Background and Originality Content
Baloxavir marboxil (trade name: Xofluza) was developed by Roche and Shionogi, and could be used to treat human influenza virus infections by inhibiting the synthesis of viral mRNA to block the proliferation of influenza virus.[1] As a third-generation anti-influenza virus chemical drug, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections in February 2018,[2] subsequently baloxavir was approved by FDA in October. Baloxavir showed superior to Tamiflu in curative effect for influenza, for this indication, a single oral dose of baloxavir is recommended to be taken as soon as possible after onset of symptoms. Due to its excellent activity, the synthesis of baloxavir has attracted much attention from organic chemists. 7,8-difluorodibenzo[b,e]thiepin-11(6H)-one (2a ) is an important intermediate of baloxavir, and baloxavir could be obtained from 2a via a stereospecific Mitsunobu-type reaction (Figure 1).
Figure 1 Structures of baloxavir of its key synthetic intermediates
Scheme 1 Background and summary of this work.
In the original research,[3] NaBH4was used for the reduction of compound 1a to obtain racemic compound 2a , the cumbersome separation and purification involved with this method greatly limits the synthetic efficiency, the development of efficient asymmetric synthesis of 2a was highly desirable. So far, only the following reports were disclosed for the preparation of chiral compound 2a . The first was carbonyl reductases (RtSCR9, EBSDR8, or PpYSDR) catalyzed reduction, which was patented by Zheng and coworkers in 2018,[4] and 99% ee was achieved (Scheme 1a). Although enzyme-catalyzed reduction had achieved good stereocontrol, the high dosage and price of enzymes limited the application in industrial production. In 2019, Zhang et al developed the asymmetric reduction of 1a with (S )-2-methyl-oxazaborolidine as the chiral catalyst and BH3 as the reductant (CBS reduction), the high catalyst loading and the low enantioselectivity (85%) greatly limited its synthetic application (Scheme 1b).[5] In 2021, a ruthenium-catalyzed asymmetric transfer hydrogenation of 1a was patented by Zi and coworkers, they used Ru(p -cymene)TsDPEN as catalyst and azeotropic mixture of formic acid and triethylamine as the hydrogen donor, and 98% ee was achieved at 70 oC, further investigation and substrate scope of the reaction was not disclosed (Scheme 1c).[6] Our group has been devoted in asymmetric hydrogenation[7] and asymmetric transfer hydrogenation[8] for more than twenty years. In 2020, we disclosed a highly diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones in cooperation with Ratovelomanana-Vidal,[9] the tethered rhodium catalyst developed by Ratovelomanana-Vidal and Wills outperformed that of other catalysts.[10] Subsequently, the tethered rhodium has been applied in the dynamic kinetic asymmetric transfer hydrogenation of α-cyano ketones[11] and 3-hydroxy-4-substituted-maleimide derivatives[12]by our group and β-substituted α-diketones by Fang and coworkers.[13] As a continuation of investigation on asymmetric transfer hydrogenation, herein, we disclose a highly enantioselective asymmetric hydrogenation of heterocyclic diaryl ketones catalyzed by tethered rhodium catalyst (Scheme 1c).
Results and Discussion
Table 1 Optimization of the reaction conditions.