Effective synthesis of optically active trifluoromethyldiazirinyl homophenylalanine and aroylalanine derivatives with the Friedel-Crafts reaction in triflic acid

Article abstract of DOI:10.1271/bbb.90027

The Friedel-Crafts reaction with 3-(3-methoxyphenyl)-3-(trifluoromethyl)- 3H-diazirine and optically active N-TFA-Asp(Cl)-OMe in triflic acid afforded homophenylalanine derivatives without any loss of the optical purity.

Full text of DOI:10.1271/bbb.90027

Biosci. Biotechnol. Biochem., 73 (6), 1377–1380, 2009
Effective Synthesis of Optically Active Trifluoromethyldiazirinyl
Homophenylalanine and Aroylalanine Derivatives
with the Friedel-Crafts Reaction in Triflic Acid
y
1
2
1;
Ryo MURASHIGE,1; Yuta MURAI, Yasumaru HATANAKA, and Makoto HASHIMOTO
*
1Department of Agricultural and Life Science, Obihiro University of Agriculture and Veterinary Medicine,
Inada-cho, Obihiro, Hokkaido 080-8555, Japan
2Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama,
2630 Sugitani, Toyama, Toyama 930-0194, Japan
Received January 13, 2009; Accepted February 26, 2009; Online Publication, June 7, 2009
[doi:10.1271/bbb.90027]
The Friedel-Crafts reaction with 3-(3-methoxy-
phenyl)-3-(trifluoromethyl)-3H-diazirine and optically
active N-TFA-Asp(Cl)-OMe in triflic acid afforded
homophenylalanine derivatives without any loss of the
optical purity.
asymmetric hydrogenation,11) these required special
reagents or precursors. It might not be sutable to apply
those for the preparation of diazirinylated hPhe, because
some conditions might reduce the diazirine function.
In this paper, we report an effective method for
providing optically active diazirinyl hPhe featuring the
Friedel-Crafts (F-C) reaction with 3-(3-methoxyphenyl)-
3-(trifluoromethyl)-3H-diazirin 112) and the ꢀ-acid chlo-
ride of aspartic acid 213) as the key step.
Key words: diazirine; photoaffinity labeling; Friedel-
Crafts reaction; triflic acid
Photoaffinity labeling is a useful biochemical method
in investigations of structural and functional relation-
ships between small biologically active compounds and
biomolecules such as enzymes, RNA, and DNA.1)
Various compounds, such as phenyldiazirine, arylazide
and benzophenone have been developed as photophores.
This is ideal, because we can provide photolabeling
groups with minimum structural alteration. It has also
been established that the (3-trifluoromethyl)phenyldia-
zirinyl function can be selectively activated without
damaging peptides and proteins by irradiating at 350
nm.2) But this usually requires manipulation steps to
introduce photophores into the target molecules, and also
independent construction of the (3-trifluoromethyl)phe-
nyldiazirinyl groups. These limitations encouraged us to
establish an effective protocol to provide the (3-trifluor-
omethyl)phenyldiazirinyl photophore.3) It is considered
that amino acid derivatives carrying a photolabeling
group would become a powerful tool in investigations
of biologically active peptides, and for studying their
metabolic pathways.
We focused on developing the (3-trifluoromethyl)dia-
zirinyl photophore into homophenylalanine (hPhe), since
interesting biological behavior has been discovered
by replacing a phenylalanine with hPhe in biological
peptides4,5) and has also been reported as a starting
material for pharmaceutical products such as benazepril
and enarapril, both of which inhibit the angiotensin
converting enzyme (ACE).6,7) The efficient synthesis of
photoactivatable optically pure hPhe is important for
this. Although several synthetic protocols for optically
active hPhe have been reported by various method
including enzymatic resolution,8) Suzuki-coupling,9)
diastereoselective Michael addition10) and catalytic
Results and Discussion
We chose the ꢀ-acid chloride form of N-trifluoro-
methyl (S)-aspartic acid ꢁ-methyl ester 2 as the electro-
philic precursor. When we first attempted the reaction
between 1 and 2 at room temperature, employing
aluminium chloride as the activator, however, the
desired reaction did not proceed and both 1 and 2 were
recovered in CH2Cl2 or CH3NO2. (Fig. 1, Runs 1 and 2)
The reflux conditions led the decomposition of 2.
