The organocatalytic enantiodivergent fluorination of β-ketodiaryl-phosphine oxides for the construction of carbon-fluorine quaternary stereocenters

Article abstract of DOI:10.1039/d0cc07770d

Commercially available cinchona alkaloids that can catalyze the enantiodivergent fluorination of β-ketodiarylphosphine oxides were developed to construct carbon-fluorine quaternary stereocenters. This protocol features a wide scope of substrates and excellent enantioselectivities, and it is scalable.

Full text of DOI:10.1039/d0cc07770d

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The organocatalytic enantiodivergent fluorination
of b-ketodiaryl-phosphine oxides for the
construction of carbon-fluorine quaternary
stereocenters†
Cite this: Chem. Commun., 2021,
57, 2069
Received 27th November 2020,
Accepted 8th January 2021
Shaolei Xie,ab Zhi-Juan He,a Ling-Hui Zhang,a Bo-Lun Huang,a Xiao-Wei Chen,a
DOI: 10.1039/d0cc07770d
ac
Zong-Song Zhana and Fu-Min Zhang
*
rsc.li/chemcomm
Commercially available cinchona alkaloids that can catalyze the their characteristics in various fields of fluorine chemistry.5
enantiodivergent fluorination of b-ketodiarylphosphine oxides Therefore, exploration of enantiodivergent construction of
were developed to construct carbon-fluorine quaternary stereo- chiral fluorine-containing quaternary stereocenters is needed
centers. This protocol features a wide scope of substrates and urgently, but is synthetically challenging.
excellent enantioselectivities, and it is scalable.
a-Substituted b-keto phosphine oxide is an important struc-
tural moiety,6 and it could be applied in different disciplines.7
The fluorine atom has unique properties, such as high electro- Preparation of this moiety has been an exciting research area in
negativity, a similar atomic radius to that of the hydrogen atom, recent years,8 and the corresponding transformations have also
and especially its switchable lipophilicity, bioavailability and been investigated.9 However, the asymmetric variant involving
metabolic stability of the corresponding parent compound. this motif has been underexplored until now. Its analogue
Hence, chiral fluorine-containing molecules have attracted b-keto phosphonate has been investigated in some asymmetric
attention from synthetic chemists, medicinal chemists, bio- transformations, and the transition metal-catalyzed asym-
chemists, and material scientists.1 Naturally available chiral metric fluorination has been developed independently by
organic fluorine-containing molecules are scarce.2 Hence, Sodeoka, Kim, and Jørgensen (Scheme 1a).10 Unfortunately,
enantioselective introduction of the fluorine atom into organic the organocatalytic asymmetric fluorination of b-keto phos-
molecules is an indispensable approach to efficiently access phine oxide or b-keto phosphonate has not been explored,
fluorine-containing compounds. Consequently, numerous especially in enantiodivergent transformations.11 Therefore,
asymmetric fluorination methodologies3 and some chiral fluo- development of asymmetric transformations involving b-keto
rinating reagents4 have been developed from synthetic com- phosphine oxide are necessary and important.
munities. Despite the significant achievements made in the
As privileged chiral organocatalysts, cinchona alkaloid (CA)
past decade, enantiodivergent preparation of two chiral com- derivatives have unique properties. In particular, they are readily
pounds with enantiotopic fluorine-containing stereocenters available chiral pseudoenantiomeric catalysts found in nature.
has not been perfectly solved. This is especially true for the Hence, an outstanding array of CA-catalyzed asymmetric reac-
production of two enantioisomers bearing a chiral fluorine- tions with excellent enantioselectivity have been developed.12
containing quaternary stereocenter for further investigation of Considering the unique catalytic abilities of CA derivatives, we
a State Key Laboratory of Applied Organic Chemistry & College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
E-mail: zhangfm@lzu.edu.cn
b Key Laboratory of Comprehensive and Highly Efficient Utilization of Salt Lake
Resources, Qinghai, Institute of Salt Lakes, Chinese Academy of Sciences,
Xining, Qinghai 810008, China
c Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Molecular Engineering, East China Normal
University, 3663 North Zhongshan Rd, Shanghai 200062, China
† Electronic supplementary information (ESI) available. CCDC 2034797, 2034799,
Scheme 1 The construction of carbon-fluorine quaternary stereocenters
from a-substituted b-keto phosphonates and phosphine oxides.
