighboring group: Examples include protonation, condensation to generate iminium salts, or acylation. This process, akin to substrate binding, has obvious parallels with enzymic catalysis, since it perturbs the conformational dynamics of the system [synclinal-endo, antiperiplanar, synclinal-exo]. This Account details the development of conformationally predictable small mols. based on the [X-Cα-Cβ-F] motif through a logical process of mol. design and illustrates their synthetic value in enantioselective catalysis.(c) Thiehoff, C.; Rey, Y. P.; Gilmour, R. The Fluorine Gauche Effect: A Brief History. Isr. J. Chem. 2017, 57, 92– 100, DOI: 10.1002/ijch.201600038Google Scholar9chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFCmsbjM&md5=d429fe6b372f943cd018490487ce67a5The Fluorine Gauche Effect: A Brief HistoryThiehoff†, Christian; Rey†, Yannick P.; Gilmour, RyanIsrael Journal of Chemistry (2017), 57 (1-2), 92-100CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)Transforming fluorine gauche effect from an academic curiosity to acyclic conformational control strategy has enriched mol. design. This approach to modulating structure has proven to be particularly valuable in construction of functional small mols., finding application in diverse disciplines, from therapeutic medicine to enantioselective catalysis. In contrast to well-established arsenal of conformational control tactics, in which conformer populations result from minimising nonbonding interactions, the effect is attributable to stabilizing interactions comprised of two components: stereoelectronic and electrostatic. Conformer populations are partially detd. by favorable, hyperconjugative interactions involving proximal electron-rich σ-bonds, π-systems, and nonbonding electron pairs with antibonding orbital of C-F σ-bond: σ→σ*, π→σ*, and n→σ*, resp. Electrostatic, charge-dipole interactions also play a role in stabilizing counter-intuitive conformations. These noncovalent interactions, permissible on account of low van der Waals radius and high electronegativity of fluorine atom, render this effect fundamentally important and practically valuable in structural chem. Contribution to Rosarium Philosophorum in honour of Prof.Jack David Dunitz FRS, we endeavour to delineate, albeit in an abridged form, evolution of fluorine gauche effect from a fundamental study to ubiquitous component of phys. org. chem.(d) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956Google Scholar9dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.
- 10(a) Sarie, J. C.; Thiehoff, C.; Neufeld, J.; Daniliuc, C. G.; Gilmour, R. Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis. Angew. Chem., Int. Ed. 2020, 59, 15069– 15075, DOI: 10.1002/anie.202005181Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFCjtbnI&md5=443ff10462246e29adb85e9b50810648Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) CatalysisSarie, Jerome C.; Thiehoff, Christian; Neufeld, Jessica; Daniliuc, Constantin G.; Gilmour, RyanAngewandte Chemie, International Edition (2020), 59 (35), 15069-15075CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The chromane nucleus is common to a plenum of bioactive small mols. where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl Ph ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.(b) Neufeld, J.; Stünkel, T.; Mück-Lichtenfeld, C.; Daniliuc, C. G.; Gilmour, R. Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2]→[CF2CHF] Isosterism. Angew. Chem., Int. Ed. 2021, 60, 13647– 13651, DOI: 10.1002/anie.202102222Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVWqsLnL&md5=d5a5f5a6f00b6f6c7932892cc0414777Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2] → [CF2CHF] IsosterismNeufeld, Jessica; Stuenkel, Timo; Mueck-Lichtenfeld, Christian; Daniliuc, Constantin G.; Gilmour, RyanAngewandte Chemie, International Edition (2021), 60 (24), 13647-13651CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Satd., fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF2 (>20 examples, up to >95%). A range of diverse substituents are tolerated under std. catalysis conditions and this is interrogated by Hammett anal. X-ray anal. indicates a preference for the CH-F bond to occupy a pseudo-axial orientation, consistent with stabilizing σC-H→σC-F* interactions. The replacement of the sym. [CH2-CH2] motif by [CF2-CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational anal. and is consistent with stereoelectronic theory.(c) Häfliger, J.; Sokolova, O. O.; Lenz, M.; Daniliuc, C. G.; Gilmour, R. Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis. Angew. Chem., Int. Ed. 2022, 61, 61, DOI: 10.1002/anie.202205277Google ScholarThere is no corresponding record for this reference.
- 11(a) Rodil, A.; Bosisio, S.; Ayoup, M. S.; Quinn, L.; Cordes, D. B.; Slawin, A. M. Z; Murphy, C. D.; Michel, J.; O’Hagan, D. Metabolism and Hydrophilicity of the Polarized ‘Janus face’ All-cis Tetrafluorocyclohexyl Ring, a Candidate Motif for Drug Discovery. Chem. Sci. 2018, 9, 3023, DOI: 10.1039/C8SC00299AGoogle ScholarThere is no corresponding record for this reference.(b) Johnson, B. M.; Shu, Y.-Z.; Zhuo, X.; Meanwell, N. A. Metabolic and Pharmaceutical Aspects of Fluorinated Compounds. J. Med. Chem. 2020, 63, 6315– 6386, DOI: 10.1021/acs.jmedchem.9b01877Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFCrs7o%253D&md5=a8163c3ebf456de6932a4b941bb52d14Metabolic and Pharmaceutical Aspects of Fluorinated CompoundsJohnson, Benjamin M.; Shu, Yue-Zhong; Zhuo, Xiaoliang; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2020), 63 (12), 6315-6386CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochem. properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated mols. are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C-F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compds. In this Perspective, we summarize the literature assocd. with the metab. of fluorinated mols., focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.
- 12(a) Meyer, S.; Hafliger, J.; Gilmour, R. Expanding Organofluorine Chemical Space: The Design of Chiral Fluorinated Isosteres Enabled by I(I)/I(III) Catalysis. Chem. Sci. 2021, 12, 10686– 10695, DOI: 10.1039/D1SC02880DGoogle Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVOmu7jN&md5=12f46b8d00ac70a8db3ebdf9165c9ed7Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(I)/I(III) catalysisMeyer, Stephanie; Haefliger, Joel; Gilmour, RyanChemical Science (2021), 12 (32), 10686-10695CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Short aliph. groups are prevalent in bioactive small mols. and play an essential role in regulating physicochem. and mol. recognition phenomena. Delineating their biol. origins and significance have resulted in landmark developments in synthetic org. chem.: Arigoni's venerable synthesis of the chiral Me group is a personal favorite. While radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chem. space for small mol. drug discovery. Accelerated by advances in I(I)/I(III) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals vols. This Perspective surveys key developments in the design and synthesis of short multivicinal fluoroalkanes under the auspices of main group catalysis paradigms.(b) Molnár, I. G.; Gilmour, R. Catalytic Difluorination of Olefins. J. Am. Chem. Soc. 2016, 138 (15), 5004– 5007, DOI: 10.1021/jacs.6b01183Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFeitL8%253D&md5=f11a1bb6120267a8333f9daded4f1159Catalytic Difluorination of OlefinsMolnar, Istvan Gabor; Gilmour, RyanJournal of the American Chemical Society (2016), 138 (15), 5004-5007CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mol. editing with fluorine is a validated strategy for modulating the structure and function of org. systems. In the current arsenal of catalytic dihalogenation technologies, the direct generation of the vicinal difluoride moiety from simple olefins without a prefunctionalization step remains conspicuously absent. Herein we report a catalytic, vicinal difluorination of olefins displaying broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are also disclosed.(c) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Catalytic, Diastereoselective 1,2-Difluorination of Alkenes. J. Am. Chem. Soc. 2016, 138 (15), 5000– 5003, DOI: 10.1021/jacs.6b02391Google Scholar12chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XltlOgurk%253D&md5=59fbca62979aa25931d0261e49a948f5Catalytic, Diastereoselective 1,2-Difluorination of AlkenesBanik, Steven M.; Medley, Jonathan William; Jacobsen, Eric N.Journal of the American Chemical Society (2016), 138 (15), 5000-5003CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities. The obsd. sense of stereoinduction implicates anchimeric assistance pathways in reactions of alkenes bearing neighboring Lewis basic functionality.(d) Molnár, I. G.; Thiehoff, C.; Holland, M. C.; Gilmour, R. Catalytic, Vicinal Difluorination of Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl and Ethyl Groups. ACS Catal. 2016, 6, 7167– 7173, DOI: 10.1021/acscatal.6b02155Google Scholar12dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWjur3J&md5=0dc8e44a2e28dd543f1bf09de52f54abCatalytic, Vicinal Difluorination of Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl and Ethyl GroupsMolnar, Istvan G.; Thiehoff, Christian; Holland, Mareike C.; Gilmour, RyanACS Catalysis (2016), 6 (10), 7167-7173CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Contemporaneous reports describing the vicinal difluorination of olefins relying on I(I)/I(III) catalysis have augmented the arsenal of dihalogenation methods and provided a soln. to this longstanding challenge in olefin functionalization. In both studies, success was contingent on the in situ generation of ArIF2 from a simple aryl iodide, HF source, and suitable terminal oxidant. The first report by Jacobsen and co-workers employed a resorcinol-derived aryl iodide/m-CPBA oxidant combination, while this lab. relied on p-iodotoluene and Selectfluor. The complementarity of these approaches ensures that a wide variety of electronically distinct olefins are viable substrates for this transformation. This perspective describes our development of a catalytic difluorination of terminal olefins as a means to efficiently construct a hybrid, chiral bioisostere of the trifluoromethyl and Et groups in the broader context of mol. design and highlights key reports from other labs. that accelerated the study.
