Convenient synthesis of racemic 4,4-difluoro glutamic acid derivatives via Michael-type additions of Ni(II)-complex of dehydroalanine Schiff bases

Article abstract of DOI:10.1016/j.jfluchem.2019.109376

Michael-type addition reactions of Ni(II)-complex of a dehydroalanine Schiff base and ethyl bromodifluoroacetate in the presence of copper for the synthesis of racemic 4,4,-difluoroglutamic acid derivatives were developed. These reactions proceeded smooth

Full text of DOI:10.1016/j.jfluchem.2019.109376

Journal Pre-proof
Convenient synthesis of racemic 4,4-difluoro glutamic acid derivatives via
Michael-type additions of Ni(II)-complex of dehydroalanine Schiff bases
Yoshinori Tokairin, Vadim A. Soloshonok, Hiroyuki Konno, Hiroki
Moriwaki, Gerd-Volker Ro¨schenthaler
PII:
S0022-1139(19)30228-3
DOI:
https://doi.org/10.1016/j.jfluchem.2019.109376
FLUOR 109376
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
2 July 2019
18 September 2019
19 September 2019
Please cite this article as: Tokairin Y, Soloshonok VA, Konno H, Moriwaki H, Ro¨schenthaler
G-Volker, Convenient synthesis of racemic 4,4-difluoro glutamic acid derivatives via
Michael-type additions of Ni(II)-complex of dehydroalanine Schiff bases, Journal of Fluorine
Chemistry (2019), doi: https://doi.org/10.1016/j.jfluchem.2019.109376
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Convenient synthesis of racemic 4,4-difluoro glutamic acid derivatives via Michael-type
additions of Ni(II)-complex of dehydroalanine Schiff bases.
Yoshinori Tokairin1*, Vadim A. Soloshonok2,3, Hiroyuki Konno4, Hiroki Moriwaki5,
,
Gerd-Volker Röschenthaler1 *
1Department of Life Sciences and Chemistry, Jacobs University Bremen gGmbH, Campus
Ring 1, 28759 Bremen, Germany.
2Department of Organic Chemistry I, Faculty of Chemistry, University of Basque Country
UPV/EHU, Paseo Manuel Lardizabal 3, 20018 San Sebastian, Spain.
3IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza, Bizkaia,
48011 Bilbao, Spain.
4Department of Biochemical Engineering, Graduate School of Science and Technology,
Yamagata University, Yonezawa, Yamagata 992-8510, Japan.
5Hamari Chemical Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024,
Japan.
*Corresponding author

e-mail: g.roeschenthaler@jacobs-university.de
Tel: +49 421 200-3138
FAX: +49 421 200-3229
e-mail: y.tokairin@jacobs-university.de
Keywords: tailor-made amino acids, fluorine-containing amino acids, Michael-type
additions, organometallic, Ni(II)-complexes
Dedication: This paper is dedicated to Professor Norio Shibata on the occasion of
receiving the 2019 ACS Award for Creative Work in Fluorine Chemistry.
Graphical abstract

Research highlights
 An efficient, operationally convenient and scalable synthesis of racemic
4,4-difluoroglutamic acid derivatives was developed.
 The synthesis is based on the Michael-type addition reactions of an in-situ derived
Cu-reagent to a Ni(II)-complex of dehydroalanine Schiff bases.
 It was revealed that these Ni(II)-complexes are stable in the presence of Cu(II)
ions and have sufficient activation of the dehydroalanine moiety for the
corresponding addition reactions.
Abstract
Michael-type addition reactions of Ni(II)-complex of a dehydroalanine Schiff base
and ethyl bromodifluoroacetate in the presence of copper for the synthesis of racemic
4,4,-difluoroglutamic acid derivatives were developed. These reactions proceeded
smoothly and gave the desired product in 80% yield. Furthermore, this procedure is of
low cost-structure, operationally convenient, and scalable.
1. Introduction
Fluorinated compounds have some great potential in numerous industrial fields.
Above all, fluorinated amino acids can exert significant effect on drug discovery [1],
peptide chemistry [2], and supramolecular science [3]. For this reason, the development
of synthetic methods for the preparation of fluorine-containing amino acids has been the
focus of many research groups [4, 5]. Nevertheless, efficient synthetic protocols for the

