Copper-Catalyzed Enantioselective Difluoromethylation of Amino Acids via Difluorocarbene

Article abstract of DOI:10.1021/jacs.1c02697

Difluoromethyl amino acids (DFAA) exhibit intriguing biological properties, making them highly desirable motifs in agrochemical and pharmaceutical science. However, stereochemical control of direct difluoromethyl transformation via the difluorocarbene spe

Full text of DOI:10.1021/jacs.1c02697

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Copper-Catalyzed Enantioselective Difluoromethylation of Amino
Acids via Difluorocarbene
Lingzi Peng, Hongyi Wang, and Chang Guo*
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ABSTRACT: Difluoromethyl amino acids (DFAA) exhibit intriguing biological properties, making them highly desirable motifs in
agrochemical and pharmaceutical science. However, stereochemical control of direct difluoromethyl transformation via the
difluorocarbene species has not been demonstrated. Here we describe an efficient copper-catalyzed asymmetric difluoromethylation
reaction that systematically delivers chiral DFAA as rationally designed mechanism-based inhibitors of PLP-dependent amino acid
decarboxylases. The reaction employs difluoromonochloromethane, an abundant raw material, as the direct precursor of
difluorocarbene species, enabling the unprecedentedly direct conversion of amino esters into corresponding valuable DFAA products
in good yields with excellent enantioselectivities. This de novo synthesis creates opportunities to integrate an asymmetric catalytic
platform for the preparation of diverse libraries of biologically important DFAA derivatives and will support efforts in both drug
discovery and development.
he fluoroalkyl moiety is a key functional group with
diverse applications in the fields of pharmaceuticals,
Scheme 1. Design Plan for the Asymmetric Synthesis of
Quaternary DFAA Using HCFC-22
T
agrochemicals, and functional materials.1−7 Direct difluoro-
methyl (−CF2H) transformation8−17 is a fundamentally
important subject of organic synthesis in both the academic
and industrial sectors owing to the increasing demand for
various difluoromethylated molecules.18−20 However, the
efficient use of low-value, industrial raw materials, such as
difluoromonochloromethane (HCFC-22, Freon 22, or R-22),
for the manufacturing of the corresponding organofluorine
compounds is a critical task in modern chemical research.21−24
Typically, HCFC-22 upon treatment with an appropriate base
is used as a source to yield the difluorocarbene species (:CF2,
in its singlet ground state),25,26 which is well suited for the
synthesis of structurally diverse gem-difluorinated com-
pounds27−29 applicable in drug discovery and development
(Scheme 1A).30,31 Although representing a long-standing
problem to access valuable chiral difluoromethylated chem-
icals32 and build up molecular complexity, the intrinsic
instability and high reactivity of the difluorocarbene
species33−38 make it formidable for the introduction of
difluoromethyl moieties in a catalytic and asymmetric fashion.
To date, the difluoromethyl amino acids (DFAA) have been
intensively studied for their intriguing chemical structures and
promising diverse biological activities (Scheme 1B).39 As
fundamental biomolecules, DFAA, bearing tailored fluorinated
functional groups designed to inactivate their target enzymes
based upon loss of a fluoride atom by an E2 elimination
mechanism, play key roles in diverse cellular processes, and a
mechanistic understanding gained from this reaction is the
basis of designing many other suicide inhibitors as potential
drug candidates.40 For instance, the enzyme ornithine
decarboxylase (ODC) is the key regulator of the biosynthesis
of polyamines, and the aberrant expression of ODC is a critical
factor contributing to oncogenesis, making it a possible target
for therapeutic interventions.41 Typically, the fluorinated
ornithine analogue α-difluoromethylornithine (DFMO), a
mechanism-based inhibitor of pyridoxal phosphate (PLP)-
dependent ODC, is naturally believed to have potential utility
as an anticancer and chemopreventive agent.42 Furthermore,
the development of new stereoisomeric drugs43 has become a
focus in regulatory guidelines for pharmaceutical research,
Received: March 11, 2021
Published: April 26, 2021
https://doi.org/10.1021/jacs.1c02697
J. Am. Chem. Soc. 2021, 143, 6376−6381
© 2021 American Chemical Society
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a
whereas the above-mentioned examples of DFMO and DFAA
drugs are still marketed as a mixture of two enantiomers.