- 13(a) Moock, D.; Wagener, T.; Hu, T.; Gallagher, T.; Glorius, F. Enantio- and Diastereoselective, Complete Hydrogenation of Benzofurans by Cascade Catalysis. Angew. Chem., Int. Ed. 2021, 60, 13677– 13681, DOI: 10.1002/anie.202103910Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCktrjN&md5=d1450f4fbfb19e932eb1ab50e917f10eEnantio- and Diastereoselective, Complete Hydrogenation of Benzofurans by Cascade CatalysisMoock, Daniel; Wagener, Tobias; Hu, Tianjiao; Gallagher, Timothy; Glorius, FrankAngewandte Chemie, International Edition (2021), 60 (24), 13677-13681CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report an enantio- and diastereoselective, complete hydrogenation of multiply substituted benzofurans in a one-pot cascade catalysis. The developed protocol facilitates the controlled installation of up to six new defined stereocenters and produces architecturally complex octahydrobenzofurans, prevalent in many bioactive mols. A unique match of a chiral homogeneous ruthenium-N-heterocyclic carbene complex and an in situ activated rhodium catalyst from a complex precursor act in sequence to enable the presented process.(b) Ponra, S.; Rabten, W.; Yang, J.; Wu, H.; Kerdphon, S.; Andersson, P. G. Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic Centers. J. Am. Chem. Soc. 2018, 140, 13878– 13883, DOI: 10.1021/jacs.8b08778Google Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVantLzE&md5=2449494df94a4a36c0c6323921c13750Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic CentersPonra, Sudipta; Rabten, Wangchuk; Yang, Jianping; Wu, Haibo; Kerdphon, Sutthichat; Andersson, Pher G.Journal of the American Chemical Society (2018), 140 (42), 13878-13883CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The synthesis of chiral fluorine contg. motifs, in particular, chiral fluorine mols. with two contiguous stereogenic centers, has attracted much interest in research due to the limited no. of methods available for their prepn. Herein, authors report an atom-economical and highly stereoselective synthesis of chiral fluorine mols. with two contiguous stereogenic centers via azabicyclo iridium-oxazoline-phosphine-catalyzed hydrogenation of readily available vinyl fluorides. Various arom., aliph., and heterocyclic systems with a variety of functional groups were compatible with the reaction and provide the highly desirable product as single diastereomers with excellent enantioselectivities.(c) Ponra, S.; Yang, J.; Kerdphon, S.; Andersson, P. G. Asymmetric Synthesis of Alkyl Fluorides: Hydro- genation of Fluorinated Olefins. Angew. Chem., Int. Ed. 2019, 58, 9282– 9287, DOI: 10.1002/anie.201903954Google ScholarThere is no corresponding record for this reference.(d) Kaukoranta, P.; Engman, M.; Hedberg, C.; Bergquist, J.; Andersson, P. G. Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins. Adv. Synth. Catal. 2008, 350, 1168– 1176, DOI: 10.1002/adsc.200800062Google Scholar13dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtVWhsLg%253D&md5=489b0c10e6920908d8371fd0384d273bIridium catalysts with chiral imidazole-phosphine ligands for asymmetric hydrogenation of vinyl fluorides and other olefinsKaukoranta, Paeivi; Engman, Mattias; Hedberg, Christian; Bergquist, Jonas; Andersson, Pher G.Advanced Synthesis & Catalysis (2008), 350 (7+8), 1168-1176CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)New chiral bidentate imidazole-phosphine ligands have been prepd. and evaluated for the iridium-catalyzed asym. hydrogenation of olefins. The imidazole-phosphine-ligated iridium catalysts hydrogenated trisubstituted olefins with the same sense of enantiodiscrimination as known iridium catalysts possessing oxazole and thiazole as N-donors. The imidazole-based catalysts were shown to hydrogenate vinyl fluorides, in some cases with the highest ee values published to date.(e) Le, D. N.; Johnson, H. C.; Lam, Y.-H.; Sun, C.; Cheng, L.; Belyk, K. M. Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation. Org. Lett. 2024, 26, 4059– 4064, DOI: 10.1021/acs.orglett.4c00982Google ScholarThere is no corresponding record for this reference.
- 14(a) Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana- Vidal, V. Synthesis 2016, 48, 2523. Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2016, 48, 2523– 2539, DOI: 10.1055/s-0035-1561648Google Scholar14ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xptl2qtbc%253D&md5=622021ab0bd3f2555593e327726f2e61Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic ResolutionEcheverria, Pierre-Georges; Ayad, Tahar; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieSynthesis (2016), 48 (16), 2523-2539CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)The transition-metal-catalyzed asym. transfer hydrogenation (ATH) and asym. hydrogenation (AH) of α- and β-substituted ketone or imine derivs. are efficient methods for accessing chiral alcs. or amines bearing up to three stereogenic centers through a dynamic kinetic resoln. (DKR) process. This review provides a summary of recent work in this field, focusing on the development of new catalytic systems and on the extension of these asym. redns. to new classes of substrates. 1 Introduction 2 Asym. Hydrogenation via Dynamic Kinetic Resoln. 2.1 α-Substituted Ketones 2.2. α-Substituted β-Keto Esters and Amides 2.3 α-Substituted β-Keto Phosphonates and Sulfones 2.4 α,α'-Disubstituted Cyclic Ketones 2.5 α,β-Disubstituted Cyclic Ketones 2.6 Imine Derivs. 3 Asym. Transfer Hydrogenation via Dynamic Kinetic Resoln. 3.1 α-Substituted β-Diketones and Ketones 3.2 α-Substituted β-Keto Esters, Amides and Phosphonates 3.3 β-Substituted α-Keto Esters and Phosphonates 3.4 β-Substituted γ-Keto Esters 3.5 β-Alkoxy Ketones 3.6 Imine Derivs. 4 Conclusion.(b) Molina Betancourt, R.; Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2021, 53, 30– 50, DOI: 10.1055/s-0040-1705918Google Scholar14bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVSqu7vE&md5=5a9197d2825a27720bf4841e39d4c368Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic ResolutionMolina Betancourt, Ricardo; Echeverria, Pierre-Georges; Ayad, Tahar; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieSynthesis (2021), 53 (1), 30-50CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)A review. Based on the ever-increasing demand for enantiomerically pure compds., the development of efficient, atom-economical and sustainable methods to produce chiral alcs. and amines was a major concern. Homogeneous asym. catalysis with transition-metal complexes including asym. hydrogenation (AH) and transfer hydrogenation (ATH) of ketones and imines through dynamic kinetic resoln. (DKR) allowing the construction of up to three stereogenic centers was the main focus of the present short review, emphasizing the development of new catalytic systems combined to new classes of substrates and their applications as well.
- 15Ros, A.; Magriz, A.; Dietrich, H.; Fernandez, R.; Alvarez, E.; Lassaletta, J. M. Enantioselective Synthesis of Vicinal Halohydrins via Dynamic Kinetic Resolution. Org. Lett. 2006, 8 (1), 127– 130, DOI: 10.1021/ol052821kGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yrs7bF&md5=797c310f7adf3afd8893de0a5bc47d1aEnantioselective Synthesis of Vicinal Halohydrins via Dynamic Kinetic ResolutionRos, Abel; Magriz, Antonio; Dietrich, Hansjoerg; Fernandez, Rosario; Alvarez, Eleuterio; Lassaletta, Jose M.Organic Letters (2006), 8 (1), 127-130CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Expanding the scope of enantioselective catalysis via dynamic kinetic resoln. (DKR), transfer hydrogenation of a variety of cyclic α-halo ketones was accomplished using the Noyori/Ikariya (R,R) or (S,S) catalysts and either HCO2H/Et3N or HCO2Na/n-Bu4NBr in H2O/CH2Cl2 as the hydrogen sources. Good yields of vicinal bromo-, chloro-, and fluorohydrins with excellent de and ee levels were achieved in most cases after a simple tuning of reaction conditions.
