a Unless otherwise specified, the reaction was conducted on 0.25 mmol scale at S/C = 200 for 6h.b S/C = 500. c S/C = 2000, 72 h. d S/C = 5000, 72 h.
We initiated our investigation with the optimization of the reaction conditions for the asymmetric transfer hydrogenation of 1a , and the results were summarized in Table 1. At first, we screened various ruthenium, iridium and rhodium catalysts with azeotropic mixture of formic acid and triethylamine as hydrogen donor and DCM as solvent with a substrate/catalyst ratio of 200/1 at rt. <5% of 2awas produced with Noyori and Ikariya’s ruthenium catalystCat1 [14] and iridium catalystCat2 15] (table 1, entry 1 and 2).[15] 99% yield and 98% ee were achieved with Noyori and Ikariya’s rhodium catalystCat3 .[15-16] The efficacy of Wills’s tethered ruthenium catalyst Cat4 [17] and Ikariya’s oxo-tethered ruthenium catalystCat5 [18] was also evaluated, 40% yield and 98% ee was observed with Wills’s catalyst Cat4 , whereas, only <5% yield was observed with Ikariya’s catalystCat5 . To our delight, the reaction with tethered rhodium catalyst Cat6 [19] proceeded smoothly to provide the desired product 2a with 99% yield and >99% ee, and Cat6 was identified as the best catalyst for the current reaction. The effect of solvent on the current was also assessed with a substrate catalyst ratio of 500/1 and 99% ee were achieved for all the solvents screened (Table 1, entries 7-11), for aprotic solvents such as THF, DCM and toluene, 57%, 35% and 56% yield was obtained respectively. The yield was decreased to 12% and 15% with protic solvent MeOH and i PrOH respectively, and THF as identified as best solvent for the current reaction. Hydrogen donors were also found to have a great effect on the reactivity of the catalyst, when the ratio of formic and triethyl amine was changed from 5:2 to 3:2 and 1:1, the yield was improved to 85% and 96% respectively (Table, entries 12-13). When the triethyl amine was replaced with DBU the yield was further elevated to 99%, whereas the yield dropped to 94% with bulky DIPEA as base. Other hydrogen donors such as sodium formate andi PrOH were also tested, and <5 and 17% yield was achieved respectively (Table 1, entries 16-17). When the substrate-catalyst ratio was increased to 2000/1, 98% yield and >99% ee were obtained in 72 h, and the yield was dropped to 65% with a substrate catalyst ratio of 5000/1 (Table 1, entries 18-19).
With the optimal reaction conditions in hand, the substrate scope of this asymmetric transfer hydrogenation was investigated, and the results were depicted in Scheme 2. For a series of dibenzoheptaheterocyclic ketones 1a -1l with a variety of diverse electron withdrawing or electron donating substituents at ortho, meta or para positions of the two phenyl rings, the corresponding (R )-dibenzoheterocyclic alcohols were obtained with high yields and excellent enantioselectivities. For oxa-cyclic substrate1m -1o , the reaction worked well to produce2m -2o with 95%-99% yield and 90%->99% ee. The absolute configuration of chiral compound 2a was unambiguously confirmed by X-ray Diffraction analysis (CCDC number: 2221153). We speculated that the remaining products 2 of ATH follow the same trend by analogy.
Scheme 2 Substrate scope of the reaction
To demonstrated the synthetic potential of the current reaction, gram-scale experiment of asymmetric transfer hydrogenation of1a was conducted with a substrate catalyst ratio of 1000/1, and >99% yield and >99% ee of 2a were achieved, which could be further transformed to baloxavir in just one step (Scheme 3).
Scheme 3 Gram-scale experiment
Conclusions
In conclusion, we have developed a highly practical and enantioselective rhodium-catalyzed asymmetric transfer hydrogenation of dibenzoheptaheterocyclic ketones with high activities and excellent enantioselectivities under mild reaction conditions. With this method, we had achieved the asymmetric reduction of a series of dibenzoheptaheterocyclic ketones, and the corresponding chiral alcohols have been obtained with 75%-99% yield and 90-99% ee. Significantly, this study provided a facile method for the asymmetric reduction of difluorodibenzo[b,e ]thiepin-11(6H)-one 1a to prepare the key chiral intermediate of baloxavir marboxil, synthetical potential of the current reaction has been demonstrated by the gram-scale amplification experiment with retention of yield and enantioselectivity with a substrate catalyst ratio of 1000/1.
