Photoinduced radical hydroperfluoroalkylation and the synthesis of fluorinated amino acids and peptides

Article abstract of DOI:10.1016/j.jfluchem.2013.02.019

The photoinduced radical hydroperfluoroalkylation of unsaturated carboxylic acids using TTMSS as a H-donor was successfully developed. The stereoselective reaction using Oppolzer's camphorsultum was also achieved to give high stereoselectivity. The reaction was also effective for N-phthalimide- dehydroamino acid and the product was easily converted to the corresponding amino acid and a peptide derivative.

Full text of DOI:10.1016/j.jfluchem.2013.02.019

Accepted Manuscript
Title: Photoinduced Radical Hydroperfluoroalkylation and the
Synthesis of Fluorinated Amino Acids and Peptides
Authors: Tomoko Yajima, Kanako Yamaguchi, Rie Hirokane,
Emiko Nogami
PII:
S0022-1139(13)00087-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2013.02.019
FLUOR 8058
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
15-2-2013
22-2-2013
25-2-2013
Please cite this article as: T. Yajima, K. Yamaguchi, R. Hirokane, E.
Nogami, Photoinduced Radical Hydroperfluoroalkylation and the Synthesis of
Fluorinated Amino Acids and Peptides, Journal of Fluorine Chemistry (2010),
http://dx.doi.org/10.1016/j.jfluchem.2013.02.019
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1. Introduction
Fluorinated amino acids have received significant attention not only in the field of pharmaceuticals but
also in the field of supramolecular sciences [1]. In particular, β-perfluoroalkyl α-amino acids are
considered to have strong potential to provide new functional compounds because their unique properties,
such as hydrophobicity, bulkiness, and electronegativity, can be adjusted by the introduction of various
perfluoroalkyl groups [2]. However, synthetic methods for efficiently preparing chiral fluorinated amino
acids are very limited [3]. We reported the synthesis of chiral β-perfluoroalkyl α-amino acids by
photoinduced perfluoroalkyl radical addition to an acrylic acid derivative [4], but this method involves
several steps. Alternatively, radical hydroperfluoroalkylation of dehydroamino acids provides a more
efficient and direct method for the synthesis of β-perfluoroalkyl α-amino acids. For instance, we reported
the indium-mediated hydroperfluoroalkylaion of dehydroamino acids, although the product yields were low
because of their instability [ 5 ]. Under such circumstances, we found that the radical
hydroperfluoroalkylation of electron-deficient olefins using tris(trimethylsilyl)silane (TTMSS) as a
H-donor proceeded smoothly, and the reaction was also effective for dehydroamino acids that contained
phthalimide as a N-protecting group. Here we report a practical and efficient method for the photoinduced
radical hydroperfluoroalkylation of olefins and dehydroamino acids. Furthermore, we demonstrate the
synthesis of chiral β-perfluoroalkyl α-amino acids by a method that employs a chiral auxiliary.
2. Results and discussion
The photoinduced reaction of perfluorohexyl iodide and ethyl acrylate in the presence of a H-donor was
examined (Table 1). First, Bu3SnH, which is the most common radical H-donor, was examined (entry 1).
The reaction was performed using two equivalents of ethyl acrylate and perfluorohexyl iodide per
equivalent of Bu3SnH under UV irradiation in CH2Cl2, but a complex mixture was obtained. Using
triethylsilane instead of Bu3SnH (entry 2), we obtained the desired product 2 in 54% yield along with the
iodinated product 3 and the iodoperfluoroalkylated product 4. The use of TTMSS suppressed the
production of 3 and gave 2 in 73% yield (entry 3). However, when excess TTMSS was used, the reaction
produced a complex mixture (entry 4), and the reaction did not proceed using only a small excess amount
of the olefin and iodide (entry 5). Next, a reaction in the presence of aqueous Na2S2O3 was attempted,
because in our previous study of the photoinduced radical iodoperfluoroalkylation of olefins, we found that
the addition of aqueous Na2S2O3 induced a clean reaction [4, 6]. As expected, the reaction proceeded very
smoothly to give 2 in 93% yield as a single product (entry 6).
Table 1. Optimization of reaction conditions
C6F13
C6F13
I
C6F13I
Hydrogen donor
+
+
CO2Et
I
CO2Et
CO2Et
hν, CH2Cl2
CO2Et
2
4
3
1
Entry
1
C6F13I
Hydrogen donor
2
3
Page 1 of 15

Photoinduced Radical Hydroperfluoroalkylation and the Synthesis of Fluorinated Amino
Acids and Peptides
Tomoko Yajima*, Kanako Yamaguchi, Rie Hirokane, and Emiko Nogami
Department of Chemistry, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-
8610, Japan
Tel & Fax: (+)81-03-5978-5715 , E-mail: yajima.tomoko@ocha.ac.jp
Abstract
The photoinduced radical hydroperfluoroalkylation of unsaturated carboxylic acids using
TTMSS as a H-donor was successfully developed. The stereoselective reaction using
Oppolzer’s camphorsultum was also achieved to give high stereoselectivity. The reaction
was also effective for N-phthalimide-dehydroamino acid and the product was easily
converted to the corresponding amino acid and a peptide derivative.
Keywords
Perfluoroalkylation, Amino acids, Peptides, Photoinduced radical reaction,
Stereoselective synthesis
R2
R1
Rf
R2
R1
RfI
h, TTMSS
Na2S2O3 aq.
CH2Cl2
EWG
EWG
R1 = H, Me, NH-Pht
R2 = H, Me
EWG = CO2Et, CN, COEt
Rf = CF3, C3F7, CF2CO2Et etc.
Rf
H2N
CO2H
N
S
O2
O