- 16Touge, T.; Nara, H.; Kida, M.; Matsumura, K.; Kayaki, Y. Convincing Catalytic Performance of Oxo-Tethered Ruthenium Complexes for Asymmetric Transfer Hydrogenation of Cyclic α-Halogenated Ketones through Dynamic Kinetic Resolution. Org. Lett. 2021, 23, 3070– 3075, DOI: 10.1021/acs.orglett.1c00739Google ScholarThere is no corresponding record for this reference.
- 17Betancourt, R. M.; Phansavath, P.; Ratovelomanana-Vidal, V. Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols Through Dynamic Kinetic Resolution. J. Org. Chem. 2021, 86, 12054– 12063, DOI: 10.1021/acs.joc.1c01415Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslegsL7O&md5=677ffe13a28ada49f288de4fdf833aeaRu(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols through Dynamic Kinetic ResolutionBetancourt, Ricardo Molina; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieJournal of Organic Chemistry (2021), 86 (17), 12054-12063CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Enantioenriched cis-3-fluoro-chroman-4-ol derivs. cis-I (R = H, 8-Me, 7-Br, 6-F, etc.; X = O, S) were conveniently prepd. by ruthenium-catalyzed asym. transfer hydrogenation of a new family of 3-fluoro chromanones II through a dynamic kinetic resoln. process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (1:1) as the hydrogen source, affording the reduced fluorinated alcs. cis-I in good yields (80-96%), high diastereomeric ratios (up to 99:1 dr) and excellent enantioselectivities (up to >99% ee).
- 18Molina Betancourt, R.; Phansavath, P.; Ratovelomanana-Vidal, V. Straightforward Access to Enantioenriched cis-3-Fluoro-Dihydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution. Molecules 2022, 27, 995, DOI: 10.3390/molecules27030995Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktFagt78%253D&md5=9e39378a858aa75c3bca147d25c0ec43Straightforward Access to Enantioenriched cis-3-Fluoro-tetrahydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic ResolutionMolina Betancourt, Ricardo; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieMolecules (2022), 27 (3), 995CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A practical method for the asym. transfer hydrogenation/dynamic kinetic resoln. of N-Boc 3-fluoro-dihydroquinolin-4-ones I [R = H, 6-Me, 7-OMe, 6,7-(OMe)2, etc.] into the corresponding cis-fluoro alcs. II in 70-96% yields, up to 99:1 diastereomeric ratio (dr) and up to >99% ee (enantiomeric excess) by using the ruthenium complex Ts-DENEB and a formic acid/triethylamine (1:1) mixt. as the hydrogen donor under mild conditions was reported.
- 19(a) Wang, T.; Phillips, E. M.; Dalby, S. M.; Sirota, E.; Axnanda, S.; Shultz, C. S.; Patel, P.; Waldman, J. H.; Alwedi, E.; Wang, X.; Zawatzky, K.; Chow, M.; Padivitage, N.; Weisel, M.; Whittington, M.; Duan, J.; Lu, T. Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process. Org. Process Res. Dev. 2022, 26, 543– 550, DOI: 10.1021/acs.oprd.1c00242Google Scholar19ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVOkurvI&md5=e55f870e8daa6622a3943225174aaa7eManufacturing Process Development for Belzutifan. Part 5: A Streamlined Fluorination-DKR ProcessWang, Tao; Phillips, Eric M.; Dalby, Stephen M.; Sirota, Eric; Axnanda, Stephanus; Shultz, C. Scott; Patel, Pratiq; Waldman, Jacob H.; Alwedi, Embarek; Wang, Xiao; Zawatzky, Kerstin; Chow, Matthew; Padivitage, Nilusha; Weisel, Mark; Whittington, Michael; Duan, Jianjun; Lu, TaotaoOrganic Process Research & Development (2022), 26 (3), 543-550CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Here, the fluorination-DKR (dynamic kinetic resoln.) process for the com. supply of belzutifan (MK-6482) is reported. Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed based on increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of fluorodiol product I with low process mass intensity (PMI).(b) McCann, S. D.; Dubina, S. H.; Kosjek, B.; Alwedi, E.; Behre, T.; Burgess, S. A.; Dal Poggetto, G.; DiRocco, D. A.; Hartmanshenn, C.; McMullen, J. P.; Padivitage, N.; Sun, A. C. Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5 – Chemoenzymatic Diastereoselective Fluorination/DKR. Org. Process Res. Dev. 2024, 28, 441– 450, DOI: 10.1021/acs.oprd.3c00421Google ScholarThere is no corresponding record for this reference.
- 20Bacheley, L.; Molina Betancourt, R.; Ravindra, R.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. Asymmetric Synthesis of Monofluorinated Carbocyclic Alcohols and Vicinal Difluorinated Heterocycles and Carbocycles. Eur. J. Org. Chem. 2023, 26, e202300383 DOI: 10.1002/ejoc.202300383Google ScholarThere is no corresponding record for this reference.
- 21Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal; , Haelsig, K. T.; Hardman, C.; Kalisiak, J.; Lawson, K. V.; Leleti, M. R.; Mailyan, A. K.; Mata, G.; Rosen, B. R.; Wang, Z.; Yu, K.; Process For Preparing Tetralin Compounds. United States Patent No. US12145901B1, Arcus Biosciences, Inc., assignee..Google ScholarThere is no corresponding record for this reference.
- 22
Structural confirmation of cis-diastereomers 10 was established after Mitsunobu reaction with 4-nitro benzoic acid and subsequent saponification to generate trans-diastereoisomer 8.
There is no corresponding record for this reference. - 23(a) Yamakawa, M.; Yamada, I.; Noyori, R. CH/π Attraction: The Origin of Enantioselectivity in Transfer Hydrogenation of Aromatic Carbonyl Compounds Catalyzed by Chiral η6-Arene-Ruthenium(II) Complexes. Angew. Chem., Int. Ed. 2001, 40, 2818– 2821, DOI: 10.1002/1521-3773(20010803)40:15<2818::AID-ANIE2818>3.0.CO;2-YGoogle Scholar23ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1Wmu7k%253D&md5=22e49243ba09c78837336a990c3026baCH/π attraction: The origin of enantioselectivity in transfer hydrogenation of aromatic carbonyl compounds catalyzed by chiral η6-arene-ruthenium(II) complexesYamakawa, Masashi; Yamada, Issaku; Noyori, RyojiAngewandte Chemie, International Edition (2001), 40 (15), 2818-2821CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)The transition state (TS) structures were studied using d. functional theory-based calcns. To fully explain the origin of the preference for the more crowded TS, a more reliable calcn. was conducted by using [RuH(OCH2CH2NH2)(η6-C6H6)] and a higher quality basis sets (RMP2/BS-III//B3LYP/BS-I). This model possessed a λ conformation for the chiral N,O-chelate ring and an S configuration at the Ru stereogenic center. Organometallic chem. often uses arene ligands and the two- to six-electron donors influence the electronic properties of the metallic center and also exert steric influences on neighboring ligands. Ring alkylation can facilitate reactions and also generate a larger asym. bias through enhanced electron donation and/or attractive secondary interaction, only if other perturbations remain similar. This study encourages a reconsideration of the origin of selectivity and reactivity noted in many other reactions promoted by transition metal-arene/cyclopentadienyl complexes and explains several exptl. findings with RuII-catalyzed asym. transfer hydrogenation.(b) Matsuoka, A.; Sandoval, C. A.; Uchiyama, M.; Noyori, R.; Naka, H. Why p-Cymene? Conformational Effect in Asymmetric Hydrogenation of Aromatic Ketones with a η6-Arene-Ruthenium(II) Catalyst. Chem.-Asian J. 2015, 10, 112– 115, DOI: 10.1002/asia.201402979Google ScholarThere is no corresponding record for this reference.
- 24Bresciani, S.; O’Hagan, D. Stereospecific Benzylic Dehydroxyfluorination Reactions Using Bio’s TMS-Amine Additive Approach with Challenging Substrates. Tetrahedron Lett. 2010, 51, 5795– 5797, DOI: 10.1016/j.tetlet.2010.08.104Google ScholarThere is no corresponding record for this reference.
- 25Valkó, K. Application of High-Performance Liquid Chromatography Based Measurements of Lipophilicity to Model Biological Distribution. Journal of Chromatography A 2004, 1037, 299– 310, DOI: 10.1016/j.chroma.2003.10.084Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvVels78%253D&md5=0a70bc59837a713de70eb041e3087954Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distributionValko, KlaraJournal of Chromatography A (2004), 1037 (1-2), 299-310CODEN: JCRAEY; ISSN:0021-9673. (Elsevier Science B.V.)A review. Octanol-water partition coeffs. are the most widely used measure of lipophilicity in modeling biol. partition/distribution. It has long been recognized that the retention of a compd. in reversed-phase liq. chromatog. is governed by its lipophilicity/hydrophobicity, and thus shows correlation with an octanol-water partition coeff. A great no. of publications have reported the efforts made to adjust HPLC conditions to measure surrogate octanol-water partition coeffs. However, there is no general consensus in this field. HPLC provides a platform to measure various types of lipophilicity that can provide relevant information about the compds.' property. In this way HPLC can be more valuable than just a surrogate for octanol-water partition. Chromatog. using biomimetic stationary phases may provide better insight for biol. partition/distribution processes. The research in this field is still ongoing and a large variety of HPLC conditions have been suggested. This review will outline approaches to overcoming the difficulties of standardization and describe different theor. approaches for comparison of HPLC lipophilicity data obtained under various conditions, along with the relation of these results to biol. partition/distribution.