2034801–2034804, 2034806, and 2034807. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d0cc07770d
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wished to further expand the asymmetric reactions of b-keto (96% ee and 77% yield). For aryl moieties at the a-position of
phosphine oxide. We also wished to continue with our research the carbonyl group, most substrates with EWGs (e.g., F, Cl, Br,
into the efficient construction of aza-quaternary C–X bonds.13 and even CF3) or EDGs (e.g., Me and OMe) reacted well,
Hence, we report here an enantiodivergent fluorination of producing the desired products (S)-2ak-(S)-2as in good-to-
a-substituted b-keto phosphine oxide catalyzed by CA-derived excellent yields (50–94%) with 90–95% ee.16 It seems that the
catalysts. This reaction resulted in two enantio-enriched isomers meta-position substituent at the aryl ring had a marginal effect
with excellent enantiomeric excess (ee) from the same starting in product yields (low conversion) but slightly influenced the
materials (Scheme 1b).
enantioselectivity, and the products (S)-2am and (S)-2ar were
Initially, we selected 2-(diphenylphosphoryl)-1,2-diphenyl- isolated in 32% and 30% yields, respectively. 2-Naphthyl, 3-thienyl,
ethanone (1aa) as a model substrate, N-fluorodibenzene-sulfon- and different functionalized diaryl-substituted substrates were well
imide (NFSI) as the fluoride source, and commercially available tolerated, and yielded the corresponding products (S)-2at-(S)-2av in
CA derivatives as catalysts to investigate the reaction conditions for moderate yields with excellent enantioselectivities. Then, diaryl
fluorination (Table 1).14 Screening of various reaction parameters oxide moieties were examined, and various EDGs (Me, OMe) and
showed that when 4-pyrrolidinopyridine (PPY)15 was used as a base EWGs (Cl, CF3) substituents at the aryl ring had a slight influence
and 10% hydroquinidine (HQD, Cat. 1) was used as a catalyst, on the reaction outcomes, and delivered the expected products
the expected product 2aa was isolated in 91% yield with 87% ee (S)-2aw-(S)-2az in good yields with high enantioselectivies. Subse-
(entry 1). Pleasingly, lowering the reaction temperature resulted in quently, replacement of aryl substituents with aliphatic substituents
excellent enantioselectivity (94% ee) and good chemical yield (86%) in the a-branched position of the carbonyl group was investigated.
(entry 2).14,16 A further decrease in the reaction temperature led to Results showed that asymmetric fluorination was also compatible
low conversion, and the starting material 1aa was recovered. Finally, with the alkyl-substituted substrates, and the expected products
NFSI was replaced by other fluorine sources to further optimize the (S)-2ba-(S)-2be were isolated in good-to-excellent yields with good-to-
reaction conditions. However, better results were not obtained.14 excellent enantioselectivity. Finally, a cyclic substrate 1ca also
Therefore, the reaction parameters listed in entry 2 were selected as produced the desired fluorinating product (S)-2ca (95% yield and
the optimal reaction conditions.
90% ee),16 whereas the linear substrate 1cb gave good enantio-
Using these optimal conditions, we explored the scope of selectivity with a low yield.14 Hence, this methodology for
substrates for the (S)-selective procedure (Method I), and the asymmetric fluorination featured a wide scope of substrates in
reaction results are shown in Scheme 2. For aryl ketones terms of substituents at carbonyl a positions (cyclic or linear
moieties, various substrates bearing electron-donating groups alkyl substituents or aryl substituents), with each case yielding
(EDGs) or electron-withdrawing groups (EWGs) on the aryl ring the expected a-fluorinated product.
