Synthesis of biphenyl tyrosine via cross-coupling Suzuki-Miyaura reaction using aryltrifluoroborate salts

Article abstract of DOI:10.5935/0103-5053.20150038

We reported a fast and easy method for obtaining biarylic units from tyrosine derivatives via Suzuki-Miyaura cross-coupling using a variety of substituted and unsubstituted potassium aryl- and heteroaryltrifluoroborate salts. The scope of the methodology

Full text of DOI:10.5935/0103-5053.20150038

http://dx.doi.org/10.5935/0103-5053.20150038
J. Braz. Chem. Soc., Vol. 26, No. 4, 765-774, 2015.
Printed in Brazil - ©2015 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
A
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using
Aryltrifluoroborate Salts
Stanley N. S. Vasconcelos, Cristiane S. Barbeiro, Amna N. Khan and Hélio A. Stefani*
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo,
Av. Prof. Lineu Prestes, 580, 05508-000 São Paulo-SP, Brazil
We reported a fast and easy method for obtaining biarylic units from tyrosine derivatives via
Suzuki-Miyaura cross-coupling using a variety of substituted and unsubstituted potassium aryl- and
heteroaryltrifluoroborate salts. The scope of the methodology was also extended to the formation of
bis-tyrosine linked dipeptide bonds, leading to biologically interesting compounds. Some biarylic
units were obtained as free amino acids through the one step cleavage reaction in good yields.
Keywords: tyrosine, boron, aryltrifluoroborates, cross-coupling, Suzuki-Miyaura
HO
Introduction
OH
The biaryl subunit is an important structural motif
that can be found in many compounds including natural
products and polymers,1 especially modified aromatic
amino acids that are present in various pharmaceuticals,
which are currently under development or have already
been introduced to the market.2
O
O
HN
COOH
H
N
H
N
8
N
N
H
N
O
O
O
O
OH
Figure 1. Arylomycin A2.
Naturally found in fungal cell wall proteins,3 dityrosine
is found as a dimer formed by 3,3’-biaryl bond formation,
as well as a biaryl ether moiety in which the tyrosine units
are linked through an oxygen atom. This latter is present
in isotrityrosine and pulcherosine, which have been
isolated from bacteria4 and plants.5 Biaryl subunits are
routinely obtained by employing palladium as a catalyst
via Suzuki-Miyaura cross-coupling, as reported recently by
Monteiro and co-workers6 in the synthesis of pharmaceutical
compounds, although Bedford et al.1 reported the rhodium
catalyzed direct ortho-arylation of 2-tert-butyl protected
tyrosine using aryl bromide substrates. One known biaryl
compound is the 3-arylated tyrosine moiety present in
the antibacterial arylomycin A2 (Figure 1), isolated from
Streptomyces strain TU6075.7,8 Roberts et al.9 exploited
the latter compound by Suzuki-Miyaura reaction for the
formation of the biaryl unit. Barluenga and co-workers10
performed in one-pot mode the iodination and arylation
of 3,5-diiodotyrosine side chains of biologically active
peptides by a Suzuki-Miyaura cross-coupling reaction.
There are some biologically important tyrosine
fragments, including monocyclic peptides such as K-13,
noncompetitive inhibitor of angiotensin I-converting enzyme
and a weak inhibitor of aminopeptidase B,11 isolated from
Micromonospora halophytica ssp. exilisia and synthetically
exploited by Ma and co-workers,12 bicyclic bouvardins, an
antitumor agent, complex polycyclic antibiotics such as
chloropeptins, an anti-human immunodeficiency virus (HIV)
drug13 and teicoplanin, used in the prophylaxis and treatment
of serious infections caused by Gram-positive bacteria.14 The
molecular structure and interesting biological activity make
these compounds attractive synthetic targets.
Results and Discussion
For our preliminary studies, we used commercially
available 3-iodotyrosine without the prior protection 1
or 2 directly for Suzuki coupling, but the product was
not observed. Therefore, tyrosine was esterified with
methanol in the presence of thionyl chloride and the amino
group protected with tert-butyloxycarbonyl group (Boc) 3
(Scheme 1).15,16
*e-mail: hstefani@usp.br

766
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using Aryltrifluoroborate Salts
J. Braz. Chem. Soc.
O
O
O
Boc2O, NaHCO3
SOCl2, MeOH
0 oC, 12 h, 92%
NH2
NH2
NHBoc
HO
O
O
MeOH, rt, 15 h, 90%
I
I
I
OH
OH
OH
1
2
3
Scheme 1. 3-Iodotyrosine protection.
The study of the optimal reaction conditions was carried
out using the coupling between phenyltrifluoroborate (4o)
and N-tert-butyloxycarbonyl-3-iodotyrosine methyl
ester (3) in MeOH with K2CO3; a yield of 73% of 5o was
observed as a model study (Table 1, entry 1).
Aryltrifluoroborates bearing electron-withdrawing groups
such as CN, CHO, and Cl substituents, all in the para-
position, were suitable substrates, giving the corresponding
cross-coupled products in low to moderate yields
ranging from 17% to 50% (Table 2, entries 1, 5 and 10).
Aryltrifluoroborate bearing the CO2H group did not yield
the desired product under the reaction conditions (Table 2,
entry 12), 43% of start material was intact recovered, we
believed that the remaining material decomposed. Other
aspects observed as the presence of homocoupling product
from organotrifluoroborate salt and a possible lability of
tyrosine under the cross coupling conditions prevented the
formation of desired products in better yields.
