Asymmetric and efficient synthesis of homophenylalanine derivatives via Friedel-Crafts reaction with trifluoromethanesulfonic acid

Article abstract of DOI:10.1016/j.tetlet.2008.09.013

An efficient Friedel-Crafts reaction of TFA-Asp(Cl)-OMe and stoichiometric amounts of benzene was established by using neat trifluoromethanesulfonic acid (TfOH) as solvent and catalyst under a mild condition. This methodology has been applied to many arom

Full text of DOI:10.1016/j.tetlet.2008.09.013

Tetrahedron Letters 49 (2008) 6566–6568
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric and efficient synthesis of homophenylalanine derivatives
via Friedel–Crafts reaction with trifluoromethanesulfonic acid
*
Ryo Murashige, Yuka Hayashi, Makoto Hashimoto
Department of Agricultural and Life Science, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro 080-8555 Hokkaido, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Friedel–Crafts reaction of TFA-Asp(Cl)-OMe and stoichiometric amounts of benzene was
established by using neat trifluoromethanesulfonic acid (TfOH) as solvent and catalyst under a mild
condition. This methodology has been applied to many aromatic compounds and enabled synthesis of
several homophenylalanine derivatives.
Received 6 August 2008
Revised 29 August 2008
Accepted 4 September 2008
Available online 7 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
Cl
COOMe
O
Homophenylalanine (hPhe) elongates methylene in a side chain
of phenylalanine (Phe). Sometimes it produces different biological
activities when displacing Phe with homoPhe in bioactive pep-
tides.1 hPhe is also known as a starting material for pharmaceutical
products such as benazepril and enarapril, which inhibit angioten-
sin converting enzyme (ACE).2 Asymmetric and efficient synthesis
of hPhe is important. Synthesis of hPhe has been reported using
various methodologies including enzymatic resolution,3 Suzuki-
coupling,4 diastereoselective Michel addition5 and catalytic asym-
metric hydrogenation.6 These methods require the preparation of
special reagents or precursors for the asymmetric synthesis of both
enantiomers. Amino acids are one of the most popular precursors
and easily available for asymmetric synthesis. Friedel–Crafts
(F–C) reactions between aromatics and a side chain of aspartic acid
(Asp) are some of the key reactions for asymmetric synthesis for
both hPhe enantiomers’ skeletons.7 It has been reported that syn-
thesis of hPhe using F–C reaction of Asp anhydride (N-unprotected
or N-protected) by AlCl3 is required for large excesses of aromatics
and refluxing in organic solvent for long durations. Smaller
amounts of aromatics at room temperature have produced lower
yields.7a It is estimated that the low solubility of Asp derivatives
makes the reaction mixture precipitate in organic solvents. There-
fore, the synthetic routes have not been applied to precious or
pyrolyzing aromatic compounds. To apply these synthetic routes
to many aromatic compounds, we established an efficient
Friedel-Crafts reaction with stoichiometric amounts of enantiopure
Asp derivatives (Fig. 1) and aromatics at low temperature, followed
by derivatization to hPhe.
O
HCl H2N
TFAHN
TFAHN
O
O
3
1
2
Figure 1. Acyl donors for Friedel–Crafts reaction with benzene.
2. Results and discussion
To establish an efficient F–C reaction, conditions, which con-
sisted of aromatics and acyl donors stoichiometrically at room
temperature, were fixed. One of the most popular acyl donors,
N-TFA-protected L
-Asp anhydride (1),8 was used as a first choice
because an acid stable N-protection group might be preferable
for the F–C reaction. Using AlCl3 (Table 1, entry 1) as a catalyst in
CH2Cl2, no reaction occurred within 12 h because the L-Asp deriv-
ative was precipitated.9 To resolve the problem, we attempted
F–C reactions in excess amounts of liquid promoters, which we
used as a solvent. TiCl4, which is normally used for an F–C reaction
for the a-carboxyl in a
-amino acid,10 was used (entry 2). However,
the reaction mixture became heterogeneous and no reaction was
observed. We chose concentrated H2SO4 (entry 3) to make the
reaction mixture homogeneous, but only a hydrolyzed product of
acyl donor (N-TFA-L-Asp-OH) was obtained. This result showed
that compound 1 could be dissolved in strong Bronsted acid. We
tried using a neat trifluoromethanesulfonic acid (TfOH) as a pro-
moter and solvent. TfOH has been used in F–C reactions because
it forms mixed anhydride which has a strong reactivity with acyl-
donor.11 As shown in entry 4, the reaction mixture became homo-
geneous in TfOH, the F–C reaction proceeded within an hour at
room temperature to obtain target compounds (4a and 4b) in
55% yield and no hydrolysis of 1 was observed. To ensure the role
of TfOH, Tf2O (entry 5), which was reported as an F–C when
* Corresponding author. Tel.: +81 155495542; fax: +81 155495577.
