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.