preparation of fluorinated amino acids are still in great demand. For example, it is
especially difficult to introduce the CF2 unit into amino acids. For example, difluorinated
glutamic acid derivatives, promising amino acid, are highly sought targets [6]. 4,4-
Difluoroglutamic acid can be easily converted into 4,4-difluoroornithine and 4,4-
difluoroglutamine, Glu derivatives being important compounds in mechanistic studies for
glutamic decarboxylase and hydrolase enzyme [7]. Taguchi’s group reported the first
synthesis of 4,4-difluoroglutamic acid (1) via a Michael-type addition of 2,3-
difluoroketene silyl acetal with ,-carbonyl compounds, followed by introducing the
amino function into the -position of the fluorinated compound [6a]. In 2013, photo-
induced radical hydroperfluoroalkylation of N-phthalimide-dehydroalanine derivative
was published by Yajima [6b]. Haufe’s group developed many excellent methods
including desulfurization-fluorination [6c] and copper-mediated Michael-type additions
[6d-f]. However, these methods have problems with the cost of starting materials, the
preparation of substrates, and the flexibility of amino acid derivatives that can be
synthesized. In order to solve this problem, we considered the Michael-type addition
reaction of a Ni(II)-complex of dehydroalanine and ethyl bromodifluoroacetate in the
presence of copper. Although this Michael-type addition reaction was originally
developed by Kumadaki et al. [8], it was Kondratov's group that showed this to be

applicable to dehydro amino acids [6d-f]. On the other hand, Ni(II)-complexes of
benzophenone derivatives with amino acids are reported to be suitable for the synthesis
of many amino acids, including unusual, specially designed, tailor-made amino acids [9].
So far, the Hamari ligands [9a] with axial chirality, the Soloshonok ligands [9b-d]
developed recently, and PBP (pyridine-2-carboxylic acid (2-benzoyl-phenyl)-amide) [9e-
g] as achiral ligands have been synthesized. These ligands have had great success in
dynamic kinetic resolution [9b, d], (S)-to-(R) interconversion of α or β amino acids [9c],
and tailor-made amino acid synthesis using electrophiles (A-C, Scheme 1) [9h-i]. The
advantages of these ligands are that they are inexpensive, scalable, easily to make, and
recyclable and reused [9j-l]. However, this approach for the synthesis of tailor-made
amino acid mainly uses the Ni(II)-complex of a ligand and an amino acid as a nucleophile,
and few examples exist where the complex is used as an electrophile (D, Scheme 1) [9m-
n]. On the other hand, it is unknown if these Ni(II) complexes can be used in the presence
of Cu(II) ions, as the latter can easily replace the former. Furthermore, it is suggested by
Kondratov [6f] that the electrophilicity of dehydroalanine is very important for this
reaction. Consequently, it remains unknown if the activation provided by the Ni(II)-
complexes structure would be sufficient for these reactions to proceed at all. Therefore, it
is necessary to investigate if these Ni complexes have sufficient stability and reactivity to

be used as the substrates in Cu-mediated additions. To avoid additional complications
with the issues of formation of diastereomers and focus solely on chemical suitability and
reactivity, we decided to dedicate a separate study using achiral tridentate ligands. We
believe the Michael-type addition reactions of achiral Ni(II)-complexes reported herein
provide a simple, operationally convenient method for preparation of difluorinated-
glutamic acid derivatives and open up a new chapter in the application of Ni(II)-
complexes of dehydroalanine for the preparation of various tailor-made amino acids.