chiral -perfluoroalkylated
amino acids
Page 2 of 15

(equiv.) (equiv.)
(equiv.)
Yield (%)
Yield (%)
1
2.0
2.0
2.0
1.0
1.2
1.2
2.0
2.0
2.0
1.0
1.2
1.2
Bu3SnH (1.0)
Et3SiH (1.0)
TTMSS (1.0)
TTMSS (1.5)
TTMSS (1.0)
TTMSS (1.0)
-
-
2a
3
54
73
-
-
93
46
27
-
-
-
4
5
6b
a Product 4 was also observed.
b In the presence of a solution of Na2S2O3 (5 equiv.) in water (0.01 mol/L).
The proposed mechanism for the reaction is shown in Scheme 1 [7]. First, perfluoroalkyl iodide is
homolytically cleaved under photoirradiation to generate a perfluoroalkyl radical. A stronger H-donor such
as Bu3SnH reacts with the perfluoroalkyl radical, and consequently, the addition reaction does not occur (eq.
1). With a weaker hydrogen donor such as triethylsilane or TTMSS, the perfluoroalkyl radical reacts faster
with the olefin than with the H-donor to give the perfluoroalkylated radical intermediate. The radical
intermediate is trapped by the H-donor (eq. 2), giving the desired product. However, the donor ability of
triethylsilane is too low to trap the intermediate radical, leading to a complex mixture.
H-donor
(Bu3SnH)
hν
Rf
(1)
RfI
RfH
H-donor
Rf
Rf
(TTMSS)
EWG
Rf
(2)
EWG
H
EWG
Scheme 1 Reaction mechanism
Next, we investigated the hydroperfluorohexylation of several electron-deficient olefins under the same
conditions as those employed in entry 6 in Table 1 (Table 2). The reaction of ethyl methacrylate gave the
desired product 6a in 99% yield (entry 1), but with ethyl crotonate, a lower yield was obtained (6b, entry 2).
The reaction of methacrylonitrile (5c) and methyl vinyl ketone (5d) also proceeded, although the yields
were lower than those of the esters (entries 3 and 4, respectively). These results show a consistent tendency
in the general radical reactivity: 1,1-disubstituted olefin (99%; Table 2, entry 1) > monosubstituted olefin
(93%; Table 1, entry 6) > 1,2-disubstituted olefin (61%; Table 2, entry 2).
Table 2. Photoinduced hydroperfluoroalkylation of electron-deficient olefins with C6F13I.a
R2
R1
C6F13I
hν , TTMSS
R2
R1
Rf
Na2S2O3 aq.
CH2Cl2
EWG
5a d
EWG
6a d
-
-
Entry
5
Time (h)
Product
Yield (%)
99
C6F13
1
5a
4
6a
CO2Et
CO2Et
Page 3 of 15

C6F13
2
3
4
5b
5c
5d
7
6
4
6b
6c
6d
61
48
54
CO2Et
CN
CO2Et
CN
C6F13
C6F13
COEt
COEt
a Reagents and conditions: 5 (1.2 equiv.), C6F13I (1.2 equiv.), TTMSS (0.2 mmol, 1.0 equiv.), CH2Cl2 (5
mL), Na2S2O3 (5 equiv.), H2O (1 mL)
Next, we investigated the hydroperfluoroalkylation of dehydroamino acids for the synthesis of fluorinated
amino acids. Initially, an N-benzyloxycarbonyl dehydroamino acid methyl ester was used, but no desired
product was obtained. In contrast, the reaction of N-phthalimide dehydroamino acid 7 proceeded smoothly
to give the corresponding hydroperfluoroalkylated product (Table 3). The reaction was effective for various
perfluoroalkyl iodides, including ethyl difluoroiodoacetate.
Table 3. Photoinduced hydroperfluoroalkylation of dehydroamino acid 7 with perfluoroalkyl iodides.a
Rf
O
O
RfI
hν, TTMSS
N
O
CO2Et
N
CO2Et
Na2S3O3 aq.
CH2Cl2
O
8a e
-
7
Entry
1
2
RfI
Product
8a
8b
8c
8d
Yield (%)
C6F13I
C3F7I
i-C3F7I
CF3I
78
78
79
93
80
3
4b
5
ICF2CO2Et 8e
a Reagents and conditions: 7 (1.2 equiv.), RfI (2.4 equiv.), TTMSS (0.2 mmol, 1.0 equiv.), CH2Cl2 (5
mL), Na2S2O3 (5 equiv.), H2O (1 mL), 6 h.
b 8.9 equiv. of CF3I was used.
The products 8a and 8e were subsequently treated with hydrazine hydrate to deprotect the
phthalimide-functionalized amine moiety (Scheme 2). The perfluorohexylated product 8a gave the
corresponding amino acid ethyl ester in 66% yield. The reaction of 8e occurred with the cyclization of the
product to afford the difluoromethylated γ-lactam 10, which is known to readily convert to fluorinated
glutamic acid by hydrolysis with HCl [8].
Page 4 of 15

