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.
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