On the other hand, aryltrifluoroborate bearing electron-
donor groups as CH3O, CH3, C2H5S, tert-butyl, OH and NH2
undergo the reaction leading to the cross-coupled products
with yields ranging from 19% to 79% (Table 2, entries
2-4, 6-9, 14 and 16). The reaction seems to be sensitive to
steric hindrance, as noted in the case of the methyl group
when present in the ortho, meta and para position on the
aromatic ring, leading to diminishing yields such as 33,
47 and 62%, respectively (Table 2, entries 6-8). Neutral
aromatic rings, such as benzene and naphthalene, gave
Using K2CO3 as the base, other palladium catalysts
were tested, resulting in the desired products; however,
these were obtained in low to moderate yields (Table 1,
entries 2-5 and 9). Only trietylamine was used as a different
base, but this led to the cross-coupled product in 20% yield
(Table 1, entry 8) and no improvement was achieved by
replacing conventional heating with microwave (Table 1,
entry 6). When MeOH was replaced with toluene, the
yield of 5o was obtained in trace amounts only (Table 1,
entry 7). The catalytic amount of Pd(OAc)2 was 0.05 mmol.
Under basic conditions and an alcoholic environment, the
saponification of the methyl ester was not observed, as
described by Stefani et al.17
With the optimized reaction conditions in hand, the
substrate scope of this Pd-catalyzed cross-coupling reaction
was investigated.Different substituents on the aromatic ring
of aryltrifluoroborate salts were tested, and the products
were generally afforded in low to good yields (Table 2).
Table 1. Survey for palladium-catalyzed coupling of aryltrifluoroborates with 3-iodotyrosinea
O
O
NHBoc
NHBoc
O
O
catalist, base
BF3K
+
I
solvent,
OH
OH
3
4o
5o
time / h
7
entry
Catalyst
Pd(OAc)2
Base
Solvent
Yield / %b
73
1
2
3
4
5
6
7
8
9
K2CO3
MeOH
PdCl2(dppf).CH2Cl2
Pd(PPh3)4
−
−
−
12
33
−
12
48
PdCl2(PPh3)2
PdPEPPSI-IPr
Pd(OAc)2
−
−
12
61
−
−
−
12
54
−
3
tracesc
traces
20
Pd(OAc)2
−
Toluene
MeOH
−
12
Pd(OAc)2
TEA
12
PdCl2(dppf).CH2Cl2
−
12
46
aConditions: 3 (0.5 mmol), 4o (0.5 mmol), catalyst (10 mol%), base (1.5 mmol), solvent (4 mL), 80°C; bisolated yield; creaction under microwave irradiation.

Vol. 26, No. 4, 2015
Vasconcelos et al.
767
Table 2. Substrate scope of cross-coupling reaction of aryltrifluoroborates to iodo-tyrosine
O
O
R
NHBoc
NHBoc
O
O
R
Pd(OAc)2, K2CO3
BF3K
+
I
MeOH, 80 °C
OH
OH
3
4a-p
5a-p
entry
1
RBF3K
Product
time / h
Yield / %a
50
O
BF3K
NHBoc
CN
O
10
4a
OH
CN
5a
O
BF3K
NHBoc
OMe
O
4b
2
3
8
79
77
OH
OMe
5b
O
NHBoc
BF3K
O
8
OMe
4c
OMe
OH
5c
O
BF3K
NHBoc
OH
O
4
5
6
7
8
4d
12
12
12
12
8
57
17
33
47
62
OH
OH
5d
O
O
BF3K
NHBoc
O
4e
OH
O
5e
O
NHBoc
BF3K
O
4f
OH
5f
O
NHBoc
BF3K
O
4g
OH
5g
O
BF3K
NHBoc
O
4h
OH
5h
O
BF3K
NHBoc
S
O
4i
9
12
45
S
OH
5i

768
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using Aryltrifluoroborate Salts
J. Braz. Chem. Soc.
Table 2. Substrate scope of cross-coupling reaction of aryltrifluoroborates to iodo-tyrosine (cont.)
entry
RBF3K
Product
time / h
12
Yield / %a
O
BF3K
NHBoc
Cl
O
10
4j
36
OH
Cl
5j
O
NHBoc
BF3K
O
11
12
13
14
15
16
12
12
12
12
7
50
nr
4k
OH
5k
O
O
BF3K
NHBoc
O
OH
4l
OH
O
OH
5l
O
NHBoc
BF3K
S
O
89
74
73
19
4m
S
OH
5m
O
BF3K
NHBoc
O
4n
OH
5n
O
NHBoc
BF3K
O
4o
OH
5o
O
NHBoc
BF3K
O
12
NH2
4p
NH2
OH
5p
aYields refer to isolated pure products.
moderate to good yields (Table 2, entries 11 and 15, 50%
and 73%, respectively) and heterocyclic thiophene gave the
highest yield in the series, 89% (Table 2, entry 13).
amino alcohol 7 in 55% yield using sodium borohydride20
(Scheme 2, route B).
Next, we did the synthesis of dipeptides21 that could
be subjected to cross-coupling reaction. For this purpose,
the compounds 3-phenyl-tyrosine methyl ester 8, obtained
from selective amino deprotection of 5o in the presence
of trifluoroacetic acid (TFA) in dichloromethane (DCM)
and 3-iodo-N-tert-butyloxycarbonyltyrosine 9, were
coupled using N-N’-diisopropylcarbodiimide (DIC) and
1-hydroxybenzotriazole (HOBt) in DCM for 15 h. After
purification, the resulting dipeptide 10 was isolated in 52%
yield. With the iodine present in the peptide fragment, this
The next step was the direct conversion of the N-Boc-
amino ester products into the correspondent free amino
acid as hydrochloride salts 6a-e (Table 3) through the one-
step cleavage reaction with 4.5 mol L−1 HCl at 70 °C for
3 h18 (Scheme 2, route A). Alternatively, the N-Boc-amino
ester 5o was first converted into free amino ester with
trifluoroacetic acid19 in 82% yield, which could be used
after a simple filtration through a short pad of silica
gel. The crude product was reduced into the respective

Vol. 26, No. 4, 2015
Vasconcelos et al.