C6F13
O
NH2NH2-H2O
Et2O
C6F13
N
CO2Et
reflux, 15 h
H2N
CO2Et
O
8a
9
66%
CF2CO2Et
CO2Et
H
N
O
NH2NH2-H2O
Et2O
O
F
CO2Et
N
O
reflux, 15 h
F
10
61%
8e
Scheme 2 Deprotection of phthalimides 8a and 8e
We then investigated the diastereoselective reaction of methacrylic acid derivatives bearing a chiral
auxiliary (Scheme 3). The reaction of menthyl methacrylate 11 gave the product in low diastereoselectivity.
The use of camphorsultam as a chiral auxiliary enhanced the stereoselectivity to afford the
hydroperfluoroalkylated product 14 as a single stereoisomer. This high selectivity was due to the bulkiness
of TTMSS.
C6F13
C6F13I
O
hν , TTMSS
O
Na2S3O3 aq.
CH2Cl2
O
O
11
12
65% (11% de)
C6F13I
hν, TTMSS
C6F13
N
N
Na2S3O3 aq.
CH2Cl2
S
S
O2
O2
O
O
14
13
76% (>98% de)
Scheme 3 Diastereoselective hydroperfluoroalkylation
For the synthesis of chiral fluorinated amino acids, the dehydroamino acid 16, containing both phtalimide
and camphorsultam moeities, was prepared and treated with various perfluoroalkyl iodides (Scheme 4). The
α-addition [9] of phthalimide to the known N-propioloyl derivatives of Oppolzer’s camphorsultam [10] 15
gave the dehydroamino acid 16 in good yield. The hydroperfluoroalkylation of 16 proceeded smoothly to
give the corresponding products 17a–17e in good yield with excellent stereoselectivity.
Page 5 of 15

17a
17b
17c
17d
17e
C6F13
t-C4F9
C3F7
(84%, d.r. = >99:1)
(51%, d.r. = >99:1)
(79%, d.r. = 92:8)
(79%, d.r. = >99:1)
(90%, d.r. = 92:8)
Rf =
Rf
O
O
O
RfI
phtalimide, PPh3
CH2Cl2, rt, 15 h
hν , TTMSS
N
N
S
S
N
N
O
N
O
S
O2
Na2S3O3 aq.
CH2Cl2
O2
i-C3F7
O2
O
b)
O
CF3
15
16
99%
17a
e
-
Scheme 4 Synthesis and hydroperfluoroalkylation of 16
Finally, we demonstrated the transformation of 17a and 17e to the corresponding amino acid and
dipeptide, respectively (Scheme 5). The removal of the sultam auxiliary via hydrolysis afforded the
carboxylates 18a and 18e in good yield. Then, 18 was treated with hydrazine hydrate to give the
β-perfluoroalkylated amino acid 19. The absolute configuration was determined by comparing the specific
optical rotation of 19e with the reported values [2c], and we found that using (+)-camphorsultam, the
(S)-amino acid was obtained. We also checked the enantiomeric purity of the product 19 by the Mosher
method [11] and confirmed that the deprotections proceeded without loss of enantiopurity. Subsequent
N-Boc protection afforded 20 in 60% yield for the two steps from 18a. The trifluorometylated product 18e
was converted to a dipeptide by EDC condensation with phenylalanine methyl ester. This reaction also
proceeded without loss of enantiopurity.
Rf
O
Rf
O
O
O
Rf
LiOH-H2O, H2O2
NH2NH2-H2O
EtOH, 80 oC
OH
N
S
OH
N
O
N
O
O2
H2N
THF / H2O
O
R = C6F13, 18a (81%)
R = CF3, 18e (96%)
R = C6F13, 19a
R = CF3, 19e (66%)
R = C6F13, 17a
R = CF3. 17e
H2N
CO2Me
EDC, HOBt
TEA, CH2Cl2
Boc2O, NaOH aq.
dioxane / H2O
C6F13
BocHN
CF3
O
H
OH
N
CO2Me
N
O
O
O
20 (60% for two steps)
21
Scheme 5 Transformation to the amino acids 19 and 20, and the peptide 21
3. Conclusion
We successfully accomplished the photoinduced radical hydroperfluoroalkylation of
electron-deficient olefins and N-phthalimide dehydroamino acid derivatives using TTMSS as a H-donor
and a perfluoroalkyl iodide as a radical precursor in the presence of aqueous Na2S2O3. The reaction was
effective for various perfluoroalkyl iodides. The use of camphorsultam as a chiral auxiliary gave high
stereoselectivity, and the product was easily converted to the corresponding amino acid and a peptide
Page 6 of 15