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- 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 7aaThermal ellipsoids are shown at 30% probability. R = MOM.
Scheme 2
Scheme 2. Proposed Model for Asymmetric InductionScheme 3
Scheme 3. Synthesis of Vicinal DifluoridesScheme 4
Scheme 4. Scaleup and Single-Crystal X-ray StructuresaaThermal ellipsoids are shown at 30% probability. R = MOM.
Scheme 5
Scheme 5. Preparation of Intermediate 19 for DerivatizationReferences
This article references 25 other publications.
- 1(a) Muller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881– 1886, DOI: 10.1126/science.11319431ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srnvVOnuw%253D%253D&md5=f624ab3733f7fc9d4b1711f2f3566ca2Fluorine in pharmaceuticals: looking beyond intuitionMuller Klaus; Faeh Christoph; Diederich FrancoisScience (New York, N.Y.) (2007), 317 (5846), 1881-6 ISSN:.Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320– 330, DOI: 10.1039/B610213C1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtVGgsw%253D%253D&md5=e6c9e3084e454c44a4ba245b98f7f1d7Fluorine in medicinal chemistryPurser, Sophie; Moore, Peter R.; Swallow, Steve; Gouverneur, VeroniqueChemical Society Reviews (2008), 37 (2), 320-330CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. It has become evident that fluorinated compds. have a remarkable record in medicinal chem. and will play a continuing role in providing lead compds. for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.(c) O’Hagan, D. Fluorine in Health Care: Organofluorine Containing Blockbuster Drugs. J. Fluorine Chem. 2010, 131, 1071– 1081, DOI: 10.1016/j.jfluchem.2010.03.0031chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKmt7vO&md5=87463907f1ea9b52185bb247e8e7650aFluorine in health care: Organofluorine containing blockbuster drugsO'Hagan, DavidJournal of Fluorine Chemistry (2010), 131 (11), 1071-1081CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A review. Org. fluorine compds. have had a profound impact on the development of bioactives for the modern pharmaceuticals market. It is estd. that up to 20% of pharmaceuticals prescribed or administered in the clinic contain a fluorine atom and 30% of the leading 30 blockbuster drugs by sales contain a fluorine. In this Highlight review, the top 10 fluorine contg. pharmaceuticals (by US Sales in 2008) are highlighted. By this measure, these are currently the most significant fluorinated compds. impacting on health care. They embrace statins (Lipitor, Crestor, Vytorin, Zetia/Ezetimibe), anti-inflammatories (fluticasone propionate, Celebrex), antacids (Prevacid), antidepressants (Lexapro), neuroleptics (Risperdal) and antibiotics (Levaquin). In each case the structures and modes of action of these important drugs compds. are reviewed and representative synthetic routes are highlighted.(d) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315– 8359, DOI: 10.1021/acs.jmedchem.5b002581dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1ajs7%252FK&md5=9995829a94a8c0b8d9fb0d21bdfd5a1dApplications of Fluorine in Medicinal ChemistryGillis, Eric P.; Eastman, Kyle J.; Hill, Matthew D.; Donnelly, David J.; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2015), 58 (21), 8315-8359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review with meta-anal. The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties assocd. with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a mol. can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addn., 18F has been established as a useful positron emitting isotope for use with in vivo imaging technol. that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug mols. and applications in positron emission tomog.(e) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822– 5880, DOI: 10.1021/acs.jmedchem.7b017881ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qu7w%253D&md5=2d0ce3326c7ff932da8d7d26972ced14Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2018), 61 (14), 5822-5880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the Me group while also acting as a functional mimetic of the carbonyl, carbinol, andnitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metab., membrane permeability, and P-gp recognition of a mol. and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.
- 2(a) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. The Polar Hydrophobicity of Fluorinated Compounds. ChemBioChem. 2004, 5, 622– 627, DOI: 10.1002/cbic.2003009102ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFeqtLs%253D&md5=bfe354a8ca8e095c2cdd6b79e964fc7cThe polar hydrophobicity of fluorinated compoundsBiffinger, Justin C.; Kim, Hong Woo; DiMagno, Stephen G.ChemBioChem (2004), 5 (5), 622-627CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review.(b) O’Hagan, D. Understanding Organofluorine Chemistry. An Introduction to the C–F Bond. Chem. Soc. Rev. 2008, 37, 308– 319, DOI: 10.1039/B711844A2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtVGnsw%253D%253D&md5=7d4111d3b05c22c8e6df282cf051fccbUnderstanding organofluorine chemistry. An introduction to the C-F bondO'Hagan, DavidChemical Society Reviews (2008), 37 (2), 308-319CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Fluorine is the most electroneg. element in the periodic table. When bound to carbon it forms the strongest bonds in org. chem. and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of specialty materials. Although highly polarized, the C-F bond gains stability from the resultant electrostatic attraction between the polarized Cδ+ and Fδ- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C-F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighboring bonds or lone pairs. In this tutorial review these fundamental aspects of the C-F bond are explored to rationalize the geometry, conformation and reactivity of individual organofluorine compds.
- 3(a) O’Hagan, D. Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene Motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044q3ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wltbg%253D&md5=fdc040b0921c21fe3c539031e2f6c624Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene MotifsO'Hagan, DavidJournal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.(b) Wu, D.; Tian, A.; Sun, H. Conformational Properties of 1,3-Difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164w3bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFKnt7Y%253D&md5=f44c4fc0316ebf223dc223162a793c04Conformational properties of 1,3-difluoropropaneWu, D.; Tian, A.; Sun, H.Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.(c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes. Angew. Chem. Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.2009019563chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.(d) O’Hagan, D. Polar Organofluorine Substituents: Multivicinal Fluorines on Alkyl Chains and Alicyclic Rings. Chem.-Eur. J. 2020, 26, 7981– 7997, DOI: 10.1002/chem.202000178There is no corresponding record for this reference.(e) Mondal, R.; Agbaria, M.; Nairoukh, Z. Fluorinated Rings: Conformation and Application. Chem.-Eur. J. 2021, 27 (25), 7193– 7213, DOI: 10.1002/chem.202005425There is no corresponding record for this reference.
- 4(a) Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O'Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane is a Facially Polarized Cyclohexane. Nat. Chem. 2015, 7, 483– 488, DOI: 10.1038/nchem.22324ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtleisr8%253D&md5=811e1998f3076508664eebee80d4ecacAll-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexaneKeddie, Neil S.; Slawin, Alexandra M. Z.; Lebl, Tomas; Philp, Douglas; O'Hagan, DavidNature Chemistry (2015), 7 (6), 483-488CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are 'up', is prepd. in a 12-step protocol. The mol. adopts a classic chair conformation with alternate C-F bonds aligned triaxially, clustering three highly electroneg. fluorine atoms in close proximity. This generates a cyclohexane with a high mol. dipole (μ = 6.2 D), unusual in an otherwise aliph. compd. X-ray anal. indicates that the intramol. Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the mols. pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in org. chem. Derivs. have potential as new motifs for the design of functional org. mols. or for applications in supramol. chem. design.(b) Wang, Y.; Lee, W.; Chen, Y.-C.; Zhou, Y.; Plise, E.; Migliozzi, M.; Crawford, J. J. Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on Physicochemical and Metabolic Properties. ACS Med. Chem. Letters 2022, 13, 1517– 1523, DOI: 10.1021/acsmedchemlett.2c003124bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitFSmsr3L&md5=6a1b2e06bf5492e5ca8a9843a4205441Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on Physicochemical and Metabolic PropertiesWang, Yong; Lee, Wendy; Chen, Yi-Chen; Zhou, Yuhui; Plise, Emile; Migliozzi, Madyson; Crawford, James J.ACS Medicinal Chemistry Letters (2022), 13 (9), 1517-1523CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The targeted introduction of substituents in order to tailor a mol.'s pharmacol., physicochem., and metabolic properties has long been of interest to medicinal chemists. The all-cis tetrafluorocyclohexyl motif-dubbed Janus face, due to its electrostatically polarized cyclohexyl ring-represents one such example where chemists might incorporate a metabolically stable, polar, lipocompatible motif. To better understand its potential utility, we have synthesized three series of matched mol. pairs (MMPs) where each MMP differs only in the cyclohexane unit, i.e., with a tetrafluorocyclohexyl or a std. cyclohexyl motif. With the introduction of the facially polarized all-cis tetrafluorocyclohexyl ring, the resulting compds. have significantly modified physicochem. properties (e.g., kinetic soly., lipophilicity and permeability) and metabolic stabilities. These results further speak to the promise of this substituent as a tactic to improve the drug-like properties of mols.