(Fig. 1, Runs 3 and 4) Although the F–C reaction
between N-aspartic anhydride derivatives and aromatics
have been reported,14–19) the aromatics had to be in
excess amounts as the solvents. It would be preferable if
we could use stoichiometric amounts of aromatics in the
process by taking account of both the operational
feasibility and economic matters. The reaction did not
proceed by employing titanium chloride, which has been
effective for formylation,20) as the activator in CH2Cl2
or under neat conditions. (Fig. 1, Runs 5 and 6) It was
found that the desired reaction proceeded smoothly at
0 ꢀC to give adducts 3 and 4 in an over 87% yield by
employing a stoichiometric amount of 1 when trifluor-
omethanesulfonic acid (TfOH) was employed as the
solvent. The suspension at the initial stage became a clear
solution upon the start of the reaction. Regioisomers
3 and 4 were readily separated by silica gel column
chromatography. The NOESY spectrum of major
0
product 3 gave the correlation signals between C2 OCH3
0
and C3 H, which disclosed the substitution pattern. In
the case of minor product 4, NOESY correlation was
0
obtained between C4 OCH3 and both C3 and C5 H.
(R)-2 was also reacted with 1 under the same condition to
0
0
y
*
To whom correspondence should be addressed. Tel: +81-155-49-5542; Fax: +81-155-49-5577; E-mail: hasimoto@obihiro.ac.jp
Present address: Department of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamioono, Himeji, Hyogo 670-8524, Japan

1378
R. MURASHIGE et al.
F3C
N
N
3'
2'
OCH3
4'
5'
4'
F3C
N
N
5'
6'
3'
2'
N
COCl
6'
condition
N
OCH3
+
+
1'
1'
CF3
O
4
O
3
F3COCHN
COOCH3
OCH3
1 (1 eq)
2 (1 eq)
F3COCHN
COOCH3
F3COCHN
COOCH3
Entry Catalyst Solvent Temperature Time (h) Yield
1
2
3
4
5
6
7
AlCl3
AlCl3
AlCl3
AlCl3
TiCl4
TiCl4
TfOH
CH2Cl2 rt
CH3NO2 rt
CH2Cl2 reflux
CH3NO2 reflux
CH2Cl2 50°C
0°C
12h
12h
12h
12h
3h
0a
0a
0b
0b
0b
0a
2h
0°C
2h
(
S
) – 71 (3), 28 (4)
(R) – 68 (3), 19 (4)
8
TfOH
50°C
2h
0b
a no reaction occurred, b the starting material 1 was decomposed.
Fig. 1. Friedel-Crafts Reaction with Diazirinyl Compound 1 and Optically Pure Aspartic Acid Derivative 2.
F3C
F3C
N
N
N
N
afford (R)-3 and 4 in good yields. (Fig. 1, Run 7) A
higher temperature afforded a complex mixture because
of the decomposition of 1 and 2. (Fig. 1, Run 8) These
results are consistent with the report that the diazirinyl
N-N double bond was easily decomposed in the presence
of a Lewis acid over 25 ꢀC.21) Unfortunately, 3-phenyl-3-
(3-trifluoromethyl)-3H-diazirine, which has no activat-
ing methoxy substituent on the benzene ring, did not
react with (S)- or (R)-2 in TfOH at 0 ꢀC. A higher
temperature decomposed the diazirinyl ring. We have
already reported that 3-phenyl-3-(3-trifluoromethyl)-3H-
diazirine easily reacted with the dichloromethyl methyl
ether to give a formylation product in TfOH.22) These
results indicated that the reactivity of both the acyl donor
and acyl acceptor also played a critical role. Furthermore,
the trifluoromethyldiazirinyl moiety acted slightly as an
electron-withdrawing group for the nucleophilic substi-
tution of aromatic compounds.23)
a
OCH3
OCH3
O
5
3
F3COCHN
COOCH3
c
F3COCHN
COOCH3
b
F3C
F3C
N
N
N
N
OCH3
OCH3
6
7
O
H2N
COOH
H2N
COOH
Scheme 1. Synthesis of the Optically Pure Diazirinyl Homopheny-
lalanine Derivatives.
Reagents and conditions: (a) triethylsilane, trifluoroacetic acid,
(S)-76%, (R)-80%; (b) NaOH, MeOH, (S)-91%, (R)-90%; (c) 6 N
HCl, acetic acid, 80 ꢀC, (S)-94%, (R)-88%.