derivative. This reaction is a new and efficient method for the synthesis of chiral β-perfluoroalkylated
amino acids.
References
4. Experimental section
4.1. General
1
All reactions were performed with a high-pressure Hg lamp (Ushio, 450W). H NMR spectra were
recorded on a JEOL ESC-400 (400 MHz) or Bruker Avance 600 (600 MHz) spectrometer with CDCl3 or
CD3OD as the solvent and tetramethylsilane as an internal standard unless otherwise noted. 13C NMR
spectra were recorded on the instruments operating at 100.5 MHz or 125.0 MHz with CDCl3 or CD3OD as
the solvent and internal standard. IR spectra were taken on a SHIMADZU FTIR-8700 spectrometer. Mass
spectra (EI+) were obtained on a JEOL JMS-700 mass spectrometer. Mass spectra (ESI) were obtained on a
Thermo Exactive. Precoated Merck Kieselgel 60 F254 and Kanto silica gel 60 (spherical neutral) were used
for thin layer chromatography and flash chromatography, respectively.
4.2. Typical procedure for photoinduced hydroperfluoroalkylation.
In a Pyrex glass tube were placed TTMSS (0.2 mmol), olefin (0.24 mmol), perfluoroalkyl iodide (0.24
mmol) and CH2Cl2 (5 mL). Then Na2S2O3 (0.5 mmol, 79 mg) and water (1 mL) were added to the mixture.
After sealing the tube, the mixture was shaken and then irradiated with a Hg lamp at room temperature.
After the reaction was completed, the mixture was extracted with CH2Cl2. The extract was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography to afford pure product.
4.2.1. Ethyl 3-perfluorohexylpropanoate (2).
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.19 (q, J = 7.2 Hz, 2H), 2.62 (m, 2H), 2.48 (m, 2H), 1.28 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 61.8, 37.2 (t, JC-F = 22.8 Hz C6F13C), 26.1, 14.7; IR
(KBr) 1735, 1240, 1195, 1146, 1025, 846 cm-1; HRMS (ESI–) m/z calcd for C11H8F13O2 [M–H]– 419.0317,
found 419.0324.
4.2.2. Ethyl 3-iodopropanoate (3).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 2H), 3.33 (m, 2H), 2.97 (m, 2H), 1.28 (t,
13
J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 171.1, 60.9, 38.6, 14.2, -3.7; HRMS (EI) m/z calcd for
C5H9IO2 [M]+ 227.9646, found 227.9685.
4.2.3. Ethyl 2-iodo-3-perfluorohexylpropanoate (4)
1
Colorless oil. H NMR (400 MHz, CDCl3) δ 4.59 (dd, J = 3.2, 10.8 Hz, 1H), 4.25 (q, J = 7.6 Hz, 2H),
3.33 (m, 1H), 2.71 (m, 1H), 1.29 (t, J = 7.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.0, 62.5, 38.6 (t, J
= 20.4 Hz, C6F13C), 13.7, 5.4; IR (neat) 2989, 1743, 1430, 1201, 1146, 961, 846, 730, 657, 530 cm-1; MS
Page 7 of 15

(EI) m/z 546 (M+, 100%), 473 (58), 363 (49), 327 (42), 203 (10); HRMS calcd for C11H8F13IO2 545.9360,
found 545.9349.
4.2.4. Ethyl 2-methyl-3-perfluorohexylpropanoate (6a).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.20 (q, J = 7.2 Hz, 2H), 2.90 (m, 1H), 2.73 (m, 1H), 2.09
(m, 1H), 1.30 (d, J = 7.6 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 174.6, 61.1, 34.9
(t, JC-F = 21.1 Hz, C6F13C), 32.8, 18.3, 14.0; IR (KBr) 2962, 1735, 1240, 1219, 1146, 806, 697 cm-1; HRMS
(ESI+) m/z calcd for C12H11F13O2Na [M+Na]+ 457.0450, found 457.0444.
4.2.5. Ethyl 3-perfluorohexylbutanoate (6b).
1
Colorless oil. H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 2H), 2.93(m, 1H), 2.77 (dd, J = 16.4,
4.0 Hz, 1H), 2.30 (dd, J = 16.4, 10.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.8, 61.0, 34.3, 33.7 (t, JC-F = 20.9 Hz, C6F13C), 14.2; IR (KBr) 2960, 1735, 1241,
1203, 1033, 841, 809 cm-1; HRMS (ESI+) m/z calcd for C12H11F13O2Na [M+Na]+ 457.0450, found
457.0442.
4.2.6. 2-Methyl-3-perfluorohexylpropionitrile (6c).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.08 (m, 1H), 2.54 (m, 1H), 2.27 (m, 1H), 1.51 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 120.4, 34.7 (t, JC-F = 22.9 Hz, C6F13C), 18.5, 18.4; IR (KBr) 2952,
2347, 1654, 1561, 1507, 1244, 837, 745 cm-1; HRMS (APCI-) calcd for C10H6F13N [M]– 387.0293, found
387.0259.
4.2.7. 5-Perfluorohexyl-3-pentanone (6d).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 2.72 (m, 2H), 2.50 (m, 2H), 2.45 (m, 2H), 1.09 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 207.6, 36.0, 32.7, 25.1 (t, JC-F = 20.9 Hz, C6F13C), 7.7; IR (KBr) 2958, 1734,
1245, 1073, 1050, 1015, 840 cm-1; HRMS (APCI-) calcd for C11H8F13O [M–H]– 419.0496, found 419.0505.
4.2.8. Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-perfluorohexylpropanoate (8a).
1
White powder. H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.78 (m, 2H), 5.32 (dd, J = 10.0, 4.0 Hz,
13
1H), 4.27 (m, 2H), 3.17 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.3, 167.0,
134.5, 131.6, 123.8, 62.9, 45.2, 29.6 (t, JC-F = 20.2 Hz, C6F13C), 14.0; IR (KBr) 2987, 1724, 1718, 1387,
1236, 1072, 860, 848, 720, 530 cm-1; HRMS (ESI-) m/z calcd for C19H11F13NO4 [M–H]– 564.0481, found
564.0479.
4.2.9. Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-perfluoropropylpropanoate (8b).
1
White powder. H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.78 (m, 2H), 5.32 (dd, J = 10.0, 4.0 Hz,
13
1H), 4.25 (m, 2H), 3.15 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.3, 167.1,
134.5, 131.6, 123.8, 62.9, 45.2, 29.6 (t, JC-F = 20.1 Hz, C3F7C), 14.0; IR (KBr) 2970, 1781, 1353, 1260,
1182, 1092, 935, 722, 529 cm-1; HRMS (ESI-) m/z calcd for C16H11F7NO4 [M–H]– 414.0576, found
414.0581.
Page 8 of 15