E-mail address: hasimoto@obihiro.ac.jp (M. Hashimoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.013

R. Murashige et al. / Tetrahedron Letters 49 (2008) 6566–6568
6567
Table 1
of a regioisomer. Although stoichiometric amounts of benzene and
3 in the presence of AlCl3 in CH2Cl2 afforded a moderate yield of
F–C products 5 (entry 7), a long reaction time was needed (10 h)
because the reaction mixture became heterogeneous. TiCl4 and
H2SO4 did not afford the F–C product 5 because it was a heteroge-
neous mixture and hydrolysis of acyl donor occurred, respectively
(entries 8 and 9). A homogeneous mixture was made using TfOH,
and compound 3 was converted to 5 in a 98% yield within an hour
(entry 10). The F–C reaction using Tf2O is not effective because Tf2O
did not dissolve the acyl donor during the reaction (entry 11).
There were some benefits to using acyl donor 3 in TfOH. First,
F–C reaction proceeded on a small scale (<0.1 mmol) in a mild con-
dition (0 °C) and produced a high yield. Second, further purification
was not needed by 1H NMR analysis after the reaction mixture was
subjected to partition (1 N HCl, saturated NaHCO3. and saturated
NaCl).15 From these results, this F–C reaction with neat TfOH could
be applied to various aromatic compounds.
Friedel–Crafts reaction of 1 or 2 or 3 and stoichiometric amounts of benzene at room
temperature by catalysts
Catalyst
1 or 2 or 3
1eq
TFAHN
Solvent
Condition
O
O
1eq
TFAHN
COOR
COOH
4b
4a R=H
R=Me
5
Entry Donor Catalyst (equiv) Solvent Reaction time (h) Product yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
3
3
3
3
AlCl3 (8)
CH2Cl2
Neat
Neat
Neat
Neat
Neat
CH2Cl2
Neat
Neat
Neat
Neat
1 or 12
1 or 12
1 or 12
1
1 or 12
1
0
0
0
TiCl4 (90)
H2SO4 (90)
TfOH (40)
Tf2O (25)
TfOH (40)
AlCl3 (8)
TiCl4 (90)
H2SO4 (90)
TfOH (40)
Tf2O (25)
4a (52), 4b (3)
0
0
5 (50)
0
0
10
We performed the F–C reaction in TfOH for compound
L- and
1 or 12
1 or 12
1
D-3 and some aromatic compounds (Table 2). Stereochemistry of
the Asp derivative 3 was retained for F–C products (entries 1 and
2) in a good yield. Aromatics, which have electron-donating sub-
stituents, easily reacted within an hour at 0 °C in a high yield, be-
cause the inductive effect of the substituents played an important
role. Toluene (entries 3 and 4) was afforded p-substituted product
(6) mainly and o-substituted product (7) of less than 5%. Xylene
derivatives (entries 5–10) were also afforded 8–10 with a good
yield. But anisole (entries 11 and 12) was afforded the same degree
of p-(11) and o-(12) isomers, which were easily purified with col-
umn chromatography. These results indicated that combinations of
TfOH and activating groups in the aromatic compounds for nucleo-
philic substitution reduced activating energy differences between
o- and p-formation more than combinations of AlCl3 and aromat-
ics.7b 1,2-Dimethoxybenzene afforded only a less hindered (13)
in a good yield (entries 13 and 14). An F–C reaction of aromatics
bearing deactivating substituents such as nitro group (entry 15)
did not proceed even though the reaction proceeded at room tem-
perature. F–C reaction of N-Ac or N-TFA-aniline also did not work
(entries 16 and 17). It was estimated that protonation of amide
10
11
5 (98)
0
1 or 12
forming mixed anhydride with carboxylic acid,12 was applied. The
reaction mixture became heterogeneous and no reaction occurred.