Consequently, an asymmetric catalytic approach toward the
stereoselective difluoromethyl functionalization of amino acids
could have a major effect on the discovery and development of
new pharmaceuticals.44
Table 1. Optimization of the Reaction Conditions
The conceptual advances of the stereoselective trans-
formation of difluorocarbene species together with the well-
established pharmaceutical interest of chiral DFAA prompted
us to target a method for enantioselective intermolecular
difluoromethylation of amino acids. Over 40 years ago,
difluoromethylation of aldimine esters with HCFC-22,
pioneered by Bey and co-workers, was reported to generate
racemic DFAA.45−48 Conventionally, existing protocols uni-
formly require stoichiometric quantities of strong and
indiscriminate base involving multistep sequences and/or
harsh conditions. We speculated that a mild reaction system
with well-established chiral transition metal complexes to
generate the N-metalated azomethine ylide49−51 as a binding
cavity might meet the aforementioned challenges, and the
proposed intermolecular reaction has advantages: readily
available feedstock, easily accessible substrate preparation,
single-step preparation, increased reaction diversity, and
asymmetric transformation of free difluorocarbene species
(Scheme 1C). Besides, enantioselective catalytic synthesis
offers flexibility in catalyst choice and facile delivery of distinct
stereoisomers by inversion of the catalyst configuration. Here,
we present a copper-catalyzed asymmetric difluoromethylation
of aldimine esters for the direct conversion of HCFC-22 to the
structurally diverse DFAA. This de novo synthesis creates
opportunities to integrate an asymmetric catalytic platform for
the preparation of diverse libraries of biologically important
DFAA derivatives and will support efforts in both drug
discovery and development.30,31
To test our hypothesis, we evaluate the feasibility of the
copper-catalyzed reaction between aldimine ester 1a and
HCFC-22 with Cs2CO3 as the base in tetrahydrofuran (THF)
(Table 1). An initial chiral ligand screen of this reaction
showed that the use of BOX ligand (R,R)-L1 led to the
difluoromethylated adduct 2a in 9% yield with 8% enantio-
meric excess (ee) (entry 1). The assessment of various ligands
displayed remarkable effects on the outcome of the reaction.
Gratifyingly, the desired 2a could be obtained in 51% yield
with 72% ee when a copper complex modified with the
Phosferrox ligand (S,Sp)-L3 was employed (entry 3).
Evaluation of a series of Phosferrox ligands revealed that the
use of Cu/(R,S,Sp)-L6 gave the best results, affording 2a in
76% yield with 96% ee (entry 6). Control experiments
confirmed that the ligand, copper catalyst, and the cofactor
base were all required for this transformation. No difluor-
omethylated adduct 2a was formed in the absence of any one
of the reaction components (ligand, copper, or base) (entries
7−9).
b
c
entry
L*
base
yield (%)
ee (%)
1
2
3
4
5
6
7
(R,R)-L1
(R)-L2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3

9
8
52
51
58
66
76
nr
nr
nr
52
72
92
94
96



(S,Sp)-L3
(S,Sp)-L4
(S,Sp)-L5
(R,S,Sp)-L6

d
8
(R,S,Sp)-L6
(R,S,Sp)-L6
9
a
Reactions were performed by using Cu(MeCN)4BF4 (10 mol %), L*
(12 mol %), 1a (0.1 mmol, 1.0 equiv), HCFC-22 (1 M), and Cs2CO3
(1 mmol, 10 equiv) in tetrahydrofuran (THF, 1 mL) at 25 °C;
hydrolysis with HCl (1 mol/L, 4 mL). Isolated yields after
chromatography are shown. The ee values were determined by
chiral high-performance liquid chromatography (HPLC) analysis. In
b
c
d
the absence of Cu(MeCN)4BF4.