Scheme 1. Application of Ni(II)-complex for amino acid synthesis and this work

2. Result and Discussion
The PBP/dehydroalanine Schiff base complex (6a) (Scheme 2) was efficiently
synthesized starting from 2-aminobenzophenone (2a) by a known method [10]. 5-Cl-
PBP/dehydroalanine (6b) was also obtained from 5-chloro-2-amino-benzophenone (2b)
in the same way. To reiterate, previous studies suggest that the electrophilicity of
dehydroalanine derivatives is important in this reaction. Therefore, in order to increase
the electrophilicity of the substrate, 5-Cl-BPB, which was available at low cost, was
prepared [6f].
Scheme 2. Preparation for PBP-dehydroalanine complex (6a) and 5-Cl-PBP

dehydroalanine complex (6b)
The results of condition optimization for Michael-type addition of 6a or 6b with
ethyl bromodifluoroacetate are summarized in Table 1. First, the reaction was performed
using 6 equivalents of activated Cu powder, 3 equivalents of bromodifluoroacetate, and
3.6 equivalents of tetramethylene ethylendiamine (TMEDA) in THF, but the chemical
yield was moderate (45%) because of several byproducts (entry 1). Reducing the amounts
of reagents to prevent the byproduct formation, the reaction did not proceed completely
(entry 2). The reaction in CH3CN gave almost the same result as using THF (entry 3). It
was found that the order of addition of reagents had an important influence on the reaction.
When the Ni(II)-complex was added to the mixture after all reagents except the complex
were mixed at reflux for 0.5 h, a lot of byproducts were observed (entry 4). To confirm
the stability of complex (6a) under the reaction conditions, we tried to work without
bromide reagents to get recovery yields 61% (entry 5). Taking into account that the low
recovery rate could be a result of replacement of Ni by a Cu ion, NiCl2 was added to the
reaction mixture, which indeed allowed us to improve the recovery rates (entry 6).
However, it was found that NiCl2 interrupted the Michael-type addition under the
conditions where all reagents, including the bromide, were added (entry 7). The

temperature is also one of the important factors, since this reaction proceeded smoothly
to give desired product 7a in 67% yield at 70 °C (entry 8-10). When 5-Cl-PBP complex
(6b) was used (entry 11-14), 70 °C was the most suitable temperature, the yield was better
than when the PBP complex (6a) was used (entry 8 and 12). From TLC, it was observed
that the Cl-PBP complex (6b) is highly active and disappeared within 20 min. As the
reaction time was reduced, the decomposition of the compound also decreased, and the
yield was improved to 80% (entry 15). The decrease in the amount of reagents caused an
incomplete progress of the reaction (entry 16), but this reaction can also be used for the
gram-scale (entry 17). Finally, we tried this reaction in the absence of copper.
Table 1. Condition optimization for Cu-mediated Michael-type addition
entry
1
R
H
H
H
H
H
H
Reagent
solvent
THF
temp. (oC)
reflux
Yield
45%
20%
46%
5%
-
Cu (6), bromide (3), TMEDA (3.6)
Cu (2.2), bromide (1.1), TMEDA (2.2)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (0), TMEDA (0.9)
2
THF
reflux
3
CH3CN
CH3CN
CH3CN
reflux
4a
5b
6c
reflux
reflux
Cu (6), bromide (0), TMEDA (0.9), NiCl2 CH3CN
reflux
-

(6)
7
H
Cu (6), bromide (3), TMEDA (0.9), NiCl2 CH3CN
(6)
reflux
0%
8
H
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (3), bromide (1.5), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (6), bromide (3), TMEDA (0.9)
Cu (0), bromide (3), TMEDA (0.9)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
67%
41%
0%
9
H
50
10
11
12
13
14
15
16d
17d,e
18f
H
r.t.
reflux
70
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
38%
70%
63%
0%
60
r.t.
70
43%
80%
65%
0%
70
70
70
a: After copper, bromide (BrCF2CO2Et), and TMEDA were mixed for 60 min, 6a was added to
the mixture and stirred for 1h. b: 61% 6a was recovered. c: 83% 6a was recovered. d: After adding
TMEDA, the mixture was stirred for 20 min. e: The reaction was conducted on a gram-scale. f: 93%
6a was recovered.
Next, we tried the disassembly of the final complex (7b) and Cbz-protection of
difluoro amino acid (Scheme 3). The procedure was attempted by using 6 M HCl/THF
(1:5) at room temperature. After the 5-Cl-PBP (3b) ligand was removed by a separation
operation, EDTA, Na2CO3, and Cbz-Cl were added to the aqueous layer, and Cbz-4,4-
difluoro glutamic acid (8) was obtained by hydrolysis of the ethyl ester. The total overall
yield was 20% over 7 steps, and 51% 5-Cl-PBP (3b) was recovered. This method is highly
efficient for this 4,4-difluoroglutamic acid derivative.