4.2.10. Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-perfluoroisopropylpropanoate (8c).
White powder. 1H NMR (400MHz, CDCl3) δ 7.90 (m, 2H), 7.78 (m, 2H), 5.28 (dd, J = 10.0, 4.0 Hz, 1H),
13
4.24 (m, 2H), 3.26 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.4, 167.0, 134.5,
131.6, 123.8, 60.4, 46.4, 27.0 (d, JC-F = 20.1 Hz, i-C3F7C), 14.2; IR (KBr) 2956, 1751, 1388, 1227, 721
cm-1; HRMS (ESI-) m/z calcd for C16H11F7NO4 [M–H]– 414.0576, found 414.0577.
4.2.11. Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-trifluoromethylpropanoate (8d).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.78 (m, 2H), 5.21 (dd, J = 8.0, 2.8 Hz, 1H),
13
4.24 (m, 2H), 3.15 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.1, 167.0, 134.5,
131.6, 123.8, 62.8, 46.3, 32.6 (q, JC-F = 29.3 Hz, CF3C), 14.1; IR (KBr) 2984, 2944, 1751, 1388, 1150, 864,
847, 721, 629 cm-1; HRMS (ESI+) m/z calcd for C14H12F3NO4Na [M+Na]+ 338.0616, found 338.0609.
4.2.12. Diethyl 4-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropentanedioate (8e).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 2H), 5.24 (dd, J = 5.6, 4.4 Hz, 1H),
4.21 (m, 4H), 3.13 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 167.7, 167.0, 163.2 (t, JC-F = 31.5 Hz, CF2CO), 134.3, 131.7, 123.7, 114.7 (t, JC-F = 250.8 Hz, CF2), 63.3,
46.0 (t, JC-F = 3.8 Hz, CF2CH2C), 33.1 (t, JC-F = 22.9 Hz, CF2C), 14.0, 13.8; IR (KBr) 2930, 1719, 1388,
1098, 1088, 849, 721 cm-1; HRMS (ESI+) m/z calcd for C17H18F2NO6 [M+H]+ 370.1102, found 370.1097.
4.2.13. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-methyl-3-perfluorohexylpropanoate (12).
Diastereomer mixture. White powder. HRMS (ESI+) m/z calcd for C20H26F13O2 [M+H] + 545.1170, found
545.1722. 1H NMR (400 MHz, CDCl3) δ 4.69 (m, 1H), 2.88 (m, 1H), 2.74 (m, 1H), 2.06 (m, 1H), 1.96 (m,
13
1H), 1.87 (m, 1H), 1.69 (m, 2H), 1.50-1.37 (m, 2H), 1.35 (m, 3H), 0.83-1.07(m, 9H), 0.74 (m, 3H); C
NMR (150 MHz, CDCl3) δ 174.1, 74.9, 47.0, 40.5, 34.0 (t, JC-F = 21.6 Hz, C6F13C), 33.1 (major isomer),
33.0 (minor isomer), 31.6 (major isomer), 31.3 (minor isomer), 26.1, 23.3, 22.0 (major isomer), 21.9 (major
isomer), 20.7 (major isomer), 20.6 (major isomer), 15.9, 14.1; IR (KBr) 1728, 1466, 1210, 1027, 697 cm-1;
[α]24 D -38.9 (c 0.10, CHCl3).
4.2.14. N-{(2R)-2-Methyl-3-perfluorohexylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam (14)
1
. White powder. H NMR (400 MHz, CDCl3) δ 3.90 (t, J = 6.8 Hz, 1H), 3.60 (m, 1H), 3.56 (d, J = 13.6
Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 2.02 (m, 1H), 1.84 (m, 2H), 1.91 (m, 2H),
13
1.40 (m, 2H), 1.30 (d, J = 6.0 Hz, 3H), 1.14 (s, 3H), 0.98 (s, 3H); C NMR (150 MHz, CDCl3) δ 173.7,
65.3, 53.1, 48.5, 47.7, 44.6, 38.0, 35.4 (t, JC-F = 21.3 Hz, C6F13C), 32.9, 32.8, 26.5, 19.9, 19.8, 18.3; IR
(KBr) 2925, 2347, 1654, 1647, 1635, 1560, 1547, 1540, 1239, 1195, 846 cm-1; [α]24 -27.3 (c 0.76,
D
CHCl3); HRMS (ESI+) m/z calcd for C20H22F13NO3SNa [M+Na]+ 626.1005, found 626.0989.
4.2.15. N-{(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-perfluorohexylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam
(17a).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.73 (m, 2H), 5.67 (dd, J = 9.4, 3.2 Hz, 1H),
Page 9 of 15

