Iridium-Catalyzed Asymmetric Hydrogenation of α-Fluoro Ketones via a Dynamic Kinetic Resolution Strategy

Article abstract of DOI:10.1021/acs.orglett.0c02565

The discrimination of a fluorine atom from a hydrogen atom has been challenging in asymmetric catalysis. We herein report iridium-catalyzed hydrogenation of α-fluoro ketones using a strategy of dynamic kinetic resolution. Both enantiomeric and diastereomeric selectivities were satisfactory in the preparation of β-fluoro alcohols. The DFT calculation revealed a C-F···Na charge-dipole interaction in the transition state of hydride transfer. This noncovalent interaction would be responsible for the diastereomeric control.

Full text of DOI:10.1021/acs.orglett.0c02565

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Letter
Iridium-Catalyzed Asymmetric Hydrogenation of α‑Fluoro Ketones
via a Dynamic Kinetic Resolution Strategy
Xuefeng Tan, Weijun Zeng, Jialin Wen,* and Xumu Zhang*
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ABSTRACT: The discrimination of a fluorine atom from a hydrogen atom has been challenging in asymmetric catalysis. We herein
report iridium-catalyzed hydrogenation of α-fluoro ketones using a strategy of dynamic kinetic resolution. Both enantiomeric and
diastereomeric selectivities were satisfactory in the preparation of β-fluoro alcohols. The DFT calculation revealed a C−F···Na
charge−dipole interaction in the transition state of hydride transfer. This noncovalent interaction would be responsible for the
diastereomeric control.
luorine atoms could be found in many small molecules,
Fsome of which show important biological activities.
Monofluorinated organic molecules play roles not only as
pharmacophores but also as important targeting compounds.1,2
With two contiguous chiral centers, chiral β-fluoro alcohols are
useful synthons for the construction of enantiopure organo-
fluorine compounds.3 Chemists have been dedicated to the
development of methods to prepare chiral β-fluoro alcohols.4
The most important and widely applied method is the ring
opening reaction of epoxides (Scheme 1a). The use of
corrosive hydrogen fluoride in this SN2 reaction5 escalates
the safety risks and therefore increases the cost in equipment.
Moreover, problems in the regioselectivity and diastereose-
lectivity have still limited the application of this synthetic
approach.6 Asymmetric reduction of α-fluoro ketones would be
an alternative to prepare chiral β-fluoro alcohols since the
asymmetric hydrogenation of ketones has been a well-
established synthetic method in asymmetric catalysis.7
Dynamic kinetic resolution (DKR) seems to be a strategy for
this chemical transformation.8 Under basic conditions, two
enantiomeric α-functionalized ketones are in equilibrium via a
ketone−enolate tautomerization.9 When metal hydride ap-
proaches the carbonyl, steric hindrance of the α-substituent
might be responsible for the diastereoselectivity as one
enantiomer reacts faster than the other (Figure 1a). Apart
from the steric effect, conformational preference is another
strategy for DKR in ketone hydrogenation (Figure 1b). In a
five- or six-membered ring created by a covalent or hydrogen
bond, the steric effect would be enhanced by the ring strain.
The challenge for α-fluoro ketones lies in the small size of the
fluorine atom. The covalent radius of the fluorine atom (0.057
nm) is the second smallest in the organic compounds, only
larger than hydrogen (0.031 nm). The discrimination of the
fluorine atom from the hydrogen atom has therefore been a
great challenge in asymmetric catalysis. Thus, intermolecular
Scheme 1. Methods to Prepare α-Fluoro Alcohols
Received: July 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02565
© XXXX American Chemical Society
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A