Experimental
Representative procedure for the rhodium-catalysed asymmetric transfer hydrogenation: To a vial were added 1a (66 mg, 0.25 mmol, 1.0 equiv.), Cat6 (0.005 equiv., S/C = 200), and the solution of formic acid/DBU (1:1) (3.0 equiv) in dried THF (5 mL), under argon atmosphere. The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solvent was removed at reduced pressure, the resulting mixture was dissolved in ethyl acetate and then washed for 2 times with water, the combined organic layer was separated and concentrated at reduced pressure. Then the crude product was purified by silica gel column chromatography to give the pure product 2a with 99% yield and 99% ee. The enantiomeric excess was determined by HPLC on chiral IA column via gradient elution method, 254 nm, 25 oC, n Hexane: i PrOH = 95:5; flow 0.8 mL/min; tR (major) = 18.38 min, tR (minor) = 15.80 min. (the HPLC gradient elution method is shown in the Table S1 in the supporting information).
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
X. Zhang is indebted to the Southern University of Science and Technology (start-up fund), Shenzhen Science and Technology Innovation Committee (No. KQTD20150717103157174), Stable Support Plan Program of Shenzhen Natural Science Fund (Program Contract No. 20200925161222002, Key-Area Research and Development Program of Guangdong Province (No. 2020B010188001), Innovative Team of Universities in Guangdong Province (No. 2020KCXTD016), and National Natural Science Foundation of China (No. 21991113). G.-Q. Chen gratefully acknowledges the National Natural Science Foundation of China (No. 22171129) and Shenzhen Science and Technology Innovation Committee (JCYJ20210324104202007) for financial support.
References
[1] Heo, Y.-A., Baloxavir: First Global Approval. Drugs2018, 78 , 693-697.
[2] Hayden, F. G.; Sugaya, N.; Hirotsu, N.; Lee, N.; de Jong, M. D.; Hurt, A. C.; Ishida, T.; Sekino, H.; Yamada, K.; Portsmouth, S.; Kawaguchi, K.; Shishido, T.; Arai, M.; Tsuchiya, K.; Uehara, T.; Watanabe, A.; Baloxavir Marboxil Investigators, G., Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N. Engl. J. Med. 2018, 379 , 913-923.
[3] Shibahara, S.; Fukui, N.; Maki, T. Polycyclic pyridone derivative, crystal and preparation method thereof. JP6212678, 2017.
[4] Zheng, X.; Zhang, Y.; Fu, C.; Wu, Y. Synthetic method of anti-influenza drug baloflavone Baloxavir marboxil. CN109504721, 2019.
[5] Zhang, F.; Jiang, L.; Qiu, Y.; Ni, G.; Wang, H.; Liu, N.; Chen, Y.; Jiang, J. Preparation method of chiral dibenzo[b,e]thiepin-11-ol for preparation of baloxavir marboxil as antiviral drug. CN110143944, 2019.
[6] Zi, C.; Zeng, L.; Wang, Y. Method for synthesizing baloxavir marboxil intermediate from 7,8-difluorodibenzo[b,e]thiepin-11(6H)-one. CN112812095, 2021.