4.06 (m, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.21 (m, 1H), 2.75 (m, 1H), 2.10 (m,
13
2H), 1.87 (m, 3H), 1.36 (m, 2H), 0.88 (s, 6H); C NMR (150 MHz, CDCl3) δ 167.6, 166.6, 134.3, 132.0,
123.5, 67.0, 53.4, 48.4, 47.6, 46.5, 45.1, 37.8, 33.3, 30.7 (t, JC-F = 29.1 Hz, C6F12C), 26.2, 20.5, 19.8; IR
(KBr) 1707, 1334, 1318, 1238, 1226, 1190 cm-1; [α]24 D -50.7 (c 0.02, CHCl3); HRMS (ESI+) m/z calcd for
C27H23F13N2O5SNa [M+Na]+ 757.1012, found 757.0995.
4.2.16.
N-{(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-perfluoro-tert-butylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam
(17b).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.74 (m, 2H), 5.70 (dd, J = 6.4, 2.8 Hz, 1H),
4.16 (dd, J = 16.2, 6.4 Hz, 1H), 4.08 (m, 1H), 3.40 (d, J = 14.0 Hz, 1H), 3.34 (d, J = 14.0 Hz, 1H), 2.17 (dd,
J = 16.6, 2.0 Hz, 1H), 2.09 (m, 2H), 1.88 (m, 3H), 1.36 (m, 2H), 0.86 (s, 3H), 0.79 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 167.6, 166.7, 134.4, 132.0, 123.5, 67.0, 53.4, 48.4, 47.6, 47.4, 45.1, 37.8, 33.2, 28.7, 26.3,
20.5, 19.7; [α]24 D -46.7 (c 0.15, CHCl3); HRMS (ESI+) m/z calcd for C25H23F9N2O5SNa [M+Na]+ 657.1076,
found 657.1065.
4.2.17. N-{(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-perfluoropropylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam
(17c).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.74 (m, 2H), 5.68 (dd, J = 11.8, 3.6 Hz, 1H),
4.06 (dd, J = 8.0, 5.2 Hz, 1H), 3.39 (d, J = 13.6 Hz, 1H), 3.22 (d, J = 13.6 Hz, 1H), 3.12(m, 1H), 2.82 (m,
1H), 2.16 (m, 1H), 2.09 (m, 1H), 1.91 (m, 3H), 1.40 (m, 2H), 0.87 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
167.5, 166.6, 134.2, 132.0, 123.5, 66.9, 53.4, 48.4, 47.6, 47.5, 45.1, 37.8, 33.6 (t, JC-F = 29.1 Hz, C3F7C),
33.4, 26.2, 20.5, 19.8; IR (KBr) 1733, 1695, 1336, 1327, 1238 cm-1; [α]24 -26.4 (c 0.34, CHCl3); HRMS
D
(ESI+) m/z calcd for C24H23F7N2O5SNa [M+Na]+ 607.1108, found 607.1096.
4.2.18.
N-{(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-perfluoroisopropylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam
(17d).
White powder. 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.75 (m, 2H), 5.67 (m, 1H), 4.06 (dd, J = 7.2,
4.8 Hz, 1H), 3.58 (m, 1H), 3.41 (d, J = 13.6 Hz, 1H), 3.34 (d, J = 13.6 Hz, 1H), 2.50 (m, 1H), 2.14 (m, 2H),
1.88 (m, 3H), 1.38 (m, 2H), 0.87 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 166.4, 134.3,
131.8, 123.5, 66.9, 53.4, 48.4, 47.6, 47.4, 45.1, 37.8, 33.3, 28.8 (d, JC-F = 20.1 Hz, i-C3F7C), 26.2, 20.5,
19.8; [α]24 -1.65 (c 7.21, CHCl3); HRMS (ESI+) m/z calcd for C24H23F7N2O5SNa [M+Na]+ 607.1108,
D
found 607.1097.
4.2.19. N-{(R)-2-(1,3-Dioxoisoindolin-2-yl)-3-trifluoromethylpropanoyl}-(1R,2S,4S)-bornane-10,2-sultam
(17e).
1
White powder. H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.76 (m, 2H), 5.55 (dd, J = 10.4, 3.2 Hz,
1H), 4.07 (dd, J = 7.2, 4.8 Hz, 1H), 3.39 (d, J = 13.6 Hz, 1H), 3.35 (d, J = 13.6 Hz, 1H), 3.17 (m, 1H), 2.76
(m, 1H), 2.15 (m, 1H), 2.09 (m, 1H), 1.91 (m, 3H), 1.37 (m, 2H), 0.88 (s, 6H); 13C NMR (100 MHz,
Page 10 of 15