769
O
R
NH2
6a-e
NH2
HO
4.5 mol L-1 HCl
70°C, 3 h
O
R
NHBoc
A
B
OR'
O
OR'
5
R
HO
1. TFA
2. NaBH4
5 6a-e
,
: R' = H
OR'
7: R = H, R' = CH3
7
Scheme 2. Functional group transformations.
Table 3. Free amino acidsa
O
O
O
O
NH2
HO
NH2
NH2
OMe
HO
HO
S
OH
OH
OH
6a
6b
6c
74%
83%
75%
O
O
NH2
Cl
NH2
HO
HO
OH
OH
6d
6e
63%
90%
aYields refer to isolated pure products. Compounds 6a to 6e were obtained as hydrochloride salts.
offered the opportunity of a new cross-coupling reaction
showing the versatility to form different biarylic subunits
in peptides fragments. To evidence this fact, dipeptide 10
was reacted with organotrifluoroborate salt 4m under Pd
catalysis to give the compound 11 in 42% yield (Scheme 3).
Similarly, the dipeptide 12 was achieved via peptide
bond between compounds 2 as hydrochloride salt and 9 in
48% yield. Enticed by the possibility of bis cross-coupling
at the same time, due to the presence of iodine atoms on the
aromatic rings, we performed the cross-coupling reaction
using two equivalents of potassium 4-methoxyphenyl-
trifluoroborate salt 4b, leading exclusively to the compound
13, from which, after flash chromatography, the product
could be obtained with high purity in 61% yield (Scheme 4).
O
NHBoc
HO
BF3K
O
O
O
O
I
O
O
O
NHR1
NHBoc
NHBoc
S
S
N
H
N
H
OH
O
9
4m
I
b
c
OH
OH
OH
10
11
OH
OH
1 = Boc
R1 = H
5o
R
a
8
Scheme 3. (a) TFA, DCM, rt, 12 h (yield 63%); (b) HOBt, DIC, DCM, rt, 15 h (yield 52%); (c) Pd(OAc)2, K2CO3, MeOH, 12 h, 70 °C, (yield 42%).

770
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using Aryltrifluoroborate Salts
J. Braz. Chem. Soc.
O
NH2
HCl
O
I
BF3K
O
O
O
O
O
O
OH
O
NHBoc
NHBoc
O
2
N
H
N
H
4b
I
a
b
O
NHBoc
HO
I
OH
OH
12
13
I
OH
OH
O
OH
9
Scheme 4. (a) HOBt, DIC, TEA, DCM, rt, 15 h (yield 48%); (b) Pd(OAc)2, K2CO3, MeOH, 10 h (yield 61%).
Surprisingly, the formation of the single coupling product
was not observed during the reaction.
system (Shimadzu). Typically, 0.1 µL sample aliquots were
injected and infused into the instrument in 50% acetonitrile,
containing 0.5% formic acid under a constant flow rate
of 0.2 mL min−1. Instrument control, data acquisition and
processing were performed by the LCMS Solution suite
(Shimadzu). ESI conditions: source temperature 200 °C,
cone voltage 4.5 kV, detector voltage 1.57 kV, nebulizing gas
flow 1.5 L min−1. Solvents and reagents were of analytical
grade or the highest grade commercially available and
were used without further purification. Palladium catalysts,
3-iodotyrosine and potassium aryltrifluroborate salts (4a-p)
were purchased from Sigma-Aldrich and used as received.
Conclusions
In conclusion, we have demonstrated that the cross-
coupling of 3-iodotyrosine with potassium heteroaryl- and
aryltrifluoroborate salts can be carried out using Pd(OAc)2
as the catalyst. Both activated and deactivated species of
trifluoroborate salts can be coupled, proven to be suitable
nucleophiles. Subsequently, the obtained biphenyl tyrosines
were transformed into the corresponding free amino acid as
hydrochloride salts. The coupled tyrosine was converted in
dipeptides and the submitted to the cross-coupling reaction
with heteroaryl- and aryltrifluoroboate salts leading to
products in moderate to good yields. The structures of
General procedure for Suzuki-Miyaura cross-coupling
reaction (5a-p)
1
all products were characterized by H nuclear magnetic
To a two-necked 25 mL round-bottomed flask under
a nitrogen atmosphere containing Pd(OAc)2 (11.23 mg,
10 mol%), potassium trifluoroborate salt (0.5 mmol),
L-N-t-butyloxycarbonyltyrosine methyl ester (210.5 mg,
0.5 mmol), and dry MeOH (4 mL) were added K2CO3
(207.6 mg, 1.5 mmol). The reaction mixture was stirred
and heated at 80 °C. The reaction was monitored by thin
layer chromatography (TLC). Then the reaction mixture
was diluted with ethyl acetate and washed with saturated
solution of NH4Cl (3 × 20 mL), the organic phase was
collected, dried with MgSO4, filtered and the solvent
was removed under vacuum. Purification by silica flash
chromatography (eluting with ethyl acetate/hexane 2:8).
resonance (NMR), 13C NMR, and high resolution mass
spectrometry (HRMS) analysis.
Experimental
All reactions were carried out under a nitrogen
atmosphere; all compounds were characterized by
1H NMR, 13C NMR and electrospray ionization-mass
spectrometry (ESI-MS). Copies of the 1H, and 13C spectra
can be found at the end of the Supplementary Information
(SI) section. NMR spectra were recorded on a 300 MHz
1
instrument. All H NMR experiments are reported in δ
units, parts per million (ppm), and were measured relative
to the signals for tetramethylsilane (TMS) (0.00 ppm). All
13C NMR spectra are reported in ppm relative to deuteron-
chloroform (77.23 ppm), unless otherwise stated, and all
were obtained with 1H decoupling. For HRMS, previously
lyophilized samples were dissolved in methanol and
deposited into the 96 well plate of the SIL-20A autosampler
for ESI-MS analysis in an IT-TOF mass spectrometer
N-tert-Butyloxycarbonyl-m-(4-cyanophenyl)-tyrosine
methyl ester (5a):Yield 99 mg (50%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.60 (d, 2H, J 8.1 Hz), 7.56 (d, 2H,
J 8.1 Hz), 6.93 (s, 1H), 6.92 (d, 1H, J 7.6 Hz), 6.74 (d, 1H,
J 7.6 Hz), 4.99 (d, 1H, J 6.4 Hz), 4.48 (d, 1H, J 5.6 Hz),
3.64 (s, 3H), 3.05-2.87 (m, 2H), 1.32 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 172.42, 155.19, 152.23, 142.84,

Vol. 26, No. 4, 2015
Vasconcelos et al.