[7] (a) Yin, C.; Jiang, Y. F.; Huang, F.; Xu, C. Q.; Pan, Y.; Gao, S.; Chen, G. Q.; Ding, X.; Bai, S. T.; Lang, Q.; Li, J.; Zhang, X., A 13-million turnover-number anionic Ir-catalyst for a selective industrial route to chiral nicotine. Nat. Commun. 2023,14 , 3718; (b) Yu, J.; Huang, F.; Fang, W.; Yin, C.; Shi, C.; Lang, Q.; Chen, G.-Q.; Zhang, X., Discovery and development of ferrocene-based tetradentate ligands for Ir-catalysed asymmetric hydrogenation of ketone. Green Synth. Catal. 2022,3 , 175-178; (c) Zhao, Q.; Chen, C.; Wen, J.; Dong, X.-Q.; Zhang, X., Noncovalent Interaction-Assisted Ferrocenyl Phosphine Ligands in Asymmetric Catalysis. Acc. Chem. Res. 2020, 53 , 1905-1921; (d) Liang, Z.; Yang, T.; Gu, G.; Dang, L.; Zhang, X., Scope and Mechanism on Iridium-f-Amphamide Catalyzed Asymmetric Hydrogenation of Ketones. Chin. J. Chem. 2018, 36 , 851-856; (e) Yu, J.; Duan, M.; Wu, W.; Qi, X.; Xue, P.; Lan, Y.; Dong, X.-Q.; Zhang, X., Readily Accessible and Highly Efficient Ferrocene-Based Amino-Phosphine-Alcohol (f-Amphol) Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones. Chem. Eur. J.2017, 23 , 970-975; (f) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.; Dong, X.-Q.; Zhang, X., Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones. Org. Lett. 2016, 18 , 2938-2941; (g) Liu, D.; Gao, W.; Wang, C.; Zhang, X., Practical synthesis of enantiopure γ-amino alcohols by rhodium-catalyzed asymmetric hydrogenation of β-secondary-amino ketones. Angew. Chem., Int. Ed. 2005,44 , 1687-1689; (h) Tang, W.; Zhang, X., A chiral 1,2-bisphospholane ligand with a novel structural motif: applications in highly enantioselective Rh-catalyzed hydrogenations. Angew. Chem., Int. Ed. 2002, 41 , 1612-1614.
[8] (a) Jiang, Y.; Jiang, Q.; Zhang, X., A New Chiral Bis(oxazolinylmethyl)amine Ligand for Ru-Catalyzed Asymmetric Transfer Hydrogenation of Ketones. J. Am. Chem. Soc. 1998,120 , 3817-3818; (b) Xiong, Z.; Pei, C.; Xue, P.; Lv, H.; Zhang, X., Highly enantioselective transfer hydrogenation of racemic alpha-substituted beta-keto sulfonamides via dynamic kinetic resolution.Chem. Commun. 2018, 54 , 3883-3886; (c) Xiong, Z.; Tian, J.; Xue, P.; Zhang, X.; Lv, H., Enantioselective synthesis of chiral multicyclic γ-lactones via dynamic kinetic resolution of racemic γ-keto carboxylic acids. Org. Chem. Front. 2020,7 , 104-108.
[9] Wang, F.; Zheng, L.-S.; Lang, Q.-W.; Yin, C.; Wu, T.; Phansavath, P.; Chen, G.-Q.; Ratovelomanana-Vidal, V.; Zhang, X., Rh(III)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors.Chem. Commun. 2020, 56 , 3119-3122.
[10] (a) Echeverria, P.-G.; Ferard, C.; Phansavath, P.; Ratovelomanana-Vidal, V., Synthesis, characterization and use of a new tethered Rh(III) complex in asymmetric transfer hydrogenation of ketones. Catal. Commun. 2015, 62 , 95-99; (b) Matharu, D. S.; Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.; Wills, M., A Stereochemically Well-Defined Rhodium(III) Catalyst for Asymmetric Transfer Hydrogenation of Ketones. Org. Lett. 2005,7 , 5489-5491.
[11] Wang, F.; Yang, T.; Wu, T.; Zheng, L.-S.; Yin, C.; Shi, Y.; Ye, X.-Y.; Chen, G.-Q.; Zhang, X., Asymmetric Transfer Hydrogenation of alpha-Substituted-beta-Keto Carbonitriles via Dynamic Kinetic Resolution. J. Am. Chem. Soc. 2021, 143 , 2477-2483.
[12] Wang, F.; Zhang, Z.; Chen, Y.; Ratovelomanana-Vidal, V.; Yu, P.; Chen, G.-Q.; Zhang, X., Stereodivergent Synthesis of Chiral Succinimides via Rh-Catalyzed Asymmetric Transfer Hydrogenation.Nat. Commun. 2022, 13 , 7794.
[13] Chen, T.; Liu, W.; Gu, W.; Niu, S.; Lan, S.; Zhao, Z.; Gong, F.; Liu, J.; Yang, S.; Cotman, A. E.; Song, J.; Fang, X., Dynamic Kinetic Resolution of β-Substituted α-Diketones via Asymmetric Transfer Hydrogenation. J. Am. Chem. Soc. 2023, 145 , 585-599.