acid (Glu) gave the desired quaternary amino esters 2a−2e in
52−76% yield and 90−97% ee. To showcase the scalability and
practicability of the present method, the enantioselective
difluoromethylation was conducted smoothly on a large scale
with a reduced catalyst loading of 5 mol % and reproducibly
provided enantioenriched 2a with equal efficiency (183 mg
scale, 80% yield, 96% ee). Moreover, homophenylalanine
(HPhe), phenylalanine (Phe), tyrosine (Tyr), tryptophan
(Trp), and veratrylglycine-derived aldimine esters could also
be tolerated without losses in reaction efficiency or
enantiocontrol, thus providing opportunities for further
elaboration of the products (2f−2j). It is worth mentioning
that both the C-difluoromethylation and O-difluoromethyla-
tion processes occurred and afforded corresponding bis-
difluoromethylated adduct 2k in 65% yield with 90% ee.
Besides, allylglycine and phenylglycine derivatives could also
be successfully converted into the corresponding difluorome-
thylated products (2l−2o) in excellent enantioselectivities
(96−98% ee). Notably, the opposite configuration of 2 can be
accessed by using the opposite enantiomer of the ligand
(R,S,Sp)-L6 under otherwise identical conditions (Table 2B).
Furthermore, a variety of ketimine esters also proved to be
excellent nucleophiles in the difluoromethylation reaction and
afforded the desired DFAA 2 in excellent enantioselectivities,
albeit in some instances with slightly diminished yield (Table
3, 2p−2t).
With these optimized reaction conditions for the asymmetric
difluoromethylation, we then explored the generality of this
reaction with various substituted amino esters (Table 2). As
shown in Table 2A, a diverse array of the aldimine esters
derived from both natural and non-natural α-amino acids
performed well in the presence of the chiral copper catalyst,
affording the desired products 2 in high yields and excellent
enantioselectivities (up to 98% enantiomeric excess). α-Alkyl-
substituted aldimine esters derived from alanine (Ala), leucine
(Leu), methionine (Met), aspartic acid (Asp), and glutamic
Specifically, DFMO was proved to be beneficial in the
treatment of African sleeping sickness,52 and the configuration
of DFMO is crucial for its anesthetic activity.44 Therefore,
concise methods for the asymmetric synthesis of DFMO in
high stereochemical purity are particularly valuable in
medicinal chemistry and pharmaceutical science. The feasi-
bility of the current methodology was evaluated to generate
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a
enantioenriched DFMO according to the following sequence.
Lysine (Lys)-derived aldimine ester 1u was subjected to the
asymmetric difluoromethylation reaction, and the correspond-
ing DFAA adduct 2u was obtained under reduction conditions
in moderate yield with excellent levels of enantioinduction
(Scheme 2A, 96% ee). Similarly, α-difluoromethyl-amino ester
Table 2. Scope of Aldimine Esters 1
Scheme 2. Synthetic Utility
2v was obtained in 56% yield after hydrolysis with 1 M HCl.
Subsequently, hydrolysis of the remaining ester group of 2v
furnished (R)-DMFO 3 in 98% yield. In contrast, the reaction
with (S,R,Rp)-L6 under otherwise identical conditions gave
DFAA adduct ent-2u and (S)-DMFO ent-3 with an opposite
absolute configuration, thereby giving comparable results to
both DFMO enantiomers (Scheme 2B).
a
Reactions were performed by using Cu(MeCN)4BF4 (10 mol %), L6
(12 mol %), 1a (0.1 mmol, 1.0 equiv), HCFC-22 (1 M), and Cs2CO3
(1 mmol, 10 equiv) in tetrahydrofuran (THF, 1 mL) at 25 °C;
hydrolysis with HCl (1 mol/L, 4 mL).