771
132.11 (2C), 131.32, 130.61, 129.93 (2C), 128.34, 126.52,
118.92, 116.61, 110.66, 80.28, 60.52, 52.35, 37.57, 28.29
(3C); HRMS (ESI-TOF) m/z calcd.: for C22H24N2O5 + Na+:
419.1583; found: 419.1576.
N-tert-Butyloxycarbonyl-m-(o-tolyl)tyrosine methyl
ester (5f): Yield 63 mg (33%); yellow oil; H NMR
1
(300 MHz, CDCl3) d 7.24-7.11 (m, 5H), 6.95-6.92 (m, 1H),
6.83-6.77 (m, 1H), 4.90 (s, 1H), 4.47 (d, 1H, J 5.4 Hz),
3.61 (s, 3H), 3.02-2.89 (m, 2H), 2.08 (s, 3H), 1.33 (s, 9H);
13C NMR (75 MHz, CDCl3) d 172.41, 151.72, 141.63,
137.32, 135.63, 131.10, 129.88, 129.28, 128.54, 127.72,
127.13, 126.42, 125.52, 115.48, 79.92, 54.59, 52.15,
37.53, 28.30 (3C), 19.72; HRMS (ESI-TOF) m/z calcd.:
for C22H27NO5 + Na+: 408.1787; found: 408.1779.
N-tert-Butyloxycarbonyl-m-(4-methoxyphenyl)
tyrosine methyl ester (5b):Yield 158 mg (79%); colorless
1
oil; H NMR (300 MHz, CDCl3) d 7.35-7.28 (m, 2H),
6.92-6.88 (m, 4H), 6.80-6.77 (m, 1H), 4.96 (d, 1H,
J 6.6 Hz), 4.48-4.44 (m, 1H), 3.77 (s, 3H), 3.64 (s, 3H),
3.03-2.81 (m, 2H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 172.49, 159.26, 154.30, 151.84, 139.07, 131.17, 130.88,
130.22, 129.95, 129.38, 127.92, 115.92, 115.05, 114.55,
80.03, 55.33, 52.30, 52.22, 37.50, 28.31 (3C); HRMS
(ESI-TOF) m/z calcd.: for C22H27NO6 + Na+: 424.1736;
found: 424.1729.
N-tert-Butyloxycarbonyl-m-(m-tolyl)tyrosine methyl
1
ester (5g): Yield 90.5 mg (47%); yellow oil; H NMR
(300 MHz, CDCl3) d 7.16 (t, 1H, J 7.6 Hz), 7.06-6.98 (m,
3H), 6.80-6.77 (m, 2H), 6.70-6.67 (m, 1H), 4.82 (s, 1H),
4.37 (d, 1H, J 5.7 Hz), 3.52 (s, 3H), 2.92-2.75 (m, 2H), 2.21
(s, 3H), 1.21 (s, 9H); 13C NMR (75 MHz, CDCl3) d 172.46,
155.13, 151.77, 138.88, 137.02, 131.13, 129.72, 129.68,
129.03, 128.56, 128.30, 127.94, 126.03, 115.95, 79.95,
60.41, 52.18, 37.50, 28.29 (3C), 21.46; HRMS (ESI-TOF)
m/z calcd.: for C22H27NO5 + Na+: 408.1787; found: 408.1784.
N-tert-Butyloxycarbonyl-m-(3-methoxyphenyl)
tyrosine methyl ester (5c): Yield 154 mg (77%); colorless
1
oil; H NMR (300 MHz, CDCl3) d 7.35-7.7.26 (m, 1H),
6.95-6.78 (m, 6H), 4.95 (s, 1H), 4.50-4.41 (m, 1H), 3.75 (s,
3H), 3.63 (s, 3H), 3.03-2.87 (m, 2H), 1.22 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 172.47, 160.17, 155.18, 151.77, 138.50,
131.03, 130.19, 129.86, 127.95, 121.23, 116.06, 115.05,
114.63, 113.49, 80.05, 55.01, 54.59, 52.23, 37.50, 28.30
(3C); HRMS (ESI-TOF) m/z calcd.: for C22H27NO6 + Na+:
424.1736; found: 424.1732.
N-tert-Butyloxycarbonyl-m-(p-tolyl)tyrosine methyl
1
ester (5h): Yield 119 mg (62%); yellow oil; H NMR
(300 MHz, CDCl3) d 7.20 (d, 2H, J 7.9 Hz), 7.11 (d, 2H,
J 7.9 Hz), 6.82 (d, 2H, J 6.3 Hz), 6.71 (d, 1H, J 8.8 Hz), 4.88
(s, 1H), 4.41 (d, 1H, J 6.0 Hz), 3.55 (s, 3H), 2.95-2.82 (m,
2H), 2.24 (s, 3H), 1.26 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 172.49, 155.17, 151.89, 137.53, 135.69, 134.17, 133.84,
131.18, 129.77, 129.53, 128.91, 128.22, 127.89, 115.96,
80.00, 54.58, 52.20, 37.49, 28.30 (3C), 21.19; HRMS
(ESI-TOF) m/z calcd.: for C22H27NO5 + Na+: 408.1787;
found: 408.1785.