[14] Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R., Asymmetric Transfer Hydrogenation of Aromatic Ketones Catalyzed by Chiral Ruthenium(II) Complexes. J. Am. Chem. Soc. 1995,117 , 7562.
[15] Murata, K.; Ikariya, T.; Noyori, R., New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. J. Org. Chem. 1999,64 , 2186-2187.
[16] Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T., Practical Synthesis of Optically Active Styrene Oxides via Reductive Transformation of 2-Chloroacetophenones with Chiral Rhodium Catalysts.Org. Lett. 2002, 4 , 4373-4376.
[17] (a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M., A Class of Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenations of Ketones. J. Am. Chem. Soc. 2005, 127 , 7318-7319; (b) Cheung, F. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills, M., ”Tethered” Ru(II) Catalysts for Asymmetric Transfer Hydrogenation of Ketones. J. Org. Chem. 2005, 70 , 3188-3197.
[18] Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T., Efficient Access to Chiral Benzhydrols via Asymmetric Transfer Hydrogenation of Unsymmetrical Benzophenones with Bifunctional Oxo-Tethered Ruthenium Catalysts. J. Am. Chem. Soc.2016, 138 , 10084-10087.
[19] (a) Molina Betancourt, R.; Phansavath, P.; Ratovelomanana-Vidal, V., Rhodium-Catalyzed Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution of 3-Benzylidene-Chromanones.Org. Lett. 2021, 23 , 1621-1625; (b) Westermeyer, A.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V., Synthesis of Enantioenriched β-Hydroxy-γ-Acetal Enamides by Rhodium-Catalyzed Asymmetric Transfer Hydrogenation. Org. Lett. 2020,22 , 3911-3914; (c) Ratovelomanana-Vidal, V.; Phansavath, P.; Molina Betancourt, R.; Echeverria, P.-G.; Ayad, T., Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2020, 53 , 30-50; (d) He, B.; Phansavath, P.; Ratovelomanana-Vidal, V., Rhodium-catalyzed asymmetric transfer hydrogenation of 4-quinolone derivatives. Org. Chem. Front. 2020, 7 , 975-979; (e) He, B.; Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V., RhIII-Catalyzed Asymmetric Transfer Hydrogenation of α-Methoxy β-Ketoesters through DKR in Water: Toward a Greener Procedure. ChemSusChem 2019,12 , 3032-3036; (f) He, B.; Phansavath, P.; Ratovelomanana-Vidal, V., Rh-Mediated Asymmetric-Transfer Hydrogenation of 3-Substituted Chromones: A Route to Enantioenriched cis-3-(Hydroxymethyl)chroman-4-ol Derivatives through Dynamic Kinetic Resolution. Org. Lett.2019, 21 , 3276-3280; (g) Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V., Synthesis of Enantioenriched α,α-Dichloro- and α,α-Difluoro-β-Hydroxy Esters and Amides by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation. Org. Lett. 2018,20 , 5107-5111; (h) Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V., Ruthenium-catalyzed dynamic kinetic asymmetric transfer hydrogenation: stereoselective access to syn 2-(1,2,3,4-tetrahydro-1-isoquinolyl)ethanol derivatives. Org. Chem. Front. 2018, 5 , 1366-1370; (i) Zheng, L.-S.; Ferard, C.; Phansavath, P.; Ratovelomanana-Vidal, V., Rhodium-mediated asymmetric transfer hydrogenation: a diastereo- and enantioselective synthesis of syn-α-amido β-hydroxy esters. Chem. Commun.2018, 54 , 283-286; (j) Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Ferard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V., Asymmetric Transfer Hydrogenation of (Hetero)arylketones with Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Complexes: Scope and Limitations. J. Org. Chem. 2017, 82 , 5607-5615; (k) Ratovelomanana-Vidal, V.; Phansavath, P.; Echeverria, P.-G.; Ayad, T., Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution. Synthesis 2016, 48 , 2523-2539; (l) Monnereau, L.; Cartigny, D.; Scalone, M.; Ayad, T.; Ratovelomanana-Vidal, V., Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted β-Ketoesters. Chem. Eur. J. 2015, 21 , 11799-11806.