With adducts 3 and 4 in hand, the newly introduced
carbonyl group was then reduced to a hPhe derivative. It
has already been reported that the diazirinyl N-N double
bond was labiel under H2–Pd/C conditions.24) We found
that selective reduction of benzylic carbonyl to methyl-
ene could be performed with the triethylsilane/TFA
system to give 5 in a good yield.25) No decomposition of
the diazirinyl ring occured during the reduction. Finally,
deprotection of (S)- and (R)-5 was performed under an
alkaline condition to afford diazirinyl hPhe 6 in a good
yield (90%). However, the conditions decomposed the
product to result in a complex mixture when aroyl
derivative 3 was employed. Deprotection of 3 could be
achieved by treating with 6 N HCl in acetic acid at
80 ꢀC, affording 7 (Scheme 1).
6
7
(S )-
(R )-
(S)-
(R)-
0
10
20
30
0
10
20
30
Time (min)
Time (min)
Fig. 2. Chiral HPLC Chromatogram of Synthetic Diazirinyl (S)- or
(R)-6 and (S)- or (R)-7.
The enantiopurity of compounds 6 and 7 was
determined by chiral HPLC (Chirobiotic T, Astec)26)
which revealed this as >98% ee, proving no racemiza-
tion during the synthesis (Fig. 2).
Condition: Chirobiotic T (Astec) 4:6 ꢁ 250 mm, eluted with 10%
EtOH–H2O; flow rate of 1.0 ml/min; UV detection at 210 nm.

Effective Synthesis of Photoreactive Homophenylalanine and Aroylalanine
1379
a
b
Fig. 3. Photolysis of 0.5 mM of (S)-6 (a) and (S)-7 (b) in Methanol with 15 W Black Light.
The photolysis reaction mixture, at the times (in min), is indicated by the numbers.
in TfOH (0.25 ml, 2.9 mmol) at 0 ꢀC. The yellow reaction mixture was
stirred for two hours at the same temperature, then poured into cold
water and AcOEt (30:30 ml). The organic layer successively was
washed with aqueous 1 M HCl, saturated NaHCO3, 1 N HCl and
saturated NaCl, then dried over MgSO4, and filtered. The filtrate was
concentrated, and the residue was subjected to silica chromatography
(AcOEt:n-hexane = 1:5) to afford pure (S)-3 (34.4 mg, 71%) and (S)-4
(13.6 mg, 28%) as a pale yellow oil.
(S)-3: ½ꢁꢂD +77ꢀ (c 1.0, CHCl3); IR (film) cmꢃ1: 3330, 1720, 1675,
1610; 1H-NMR (CDCl3) ꢂ: 7.79 (1H, d, J ¼ 8:0 Hz), 7.54 (1H, brd,
J ¼ 8:0 Hz), 6.80 (1H, d, J ¼ 8:0 Hz), 6.66 (1H, s), 4.89–4.86 (1H, m),
3.91 (3H, s), 3.78 (1H, dd, J ¼ 19:2, 4.3 Hz), 3.73 (3H, s), 3.57 (1H,
dd, J ¼ 18:9, 4.0 Hz); 13C-NMR (CDCl3) ꢂ: 197.34, 170.12, 159.47,
The photolysis properties of the diazirinyl compounds
were examined under black light (15 W). We have
already demonstrated that the concentration of the
diazirinyl compound had to be set to less than 1 mM to
minimize isomerization to the diazo compound.27) The
maximum absorption at 360 nm for 6 and 7 was
decreased by increasing irradiation time (Fig. 3). The
half-life of 6 and 7 was determined to be 8.5 and
3.2 min, respectively, based on the intensity at 360 nm.
We concluded the values were appropriate for photo-
affinity labeling.
We developed in these studies an effective synthesis
of photoreactive and enantiomerically pure hPhe and 2-
methoxybenzoylalanine from the 3-(3-methoxyphenyl)-
3-(trifluoromethyl)-3H-diazirin and (S)- and (R)-aspartic
acid derivative as an effective photolabeling probe
without racemization. The key F–C reaction proceeded
by employing trifluoromethanesulfonic acid as the
solvent. The subsequent silane promoted reduction to
enable transformation of the benzylic carbonyl to
methylene. The results will contribute to studies on the
structure-activity relationship for the side chain of
aromatic ꢁ-amino acids.
156.91 (q, 2JCF ¼ 37:6 Hz), 136.06, 131.46, 126.42, 121.77 (q, 1JCF
¼
1
274:7 Hz), 118.80, 115.63 (q, JCF ¼ 287:9 Hz), 109.63, 55.85, 53.15,
48.92, 45.29, 28.45 (q, 2JCF ¼ 40:4 Hz); 19F-NMR (CDCl3) ꢂ: ꢃ63:18,
ꢃ74:34; ESI-MS m=z: 442 ðM þ HÞþ; ESI-HRMS: calcd. for
C16H14F6N4O5 ðM þ HÞþ, 442.0832; found, m=z 442.0826.