N-tert-Butyloxycarbonyl-m-(4-hydroxyphenyl)tyrosine
methyl ester (5d):Yield 110 mg (57%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.24-7.18 (m, 1H), 6.90-6.86 (m, 3H),
6.84 (s, 1H), 6.77 (d, 2H, J 8.7 Hz), 5.00 (d, 1H, J 7.8 Hz),
4.48 (d, 1H, J 6.3 Hz), 3.62 (s, 3H), 2.95 (ddd, 2H, J 5.8,
13.8, 19.1 Hz), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 172.65, 155.34, 151.66, 138.47, 130.98, 130.95, 130.40
(2C), 129.82, 127.91 (2C), 120.81, 116.09, 114.99, 80.33,
60.52, 54.64, 52.35, 28.28 (3C); HRMS (ESI-TOF) m/z
calcd.: for C21H25NO6 + Na+: 410.1580; found: 410.1576.
N-tert-Butyloxycarbonyl-m-(4-ethylthylphenyl)tyrosine
methyl ester (5i): Yield 97 mg (45%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.31 (s, 4H), 6.89 (d, 2H, J 6.6 Hz),
6.77 (d, 1H, J 8.8 Hz), 5.62 (s, 1H), 4.96 (d, 1H, J 7.3 Hz),
4.49-4.41 (m, 1H), 3.63 (s, 3H), 3.03-2.97 (m, 2H), 2.90
(q, 2H, J 7.3 Hz), 1.32 (s, 9H), 1.27 (t, 3H, J 7.3 Hz);
13C NMR (75 MHz, CDCl3) d 172.45, 155.18, 151.86,
139.08, 136.47, 134.60, 131.14, 129.71, 129.49, 129.12,
128.04, 127.65, 116.16, 115.04, 80.04, 60.45, 54.57, 52.24,
28.30 (3C), 27.48, 14.37; HRMS (ESI-TOF) m/z calcd.: for
C23H29NO5S + Na+: 454.1664; found: 454.1659.
N-tert-Butyloxycarbonyl-m-(4-formylphenyl)tyrosine
methyl ester (5e):Yield 33 mg (17%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 9.96 (s, 1H), 7.94 (s, 1H), 7.78 (d, 1H,
J 7.6 Hz), 7.70 (d, 1H, J 7.6 Hz), 7.52 (t, 1H, J 7.6 Hz),
6.97-6.91 (m, 2H), 6.78 (d, 1H, J 8.0 Hz), 5.70 (s, 1H),
4.97 (d, 1H, J 7.5 Hz), 4.05 (d, 1H, J 6.1 Hz), 3.65 (s, 3H);
3.06-2.89 (m, 2H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 192.21, 172.43, 155.15, 151.88, 138.64, 136.77, 135.20
(2C), 131.38, 130.58, 130.24, 129.35, 128.57, 126.93,
116.45, 80.16, 54.59, 52.31, 37.61, 28.29 (3C); HRMS
(ESI-TOF) m/z calcd.: for C22H25NO6 + Na+: 422.1580;
found: 422.1577.
N-tert-Butyloxycarbonyl-m-(4-chlorophenyl)tyrosine
methyl ester (5j):Yield 73 mg (36%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.34 (s, 4H), 6.92-6.89 (m, 2H), 6.77
(d, 1H, J 7.9 Hz), 4.92 (s, 1H), 4.48 (d, 1H, J 4.9 Hz),
3.64 (s, 3H), 3.04-2.88 (m, 2H), 1.33 (s, 9H); 13C NMR

772
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using Aryltrifluoroborate Salts
J. Braz. Chem. Soc.
(75 MHz, CDCl3) d 172.39, 155.08, 151.68, 135.72, 133.71,
131.18, 130.46 (2C), 130.02, 129.07 (2C), 128.29, 127.09,
116.26, 80.05, 60.42, 52.24, 37.51, 28.30 (3C); HRMS
(ESI-TOF) m/z calcd.: for C21H24ClNO5 + Na+: 428.1241;
found: 428.1240.
N-tert-Butyloxycarbonyl-m-(3-aminophenyl)tyrosine
methyl ester (5p):Yield 36 mg (19%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.07 (d, 1H, J 7.5 Hz), 6.99 (d, 1H,
J 7.5 Hz), 6.78 (s, 1H), 6.71-6.68 (m, 2H), 6.60 (d, 1H,
J 7.5 Hz), 6.52 (s, 1H), 4.79 (d, 1H, J 6.1 Hz), 4.36 (d, 1H,
J 6.6 Hz), 3.52 (s, 3H), 2.93-2.76 (m, 2H), 1.21 (s, 9H);
13C NMR (75 MHz, CDCl3) d 172.46, 146.15, 142.65,
130.76, 130.38, 129.78, 129.53, 127.91, 118.80, 117.69,
115.28, 114.62, 114.10, 113.94, 52.19, 28.30 (3C); HRMS
(ESI-TOF) m/z calcd.: for C21H26N2O5 + Na+: 409.1739;
found: 409.1738.
N-tert-Butyloxycarbonyl-m-(naphthalene-1-yl)tyrosine
methyl ester (5k):Yield 105 mg (50%); yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.84-7.74 (m, 4H), 7.49 (dd, 1H, J 1.6,
8.5 Hz), 7.44 (m, 2H), 7.00 (d, 1H, J 2.0 Hz), 6.93 (dd,
1H, J 2.2, 8.5 Hz), 6.85 (m, 1H), 5.70 (s, 1H), 4.98 (d, 1H,
J 7.5 Hz), 4.50 (d, 1H, J 6.3 Hz), 3.62 (s, 3H), 3.05-2.88
(m, 2H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) d 172.50,
155.20, 152.05, 134.68, 133.57, 132.69, 131.43, 129.86,
128.76, 128.20, 128.11, 128.04, 127.84, 127.74, 127.21,
126.49, 126.31, 116.20, 80.07, 60.45, 52.24, 37.56, 28.32
(3C); HRMS (ESI-TOF) m/z calcd.: for C25H27NO5 + Na+:
444.1787; found: 428.1782.