CDCl3) δ 167.6, 166.6, 134.3, 132.0, 123.5, 67.0, 53.4, 48.4, 47.6, 46.4, 45.1, 37.8, 33.3, 30.2, 26.2 (q, JC-F
= 29.3 Hz, CF3C), 20.5, 19.8; IR (KBr) 1785, 1699, 1400, 1298, 1207, 1120, 1085, 1039 cm-1; [α]24 D -33.9
(c 0.10, CHCl3); HRMS (ESI+) m/z calcd for C22H23F3N2O5SNa [M+Na]+ 507.1172, found 507.1166.
4.3 Typical procedure for deprotection of the phthalimide group.
To a solution of a substrate (0.30 mmol) in EtOH (3 mL) were added hydrazine hydrate (0.90 mmol).
o
The mixture was stirred at 80 C for 15 h. After the reaction was completed, the solution was cooled to
room temperature, and filtered with celite and Na2SO4. The filtrate was concentrated in vacuo. The resulting
residue was purified by column chromatography on silica gel to give pure amino acid.
4.3.1. Ethyl 2-amino-3-fluoropropanoate (9).
1
White powder. H NMR (400 MHz, CDCl3) δ 4.23 (q, J = 7.2 Hz, 2H), 3.90 (dd, J = 7.2, 4.8 Hz, 1H),
13
2.70 (m, 1H), 2.38 (m, 1H), 1.72 (br, 2H), 1.30 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 173.2,
61.8, 48.8, 35.6 (t, JC-F = 17.3 Hz, C6F13C), 14.0; IR (KBr) 2927, 2313, 1734, 1654, 1560, 1507, 1239, 1145
cm-1; MS (EI) m/z 462 (M+-CO2Et, 76%), 363(11) 69 (16), 59 (12), 57 (100); HRMS calcd for C8H5F13N
362.0215, found 362.0249.
4.3.2. Ethyl 4,4-difluoro-5-oxopyrrolidine-2-carboxylate (10).
White powder. 1H NMR (400 MHz, CDCl3) δ 6.98 (br, 1H), 4.30 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.91
(m, 1H), 2.69 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.9, 169.2 (t, JC-F = 24.2
Hz, CF2CO), 62.6, 49.9, 34.3 (t, JC-F = 24.2 Hz, CF2C), 14.0; IR (KBr) 3274, 3169, 1735, 1718, 1195, 1080,
756 cm-1; HRMS (ESI+) m/z calcd for C7H9F2NO3Na [M+Na]+ 216.0448, found 216.0452.
4.4 Synthesis of N-{2-(1,3-Dioxoisoindolin-2-yl)acryloyl}-(1R,2S,4S)-bornane-10,2-sultam (16).
To a solution of 15 (0.52 g, 1.95 mmol) in CH2Cl2 (20 mL) were added phthalimide (0.29 g, 1.95 mmol)
and PPh3 (54 mg, 0.21 mmol). The mixture was stirred at room temperature overnight. After the reaction
was completed, the mixture was concentrated in vacuo. The resulting residue was purified by column
chromatography on silica gel (hexane / ethyl acetate = 1 : 1) to give 16 (0.80 mg, 99%). White powder. 1H
NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.76 (m, 2H), 6.22 (s, 1H), 6.20 (s, 1H), 4.13 (m, 1H), 3.45 (s,
13
2H), 2.13 (m, 2H), 1.94 (m, 3H), 1.38 (m, 2H), 1.14 (s, 3H), 0.96 (s, 3H); C NMR (150 MHz, CDCl3) δ
165.8, 164.0, 135.2, 131.8 130.5, 124.3, 121.7, 66.2, 53.4, 48.1, 47.6, 45.1, 38.0, 33.2, 26.3, 20.8, 19.9;
[α]24 17.3 (c 0.14, MeOH); HRMS (ESI+) m/z calcd for C21H22N2O5SNa [M+Na]+ 437.1142, found
D
437.1128.
4.5 Typical procedure for hydrolysis of the camphorsultam group.
To a solution of a substrate (0.33 mmol) in THF/H2O (3 : 1, 3.2 mL) at 0 oC were added LiOH-H2O (0.42
mmol) and H2O2 30% aq. (0.80 mmol). The mixture was stirred at room temperature for 1-2 h. After the
reaction was completed, the solution was extracted with ethyl acetate and sat. NaHCO3 aq. The extract was
washed with 1 N HCl aq., dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel to give pure product.
Page 11 of 15

4.5.1. (R)-2-(1,3-Dioxoisoindolin-2-yl)-3-perfluorohexylpropanoic acid (18a).
White powder. 1H NMR (400 MHz, CD3OD) δ 7.88 (m, 2H), 7.84 (m, 2H), 5.12 (m, 1H), 3.26 (m, 2H);
13C NMR (100 MHz, CD3OD) δ 172.3, 169.2, 135.6, 133.3, 124.3, 58.3, 32.3 (t, JC-F = 21.3 Hz, C6F13C);
IR (KBr) 1707, 1324, 1238, 1190 cm-1; [α]24 -4.3 (c 0.28, MeOH); HRMS (ESI-) m/z calcd for
D
C17H7F13NO4 [M–H]– 536.0167, found 536.0165.
4.5.2. (R)-2-(1,3-Dioxoisoindolin-2-yl)-3-trifluoromethylpropanoic acid (18e).
1
White powder. H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.78 (m, 2H), 5.28 (dd, J = 10.4, 3.2 Hz,
13
1H), 3.23 (m, 1H), 3.05 (m, 1H); C NMR (100 MHz, CDCl3) δ 172.3, 166.9, 134.6, 131.4 124.0, 45.8,
32.5 (q, JC-F = 29.5 Hz, CF3C); IR (KBr) 1700, 1645, 1320, 967 cm-1; [α]24 D -17.5 (c 0.09, MeOH); HRMS
(ESI-) m/z calcd for C12H7F3NO4 [M–H]– 286.0322, found 286.0330.
4.6 Synthesis of (R)-2-(tert-Butoxycarbonylamino)-3-perfluorohexylbutanoic acid (20)
To a solution of amino acid 18 (0.32 mmol) in EtOH (3 mL) was added hydrazine hydrate (0.96 mmol).
The mixture was stirred at 80 oC for 1 h. After the reaction was completed, the solution was cooled to room
temperature, and filtered with Celite and Na2SO4. The filtrate was concentrated in vacuo. The resulting
residue was purified by column chromatography on silica gel to give pure amino acid. To a solution of the
amino acid (0.12 mmol) in dioxane / H2O (3 : 2, 2 mL) were added 1 N NaOH aq. (0.24 ml) and (Boc)2O
(0.26 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the
solution was cooled on ice, and added ethyl acetate and 1 N HCl aq. to pH 2-3. The mixture was extracted
with ethyl acetate, and washed with water and brine. The extract was dried with Na2SO4, filtered, and
concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give
pure 20. White powder. 1H NMR (400 MHz, CDCl3) δ 4.71 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H), 1.44 (s,
13
9H); C NMR (100 MHz, CDCl3) δ 169.6, 155.0, 82.1, 47.1, 31.9 (m, C6F13C), 28.1; HRMS (ESI-) m/z
calcd for C14H13O4NF13 [M–H]– 506.0632, found 506.0634.
4.7
Synthesis
of
methyl
(S)-2-{(R)-2-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluorobutanamido}-3-phenylpropanoate (21).
Amino acid 19e (26.6 mg, 0.09 mmol) and L-phenylalanine methyl ester (16.5 mg, 0.09 mmol) were
dissolved in CH2Cl2. The solution was cooled to 0 oC where TEA (13 μl, 0.09 mmol), EDC (19.1 mg, 0.10
mmol), and HOBt (12.8 mg, 0.09 mmol) were added. The mixture was stirred at 0 oC for 1 h, warmed to
room temperature and stirred overnight. The reaction mixture was extracted with CH2Cl2 and sat. NaHCO3
aq.. The extract was dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel (hexane / ethyl acetate = 1 : 1) to give pure 21 (20.8 mg,
1
32%). White powder. H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.80 (m, 2H), 6.97 (m, 5H), 6.11 (br,
1H), 5.12 (dd, J = 11.0, 3.0 Hz, 1H), 4.84 (m, 1H), 3.72 (s, 3H), 3.21 (m, 1H), 3.09 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 171.3, 166.9, 165.9, 134.7, 131.3, 129.1, 128.4, 127.1, 124.0, 123.6, 76.7, 53.2, 47.7, 37.5,
31.4 (q, JC-F = 22.9 Hz, CF3C); IR (KBr) 1675, 1616, 1498, 1373, 1139 cm-1; [α]24 D -16.8 (c 0.01, CHCl3);
HRMS (ESI+) m/z calcd for C22H19F13N2O5Na [M+Na]+ 471.1138, found 471.1136.
Page 12 of 15