(S)-4: ½ꢁꢂD +57ꢀ (c 1.0, CHCl3); IR (film) cmꢃ1: 3330, 1725, 1690,
1610; 1H-NMR (CDCl3) ꢂ: 7.82 (1H, d, J ¼ 8:6 Hz), 7.63 (1H, brd,
J ¼ 7:4 Hz), 7.19 (1H, s), 7.02 (1H, d, J ¼ 8:6 Hz), 4.97–4.94 (1H, m),
3.91 (3H, s), 3.86–3.82 (4H, m), 3.56 (1H, dd, J ¼ 18:3, 3.4 Hz);
2
13C-NMR (CDCl3) ꢂ: 196.22, 169.70, 163.71, 157.05 (q, JCF
¼
38:0 Hz), 132.51, 130.09, 129.53, 121.62 (q, 1JCF ¼ 275:1 Hz), 117.60,
115.56 (q, 1JCF ¼ 287:5 Hz), 115.20, 55.87, 53.25, 48.71, 40.81, 29.22
2
(q, JCF ¼ 40:0 Hz); 19F-NMR (CDCl3) ꢂ: ꢃ66:75, ꢃ72:86; ESI-MS
m=z: 442 ðM þ HÞþ; ESI-HRMS: calcd. for C16H14F6N4O5 ðM þ HÞþ,
442.0832; found, m=z 442.0828.
Experimental
(R)-Methyl 4-(2-methoxy-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)
phenyl)-4-oxo-2-(2,2,2-trifluoroacetamido)butanoate ((R)-3) and (R)-
methyl 4-(4-methoxy-2-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)-
4-oxo-2-(2,2,2-trifluoroacetamido)butanoate ((R)-4). The same treat-
ment of 1 (24.7 mg, 0.11 mmol) and (R)-2 (29.0 mg, 0.11 mmol) as that
just described gave (R)-3 (33.0 mg, 68%) and (R)-4 (9.2 mg, 19%) as
yellow oil. The 1H-, 13C-NMR and IR data for these samples were
identical with these recorded for (S)-3 and 4.
General methods. Optical rotation values were measured by a Jasco
DIP-370 polarimeter, and IR spectra were measured by a Jasco FTIR-
4100 instrument. 1H-, 13C- and 19F-NMR spectra were measured by a
Jeol ECA 500 spectrometer. In the 1H-NMR spectra, the chemical
shifts are expressed in ppm downfield from the signal for tetrame-
thylsilane that was used as an internal standard. Splitting patterns are
designated as s (singlet), d (doublet), t (triplet), and m (multiplet). In
the 13C-NMR spectra, the 13C chemical shifts of the solvents were used
(R)-3, ½ꢁꢂD ꢃ76ꢀ (c 1.0, CHCl3); (R)-4, ½ꢁꢂD ꢃ58ꢀ (c 1.0, CHCl3)
as the internal standards
(
13CDCl3, 77.0 ppm; and 13CD3OD,
49.5 ppm). In the 19F-NMR spectra, the chemical shifts are reported
as default values without correction. MS data were obtained with a
Hitachi NanoFrontier LD mass spectrometer. Chiral HPLC was
performed with Chirobiotic T (Astec), 4:6 ꢁ 250 mm, eluted with
10% EtOH–H2O; flow rate, 1.0 ml/min; UV detection at 210 nm.
(S)-Methyl 4-(2-methoxy-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)
phenyl)-2-(2,2,2-trifluoroacetamido)butanoate ((S)-5). To a solution of
(S)-3 (169 mg, 0.38 mmol) in TFA (1.5 ml, 20 mmol), Et3SiH (0.30 ml,
1.9 mmol) was added dropwise. The reaction mixture was stirred for
two hours and then partitioned with AcOEt (80 ml). The organic layer
was successively washed with saturated NaHCO3, 1 N HCl and
saturated NaCl, then dried over MgSO4 and filtered. After the filtrate
had been concentrated, the residue was subjected to silica chromatog-
raphy (AcOEt:n-hexane = 1:10) to afford a colorless amorphous mass
(115 mg, 76%).
(S)-Methyl 4-(2-methoxy-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)
phenyl)-4-oxo-2-(2,2,2-trifluoroacetamido)butanoate ((S)-3) and (S)-
methyl 4-(4-methoxy-2-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)-
4-oxo-2-(2,2,2-trifluoroacetamido)butanoate ((S)-4). Compounds 112)
(24.7 mg, 0.11 mmol) and (S)-213) (29.0 mg, 0.11 mmol) were dissolved

1380
R. MURASHIGE et al.
½ꢁꢂD +65ꢀ (c 1.0, CHCl3); IR (film) cmꢃ1: 3320, 1720, 1610;
replacing the inner atmosphere with nitrogen, photolysis was carried
out with 15 W black-light (UVP, San Gabriel, California, USA) at a
distance 2 cm from the surface of light source.
