Palladium-catalyzed cross-coupling of unactivated alkylzinc reagents with 2-bromo-3,3,3-trifluoropropene and its application in the synthesis of fluorinated amino acids

Article abstract of DOI:10.1039/c8cc10212k

A palladium-catalyzed cross-coupling of unactivated alkylzinc reagents with 2-bromo-3,3,3-trifluoropropene (BTP) has been developed, which was used as a key step to prepare a series of trifluoromethylated and difluoromethylated amino acids that are of great interest in peptide/protein based chemical biology. The advantages of the synthesis of these fluorinated amino acids are synthetic simplicity and diversity from a simple and readily available key intermediate α-trifluoromethylalkene-containing amino acid, providing a facile route for applications in medicinal chemistry and life science.

Full text of DOI:10.1039/c8cc10212k

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DOI: 10.1039/C8CC10212K
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Palladium-Catalyzed Cross-Coupling of Unactivated Alkylzinc
Reagents with 2-Bromo-3,3,3-Trifluoropropene and Its Application
in the Synthesis of Fluorinated Amino Acids
Received 00th January 20xx,
Accepted 00th January 20xx
Yue-Guang Lou, a An-Jun Wang, a Liang Zhao, a Lin-Feng He, a Xiao-Fei Li, a Chun-Yang He,*,a Xingang
Zhang*, b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A palladium-catalyzed cross-coupling of unactivated alkylzinc can enable access to a key intermediate for the diversity-
reagents with 2-bromo-3, 3, 3-trifluoropropene (BTP) has been oriented synthesis would facilitate preparation of diversified
developed, which was used as a key step to prepare a series of trifluoromethylated and difluoromethylated amino acids. 2-
trifluoromethylated and difluoromethylated amino acids that are Bromo-3,3,3-trifluoropropene (BTP) is a readily available and
of great interests in peptides/proteins based chemical biology. The versatile building block, and has important applications in
advantage of synthesis of these fluorinated amino acids are organic synthesis.9 The cross-coupling of BTP with protected
synthetic simplicity and diversity from a simple and readily amino acid zinc reagent would lead to a key fluorinated amino
available key intermediate α-trifluoromethylalkene-containing acid for diversity-oriented synthesis by simple transformations
amino acid, providing a facile route for applications in medicinal of its carbon-carbon double bond (Scheme 1). Herein, we report
chemistry and life science.
an efficient and practical strategy to prepare
trifluoromethylated and difluoromethylated amino acids with a
palladium-catalyzed cross-coupling between unactivated
alkylzinc reagent and BTP as a key step. This strategy can enable
access to diversified fluorinated amino acids from a key
intermediate via simple transformations, thus providing a facile
route for applications in peptides/proteins based chemistry.
Due to the unique properties of fluorine atom,1 fluorinated
amino acids play a privileged role in discovering new bioactive
molecules, peptide engineering and protein structural biology.2
For examples, fluorinated amino acids have been used as
antivirus and antitumor agents,3 and incorporation of
fluorinated amino acids into proteins can enhance their
structural stability. Furthermore, peptides or proteins contain
such valuable structural motifs can serve as probes for
investigation of enzyme kinetics4 and protein-protein
interactions,5 even as PET-imaging agents.6 Among the
fluorinated amino acids, trifluoromethyl (CF3) and
difluoromethyl (CF2H) containing amino acids have attracted
great attention in peptides/proteins engineering because CF3
possess high hydrophobicity7 and CF2H can serve as a lipophilic
O
Versatile
Functional Group
O
*
RO
BocHN
CF3
RO
ZnX
NHBoc
O
O
1
Transformations
cat. M
RO
BocHN
R1
*
+
RO
CF3
CF2
H
BocHN
O
Br
CF3
CF2R2
RO
BocHN
2, BTP
3, Key Intermediate
hydrogen bond donor8
， which can enhance the
Scheme 1 Strategy for the diversified synthesis of fluorinated amino acids
pharmacological properties of peptides and proteins. However,
efficient and practical methods to access such valuable
fluorinated amino acids are limited.