General amino acid deprotection procedure (6a-e)
The protected amino acid (0.25 mmol) was heated at
70 °C with 4.5 mol L−1 HCl (2 mL) for 3 h. After cooling,
the aqueous phase was diluted with water (10 mL) and
washed with diethyl ether (10 mL). The aqueous phase was
then evaporated under reduced pressure delivering a solid,
which was triturated with diethyl ether.After decanting and
drying, the product was obtained.15
N-tert-Butyloxycarbonyl-m-(tiophen-3-yl)tyrosine
methyl ester (5m):Yield 168 mg (89%); brow oil; 1H NMR
(300 MHz, CDCl3) d 7.41-7.35 (m, 2H), 7.22-7.18 (m, 1H),
7.02 (s, 1H), 6.89-6.88 (m, 2H), 6.79-6.76 (m, 1H), 5.57 (s,
1H), 4.94 (d, 1H, J 5.8 Hz), 4.48 (d, 1H, J 6.0 Hz), 3.64 (s,
3H), 3.03-2.93 (m, 2H), 1.33 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 172.46, 155.14, 151.94, 137.44, 130.59, 129.53,
128.06, 128.02, 126.54, 123.06, 123.01, 116.16, 80.06,
54.57, 52.23, 37.53, 28.30 (3C); HRMS (ESI-TOF) m/z
calcd.: for C19H23NO5S + Na+: 400.1195; found: 400.1191.
3-(Tiophen-3-yl)tyrosine hydrochloride (6a): Yield
62 mg (83%); white solid; 1H NMR (300 MHz, D2O) d 7.59
(s, 1H), 7.46-7.43 (m, 1H), 7.35 (d, 1H, J 4.0 Hz, 1H), 7.24
(s, 1H), 7.06 (d, 1H, J 8.3 Hz), 6.92 (d, 1H, J 8.2 Hz), 4.20
(t, 1H, J 6.5 Hz), 3.19 (dd, 1H, J 6.5, 14.7 Hz), 3.06 (dd, 1H,
J 6.5, 14.7 Hz); 13C NMR (75 MHz, D2O) d 171.69, 152.45,
137.54, 130.76, 129.52, 128.15, 125.99 (2C), 123.78, 123.69,
116.90, 54.44, 34.93; HRMS (ESI-TOF) m/z calcd.: for
C13H13NO3S + H+: 264.0694; found: 264.0689.
N-tert-Butyloxycarbonyl-m-(4-tert-butylphenyl)
tyrosine methyl ester (5n): Yield 157 mg (74%); yellow
1
oil; H NMR (300 MHz, CDCl3) d 7.41-7.31 (m, 4H),
3-(4-Formylphenyl)tyrosine hydrochloride (6b):
1
6.91-6.78 (m, 3H), 5.52 (d, 1H, J 19.8 Hz), 4.94 (s, 1H),
4.48 (s, 1H), 3.62 (s, 3H), 2.96 (s, 2H), 1.32 (s, 9H), 1.28
(s, 9H); 13C NMR (75 MHz, CDCl3) d 172.50, 155.19,
151.88, 150.79, 134.11, 134.07, 131.21, 129.56, 128.70,
128.13, 127.94, 126.07, 115.98, 79.99, 54.60, 52.22, 37.53,
37.50, 34.64, 31.34 (3C), 28.31 (3C); HRMS (ESI-TOF)
m/z calcd.: for C25H33NO5 + H+: 428.2437; found: 428.2432.
Yield 60 mg (75%); white solid; H NMR (300 MHz,
D2O) d 9.80 (s, 1H), 7.85 (s, 1H), 7.79 (d, 1H, J 7.6 Hz),
7.71 (d, 1H, J 7.6 Hz), 7.52 (t, 1H, J 7.6 Hz), 7.15-7.12
(m, 1H), 7.04 (s, 1H), 6.95 (d, 1H, J 8.2 Hz), 4.22 (t,
1H, J 6.5 Hz), 3.19 (dd, 1H, J 6.5, 14.7 Hz), 2.95 (dd,
1H, J 6.5, 14.7 Hz); 13C NMR (75 MHz, D2O) d 196.32,
171.75, 152.37, 138.50, 135.98, 135.76, 131.60, 130.49,
129.37, 129.32, 129.10, 127.75, 126.21, 116.85, 54.47,
34.94; HRMS (ESI-TOF) m/z calcd.: for C16H15NO4 + H+:
286.1079; found: 286.1072.
N-tert-Butyloxycarbonyl-m-phenyltyrosine methyl
1
ester (5o): Yield 135 mg (73%); colorless oil; H NMR
(300 MHz, CDCl3) d 7.47 (d, 4H, J 4.4 Hz), 7.42-7.35
(m, 1H), 7.01-6.98 (m, 2H), 6.90-6.87 (m, 1H), 5.66 (d,
1H, J 5.3 Hz), 4.57 (d, 1H, J 6.1 Hz), 3.72 (s, 3H), 3.13-
3.03 (m, 2H), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 172.48, 155.17, 151.82, 137.22, 131.25, 129.73, 129.08
(2C), 129.02 (2C), 128.25, 127.98, 127.71, 116.09, 80.04,
54.58, 50.69, 37.48, 28.29 (3C); HRMS (ESI-TOF) m/z
calcd.: for C21H25NO5 + Na+: 394.1630; found: 394.1627.
3-(4-Methoxyphenyl)tyrosine hydrochloride (6c):Yield
59 mg (74%); white solid; 1H NMR (300 MHz, D2O) d 7.35
(d, 2H, J 4.0 Hz), 7.16-7.07 (m, 1H), 7.03 (s, 1H), 6.96 (d,
2H, J 9.0 Hz), 6.92-6.84 (m, 1H), 4.21 (t, 1H, J 6.0 Hz),
3.79 (s, 3H), 3.21-3.03 (m, 2H); 13C NMR (75 MHz, D2O)
d 171.61, 158.21, 152.23, 131.58, 130.89, 130.47, 130.42,
129.51, 128.82, 126.04, 116.70, 116.07, 114.05, 55.46,

Vol. 26, No. 4, 2015
Vasconcelos et al.