1H-NMR (CDCl3) ꢂ: 7.11 (1H, d, J ¼ 7:4 Hz), 7.04 (1H, d,
J ¼ 7:4 Hz), 6.74 (1H, brd, J ¼ 6:9 Hz), 6.57 (1H, s), 4.64–4.62 (1H,
m), 3.81 (1H, s), 3.68 (1H, s), 2.64 (2H, t, J ¼ 7:7 Hz), 2.25–2.22 (1H,
m), 2.10–2.03 (1H, m); 13C-NMR (CDCl3) ꢂ: 171.00, 157.40, 156.74
Acknowledgments
2
1
(q, JCF ¼ 37:2 Hz), 130.41, 130.21, 128.69, 122.07 (q, JCF
¼
1
274:3 Hz), 118.90, 115.63 (q, JCF ¼ 287:5 Hz), 108.12, 55.24,
This research was partially supported by a Ministry of
Education, Culture, Sports, Science, and Technology
grant for scientific research on a priority area, 18032007,
for Scientific Research (C), 19510210, and for scientific
research on innovative areas. R.M. thanks Obihiro
University of Agriculture and Veterinary Medicine
Committee for financial support for the study.
52.65, 52.18, 31.03, 28.37 (q, JCF ¼ 40:0 Hz), 25.32; 19F-NMR
2
(CDCl3) ꢂ: ꢃ66:54, ꢃ75:28. ESI-MS m=z: 400 ðM ꢃ N2 þ HÞþ;
ESI-HRMS: calcd. for C16H16F6NO4 ðM ꢃ N2 þ HÞþ, 400.0978;
found, m=z 400.0989.
(R)-Methyl 4-(2-methoxy-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)
phenyl)-2-(2,2,2-trifluoroacetamido)butanoate ((R)-5). The same treat-
ment of (R)-3 (168 mg, 0.38 mmol) as that just described gave (R)-5
(121 mg, 80%) as yellow oil. The 1H-, 13C-NMR and IR data for these
samples were identical to these recorded for (S)-5.
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159.24, 132.56, 131.76, 129.42, 123.65 (q, JCF ¼ 273:5 Hz), 119.90,
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8:6 Hz), 6.81 (1H, s), 3.99–3.97 (4H, m), 3.72 (1H, d, J ¼ 19:5 Hz),
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111.08, 56.54, 51.84, 29.54 (q, JCF ¼ 40:4 Hz), 23.2; 19F-NMR
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(2001).
(CD3OD) ꢂ: ꢃ66:83; ESI-MS m=z: 332 ðM þ HÞþ; ESI-HRMS: calcd.
for C13H13F3N3O4 ðM þ HÞþ, 332.0853; found, m=z 332.0866; chiral
HPLC tR ¼ 10:2 min.
22) Nakashima H, Hashimoto M, Sadakane Y, Tomohiro T, and
Hatanaka Y, J. Am. Chem. Soc., 128, 15092–15093 (2006).
23) Hashimoto M, Kato Y, and Hatanaka Y, Tetrahedron Lett., 47,
3391–3394 (2006).
(R)-2-Amino-4-(2-methoxy-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)
phenyl)-4-oxobutanoic acid ((R)-7). The same treatment of (R)-4
(31.8 mg, 72 mmol) as that just described gave (R)-7 (21.0 mg, 88%) as
yellow oil. The 1H-, 13C-NMR and IR data for these samples were
identical to these recorded for (S)-6.
24) Ambroise Y, Miskowski C, Djega-Mariadassou G, and
Rousseau B, J. Org. Chem., 65, 7183–7186 (2000).
25) Hashimoto M, Hatanaka Y, and Nabeta K, Heterocycles, 59,
395–398 (2003).
26) Murashige R, Hayashi Y, and Hashimoto M, Tetrahedron Lett.,
49, 6566–6568 (2008).
½ꢁꢂD +14ꢀ (c 2.0, MeOH); chiral HPLC tR ¼ 15:0 min
27) Hashimoto M and Hatanaka Y, Anal. Biochem., 348, 154–156
(2006).
Photolysis of the diazirinyl compounds in methanol. A methanolic
solution of (S)-6 or 7 (0.5 mM) was placed in a quartz cuvette. After