From the point of view of synthetic simplicity and diversity, we
envisioned that the development of an efficient method that
According to our hypothesis, initially, we chose an unactivated
alkylzinc reagent 4a as a model substrate to establish a method
for construction of the key intermediate 3 (Table 1). To the best
of our knowledge, the cross-coupling of unactivated alkylzinc
reagents with BTP 2 has not been reported thus far due to the
difficulty in suppressing the -hydride elimination of
unactivated alkylzinc reagents. To our delight, an 8% yield of
cross-coupling product 5a was obtained when 4a was treated
with BTP 2 in the presence of Pd(OAc)2 (2.5 mol%) and John-
a. Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi
Medical University, Zunyi, Guizhou, 563003, P. R. China. E-mail:
hechy2002@163.com
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China. E-mail: xgzhang@mail.sioc.ac.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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yield of the isolated product. cReaction runs at 90 oC. dReaction runs at
Phos (5 mol%) in THF at 110 oC for 8 h (entry 1). A survey of the
phosphine ligands revealed that S-Phos could provide 5a in 46%
yield (entry 5), but other ligands, such as X-Phos, Brett-Phos,
and Me-Phos, showed less or no activity (entries 2-4). The
choice of solvent is critical to the reaction efficiency. Among the
tested solvents (entries 6-9), THF remained the best reaction
medium (entry 5). Decreasing the loading amount of S-Phos
could improve the yield to 57% (entry 10). Further optimization
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80 oC.
DOI: 10.1039/C8CC10212K
To examine the substrate scope of this palladium-catalyzed
process, a variety of unactivated alkylzinc reagents were tested
(Table 2). Generally, good to high yields of desired products 5
were obtained. The reaction exhibits good-functional group
tolerance. Substrates 4 bearing indole, isoindoline-1,3-dione,
morpholine, ester, cyano and fluoride all underwent the cross-
of the reaction conditions by examining different palladium coupling smoothly (5b-i). It should be mentioned that ,-
unsaturated ester (5j) and thenyl group (5k) containing alkylzinc
reagents were also applicable to the reaction, providing the
corresponding products with high efficiency. Importantly, the
enolizable carboxylic acid ester did not interfere with the
reaction (5l), thus demonstrating the advantage of current
process. Furthermore, the reaction was not restricted to
primary alkylzinc reagents, as the secondary alkylzinc reagent
was also competent coupling partner as shown in 5m.
sources (entries 11-14) showed that palladacyclic complex
Cphos-Pd-G310 is superior to other tested palladium catalysts
(entry 14), providing 5a in 72% yield, of which the formation of
alkene generated by the β-hydride elimination of 4a was
significantly suppressed. The significant reactivity of Cphos-Pd-
G3 in the reaction is probablly because an active Pd(0)L species
was generated through the reductive elimination of this
palladacyclic complex. Decreasing the reaction temperature to
90 oC did not affect the reaction efficiency (entry 15), but 80 oC
deminished the yield (entry 16). Notably, the absence of S-Phos
still provided 5a in a comparable yield (71% upon isolation,
entry 17), demonstrating that C-Phos is also a suitable ligand in
promotion of the reaction.