773
54.39, 34.91; HRMS (ESI-TOF) m/z calcd.: for C16H17NO4
+ H+: 288.1236; found: 288.1230.
Synthesis of dipeptides 10
A solution of 9 (203 mg, 0.5 mmol) in dry DCM was
cooled to 0 °C and 1-hydroxybenzotriazole (1.1 equivalent)
was added, followed by N-N’-diisopropylcarbodiimide
(1.2 equivalent). After 1 h, the mixture was allowed to
warm to room temperature then compound 5o dissolved
in DCM was added. The reaction mixture was stirred for
15 h. The urea was filtered out, the supernatant was dried
to get the crude compound.18 Purification by silica flash
chromatography (eluting with ethyl acetate/hexane 5:5).
3-(4-Chlorophenyl)tyrosine hydrochloride (6d): Yield
73 mg (90%); white solid; 1H NMR (300 MHz, D2O) d 7.41
(s, 2H), 7.17-7.12 (m, 2H), 7.10-6.95 (m, 1H), 6.86 (d, 2H,
J 8.3 Hz), 4.22-4.18 (m, 1H), 3.26-3.06 (m, 2H); 13C NMR
(75 MHz, D2O) d 171.95, 155.17, 152.31, 131.59, 131.53,
130.98 (2C), 130.89, 130.69, 128.51, 125.91, 116.02
(2C), 53.58, 34.95; HRMS (ESI-TOF) m/z calcd.: for
C15H14ClNO3 + H+: 292.0740; found: 292.0732.
3-(4-tert-Butylphenyl)tyrosine hydrochloride (6e):
Yield 55 mg (63%); white solid; 1H NMR (300 MHz, D2O)
d 7.20-7.05 (m, 4H), 7.01-6.82 (m, 3H), 3.92-3.84 (m,
1H), 3.01-2.84 (m, 2H), 0.99 (s, 9H); 13C NMR (75 MHz,
D2O) d 169.70, 152.57, 149.58, 134.94, 134.89, 131.54,
128.97 (2C), 128.66, 126.03, 124.99 (2C), 116.57, 67.85,
33.98, 31.00, 25.07 (3C); HRMS (ESI-TOF) m/z calcd.: for
C19H24NO3 + H+: 314.1756; found: 314.1750.
N-tert-Butyloxycarbonyl-di-tyrosine methyl ester (10):
Yield 171 mg (52%); white solid; H NMR (300 MHz,
1
CDCl3) d 7.37-7.35 (m, 5H), 6.88 (d, 1H, J 7.5 Hz), 6.82
(s, 1H), 6.77-6.76 (m, 2H), 6.68 (d, 1H, J 8.2 Hz), 6.35 (d,
1H, J 7.5 Hz), 5.78 (s, 1H), 4.95 (s, 1H), 4.73-4.67 (m, 1H),
4.17 (s, 1H), 3.61 (s, 3H), 2.96-2.93 (m, 2H), 2.81-2.79 (m,
2H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) d 171.52,
170.83, 155.35, 154.33, 151.93, 139.10, 137.12, 131.08,
130.82, 130.19, 129.68, 129.06 (5C), 128.38, 127.75,
127.53, 116.21, 115.17, 85.30, 52.46, 42.38, 37.19, 37.01,
28.27 (3C), 23.45; HRMS (ESI-TOF) m/z calcd.: for
C30H33IN2O7 + H+: 661.1411; found: 661.1407.
General amino alcohol procedure (7)
A solution of 5 (128 mg, 0.5 mmol) and TFA (1.5 mL)
in DCM (3 mL) was stirred until complete consume of
start material, monitored by TLC.After, NaHCO3 saturated
solution was added slowly, the mixture was extracted with
DCM, the organic layer was collected, dried with MgSO4,
filtered and the solvent was removed under vacuum. A
MeOH (4 mL) solution of 8 was cooled to 0 °C, and
NaBH4 (8 equivalent) was added in one portion. The
resulting solution was stirred under ambient temperature
for 24 h. After the reaction was complete (monitored by
TLC), the organic solvents were evaporated under vacuum.
Water (5 mL) was added, and after phase separation, the
corresponding aqueous phase was extracted with EtOAc
(3 × 3 mL). The combined organic extracts were washed
with brine, dried (MgSO4), and then concentrated under
high vacuum. The crude product was purified directly by
silica gel column chromatography17 (eluting with ethyl
acetate/hexane 9:1).
For compound 11, see general procedure for Suzuki-
Miyaura cross-coupling reaction.
N-tert-Butyloxycarbonyl-di-tyrosine methyl ester (11):
1
Yield 64 mg (42%); white solid; H NMR (300 MHz,
CDCl3) d 7.36-7.28 (m, 7H), 7.22-7.19 (m, 1H), 7.07 (s,
1H), 6.86-6.79 (m, 2H), 6.76-6.67 (m, 3H), 6.30 (d, 1H,
J 7.5 Hz), 6.11 (s, 1H), 5.75 (s, 1H), 4.96 (s, 1H), 4.69-
4.65 (m, 1H), 4.22 (s, 1H), 3.55 (s, 3H), 2.95-2.75 (m, 4H),
1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) d 171.52, 171.07,
152.12, 151.90, 137.51, 137.13, 131.02, 130.59, 129.68,
129.29, 129.05 (4C), 129.03 (2C), 128.36, 128.09, 127.71,
127.56, 126.05, 123.05, 116.41, 116.17, 60.44, 53.44,
52.30, 42.34, 37.18, 28.25 (3C), 23.45, 14.19; HRMS
(ESI-TOF) m/z calcd.: for C34H36N2O7S + H+: 617.2321;
found: 617.2318.