- 5Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal, B.; Hardman, C.; Mailyan, A. K.; Lawson, K. V.; Leleti, M. R.; Liu, D.; Mata, G.; Podunavac, M.; Powers, J. P.; Rosen, B. R.; Yu, K. Arcus Biosciences, Inc., assignee. Inhibitors of HIF-2α and methods of use thereof. United States Patent No. US12071411B2, 2024.There is no corresponding record for this reference.
- 6Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal, B.; Guney, T.; Haelsig, K. T.; Hardman, C.; Jacob, S. D.; Jeffrey, J. L.; Kalisiak, J.; Lawson, K. V.; Leleti, M. R.; Lindsey, E. A.; Mailyan, A. K.; Mandal, D.; Mata, G.; Moon, H.; Powers, J. P.; Rosen, B. R.; Su, Y.; Tran, A. T.; Wang, Z.; Yan, X.; Yu, K. Tetralin and Tetrahydroquinoline Compounds as Inhibitors of HIF-2α, WO-2021188769-A1, 2021Arcus Biosciences, Inc., assignee..There is no corresponding record for this reference.
- 7(a) Lawson, K. V.; Sivick Gauthier, K. E.; Mailyan, A. K.; Fournier, J. T.; Beatty, J. W.; Drew, S. L.; Kalisiak, J.; Gal, B.; Mata, G.; Wang, Z. Abstract 1206: Discovery and characterization of AB521, a novel, potent, and selective hypoxia-inducible factor (HIF)-2α inhibitor. Cancer Res. 2021, 81, 1206, DOI: 10.1158/1538-7445.AM2021-1206There is no corresponding record for this reference.(b) Lawson, K. V.; Sivick Gauthier, K. E.; Piovesan, D.; Mailyan, A.; Mata, G.; Fournier, J. T.; Yu, K.; Liu, S.; Soriano, F.; Jin, L. 46P AB521, a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor, for the treatment of renal cell carcinoma. Ann. Oncol. 2022, 33, S21, DOI: 10.1016/j.annonc.2022.01.055There is no corresponding record for this reference.(c) Liao, K.; Foster, P.; Seitz, L.; Cheng, T.; Gauthier, K.; Lawson, K.; Jin, L.; Paterson, E. HIF-2α inhibitor AB521 modulates erythropoietin levels in healthy volunteers following a single oral dose. Eur. J. Cancer. 2022, 174, S20, DOI: 10.1016/S0959-8049(22)00856-5There is no corresponding record for this reference.
- 8(a) Atkins, M. B.; Tannir, N. M. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat. Rev. 2018, 70, 127– 137, DOI: 10.1016/j.ctrv.2018.07.0098ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVWrt7bI&md5=d181337092e8b4b707c0644f76f99886Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinomaAtkins, Michael B.; Tannir, Nizar M.Cancer Treatment Reviews (2018), 70 (), 127-137CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)A review. There has been significant progress in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC), with improved knowledge of disease biol. and the introduction of targeted agents and immunotherapies. In this review, we discuss current and emerging first-line treatment options, including recent approvals of the tyrosine kinase inhibitor (TKI) cabozantinib and the immunotherapy combination of nivolumab (anti-programmed cell death 1 [PD-1])/ipilimumab (anti-cytotoxic T-lymphocyte-assocd. antigen 4 [CTLA-4]), and initial outcomes with the combination of atezolizumab (anti-PD-ligand 1 [PD-L1])/bevacizumab (anti-vascular endothelial growth factor [VEGF]). Key clin. data are reviewed, as these novel first-line treatments offer significant improvement, particularly for patients classified as intermediate/poor risk for whom previously available therapies have demonstrated limited efficacy. Treatment recommendations based on clin. evidence and expert opinion are discussed. We also review ongoing studies investigating combinations of checkpoint inhibitors with TKIs, including cabozantinib and axitinib, and with other novel immunomodulatory agents, and the potential role of single-agent immunotherapy for select patients. With a growing treatment armamentarium, identification and validation of biomarkers will be crucial for optimizing first-line selection and treatment sequences.(b) Nickerson, M. L.; Jaeger, E.; Shi, Y.; Durocher, J. A.; Mahurkar, S.; Zaridze, D.; Matveev, V.; Janout, V.; Kollarova, H.; Bencko, V.; Navratilova, M.; Szeszenia-Dabrowska, N.; Mates, D.; Mukeria, A.; Holcatova, I.; Schmidt, L. S.; Toro, J. R.; Karami, S.; Hung, R.; Gerard, G. F.; Linehan, W. M.; Merino, M.; Zbar, B.; Boffetta, P.; Brennan, P.; Rothman, N.; Chow, W.-H.; Waldman, F. M.; Moore, L. E. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 2008, 14, 4726– 4734, DOI: 10.1158/1078-0432.CCR-07-4921There is no corresponding record for this reference.
- 9(a) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b014559ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGmsrzM&md5=20d7a36b75501c02570744857c82f325Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug DiscoveryHuchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, KlausJournal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.(b) Aufiero, M.; Gilmour, R. Informing Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis. Acc. Chem. Res. 2018, 51, 1701– 1710, DOI: 10.1021/acs.accounts.8b001929bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSltL%252FJ&md5=cdfe3b6d51933baa54b098102d7d54ccInforming Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in CatalysisAufiero, Marialuisa; Gilmour, RyanAccounts of Chemical Research (2018), 51 (7), 1701-1710CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)The axioms of stereoelectronic theory constitute an atlas to navigate the contours of mol. space. All too rarely lauded, the advent and development of stereoelectronic theory has been one of org. chem.'s greatest triumphs. Inevitably, however, in the absence of a comprehensive treatise, many of the field's pioneers do not receive the veneration that they merit. Rather their legacies are the stereoelectronic pillars that persist in teaching and research. This ubiquity continues to afford practitioners of org. chem. with an abundance of opportunities for creative endeavor in reaction design, in conceiving novel activation modes, in preorganizing intermediates, or in stabilizing productive transition states and products. Antipodal to steric governance, which mitigates destabilizing nonbonding interactions, stereoelectronic control allows well-defined, often complementary, conformations to be populated. Indeed, the prevalence of stabilizing hyperconjugative interactions in biosynthetic processes renders this approach to mol. preorganization decidedly biomimetic and, by extension, expansive. In this Account, the evolution and application of a simple donor-acceptor model based on the fluorine gauche effect is delineated. Founded on reinforcing hyperconjugative interactions involving C(sp3)-H bonding orbitals and C(sp3)-X antibonding orbitals [σC-H → σC-X*], this general stratagem has been used in conjunction with an array of secondary noncovalent interactions to achieve acyclic conformational control (ACC) in structures of interest. These secondary effects range from 1,3-allylic strain (A1,3) through to electrostatic charge-dipole and cation-π interactions. Synergy between these interactions ensures that rotation about strategic C(sp3)-C(sp3) bonds is subject to the stereoelectronic requirement for antiperiplanarity (180°). Logically, in a generic [X-CH2-CH2-Y] system (X, Y = electron withdrawing groups) conformations in which the two C(sp3)-X bonds are synclinal (i.e., gauche) are significantly populated. As such, simple donor-acceptor models are didactically and predictively powerful in achieving topol. preorganization. In the case of the gauche effect, the low steric demand of fluorine ensures that the remaining substituents at the C(sp3) hybridized center are placed in a predictable area of mol. space: An exit vector analogy is thus appropriate. Furthermore, the intrinsic chem. stability of the C-F bond is advantageous, thus it may be considered as an inert conformational steering group: This juxtaposition of size and electronegativity renders fluorinated org. mols. unique among the organo-halogen series. Cognizant that the replacement of one fluorine atom in the difluoroethylene motif by another electron withdrawing group preserves the gauche conformation, it was reasoned that β-fluoroamines would be intriguing candidates for investigation. The burgeoning field of Lewis base catalysis, particularly via iminium ion activation, provided a timely platform from which to explore a postulated fluorine-iminium ion gauche effect. Necessarily, activation of this stereoelectronic effect requires a process of intramolecularization to generate the electron deficient neighboring group: Examples include protonation, condensation to generate iminium salts, or acylation. This process, akin to substrate binding, has obvious parallels with enzymic catalysis, since it perturbs the conformational dynamics of the system [synclinal-endo, antiperiplanar, synclinal-exo]. This Account details the development of conformationally predictable small mols. based on the [X-Cα-Cβ-F] motif through a logical process of mol. design and illustrates their synthetic value in enantioselective catalysis.(c) Thiehoff, C.; Rey, Y. P.; Gilmour, R. The Fluorine Gauche Effect: A Brief History. Isr. J. Chem. 2017, 57, 92– 100, DOI: 10.1002/ijch.2016000389chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFCmsbjM&md5=d429fe6b372f943cd018490487ce67a5The Fluorine Gauche Effect: A Brief HistoryThiehoff†, Christian; Rey†, Yannick P.; Gilmour, RyanIsrael Journal of Chemistry (2017), 57 (1-2), 92-100CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)Transforming fluorine gauche effect from an academic curiosity to acyclic conformational control strategy has enriched mol. design. This approach to modulating structure has proven to be particularly valuable in construction of functional small mols., finding application in diverse disciplines, from therapeutic medicine to enantioselective catalysis. In contrast to well-established arsenal of conformational control tactics, in which conformer populations result from minimising nonbonding interactions, the effect is attributable to stabilizing interactions comprised of two components: stereoelectronic and electrostatic. Conformer populations are partially detd. by favorable, hyperconjugative interactions involving proximal electron-rich σ-bonds, π-systems, and nonbonding electron pairs with antibonding orbital of C-F σ-bond: σ→σ*, π→σ*, and n→σ*, resp. Electrostatic, charge-dipole interactions also play a role in stabilizing counter-intuitive conformations. These noncovalent interactions, permissible on account of low van der Waals radius and high electronegativity of fluorine atom, render this effect fundamentally important and practically valuable in structural chem. Contribution to Rosarium Philosophorum in honour of Prof.Jack David Dunitz FRS, we endeavour to delineate, albeit in an abridged form, evolution of fluorine gauche effect from a fundamental study to ubiquitous component of phys. org. chem.(d) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.2009019569dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFSqtb0%253D&md5=76c049e74a5ebf68bbc4800eb2a82afcSynthesis and Structure of Stereoisomeric Multivicinal HexafluoroalkanesHunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, DavidAngewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.