Table 2 Pd-catalyzed cross-coupling of unactivated alkylzinc reagents 4 with BTP 2a
Br
Alkyl
Cphos-Pd-G3 (2.5 mol%)
THF, 90 oC, 8 h
Alkyl ZnBr
+
F3
C
CF3
5
4
2
O
CF3
N
N
CF3
CF3
Table 1 Representative results for optimization of Pd-catalyzed cross-coupling of 4a with
BTP 2a
O
5a, 71%
5b, 76%
5c, 76%
O
O
O
N
Br
[Pd] (2.5 mol%)
O
ZnBr
O
CF3
+
L
(x mol%)
CF3
CF3
MeO
CF3
F3C
Solvent, 110 oC, 8 h
5d, 64%
5e, 91%
5f, 84%
4a
2
5a
O
Entry
1
[Pd]
L (x)
Solvent Yield(%), 3ab
O
O
O
O
O
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
John-Phos (5)
X-Phos (5)
THF
THF
8
CF3
O
CF3
CF3
NC
F
O
15
2
5g, 71%
5h, 78%
5i, 90%
Brett-Phos (5) THF
Trace
33
3
O
O
CF3
Me-Phos (5)
S-Phos (5)
S-Phos (5)
S-Phos (5)
S-Phos (5)
S-Phos (5)
S-Phos (2.5)
S-Phos (2.5)
S-Phos (2.5)
S-Phos (2.5)
S-Phos (2.5)
S-Phos (2.5)
S-Phos (2.5)
----
THF
C
O
4
O
Boc
N
EtOOC
CF3
CF3
S
CF3
THF
46
5
5j, 83%
5k, 73 %
5l, 76 %
5m, 90%
aReaction conditions (unless otherwise specified): 4a (0.3 mmol, 1.0
equiv), 2 (0.6 mmol, 2.0 equiv), THF (2.0 mL). All reported yields are
DMF
DCE
5
6
13
7
isolated
yields.
Dioxane
Diglyme
THF
3
8
With this palladium-catalyzed cross-coupling reaction in hand,
we then turned our attention to the synthesis of fluorinated
amino acids. Trifluorovaline has important applications in
peptide and protein structural biology due to the CF3 group can
enhance the stability of peptides and proteins structure.11
However, the synthesis of optically pure trifluorovaline usually
requires multiple-steps procedure,12 which restricts its wide-
spread synthetic applications. But on the basis of this developed
palladium-catalyzed process, optically pure L-trifluorovaline can
be easily prepared by cross-coupling of BTP with alkylzinc
reagent 4n, followed by hydrogenation. As shown in Scheme 2a,
the key intermediate 3 can be obtained on gram-scale with 90%
yield, in which Pd(OAc)2/S-Phos instead of Cphos-Pd-G3 was
used as a catalyst, thus demonstrating the reliability and
practicability of this protocol. Alkene 3 was subsequently
reduced by H2 (6 atm) in the presence of Pd(OH)2/C to afford a
mixture of trifluorovaline diastereoisomers 6. This mixture can
be readily separated by silica gel chromatography. The absolute
configuration of (2S,4R)-trifluorovaline 6a was assigned by the
3
9
57
10
11
12
13
14
15c
16d
17c
Pd(PPh3)4
THF
8
Pd(PPh3)2Cl2
Pd(dppf)Cl2
THF
42
THF
43
Cphos-Pd-G3
Cphos-Pd-G3
Cphos-Pd-G3
Cphos-Pd-G3
THF
72
THF
73 (70)
43
THF
THF
72 (71)
PCy2
PCy2
NMe2
MeO
OMe
Me2
N
Pd NH2
Cphos
OMs
Cphos-Pd-G3 :
S-phos:
Cphos:
aReaction conditions (unless otherwise specified): 4a (0.2 mmol, 1.0
equiv),
2 (0.4 mmol, 2.0 equiv), anhydrous solvent (2.0 mL).
bDetermined by 19F NMR spectroscopy using fluorobenzene as an
internal standard, and the number within parentheses represents the
2 | J. Name., 2012, 00, 1-3
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X-ray structure analysis of amino acid 7a,13 which was obtained
by saponification of 6 with LiOH. Compared to previous
reports,12 the current synthesis of optically pure L-
trifluorovalines 6a and 6b features synthetic simplicity and
convenience (2 steps vs 5 steps12b) without specific procedure,
such as enzymatic resolution12a. The key intermediate 3 can also
be used for the synthesis of difluoromethylated amino acids
that otherwise are difficult to prepare by conventional methods.