References
[1] For reviews, see: a) Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects
to Clinical Applications, Gouverneur V.; Müller K. Ed.; Imperial College Press, London, 2012. b)
Fluorous Chemistry, Horváth I T. Eds.; Springer-Verlag, Berlin, 2011. c) Fluorine in Medicinal
Chemistry and Chemical Biology, Ojima, I. Eds.; Blackwell Pub., United Kingdom, 2009. d) Bégué,
J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons, New
Jersey, 2008. e) Uneyama, K. Organofluorine Chemistry, Blackwell Pub., United Kingdom, 2006.
[2] a) T. Vagt, E. Nyakatura, M. Salwiczek, C. Jäckel, B. Koksch, Org. Biomol. Chem., 8, (2010)
1382–1386. b) E. N. G. Marsh, B. C. Buer, A. Ramamoorthy, Mol. BioSyst., 5, (2009) 1143–1147. c)
H. -P. Chiu, Y. Suzuki, D. Gullickson, R. Ahmad, B. Kokona, R. Fairman, R. P. Cheng, J. Am. Chem.
Soc. 128, (2006) 15556–15557.
[3] Z. Hu, W. Han, Tetrahedron Lett., 49, (2008) 901–902.
[4] T. Yajima, H. Nagano, Org. Lett., 9, (2007) 2513–2515.
[5] T. Yajima, T. Tonoi, H. Nagano, Y. Tomita, K. Mikami, Eur. J. Org. Chem., (2010) 2461–2464.
[6] T. Yajima, I. Jahan, T. Tonoi, M. Shinmen, A. Nishikawa, K. Yamaguchi, I. Sekine, H. Nagano,
Tetrahedron, 68, (2012) 6856–6861
[7] (a) X. X. Rong, H.-Q. Pan, W. R. Dolbier, Jr, J. Am. Chem. Soc., 116, (1994) 4521–4522. (b) S.
Barata-Vallejo, A. Postigo, J. Org. Chem., 75, (2010) 6141–6148.
[8] (a) D. W. Konas, J. K. Coward, J. Org. Chem., 66, (2001) 2461–2464. (b) D. W. Konas, J. K. Coward,
Org. Lett., 1, (1999) 2105–2107.
[9] B. M. Trost, G. R. Dake, J. Am. Chem. Soc., 119, (1997) 7595–7596.
[10] K. Takao, N. Hayakawa, R. Yamada, T. Yamaguchi, U. Morita, S. Kawasaki, K. Tadano, Angew.
Chem. Int. Ed. Engl., 47, (2008) 3426–3429.
[11] U. Larsson, R. Carlson, J. Leroy, Acta. Chem. Scand., 47, (1993) 380–390.
Page 13 of 15

Highlights
１．Development of photo-induced radical hydroperfluoroalkylation of olefins including dehydroamino
acid, using TTMSS as a H-donor.
２．Highly stereoselective reaction via chiral auxiliary method.
３．Efficient method for the synthesis of chiral β-perfluoroalkylated amino acids.
Page 14 of 15

R
EWG
CH2Cl2
R1 = H, Me, NH-Pht
R2 = H, Me
EWG = CO2Et, CN, COEt
Rf = CF3, C3F7, CF2CO2Et etc.
Rf
H2N
CO2H
N
S
O2
O
β
chiral -perfluoroalkylated
amino acids
Page 15 of 15