- 10(a) Sarie, J. C.; Thiehoff, C.; Neufeld, J.; Daniliuc, C. G.; Gilmour, R. Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis. Angew. Chem., Int. Ed. 2020, 59, 15069– 15075, DOI: 10.1002/anie.20200518111ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFCjtbnI&md5=443ff10462246e29adb85e9b50810648Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) CatalysisSarie, Jerome C.; Thiehoff, Christian; Neufeld, Jessica; Daniliuc, Constantin G.; Gilmour, RyanAngewandte Chemie, International Edition (2020), 59 (35), 15069-15075CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The chromane nucleus is common to a plenum of bioactive small mols. where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl Ph ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.(b) Neufeld, J.; Stünkel, T.; Mück-Lichtenfeld, C.; Daniliuc, C. G.; Gilmour, R. Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2]→[CF2CHF] Isosterism. Angew. Chem., Int. Ed. 2021, 60, 13647– 13651, DOI: 10.1002/anie.20210222211bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVWqsLnL&md5=d5a5f5a6f00b6f6c7932892cc0414777Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2] → [CF2CHF] IsosterismNeufeld, Jessica; Stuenkel, Timo; Mueck-Lichtenfeld, Christian; Daniliuc, Constantin G.; Gilmour, RyanAngewandte Chemie, International Edition (2021), 60 (24), 13647-13651CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Satd., fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF2 (>20 examples, up to >95%). A range of diverse substituents are tolerated under std. catalysis conditions and this is interrogated by Hammett anal. X-ray anal. indicates a preference for the CH-F bond to occupy a pseudo-axial orientation, consistent with stabilizing σC-H→σC-F* interactions. The replacement of the sym. [CH2-CH2] motif by [CF2-CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational anal. and is consistent with stereoelectronic theory.(c) Häfliger, J.; Sokolova, O. O.; Lenz, M.; Daniliuc, C. G.; Gilmour, R. Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis. Angew. Chem., Int. Ed. 2022, 61, 61, DOI: 10.1002/anie.202205277There is no corresponding record for this reference.
- 11(a) Rodil, A.; Bosisio, S.; Ayoup, M. S.; Quinn, L.; Cordes, D. B.; Slawin, A. M. Z; Murphy, C. D.; Michel, J.; O’Hagan, D. Metabolism and Hydrophilicity of the Polarized ‘Janus face’ All-cis Tetrafluorocyclohexyl Ring, a Candidate Motif for Drug Discovery. Chem. Sci. 2018, 9, 3023, DOI: 10.1039/C8SC00299AThere is no corresponding record for this reference.(b) Johnson, B. M.; Shu, Y.-Z.; Zhuo, X.; Meanwell, N. A. Metabolic and Pharmaceutical Aspects of Fluorinated Compounds. J. Med. Chem. 2020, 63, 6315– 6386, DOI: 10.1021/acs.jmedchem.9b0187710bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFCrs7o%253D&md5=a8163c3ebf456de6932a4b941bb52d14Metabolic and Pharmaceutical Aspects of Fluorinated CompoundsJohnson, Benjamin M.; Shu, Yue-Zhong; Zhuo, Xiaoliang; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2020), 63 (12), 6315-6386CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochem. properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated mols. are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C-F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compds. In this Perspective, we summarize the literature assocd. with the metab. of fluorinated mols., focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.
- 12(a) Meyer, S.; Hafliger, J.; Gilmour, R. Expanding Organofluorine Chemical Space: The Design of Chiral Fluorinated Isosteres Enabled by I(I)/I(III) Catalysis. Chem. Sci. 2021, 12, 10686– 10695, DOI: 10.1039/D1SC02880D12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVOmu7jN&md5=12f46b8d00ac70a8db3ebdf9165c9ed7Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(I)/I(III) catalysisMeyer, Stephanie; Haefliger, Joel; Gilmour, RyanChemical Science (2021), 12 (32), 10686-10695CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Short aliph. groups are prevalent in bioactive small mols. and play an essential role in regulating physicochem. and mol. recognition phenomena. Delineating their biol. origins and significance have resulted in landmark developments in synthetic org. chem.: Arigoni's venerable synthesis of the chiral Me group is a personal favorite. While radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chem. space for small mol. drug discovery. Accelerated by advances in I(I)/I(III) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals vols. This Perspective surveys key developments in the design and synthesis of short multivicinal fluoroalkanes under the auspices of main group catalysis paradigms.(b) Molnár, I. G.; Gilmour, R. Catalytic Difluorination of Olefins. J. Am. Chem. Soc. 2016, 138 (15), 5004– 5007, DOI: 10.1021/jacs.6b0118312bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFeitL8%253D&md5=f11a1bb6120267a8333f9daded4f1159Catalytic Difluorination of OlefinsMolnar, Istvan Gabor; Gilmour, RyanJournal of the American Chemical Society (2016), 138 (15), 5004-5007CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mol. editing with fluorine is a validated strategy for modulating the structure and function of org. systems. In the current arsenal of catalytic dihalogenation technologies, the direct generation of the vicinal difluoride moiety from simple olefins without a prefunctionalization step remains conspicuously absent. Herein we report a catalytic, vicinal difluorination of olefins displaying broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are also disclosed.(c) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Catalytic, Diastereoselective 1,2-Difluorination of Alkenes. J. Am. Chem. Soc. 2016, 138 (15), 5000– 5003, DOI: 10.1021/jacs.6b0239112chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XltlOgurk%253D&md5=59fbca62979aa25931d0261e49a948f5Catalytic, Diastereoselective 1,2-Difluorination of AlkenesBanik, Steven M.; Medley, Jonathan William; Jacobsen, Eric N.Journal of the American Chemical Society (2016), 138 (15), 5000-5003CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities. The obsd. sense of stereoinduction implicates anchimeric assistance pathways in reactions of alkenes bearing neighboring Lewis basic functionality.(d) Molnár, I. G.; Thiehoff, C.; Holland, M. C.; Gilmour, R. Catalytic, Vicinal Difluorination of Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl and Ethyl Groups. ACS Catal. 2016, 6, 7167– 7173, DOI: 10.1021/acscatal.6b0215512dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWjur3J&md5=0dc8e44a2e28dd543f1bf09de52f54abCatalytic, Vicinal Difluorination of Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl and Ethyl GroupsMolnar, Istvan G.; Thiehoff, Christian; Holland, Mareike C.; Gilmour, RyanACS Catalysis (2016), 6 (10), 7167-7173CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Contemporaneous reports describing the vicinal difluorination of olefins relying on I(I)/I(III) catalysis have augmented the arsenal of dihalogenation methods and provided a soln. to this longstanding challenge in olefin functionalization. In both studies, success was contingent on the in situ generation of ArIF2 from a simple aryl iodide, HF source, and suitable terminal oxidant. The first report by Jacobsen and co-workers employed a resorcinol-derived aryl iodide/m-CPBA oxidant combination, while this lab. relied on p-iodotoluene and Selectfluor. The complementarity of these approaches ensures that a wide variety of electronically distinct olefins are viable substrates for this transformation. This perspective describes our development of a catalytic difluorination of terminal olefins as a means to efficiently construct a hybrid, chiral bioisostere of the trifluoromethyl and Et groups in the broader context of mol. design and highlights key reports from other labs. that accelerated the study.