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Letter
a
Table 1. Reaction Condition Optimization
Figure 1. Dynamic kinetic resolution in asymmetric hydrogenation of
ketones.
interactions other than steric hindrance would be more
practical.
The NH effect in transition metal-catalyzed homogeneous
hydrogenation10 has been demonstrated to be important for
carbonyl substrates. One plausible explanation involved
intermolecular hydrogen bonding between the NH proton
and the carbonyl oxygen atom. However, DFT computational
studies by Dub et al.11 and our group12 revealed an alternative
participation of alkali metal cation to NH proton in ruthenium-
and iridium-catalyzed hydrogenation of ketones. We envi-
sioned that either the hydrogen bonding between the covalent
fluorine atom and the protic NH or the through-space
interaction between the fluorine atom and alkali metal cation
could be utilized to discriminate fluorine from the hydrogen
atom in the DKR13 (Figure 1c).
Our study was initiated with the discovery of the
advantageous catalytic system. 2-Fluoro-1-phenylpropan-1-
one (1a) was selected as the model substrate, and both
ruthenium and iridium catalysts were tested at the beginning.
In order to ensure a well-established equilibrium between the
two enantiomeric starting materials, the hydrogenation rate
should be limited to a low level. We therefore carried out the
hydrogenation reaction in isopropanol under mild conditions
(room temperature, 10 bar of hydrogen pressure). In addition,
a relatively high base concentration was applied to promote the
ketone−enolate interconversion. With potassium tert-butoxide
as the base, Noyori and co-workers’s Ru(II) bisphosphine/
diamine catalyst14 yielded α-fluoro alcohol with full conversion
and high enantioselectivity (93% ee for the major diaster-
eomer), but the diastereoselectivity was poor (Table 1, entry
1). The iridium tridentate catalysts developed by our group,
Ir/f-amphox,15 Ir/f-amphol,16 and Ir/f-ampha,17 gave a desired
reactivity (full conversion) and enantioselectivity (>95% ee) as
expected. However, the diastereomeric induction was not
satisfactory. The highest dr value was obtained with Ir/f-ampha
L7 (entry 8, 76:24). After systematically screening different
bases, we found that 10 mol % sodium hydroxide gave much
improved diastereoselectivity under 1 bar of hydrogen pressure
(entry 10).
entry
catalyst
base (mol %)
dr
ee (%)
1
2
3
4
5
6
7
8
9
[Ru]
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
NaOH (10)
54:46
47:53
56:44
71:29
67:33
76:24
69:31
76:24
71:29
88:12
93
98
97
99
98
98
98
99
>99
99
L1/[Ir(COD)Cl]2
L2/[Ir(COD)Cl]2
L3/[Ir(COD)Cl]2
L4/[Ir(COD)Cl]2
L5/[Ir(COD)Cl]2
L6/[Ir(COD)Cl]2
L7/[Ir(COD)Cl]2
L8/[Ir(COD)Cl]2
L7/[Ir(COD)Cl]2
b
10
a
Reaction conditions: substrate (0.2 mmol), iPrOH (0.5 mL), H2 (10
bar), 25 °C. H2 (1 bar).
b
dr and ee values. The absolute configurations of products 2e
and 2p were determined by XRD analysis of a single crystal
structure, and an anti-selectivity was presented. This reaction
could be carried out at a larger scale without erosion of either
the dr or ee value (2d).
DFT computational studies (for details, see the Supporting
Information) were carried out to get insights into how both
enantioselectivity and diastereoselectivity were achieved in this
chemical transformation. Since the hydrogen activation was
already understood in our previous studies,11,12,16 we only
focused on the catalyst−substrate complexation in the
transition states of the hydride transfer step. The structures
of the transition states that lead to two pairs of diastereomers
were optimized in isopropanol (Figure 2). Due to the steric
hindrance of the bulky aryl group on the phosphorus atom, the
phenyl group from the substrate should only be placed at the
coordinating oxygen side. The calculated diastereomeric and
enantiomeric ratios18 were roughly in agreement with the
observed values (dr calculated 14:1 vs observed 9:1; ee
calculated >99.9% vs observed 99%). The stereocenter of
benzylic carbon was dictated by the facial approach of the
ketone substrate to the catalyst (top or bottom). Interestingly,
the Na−F and Na−O distances indicated a pronounced O,F-
bidentate chelation with sodium cation was present. This
charge−diploe interaction19 was believed to lower the energy
barriers in the hydride transfer step and therefore enhance the
With this optimized condition, we examined the reaction
scope of this chemical transformation (Table 2). When a
phenyl is attached to the carbonyl group, both the
enantioselectivities and diastereoselectivities were satisfactory
with 0.1% catalyst loading. The substituents on the benzene
ring, regardless of the position, did not have a significant
influence on the conversion and the stereoselectivities. The
substituent adjacent to the targeting C−F bond could vary
from alkyl group to aryl group (2p), with the retention of high
B
https://dx.doi.org/10.1021/acs.orglett.0c02565
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Table 2. Reaction Scope for Asymmetric α-Fluoro Ketones
c
via DKR
Figure 2. DFT optimized structures of the transition states for two
pairs of diastereomers and their relative energies. Gibbs free energies
are given in kcal/mol.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02565.
a
b
2e′ was derived from 2e using 4-nitrobenzoyl chloride and NEt3. 3
Experimental details, DFT calculations, and character-
ization data of compounds (PDF)
c
bar H2 pressure Reaction conditions: substrate 1 (0.2 mmol), iPrOH
(0.5 mL), H2 (1 bar), 25 °C.
Accession Codes
CCDC 2000463 and 2000464 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
diastereoselectivity (TS(R)-1 vs TS(R)-2 and TS(S)-1 vs
TS(S)-2, R or S refers to the benzylic chiral carbon).
In summary, we have developed a synthetic method to
prepare chiral fluoro alcohols via DKR. Both high enantiose-
lectivities and diastereoselectivities have been achieved in the
Ir-catalyzed hydrogenation of α-fluoro ketones. The DFT
calculation revealed an intramolecular C−F···Na interaction in
the hydride transfer step. This charge−dipole interaction
should be responsible for the diastereomeric control. We
believe that this strategy to discriminate a fluorine atom from a
hydrogen atom would be beneficial for asymmetric catalysis.
AUTHOR INFORMATION
Corresponding Authors
■
Jialin Wen − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis and Academy for Advanced
Interdisciplinary Studies, Southern University of Science and
C
https://dx.doi.org/10.1021/acs.orglett.0c02565
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Technology, Shenzhen, Guangdong 518055, China;
pubs.acs.org/OrgLett
Letter
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orcid.org/0000-0003-3328-3265; Email: wenjl@
sustech.edu.cn
Mechanism of asymmetric hydrogenation of ketones catalyzed by
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Xumu Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen, Guangdong 518055, China;
orcid.org/0000-0001-5700-0608; Email: zhangxm@
sustech.edu.cn
Authors
Xuefeng Tan − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen, Guangdong 518055, China
Weijun Zeng − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen, Guangdong 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02565
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was financially supported by the National Natural
Science Foundation of China (21801118) and the Science,
Technology and Innovation Commission of Shenzhen
(KQTD20150717103157174 and JCYJ20190807155201669).
(15) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.;
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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
(4), 970−975.
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D
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