Scheme 3. Synthesis of Cbz-4,4-difluoroglutamic acid (8).
3. Conclusion
We successfully accomplished the Michael-type addition reaction of Ni(II)-complex
of dehydroalanine and ethyl bromodifluoroacetate in the presence of copper. The reaction
was easily scaled up for a quite efficient synthesis of 4,4-difluoro glutamic acid and its
N-protected derivatives.
4. Experimental
General. IR spectra of samples were obtained as films with a Thermo Avatar 370 FT-IR
1
spectrometer. H NMR (400 MHz), 13C NMR (100 MHz), and 19F NMR (376 MHz)
spectra were recorded on a JNM-ECX400 spectrometer. Chemical shifts are reported in
ppm with reference to tetramethylsilane [1H NMR: CDCl3 (0.00)], or solvent signals [1H
NMR: CDCl3 (7.26), CD4CN (1.94); 13C NMR: CDCl3 (77.16), CD4CN (1.32), 19F NMR:
CFCl3 (0.00)]. High-resolution mass spectra were recorded on a JEOL AccuTOF JMS-

T100LC spectrometer (ESI-MS).
5-Chloro-2-(picolinoylamino) benzophenone (3b)
To a solution of picolinic acid (12.9 mmol, 1.59 g) in CH2Cl2 was added Et3N (32.4 mmol,
4.52 ml), TsCl (12.9 mmol, 2.46 g), and 5-Cl-benzophenone 2b (10.8 mmol, 2.5 g) while
o
being held in an ice/water bath. After 15 min, the mixture was stirred at 50 C for 12 h.
The mixture was quenched with 5% AcOH, and the organic layer was washed with H2O
three times and evaporated in vacuo. The residue was washed with ether to give the title
compound (3b) (2.95 g, 8.76 mmol, 81%) as a pale purple solid.
IR (film) max: 1685, 1641, 1597, 1571, 1512, 1463, 1448, 1429, 1399, 1320, 1291, 1255,
1181, 1155, 1143, 1131, 1096, 1086, 997, 995, 940, 897, 839, 832, 814, 806, 744, 712,
692, 661, 641, 620, 530, 462. 1H NMR (400 MHz, CDCl3):  = 7.45-7.63 (6H, m), 7.76-
7.78 (2H, m), 7.88 (1H, td, J = 8.0, 2.0 Hz), 8.26 (1H, ddd, J = 7.6, 1.2, 1.2 Hz), 8.73 (1H,
ddd, J = 4.8, 1.6, 1.2 Hz), 8.86 (1H, d, J = 8.8 Hz) ppm. 13C NMR (100 MHz, CDCl3): 
= 122.8, 123.2, 126.3, 126.7, 127.7, 128.6, 130.2, 132.6, 133.0, 133.7, 137.6, 138.1, 138.3,
148.8, 150.0, 163.6, 197.7 ppm. HRMS-ESI: m/z [M+H]+ calcd for
C19H14ClN2O2:337.0744; found:337.0738.