To investigate the catalytic mechanism, the racemate and
both enantiomers of aldimine esters 1m were used in the
copper catalytic process (Figure 1A). The chiral ligand
(R,S,Sp)-L6 effectively controls the absolute configuration of
the product 2m, regardless of the stereochemistry of the
starting nucleophiles 1m. The racemization profile of (R)-1m
(97% ee) was subsequently investigated (see Supporting
Information for details). We found that Cs2CO3 showed a
superior ability to promote rapid racemization of chiral imino
ester (R)-1m within 10 min (Figure 1B), which supported the
hypothesis that the nucleophilic N-metalated azomethine ylide
was responsible for the high catalytic activity and the observed
enantioinduction of this system.
a
Table 3. Scope of Ketimine Esters 1
When the reaction was performed with deuterated water
under otherwise standard conditions, the newly formed
product 2a′ was detected partially labeled with deuterium
(40% D), which is in line with literature reports,21,53 suggesting
the generation of the free difluorocarbene species (Figure 1C).
The addition of radical scavengers (TEMPO or BHT)
displayed little effect on the outcome of the reaction (see
Supporting Information for details), thereby ruling out the
possibility of a radical mechanism.54−57 Moreover, the
nonlinear effect study revealed a linear relationship between
a
Reactions were performed by using Cu(MeCN)4BF4 (10 mol %),
(R,S,Sp)-L6 (12 mol %), 1a (0.1 mmol, 1.0 equiv), HCFC-22 (1 M),
and Cs2CO3 (1 mmol, 10 equiv) in tetrahydrofuran (THF, 1 mL) at
25 °C.
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Figure 1. Mechanistic studies. (A) Control experiments with the racemate and both enantiomers of aldimine esters 1m. (B) Racemization profile of
(R)-1m with Cs2CO3 as the base. (C) Deuterium experiments. (D) Nonlinear effect. (E) Proposed catalytic cycles.
the ee of the product 2a and the enantiopurity of the
phosphine ligand L6, indicating a single chiral ligand is likely
involved in the enantio-determining transition state (Figure
1D).58 To further identify the active catalyst, Cu(I)/(S,Sp)-L3
(I) was synthesized under argon conditions and characterized
by X-ray crystallography (Figure 1E). The copper complex I
was found to catalyze the asymmetric difluoromethylation of
aldimine ester 1 as efficiently and enantioselectively as in the
standard reaction conditions. In contrast, the treatment of
Phosferrox ligand (S,Sp)-L3 with Cu(MeCN)4BF4 under air
conditions led to the tetrahedral N,N,O,O-coordinated Cu(II)
complex II, which was unambiguously confirmed by X-ray
crystallography. However, no product was formed when the
copper complex II was used as a catalyst in place of copper
complex I under otherwise standard reaction conditions, thus
confirming the critical role of the chiral ligand.
transformation is initiated by the coordination of aldimine
ester 1 to the copper complex I, followed by the formation of
an N-metalated azomethine ylide (IV) upon deprotonation.
Meanwhile, the addition of base to the HCFC-22 gives rise to
the electrophilic difluorocarbene species. At this point, N-
metalated azomethine ylide (IV), which may serve as a chiral
carbon-based nucleophile, can undergo nucleophilic addition
to the in situ formed difluorocarbene species to afford the
intermediate V along with regeneration of the reactive copper
complex I. Subsequently, protonation and hydrolysis of V give
rise to the final product 2, and the absolute configuration of 2h
was assigned by single-crystal X-ray diffraction analysis.