at ortho, meta, or para positions were first evaluated, which all
Two enantioisomers with chiral fluorine-containing stereo-
afforded the corresponding products (S)-2ab-(S)-2ai in good-to- centers, in general, showed very distinct properties in organic
excellent yields (54–92%) with excellent enantioselectivities functional molecules. Therefore, after completing expansion of
(r96% ee).16 Moreover, substrate 1aj with a-naphthyl group the substrate scope of (S)-products, we turned our attention to
was tolerated, and generated the desired product (S)-2aj enantiodivergent transformation. The pseudo-enantiomeric
catalyst hydroquinine (HQ, Cat. 2) was used to replace Cat. 1
under the optimal reaction conditions (entry 3, Table 1,
Method II) to prepare the corresponding (R)-configuration
Table 1 Optimization of the reaction conditionsa
products starting from the same materials. To our pleasure,
almost all expected (R)-products were synthesized readily merely
by varying the catalyst (Scheme 2).14 Various substrates bearing
EDGs or EWGs at different positions of three aryl rings or alkyl
substituents at the a-position of carbonyl group were also
compatible, and resulted in the desired products (R)-2 obtained
in good-to-excellent yields with excellent enantioselectivity, in
most cases.16 These results demonstrated that enantiodivergent
fluorinated products could be obtained concisely by varying
commercially available catalysts. However, in comparison with
Entry Cat.
Base
Temp. (1C) Time (h) Yieldb (%) eec (%)
the reaction results from its isomer Cat. 1, the yield and ee value of
(R)-2 products catalyzed by Cat. 2 were relatively lower in some
cases. To improve these unsatisfactory results, we screened other
commercially available cinchona catalysts (entries 4–6).14 Pleasingly,
when the dimetric catalyst Cat. 5 was used, the (R)-2aa product was
obtained in 95% yield with 95% ee through changing the base to
Cs2CO3 and the solvent to acetone (entry 6, Table 1, Method III).14
Therefore, these slightly changed reaction conditions were used to
improve some low yields and enantioselectivities of (R)-selective
1
2
3
4
5
6
Cat. 1 PPY
Cat. 1 PPY
Cat. 2 PPY
Cat. 3 PPY
Cat. 4 PPY
r.t.
24
72
72
72
72
72
91
86
50
36
43
95
À87d
À94
+92e
À94
+93
À10
À10
À10
À10
Cat. 5 Cs2CO3 À10
+95 f
a
b
Reaction was undertaken using substrate 1aa (0.1 mmol). Isolated
yield. ee was determined via UPC2. The (S)-2aa product was
obtained. The (R)-2aa product was obtained. 1.2 eq. Cs2CO3 was
used in 1.5 mL of acetone.
c
d
e
f
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a
Scheme 2 The substrate scope of the enantiodivergent fluorination of b-keto diarylphosphine oxides. The reaction was undertaken on a 0.1 mmol
scale, and isolated yield and ee values were determined via UPC2; b Method I was applied; c Method II was applied; d Method III was applied; e the reaction
was undertaken on a 1 g scale.
transformation, and some representative results are listed in moderate-to-excellent yields (r95%). This transformation
Scheme 2.14
features a wide scope of substrates, switchable enantioselec-
Furthermore, two gram-scale model reactions were carried tivity, and a scalable procedure.
out, and (S)-2aa was isolated in 94% ee with 85% yield, whereas
We are grateful to the NSFC (21772076, 21971095, 91956203)
(R)-2aa was isolated in 91% ee with 76% yield (Scheme 2). for financial support of this work.
Remarkably, a single recrystallization of two resulting products
could increase the ee value to 99%. These results indicated that
our methodology was practical for the preparation of fluo-
Conflicts of interest
rinated b-keto diarylphosphine oxide.
There are no conflicts to declare.
In conclusion, we developed, for the first time, the enantio-
divergent fluorination of a-substituted b-keto diarylphosphine
oxides catalyzed by commercially available CA derivatives. Two
desired enantioisomers with a fluorine-containing quaternary
stereocenter were obtained conveniently at r98% ee with
Notes and references
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2034804 ((R)-2ak) and 2034799 ((S)-2ca)†.
2072 | Chem. Commun., 2021, 57, 2069À2072
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