Ni(II)-5-chloro-2-(picolinoylamino) benzophenone/glycine Schiff base complex (4b)
A solution of 5-chloro-2-(picolinoylamino) benzophenone 2b (2.95 g, 8.76 mmol), Gly
(43.8 mmol, 3.29 g), NiCl2 (17.5 mmol, 2.27 g), NaOH (61.3 mmol, 2.45 g) in MeOH
was stirred at 60 oC for 4 h and at ambient temperature for 12 h. The reaction mixture was
quenched with ice/water and AcOH (6 ml). The precipitate was filtered off and washed
with petroleum ether to give the title compound 4b (3.60 g, 7.99 mmol, 91%) as a red
powder.
IR (film) max : 3443, 1678, 1633, 1606, 1537, 1485, 1464, 1447, 1393, 1357, 1328,
1304, 1294, 1277, 1263, 1231, 1169, 1108, 815, 755, 714, 700, 676. 1H NMR (400 MHz,
CDCl3):  = 3.81 (1H, d, J = 2.0 Hz), 6.83 (1H, d, J = 2.0 Hz), 7.11 (2H, d, J = 6.0 Hz),
7.30 (1H, dd, J = 9.2, 1.6 Hz), 7.45 (1H, t, J = 6.4 Hz), 7.54-7.58 (3H, m), 7.88 (1H, d, J
= 7.6 Hz), 8.00 (1H, dd, J = 7.2, 7.2 Hz), 8.26 (1H, d, J = 4.8 Hz), 9.01 (1H, d, J = 9.2
Hz) ppm. 13C NMR (100 MHz, CDCl3):  = 62.3, 124.3, 125.6, 126.0, 126.5, 127.0, 127.4,
130.1, 130.3, 133.2, 133.4, 134.1, 140.9, 142.1, 147.2, 153.1, 170.7, 172.5, 177.2 ppm.
HRMS-ESI: m/z [M+H]+ calcd for C21H16ClN3NiO3: 450.0155; found:450.0150.
Ni(II)-5-chloro-2-(Picolinoylamino) benzophenone/serine Schiff base complex (5b)
To a solution of 5-Cl-BPB/Gly complex 4b (7.99 mmol, 3.60 g) in CH3OH (30.0 ml)

were added 25 wt% CH3ONa (7.40 ml) and (CH2O)n (22.4 mmol, 672 mg). The mixture
was stirred under reflux for 2 h. The reaction mixture was cooled down to r.t. and
quenched with 5% AcOH. The precipitate was filtered off and washed with water and
dried. A solution of the product in CHCl3 was stirred at r.t. for 1 h. The precipitate was
filtered off and dried to give 5b (3.01 g, 6.26 mmol, 78%). IR (film) max: 3354, 3079,
2958, 1656, 1607, 1533, 1464, 1443, 1400, 1333, 1306, 1276, 1270, 1259, 1234, 1173,
1112, 1073, 837, 768, 708, 682. 1H NMR (400 MHz, CDCl3):  = 3.80 (1H, dd, J = 10.8,
4.0 Hz), 3.92 (1H, dd, J = 11.6, 6.8 Hz), 4.08 (1H, dd, J = 6.0, 3.6 Hz), 6.74 (1H, d, J =
2.8 Hz), 7.12 (1H, dd, J = 6.8, 1.6 Hz), 7.28 (1H, overlapped), 7.31 (2H, dd, J = 9.6, 2.8
Hz), 7.45 (1H, t, J = 6.0 Hz), 7.54-7.58 (3H, m), 7.90 (1H, d, J = 7.6 Hz), 8.00 (1H, ddd,
J = 8.0, 8.0, 1.2 Hz), 8.21 (1H, d, J = 5.6 Hz), 8.96 (1H, d, J = 9.2 Hz) ppm. 13C NMR
(100 MHz, CDCl3):

=
ppm. HRMS-ESI: m/z [M+H]+ calcd for
C22H17ClN3NiO4:480.0261; found:480.0256.
Ni(II)-5-chloro-2-(Picolinoylamino) benzophenone/dehydroalanine Schiff base
complex (6b)
To a solution of 5-Cl-BPB/Ser complex 5b (6.24 mmol, 3.0 g) in CH3CN (23 ml) was
added Ac2O (5.1 ml), and the mixture was stirred at reflux for 1 h. Na2CO3 (18.7 mmol,