These results showed that TfOH not only improved the solubility of
1 but also promoted an effective F–C reaction. A regioisomer was
formed in the condition, because compound 1 had two F-C reaction
sites, b- and
a-carboxyl (4a:4b = 95:5). The proportion of the reg-
ioisomer was identical to that used in previous reports, which used
AlCl3 in excess benzene with refluxing.8 N-unprotected
L-Asp anhy-
dride (2)13, which is another popular donor, was subjected to the
F–C condition in TfOH, and no products were formed because the
reaction mixture became heterogeneous (entry 6). To improve
the reaction, TFA-L-Asp(Cl)-OMe (3) that was obtained via methan-
olyzing 1 with MeOH, then treating the product with SOCl2,14 was
used as an acyl donor. As expected, compound 3 was more reactive
than 1 or 2 and it had only one acylation site to prevent formation
Table 2
Friedel–Crafts reaction of 3 and stoichiometric amounts of aromatics
5 R1, R2, R3, R4 = H
R1
6 R1 = CH , R2, R3, R4 = H
7 R1, R2 =3H, R3 = CH
R2
R3
8 R1, R2 = CH , R3, R43 = H
9 R1, R3 = CH3, R2, R4 = H
R1
O
R2
R4
10 R2, R4= CH 3, R1, R3 = H
TfOH
Cl
3
Condition
11 R1 = OCH3, R2, R3 = H
12 R1, R2 = H, R3 = OCH3
13 R1, R2 = OCH3, R3 = H
O
R4
R3
TFAHN
COOMe
3
TFAHN
COOMe
Entry
R1
R2
R3
R4
Configuration of 3
Conditions
Product (proportiona)
-5
-5
-6, 7 (95: 5)
-6, 7 (95: 5)
-8
-8
-9
-9
-10
-10
-11, 12 (5: 4)
-11, 12 (5: 4)
-13
-13
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
Me
Me
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
L-
0 °C to rt, 1 h
0 °C to rt, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
L
98
97
99
99
97
96
98
98
96
97
97
98
99
99
0
D
-
-
-
-
-
-
-
D
L
-
L
D
D
L
-
L
D
D
L
-
L
H
D
D
H
H
Me
Me
H
L
-
L
D
D
OMe
OMe
OMe
OMe
NO2
NHAc
NHTFA
L
-
L
H
D
D
OMe
OMe
H
H
H
L
-
L
D
0 °C, 1 h
D
L
L
L
-
-
-
0 °C to rt, 1 h
0 °C to rt, 1 h
0 °C to rt, 1 h
—
—
—
0
0
a
The ratios of both isomers were calculated with 1H NMR.

6568
R. Murashige et al. / Tetrahedron Letters 49 (2008) 6566–6568
R1
R1
R1
R2
R3
R2
R3
R2
R3
R4
R4
R4
6N HCl aq.
5 R1, R2, R3, R4 = H
H2, Pd/C
6 R1 = CH , R2, R3, R4 = H
8 R1, R2 =3CH , R3, R4 = H
9 R1, R3 = CH3, R2, R4 = H
O
AcOH
r.t.
1 h
80 °C
6 h
10 R2, R4= CH 3, R1, R3 = H
Me
TFAHN
COOMe
5, 6, 8-13
TFAHN
COO
HCl H2N
COOH
3
11 R1 = OCH3, R2, R3 = H
12 R1, R2 = H, R3 = OCH3
13 R1, R2 = OCH3, R3 = H
5b L-99%, D-98%
6b L-96%, D-99%
8b L-97%, D-98%
9b L-98%, D-99%
10a L-98%, D-96%
11b L-98%, D-95%
12b L-99%, D-99%
13b L-98%, D-99%
5a L-96%, D-94%
6a L-95%, D-98%
8a L-98%, D-97%
9a L-94%, D-95%
10a L-98%, D-96%
11a L-97%, D-96%
12a L-99%, D-98%
13a L-97%, D-98%
Scheme 1. Synthesis of hPhe derivatives.
nitrogen with TfOH may decrease acidity in reaction mixture. F–C
products or -5, 6, and 8–13) subsequently underwent
Supplementary data
(L-
D
hydrogenolysis of benzyl carbonyl with H2/Pd–C in acetic acid fol-
lowed by deprotection of TFA and methyl ester by 6 N HCl aq at
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.013.