- 13(a) Moock, D.; Wagener, T.; Hu, T.; Gallagher, T.; Glorius, F. Enantio- and Diastereoselective, Complete Hydrogenation of Benzofurans by Cascade Catalysis. Angew. Chem., Int. Ed. 2021, 60, 13677– 13681, DOI: 10.1002/anie.20210391013ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCktrjN&md5=d1450f4fbfb19e932eb1ab50e917f10eEnantio- and Diastereoselective, Complete Hydrogenation of Benzofurans by Cascade CatalysisMoock, Daniel; Wagener, Tobias; Hu, Tianjiao; Gallagher, Timothy; Glorius, FrankAngewandte Chemie, International Edition (2021), 60 (24), 13677-13681CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report an enantio- and diastereoselective, complete hydrogenation of multiply substituted benzofurans in a one-pot cascade catalysis. The developed protocol facilitates the controlled installation of up to six new defined stereocenters and produces architecturally complex octahydrobenzofurans, prevalent in many bioactive mols. A unique match of a chiral homogeneous ruthenium-N-heterocyclic carbene complex and an in situ activated rhodium catalyst from a complex precursor act in sequence to enable the presented process.(b) Ponra, S.; Rabten, W.; Yang, J.; Wu, H.; Kerdphon, S.; Andersson, P. G. Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic Centers. J. Am. Chem. Soc. 2018, 140, 13878– 13883, DOI: 10.1021/jacs.8b0877813bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVantLzE&md5=2449494df94a4a36c0c6323921c13750Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic CentersPonra, Sudipta; Rabten, Wangchuk; Yang, Jianping; Wu, Haibo; Kerdphon, Sutthichat; Andersson, Pher G.Journal of the American Chemical Society (2018), 140 (42), 13878-13883CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The synthesis of chiral fluorine contg. motifs, in particular, chiral fluorine mols. with two contiguous stereogenic centers, has attracted much interest in research due to the limited no. of methods available for their prepn. Herein, authors report an atom-economical and highly stereoselective synthesis of chiral fluorine mols. with two contiguous stereogenic centers via azabicyclo iridium-oxazoline-phosphine-catalyzed hydrogenation of readily available vinyl fluorides. Various arom., aliph., and heterocyclic systems with a variety of functional groups were compatible with the reaction and provide the highly desirable product as single diastereomers with excellent enantioselectivities.(c) Ponra, S.; Yang, J.; Kerdphon, S.; Andersson, P. G. Asymmetric Synthesis of Alkyl Fluorides: Hydro- genation of Fluorinated Olefins. Angew. Chem., Int. Ed. 2019, 58, 9282– 9287, DOI: 10.1002/anie.201903954There is no corresponding record for this reference.(d) Kaukoranta, P.; Engman, M.; Hedberg, C.; Bergquist, J.; Andersson, P. G. Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins. Adv. Synth. Catal. 2008, 350, 1168– 1176, DOI: 10.1002/adsc.20080006213dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtVWhsLg%253D&md5=489b0c10e6920908d8371fd0384d273bIridium catalysts with chiral imidazole-phosphine ligands for asymmetric hydrogenation of vinyl fluorides and other olefinsKaukoranta, Paeivi; Engman, Mattias; Hedberg, Christian; Bergquist, Jonas; Andersson, Pher G.Advanced Synthesis & Catalysis (2008), 350 (7+8), 1168-1176CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)New chiral bidentate imidazole-phosphine ligands have been prepd. and evaluated for the iridium-catalyzed asym. hydrogenation of olefins. The imidazole-phosphine-ligated iridium catalysts hydrogenated trisubstituted olefins with the same sense of enantiodiscrimination as known iridium catalysts possessing oxazole and thiazole as N-donors. The imidazole-based catalysts were shown to hydrogenate vinyl fluorides, in some cases with the highest ee values published to date.(e) Le, D. N.; Johnson, H. C.; Lam, Y.-H.; Sun, C.; Cheng, L.; Belyk, K. M. Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation. Org. Lett. 2024, 26, 4059– 4064, DOI: 10.1021/acs.orglett.4c00982There is no corresponding record for this reference.
- 14(a) Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana- Vidal, V. Synthesis 2016, 48, 2523. Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2016, 48, 2523– 2539, DOI: 10.1055/s-0035-156164814ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xptl2qtbc%253D&md5=622021ab0bd3f2555593e327726f2e61Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic ResolutionEcheverria, Pierre-Georges; Ayad, Tahar; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieSynthesis (2016), 48 (16), 2523-2539CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)The transition-metal-catalyzed asym. transfer hydrogenation (ATH) and asym. hydrogenation (AH) of α- and β-substituted ketone or imine derivs. are efficient methods for accessing chiral alcs. or amines bearing up to three stereogenic centers through a dynamic kinetic resoln. (DKR) process. This review provides a summary of recent work in this field, focusing on the development of new catalytic systems and on the extension of these asym. redns. to new classes of substrates. 1 Introduction 2 Asym. Hydrogenation via Dynamic Kinetic Resoln. 2.1 α-Substituted Ketones 2.2. α-Substituted β-Keto Esters and Amides 2.3 α-Substituted β-Keto Phosphonates and Sulfones 2.4 α,α'-Disubstituted Cyclic Ketones 2.5 α,β-Disubstituted Cyclic Ketones 2.6 Imine Derivs. 3 Asym. Transfer Hydrogenation via Dynamic Kinetic Resoln. 3.1 α-Substituted β-Diketones and Ketones 3.2 α-Substituted β-Keto Esters, Amides and Phosphonates 3.3 β-Substituted α-Keto Esters and Phosphonates 3.4 β-Substituted γ-Keto Esters 3.5 β-Alkoxy Ketones 3.6 Imine Derivs. 4 Conclusion.(b) Molina Betancourt, R.; Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2021, 53, 30– 50, DOI: 10.1055/s-0040-170591814bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVSqu7vE&md5=5a9197d2825a27720bf4841e39d4c368Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic ResolutionMolina Betancourt, Ricardo; Echeverria, Pierre-Georges; Ayad, Tahar; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieSynthesis (2021), 53 (1), 30-50CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)A review. Based on the ever-increasing demand for enantiomerically pure compds., the development of efficient, atom-economical and sustainable methods to produce chiral alcs. and amines was a major concern. Homogeneous asym. catalysis with transition-metal complexes including asym. hydrogenation (AH) and transfer hydrogenation (ATH) of ketones and imines through dynamic kinetic resoln. (DKR) allowing the construction of up to three stereogenic centers was the main focus of the present short review, emphasizing the development of new catalytic systems combined to new classes of substrates and their applications as well.
- 15Ros, A.; Magriz, A.; Dietrich, H.; Fernandez, R.; Alvarez, E.; Lassaletta, J. M. Enantioselective Synthesis of Vicinal Halohydrins via Dynamic Kinetic Resolution. Org. Lett. 2006, 8 (1), 127– 130, DOI: 10.1021/ol052821k15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yrs7bF&md5=797c310f7adf3afd8893de0a5bc47d1aEnantioselective Synthesis of Vicinal Halohydrins via Dynamic Kinetic ResolutionRos, Abel; Magriz, Antonio; Dietrich, Hansjoerg; Fernandez, Rosario; Alvarez, Eleuterio; Lassaletta, Jose M.Organic Letters (2006), 8 (1), 127-130CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Expanding the scope of enantioselective catalysis via dynamic kinetic resoln. (DKR), transfer hydrogenation of a variety of cyclic α-halo ketones was accomplished using the Noyori/Ikariya (R,R) or (S,S) catalysts and either HCO2H/Et3N or HCO2Na/n-Bu4NBr in H2O/CH2Cl2 as the hydrogen sources. Good yields of vicinal bromo-, chloro-, and fluorohydrins with excellent de and ee levels were achieved in most cases after a simple tuning of reaction conditions.
- 16Touge, T.; Nara, H.; Kida, M.; Matsumura, K.; Kayaki, Y. Convincing Catalytic Performance of Oxo-Tethered Ruthenium Complexes for Asymmetric Transfer Hydrogenation of Cyclic α-Halogenated Ketones through Dynamic Kinetic Resolution. Org. Lett. 2021, 23, 3070– 3075, DOI: 10.1021/acs.orglett.1c00739There is no corresponding record for this reference.