In conclusion, a novel copper-catalyzed enantioconvergent
difluoromethylation of amino esters with the abundant
chemical feedstock HCFC-22 has been described. The
simplicity and generality of this method in achieving
stereochemical control of the highly reactive difluorocarbene
species provide an unprecedentedly easy entry to valuable
enantioenriched quaternary DFAA in high yields with good
functional group compatibility. The reaction proceeds
smoothly at ambient temperature with high synthetic efficiency
and exhibits unprecedented functional group tolerance
Taking into account the combined results of our mechanistic
studies, the challenging asymmetric difluoromethylation was
successfully realized through concomitant in situ generations of
two reactive species: a nucleophilic N-metalated azomethine
ylide and an electrophilic difluorocarbene species. Herein, a
plausible mechanistic cycle is outlined in Figure 1E. The
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(5) Wang, J.; Sánchez-Roselló, M.; Acen
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a, J. L.; del Pozo, C.;
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products of broad structural diversity. It is expected that the
chemistry reported herein and the direct access to chiral
difluoromethylated derivatives will have a major effect on the
discovery and development of new pharmaceuticals.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02697.
■
sı
Experimental procedures for all reactions and character-
ization data for all products, including 1H and 13C NMR
spectra, HPLC spectra, and crystal data (PDF)
(9) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.;
Masood, K.; Swabeck, J. K.; Olah, G. A. Copper-mediated
difluoromethylation of (hetero)aryl Iodides and β-styryl halides
with tributyl(difluoromethyl)stannane. Angew. Chem., Int. Ed. 2012,
51, 12090−12094.
Accession Codes
CCDC 2055474−2055476 contain the supplementary crys-
tallographic 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.
(10) Fier, P. S.; Hartwig, J. F. Synthesis of difluoromethyl ethers with
difluoromethyltriflate. Angew. Chem., Int. Ed. 2013, 52, 2092−2095.
(11) Li, L.; Wang, F.; Ni, C.; Hu, J. Synthesis of gem-
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AUTHOR INFORMATION
Corresponding Author
■
(12) Gu, Y.; Leng, X.; Shen, Q. Cooperative dual palladium/silver
catalyst for direct difluoromethylation of aryl bromides and iodides.
Nat. Commun. 2014, 5, 5405−5412.
Chang Guo − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China;
orcid.org/0000-0003-4022-9582; Email: guochang@
ustc.edu.cn
(13) Xu, L.; Vicic, D. A. Direct difluoromethylation of aryl halides
via base metal catalysis at room temperature. J. Am. Chem. Soc. 2016,
138, 2536−2539.
(14) Zhu, J.; Liu, Y.; Shen, Q. Direct difluoromethylation of alcohols
with an electrophilic difluoromethylated sulfonium ylide. Angew.
Chem., Int. Ed. 2016, 55, 9050−9054.
Authors
Lingzi Peng − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University
of Science and Technology of China, Hefei 230026, China
Hongyi Wang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, China
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for consecutive bond-forming reactions. Acc. Chem. Res. 2018, 51,
1272−1280.
(16) Xie, Q.; Zhu, Z.; Li, L.; Ni, C.; Hu, J. A general protocol for C−
H difluoromethylation of carbon acids with TMSCF2Br. Angew.
Chem., Int. Ed. 2019, 58, 6405−6410.
(17) Ma, X.; Song, Q. Recent progress on selective deconstructive
modes of halodifluoromethyl and trifluoromethyl-containing reagents.
Chem. Soc. Rev. 2020, 49, 9197−9219.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02697
(18) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine
and fluorine-containing functional groups. Angew. Chem., Int. Ed.
2013, 52, 8214−8264.
Notes
The authors declare no competing financial interest.
(19) Chen, B.; Vicic, D. A. Transition-metal-catalyzed difluorome-
thylation, difluoromethylenation, and polydifluoromethylenation
reactions. Top. Organomet. Chem. 2014, 52, 113−142.
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catalytic enantioselective fluorination, mono-, di-, and trifluorome-
thylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015,
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (grant no. 21971227), the Anhui Provincial Natural
Science Foundation (grant no. 1808085MB30), and the
Fundamental Research Funds for the Central Universities
(WK2340000090).
(21) Feng, Z.; Min, Q.-Q.; Fu, X.-P.; An, L.; Zhang, X.
Chlorodifluoromethane-triggered formation of difluoromethylated
arenes catalysed by palladium. Nat. Chem. 2017, 9, 918−923.
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