1.98 g) was added to the mixture, and the reaction mixture was stirred at the same
temperature for 2 h. The reaction mixture was cooled down to r.t. and quenched with H2O.
The precipitate was filtered off and washed with water and dried. A solution of the
product in MeOH was stirred at reflux for 1h. The precipitate was filtered and dried to
give the title compound (6b) (2.00 g, 4.32 mmol, 69 %).
IR (film) max: 3416, 1671, 1646, 1610, 1564, 1520, 1486, 1455, 1391, 1328, 1303, 1274,
1259, 1229, 1200, 1155, 1139, 1102, 925, 888. 1H NMR (400 MHz, CDCl3):  = 4.21 (1H,
d, J = 1.2Hz), 5.65 (1H, s), 6.93 (1H, d, J = 2.4 Hz), 7.20 (2H, d, J = 6.8 Hz), 7.27 (1H,
dd, J = 9.2, 2.4 Hz), 7.43-7.56 (4H, m), 7.87 (1H, d, J = 7.2 Hz), 7.99 (1H, ddd, J = 8.8,
7.6, 1.2 Hz), 8.20 (1H, d, J = 5.6 Hz), 8.91 (1H, d, J = 10.0 Hz) ppm. 13C NMR (100 MHz,
CDCl3):  = 117.1, 124.4, 124.7, 126.3, 127.4, 128.2, 128.7, 129.7, 130.8, 134.0, 134.1,
135.1, 140.9, 143.0, 147.0, 147.2, 152.9, 169.9, 170.0, 170.4 ppm. HRMS-ESI: m/z
[M+H]+ calcd for C22H15ClN3NiO3:462.0155; found:462.0150.
Ni(II)-5-chloro-2-(picolinoylamino)benzophenone/4-amino-2,2-difluoropentane-
1,5-dioic acid 5-ethyl ester Schiff base complex (7b)
A solution of dehydroalanine complex 6b (100 mg, 0.216 mmol), activated Cu [10]
powder (1.30 mmol, 82 mg), and ethyl bromodifluoroacetate (0.639 mmol, 84.0 l) in

o
acetonitrile (10.0 ml) was stirred at 70 C for 1 h. TMEDA (0.194 mmol, 29.0 l) was
added to the mixture, which was stirred at the same temperature for 20 min. The reaction
mixture was quenched with 5% AcOH, and the aqueous layer extracted twice with
CH2Cl2. The organic layer was washed with H2O and brine, dried over magnesium sulfate,
and evaporated in vacuo. The residue was purified by column chromatography (CHCl3)
to give the title compound (7b) (101 mg, 0.172 mmol, 80%) as a red powder.
IR (film) max: 3416, 1671, 1646, 1610, 1564, 1520, 1486, 1455, 1391, 1328, 1303, 1274,
1
1259, 1229, 1200, 1155, 1139, 1102, 925, 888, 817, 808, 762, 709, 696, 687, 540. H
NMR (400 MHz, CDCl3):  = 1.25 (3H, t, J = 7.2 Hz), 2.47 (1H, ddd, J = 28.8, 14.8, 2.4
Hz), 2.61-2.75 (1H, m), 4.17-4.23 (3H, m), 6.74 (1H, d, J = 2.4 Hz), 7.21-7.22 (1H, m),
7.26-7.31(2H, m), 7.46 (1H, td, J = 5.6, 1.2 Hz), 7.57-7.60 (3H, m), 7.89 (1H, d, J = 7.6
Hz), 8.01 (1H, t, J = 7.6 Hz), 8.21 (1H, d, J = 5.2 Hz), 8.99 (1H, d, J = 9.2 Hz) ppm. 13C
NMR (100 MHz, CDCl3):  = 13.9, 37.2 (t, J = 20.1 Hz), 63.5, 66.6 (t, J = 5.7 Hz), 114.8
(dd, J = 254.5, 248.7 Hz), 124.3, 125.0, 126.3, 126.8, 127.5, 127.7, 128.0, 129.5, 129.8,
130.8, 133.1, 133.5, 133.8, 140.9, 142.3, 147.2, 152.9, 163.4 (t, J = 31.6 Hz), 170.3, 173.6,
178.0 ppm. 19F NMR (376 MHz, CDCl3):  = -103.56 (ddd, J = 274.1, 19.6, 15.0 Hz), -
96.5 (dt, J = 2743.4, 13.2 Hz) ppm. HRMS-ESI: m/z [M+H]+ calcd for
C26H21ClF2N3NiO5:586.0491; found:586.0486.