For example, borylation-defluorination of 3 catalyzed by
copper14 afforded gem-difluoroalkene containing amino acid 8
efficiently, which can serve as a versatile building block for the
further transformations. As shown in scheme 2b, oxidation of C-
B bond of 8,15 followed by hydrogenation resulted in
difluormethylated amino acids 10 efficiently as a mixture of 1:1
diastereoisomers. This diastereoisomeric mixture of amino
acids 10 can also be separated by cyclization to form an optical
pure six-membered lactone 11. Furthermore, the borylated
amino acid 8 can also be used as a coupling partner for the
cross-coupling reaction. Interestingly, the gem-difluoroallylic
benzene 12 instead of gem-difluoroalkene 13 was obtained by
treatment of 8 with phenyl iodide via Suzuki reaction (Scheme
2c). This regio-selectivity is probably due to the stronger Pd-
CF2R -bond as a result of strong electron-withdrawing effect of
CF2 group.16 Given the fact that the presence of CF2 at benzylic
position can improve the metabolic stability of benzyl-
View Article Online
DOI: 10.1039/C8CC10212K
Figure 1 X-ray crystal structure of amino acid 7a
In conclusion, we have developed a diversity-oriented synthetic
strategy to access trifluoromethylated and difluoromethylated
amino acids from a simple and versatile intermediate, in which
the palladium-catalyzed cross-coupling between unactivated
alkylzinc reagents with BTP was established as a key step. The
advantage of this strategy is the synthetic simplicity and
diversity. All the resulting difluoromethylated and gem-
difluoroalkene containing amino acids are unknown and can
serve as useful building blocks for further transformations or be
used for peptides/proteins based chemical biology and drug
discovery and development.
This work was financially supported by the National Natural
Science Foundation of China (No. 21425208, 21672238,
containing amino acids,17 this transformation may have 81760624, 21702241), the Strategic Priority Research Program
potential applications in discovering some interesting new
bioactive molecules. On the other hand, boronic amino acids
have important applications in pharmaceuticals,18 but efficient
methods to access them are limited. This method also provides
an efficient route to access this kind of amino acids.
of the Chinese Academy of Sciences (No. XDB20000000), the
Young Elite Scientists Sponsorship Program by Cast of the China
Association for Science and Technology (No. 2015-41), and
Programs of Guizhou Province (No. 2017-1225, 2018-1427).
O
O
Pd(OAc)2 (2.5 mol%)
S-Phos (5 mol%)
+
a)
MeO
ZnI
MeO
BocHN
Br
CF3
THF, 90 oC, 8 h
Conflicts of interest
There are no conflicts to declare.
NHBoc
CF3
2, BTP
4n
3
90% gram scale
O
O
O
1) H2 (6 atm)
Pd(OH)2 / C, 50 o
C
MeO
+
MeO
MeO
BocHN
CF3
2) silica gel chromatography
BocHN
CF3
CF3
BocHN
Notes and references
3
6a, 58%
6b, 37%
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O
O
LiOH r.t. 3 h
THF / MeOH
HO
BocHN
MeO
BocHN
CF3
CF3
6a
7a, 90%
O
O
O
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NaBO3 H2
O
cat. CuCl
MeO
OH
b)
MeO
MeO
Bpin
BocHN
CF2
B2pin2, MeONa
CF3
CF2
THF / H2O r.t.
BocHN
BocHN
3
9, 60%, 2 steps
8
O
*
O
BocHN
O
.
Pd(OH)2/C, H2
r.t. 2 h
cat. TsOH H2
O
MeO
BocHN
OH
CF2
H
toluene, 80 o
C
CF2H
10, 72%, dr=1:1
11, 34%
O
O
O
F
F
c)
MeO
BocHN
Ph
MeO
Ph
Pd(PPh3
)
MeO
BocHN
Bpin
4
Ph-I
+
BocHN
CF2
CF2
Dioxane 100 o
C
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13, not observed
12, 55%
8
Scheme 2 Synthesis of key intermediate 3 and its applications in diversified
synthesis of fluorinated amino acids
6 M. B. Nodwell, H. Yang, M. Colovic, Z. Yuan, H. Merkens, R. E.
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DOI: 10.1039/C8CC10212K
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