O-Methyl-3-(phenyl)tyrosinol (7):Yield 35 mg (55%);
yellow oil; 1H NMR (300 MHz, CDCl3) d 7.44-741 (m, 2H),
7.34-7.29 (m, 2H), 7.26-7.23 (m, 1H), 7.06-7.01 (m, 2H),
6.84 (d, 1H, J 8.9 Hz, 1H), 3.70 (s, 1H), 3.62-3.56 (m, 2H),
3.39-3.34 (m, 1H), 3.75-3.69 (m, 1H), 3.56-3.49 (m, 1H);
13C NMR (75 MHz, CDCl3) d 155.32, 138.29, 131.64,
130.94, 130.19, 129.48 (2C), 129.17, 128.01 (2C), 127.02,
111.60, 65.29, 55.72, 54.36, 29.10; HRMS (ESI-TOF) m/z
calcd.: for C16H19NO2 + H+: 258.1494; found: 258.1485.
A solution of 9 (203 mg, 0.5 mmol) in dry DCM was
cooled to 0 °C and 1-hydroxybenzotriazole (1.1 equivalent)
was added, followed by N-N’-diisopropylcarbodiimide
(1.2 equivalent). After 1 h, the mixture was allowed to
warm to room temperature, then compound 2 dissolved
in DMF was added, followed by triethylamine (TEA)
(1.2 equivalent). The reaction mixture was stirred for 15 h.
The precipitated dicyclohexylurea was filtered off and
washed with DCM. The filtrated was evaporated under high

774
Synthesis of Biphenyl Tyrosine Via Cross-Coupling Suzuki-Miyaura Reaction Using Aryltrifluoroborate Salts
J. Braz. Chem. Soc.
vacuum, the crude compound was acidified under ice cold
condition with 1 mol L−1 HCl to pH 2-3 and extracted with
DCM, the organic layer was collected, dried with MgSO4,
filtered and the solvent was removed under vacuum.5
Purification by silica flash chromatography (eluting with
ethyl acetate/hexane 5:5).
References
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N-tert-Butyloxycarbonyl-di-tyrosine methyl ester (12):
Yield 170 mg (48%); yellow solid; H NMR (300 MHz,
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1
CDCl3) d 7.49 (d, 1H, J 1.8 Hz), 7.36 (d, 1H, J 1.8 Hz),
7.25-7.20 (m, 2H), 7.00 (d, 1H, J 7.9 Hz), 6.86 (dd, 1H,
J 1.8, 8.3 Hz), 6.78 (d, 1H, J 8.0 Hz), 6.66 (d, 1H, J 7.7 Hz),
5.19 (d, 1H, J 7.2 Hz), 4.74 (dd, 1H, J 6.0, 13.0 Hz), 4.47
(d, 1H, J 7.8 Hz), 4.30 (s, 1H), 3.69 (s, 3H), 3.02-2.89 (m,
4H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) d 171.35
(2C), 157.55, 155.57, 154.78, 154.67, 139.28 (2C), 130.72,
130.62, 129.83, 129.13, 115.31, 115.26, 84.93, 60.55,
53.48, 52.64, 42.34, 28.32 (3C), 23.46, 14.19; HRMS
(ESI-TOF) m/z calcd.: for C24H28I2N2O7 + H+: 710.2973;
found: 710.2965.
6. Biajoli,A. F. P.; Schwalm, C. S.; Limberger, J.; Claudino, T. S.;
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2002, 55, 571.
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Sussmuth, R.; Muller, J.; Pukall, R.; Fiedler, H. P.; J. Antibiot.
2002, 55, 565.
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10. Vilaró, M.; Arsequell, G.; Valencia, G.; Ballesteros, A.;
Barluenga, J.; Org. Lett. 2008, 10, 3243.
For compound 13, see general procedure for Suzuki-
Miyaura cross-coupling reaction.
11. Kase, H.; Kaneko, M.;Yamada, K.; J. Antibiot. 1987, 40, 450.
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Matsumoto, A.; Ikeda, H.; Woodruff, H. B.; Omura S.;
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N-tert-Butyloxycarbonyl-di-tyrosine methyl ester (13):
Yield 102 mg (61%); white solid; H NMR (300 MHz,
1
CDCl3) d 7.35 (d, 4H, J 8.4 Hz), 7.02-6.96 (m, 6H),
6.87-6.79 (m, 4H), 6.42 (d, 1H, J 7.6 Hz), 5.70 (s, 1H), 5.04
(s, 1H), 4.80-4.74 (m, 1H), 4.32 (s, 1H), 3.84 (s, 6H), 3.65
(s, 3H), 2.99-2.88 (m, 4H), 1.40 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 171.53, 171.05, 159.22, 159.20, 151.93, 131.17,
130.99, 130.21, 129.31, 128.31, 128.06, 128.02, 127.54,
116.08, 116.01, 114.53, 114.48, 55.34 (2C), 53.44, 52.28,
42.32, 28.25 (3C), 23.46; HRMS (ESI-TOF) m/z calcd.: for
C38H32N2O9 + H+: 671.2969; found: 671.2960.
14. Lalla, F.; Nicolin, R.; Rinaldi, E.; Scarpellini, P.; Rigoli, R.;
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Supplementary Information
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Supplementary information (experimental details and
analytical data for all new compounds, as well as the copies
of 1H and 13C NMR spectra) is available free of charge at
http://jbcs.sbq.org.br as PDF file.
Acknowledgements
21. Joshi, K. B.;Verma, S.; Angew. Chem., Int. Ed. 2008, 47, 2860.
The authors gratefully acknowledge the financial
support from the São Paulo Research Foundation (FAPESP,
grant 2012/00424-2 and fellowship 2013/17960-7 to S.
N. S. V. and 2012/20483-3 to A. N. K.) and the National
Council for Technological and Scientific Development
(CNPq) for a fellowship (308.320/2010-7 to H. A. S.).
Submitted: November 19, 2014
Published online: February 12, 2015
FAPESP has sponsored the publication of this article.