Ni(II)-2-(picolinoylamino)
benzophenone/4-amino-2,2-difluoropentane-1,5-dioic
acid 5-ethyl ester Schiff base complex (7a)
A solution of dehydroalanine complex 6a (100 mg, 0.234 mmol), activated Cu [11]
powder (1.40 mmol, 89.0 mg), and ethyl bromodifluoroacetate (0.639 mmol, 83.0 l) in
o
acetonitrile (10.0 ml) was stirred at 70 C for 1 h. TMEDA (0.211 mmol, 31.0 l) was
added to the mixture, and stirring was continued at the same temperature for 1 h. The
mixture was quenched with 5% AcOH, and the aqueous layer was extracted twice with
CH2Cl2. The organic layer was washed with H2O and brine, dried over magnesium sulfate,
filtered, and then evaporated in vacuo. The residue was purified by column
chromatography (CHCl3) to give the title compound (7a) (86.0 mg, 0.156 mmol, 67%) as
a red powder.
IR (film) max: 3458, 2984, 1762, 1681, 1642, 1605, 1590, 1546, 1471, 1440, 1377, 1329,
1274, 1259, 1237, 1192, 1168, 1110, 1059, 1021, 776, 754, 713, 682. 1H NMR (400 MHz,
CDCl3):  = 1.23 (3H, t, J = 7.2 Hz), 2.47 (1H, dd, J = 28.4, 14, 2.8 Hz), 2.65-2.79 (1H,
m), 4.18 (2H, q, J = 6.8 Hz), 4.23 (1H, dd, J = 8.0, 2.8 Hz), 6.76-6.83 (2H, m), 7.20-7.23
(1H, m), 7.27-7.29 (1H, m), 7.36 (1H, ddd, J = 8.4, 6.4, 1.6 Hz), 7.44 (1H, ddd, J = 6.8,
5.6, 0.8 Hz) 7.54-7.57 (3H, m), 7.90 (1H, d, J = 7.2 Hz), 8.00 (1H, ddd, J = 7.6, 7.6, 0.8

Hz), 8.21 (1H, d, J = 5.6Hz), 8.97 (1H, d, J = 8.8 Hz) ppm. 13C NMR (100 MHz, CDCl3):
 = 13.9, 37.4 (t, J = 23.8 Hz), 63.5, 66.0 (d, J = 5.7 Hz), 114.76 (dd, J = 255.7, 247.9
Hz), 121.6, 123.7, 124.3, 126.5, 126.9, 127.2, 128.2, 129.2, 129.6, 130.4, 133.8, 134.1,
19
135.0, 140.7, 143.6, 147.1, 153.3, 163.5 (t, J = 31.4 Hz), 170.2, 174.3, 178.0 ppm. F
NMR (376 MHz, CDCl3):  = -103.97 (ddd, J = 274.5, 21.4, 14.3 Hz), -96.12 (dt, J =
274.5, 12.8 Hz) ppm. HRMS-ESI: m/z [M+H]+ calcd for C26H22F2N3NiO5:552.0881;
found:552.0875.
Cbz-4,4-difluoro-Glu-OH (8)
To a solution of complex 7b (250 mg, 0.426 mmol) in THF (2 ml) was added 6 M HCl
(0.4 ml) at room temperature, and the mixture was stirred for 30 min. The mixture was
distilled with H2O, and the aqueous layer was washed twice with AcOEt. EDTA disodium
salt dihydrate (0.426 mmol, 159 mg), Na2CO3 (500 mg), Cbz-Cl (1.70 mmol, 0.243 ml),
and 1,4-dioxane (6 ml) were added to the aqueous solution, and the mixture was stirred
at room temperature for 12 h. Et2O was added to the mixture and the aqueous phase was
washed with Et2O twice. To the aqueous phase was added 2M HCl and extracted with
AcOEt three times. The combined organic layer was washed with brine, dried over
MgSO4, and evaporated in vacuo to give the amino acid 8 (81 mg, 0.255 mmol, 60%) as

a white solid.
The analytical data are in a good agreement with those from the publication.
Conflict of Interest
This work was supported in part by the German Research Foundation (Grant RO 362/80-
1). We gratefully acknowledge the financial support from the Ikerbasque, the Basque
Foundation for Science.
Acknowledgements
This work was supported in part by the German Research Foundation (Grant RO 362/80-
1). We gratefully acknowledge the financial support from the Ikerbasque, the Basque
Foundation for Science.
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[11] activated Cu
Asolution of Cu powder in 2% I2/acetone was stirring at room temperature for 10 minutes.
Cu powder was filtered off and washed with acetone. The resulting Cu was added to 50%
12 M HCl/acetone and stirred for 5 minutes. The activated copper was obtained by
filtering again, washing with acetone and drying.