- 17Betancourt, R. M.; Phansavath, P.; Ratovelomanana-Vidal, V. Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols Through Dynamic Kinetic Resolution. J. Org. Chem. 2021, 86, 12054– 12063, DOI: 10.1021/acs.joc.1c0141517https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslegsL7O&md5=677ffe13a28ada49f288de4fdf833aeaRu(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols through Dynamic Kinetic ResolutionBetancourt, Ricardo Molina; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieJournal of Organic Chemistry (2021), 86 (17), 12054-12063CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Enantioenriched cis-3-fluoro-chroman-4-ol derivs. cis-I (R = H, 8-Me, 7-Br, 6-F, etc.; X = O, S) were conveniently prepd. by ruthenium-catalyzed asym. transfer hydrogenation of a new family of 3-fluoro chromanones II through a dynamic kinetic resoln. process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (1:1) as the hydrogen source, affording the reduced fluorinated alcs. cis-I in good yields (80-96%), high diastereomeric ratios (up to 99:1 dr) and excellent enantioselectivities (up to >99% ee).
- 18Molina Betancourt, R.; Phansavath, P.; Ratovelomanana-Vidal, V. Straightforward Access to Enantioenriched cis-3-Fluoro-Dihydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution. Molecules 2022, 27, 995, DOI: 10.3390/molecules2703099518https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktFagt78%253D&md5=9e39378a858aa75c3bca147d25c0ec43Straightforward Access to Enantioenriched cis-3-Fluoro-tetrahydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic ResolutionMolina Betancourt, Ricardo; Phansavath, Phannarath; Ratovelomanana-Vidal, VirginieMolecules (2022), 27 (3), 995CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A practical method for the asym. transfer hydrogenation/dynamic kinetic resoln. of N-Boc 3-fluoro-dihydroquinolin-4-ones I [R = H, 6-Me, 7-OMe, 6,7-(OMe)2, etc.] into the corresponding cis-fluoro alcs. II in 70-96% yields, up to 99:1 diastereomeric ratio (dr) and up to >99% ee (enantiomeric excess) by using the ruthenium complex Ts-DENEB and a formic acid/triethylamine (1:1) mixt. as the hydrogen donor under mild conditions was reported.
- 19(a) Wang, T.; Phillips, E. M.; Dalby, S. M.; Sirota, E.; Axnanda, S.; Shultz, C. S.; Patel, P.; Waldman, J. H.; Alwedi, E.; Wang, X.; Zawatzky, K.; Chow, M.; Padivitage, N.; Weisel, M.; Whittington, M.; Duan, J.; Lu, T. Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process. Org. Process Res. Dev. 2022, 26, 543– 550, DOI: 10.1021/acs.oprd.1c0024219ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVOkurvI&md5=e55f870e8daa6622a3943225174aaa7eManufacturing Process Development for Belzutifan. Part 5: A Streamlined Fluorination-DKR ProcessWang, Tao; Phillips, Eric M.; Dalby, Stephen M.; Sirota, Eric; Axnanda, Stephanus; Shultz, C. Scott; Patel, Pratiq; Waldman, Jacob H.; Alwedi, Embarek; Wang, Xiao; Zawatzky, Kerstin; Chow, Matthew; Padivitage, Nilusha; Weisel, Mark; Whittington, Michael; Duan, Jianjun; Lu, TaotaoOrganic Process Research & Development (2022), 26 (3), 543-550CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Here, the fluorination-DKR (dynamic kinetic resoln.) process for the com. supply of belzutifan (MK-6482) is reported. Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed based on increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of fluorodiol product I with low process mass intensity (PMI).(b) McCann, S. D.; Dubina, S. H.; Kosjek, B.; Alwedi, E.; Behre, T.; Burgess, S. A.; Dal Poggetto, G.; DiRocco, D. A.; Hartmanshenn, C.; McMullen, J. P.; Padivitage, N.; Sun, A. C. Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5 – Chemoenzymatic Diastereoselective Fluorination/DKR. Org. Process Res. Dev. 2024, 28, 441– 450, DOI: 10.1021/acs.oprd.3c00421There is no corresponding record for this reference.
- 20Bacheley, L.; Molina Betancourt, R.; Ravindra, R.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. Asymmetric Synthesis of Monofluorinated Carbocyclic Alcohols and Vicinal Difluorinated Heterocycles and Carbocycles. Eur. J. Org. Chem. 2023, 26, e202300383 DOI: 10.1002/ejoc.202300383There is no corresponding record for this reference.
- 21Beatty, J. W.; Drew, S. L.; Epplin, M.; Fournier, J. T. A.; Gal; , Haelsig, K. T.; Hardman, C.; Kalisiak, J.; Lawson, K. V.; Leleti, M. R.; Mailyan, A. K.; Mata, G.; Rosen, B. R.; Wang, Z.; Yu, K.; Process For Preparing Tetralin Compounds. United States Patent No. US12145901B1, Arcus Biosciences, Inc., assignee..There is no corresponding record for this reference.
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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.
There is no corresponding record for this reference. - 23(a) Yamakawa, M.; Yamada, I.; Noyori, R. CH/π Attraction: The Origin of Enantioselectivity in Transfer Hydrogenation of Aromatic Carbonyl Compounds Catalyzed by Chiral η6-Arene-Ruthenium(II) Complexes. Angew. Chem., Int. Ed. 2001, 40, 2818– 2821, DOI: 10.1002/1521-3773(20010803)40:15<2818::AID-ANIE2818>3.0.CO;2-Y23ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1Wmu7k%253D&md5=22e49243ba09c78837336a990c3026baCH/π attraction: The origin of enantioselectivity in transfer hydrogenation of aromatic carbonyl compounds catalyzed by chiral η6-arene-ruthenium(II) complexesYamakawa, Masashi; Yamada, Issaku; Noyori, RyojiAngewandte Chemie, International Edition (2001), 40 (15), 2818-2821CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)The transition state (TS) structures were studied using d. functional theory-based calcns. To fully explain the origin of the preference for the more crowded TS, a more reliable calcn. was conducted by using [RuH(OCH2CH2NH2)(η6-C6H6)] and a higher quality basis sets (RMP2/BS-III//B3LYP/BS-I). This model possessed a λ conformation for the chiral N,O-chelate ring and an S configuration at the Ru stereogenic center. Organometallic chem. often uses arene ligands and the two- to six-electron donors influence the electronic properties of the metallic center and also exert steric influences on neighboring ligands. Ring alkylation can facilitate reactions and also generate a larger asym. bias through enhanced electron donation and/or attractive secondary interaction, only if other perturbations remain similar. This study encourages a reconsideration of the origin of selectivity and reactivity noted in many other reactions promoted by transition metal-arene/cyclopentadienyl complexes and explains several exptl. findings with RuII-catalyzed asym. transfer hydrogenation.(b) Matsuoka, A.; Sandoval, C. A.; Uchiyama, M.; Noyori, R.; Naka, H. Why p-Cymene? Conformational Effect in Asymmetric Hydrogenation of Aromatic Ketones with a η6-Arene-Ruthenium(II) Catalyst. Chem.-Asian J. 2015, 10, 112– 115, DOI: 10.1002/asia.201402979There is no corresponding record for this reference.
- 24Bresciani, S.; O’Hagan, D. Stereospecific Benzylic Dehydroxyfluorination Reactions Using Bio’s TMS-Amine Additive Approach with Challenging Substrates. Tetrahedron Lett. 2010, 51, 5795– 5797, DOI: 10.1016/j.tetlet.2010.08.104There is no corresponding record for this reference.
- 25Valkó, K. Application of High-Performance Liquid Chromatography Based Measurements of Lipophilicity to Model Biological Distribution. Journal of Chromatography A 2004, 1037, 299– 310, DOI: 10.1016/j.chroma.2003.10.08425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvVels78%253D&md5=0a70bc59837a713de70eb041e3087954Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distributionValko, KlaraJournal of Chromatography A (2004), 1037 (1-2), 299-310CODEN: JCRAEY; ISSN:0021-9673. (Elsevier Science B.V.)A review. Octanol-water partition coeffs. are the most widely used measure of lipophilicity in modeling biol. partition/distribution. It has long been recognized that the retention of a compd. in reversed-phase liq. chromatog. is governed by its lipophilicity/hydrophobicity, and thus shows correlation with an octanol-water partition coeff. A great no. of publications have reported the efforts made to adjust HPLC conditions to measure surrogate octanol-water partition coeffs. However, there is no general consensus in this field. HPLC provides a platform to measure various types of lipophilicity that can provide relevant information about the compds.' property. In this way HPLC can be more valuable than just a surrogate for octanol-water partition. Chromatog. using biomimetic stationary phases may provide better insight for biol. partition/distribution processes. The research in this field is still ongoing and a large variety of HPLC conditions have been suggested. This review will outline approaches to overcoming the difficulties of standardization and describe different theor. approaches for comparison of HPLC lipophilicity data obtained under various conditions, along with the relation of these results to biol. partition/distribution.
Supporting Information
Supporting Information
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)
Deposition Numbers 2401479–2401481 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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