80 °C16 to give hPhe derivatives in a good yield (Scheme 1). Enan-
7f,17
tiomeric excess of these compounds was measured [
a]
and
D
References and notes
chiral HPLC (CHIROBIOTIC T; eluted with 10% EtOH–H2O; flow rate
1.0 ml/min; UV detection at 210 nm) for both enantiomers. Enan-
tiomeric excess of all of the deprotected compounds was calcu-
lated >99% in order to succeed asymmetric synthesis of hPhe
derivatives.
1. (a) Mosberg, H. I.; Heyl, D. L.; Haaseth, R. C.; Omnaas, J. R.; Medzihradsky, F.;
Smith, C. B. Mol. Pharmacol. 1990, 38, 924; (b) Abiko, T.; Sekino, H. Drug Dev. Ind.
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3. Conclusion
5. Yamada, M.; Nagashima, N.; Hasegawa, J.; Takahashi, S. Tetrahedron Lett. 1998,
39, 9019.
We established an efficient Friedel–Crafts reaction with stoichio-
metric amounts of aromatics and easily preparable Asp derivatives
3 as acyl donor, in good yields under mild conditions in TfOH at
room temperature. Furthermore, the F–C reaction, which in previ-
ous reports7 had taken more than several hours with various Asp
derivatives, was completed within an hour. Because amino acid
derivatives, which are not easily dissolved in organic solvents,
could be dissolved in TfOH, the reaction mixture became a homo-
geneous system. After the reduction of the benzyl carbonyl group
6. Xie, Y.; Lou, R.; Li, Z.; Mi, A.; Jiang, Y. Tetrahedron: Asymmetry 2000, 11, 1487.
7. (a) Reifenrath, W. G.; Bertelli, D. J.; Micklus, M. J.; Fries, D. S. Tetrahedron Lett.
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by using H2–Pd/C, deprotection of TFA at
a-amino group and
80 h.7a
.
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407.
methyl ester at -carboxyl group, hPhe derivatives were afforded
a
in a good overall yield (>90%), and the asymmetric center of the
product retained its configuration starting from Asp derivatives.
These synthetic routes will be applied to precious aromatics to
derivatize side chain elongated aromatic amino acid derivatives
via F–C reactions in short steps.
11. (a) Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl. 1972, 11, 299; (b)
Germain, A.; Commeyras, A. J. Chem. Soc., Chem. Commun. 1972, 24, 1345; (c)
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14. Svete, J.; Stanocnik, B. J. Heterocycl. Chem. 1994, 31, 1259–1266.
15. General method for Friedel–Crafts reaction with TfOH; Compound 3 (0.1 mmol)
and aromatic compound (0.1 mmol) were dissolved in TfOH (0.5 ml,
5.69 mmol) at 0 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 1 h, then poured into cold-H2O/AcOEt (40/40 ml)
to quench the reaction mixture. The organic layer was washed with 1 N HCl aq,
satd NaHCO3 aq, 1 N HCl aq and satd NaCl aq, and dried over MgSO4, then
filtrated. The filtrate was concentrated to afford a F–C product.
16. Kirk, K. L. J. Org. Chem. 1980, 45, 2015.
Acknowledgments
This research was partially supported by a Ministry of Educa-
tion, Science, Sports and Culture, Grant-in-Aid for Scientific
Research on a Priority Area, 18032007, and for Scientific Research
(C), 19510210. M.H. also thanks the Fugaku Foundation and
Research for Promoting Technological Seeds for financial support
for the study. R.M. thanks Obihiro University of Agriculture and
Veterinary Medicine Committee for financial support for the study.
17. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445; (b) Long, A.;
Baldwin, S. W. Tetrahedron Lett. 2001, 42, 5343; (c) Sabat, M.; Johnson, C. R. Org.
Lett. 2000, 2, 1089.