Biaryl peptides from 4-Iodophenylalanine by solid-phase borylation and Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1002/ejoc.200901350

Resin-bound phenylalanine boronates were prepared by solid-phase Miyaura borylation of 4-iodophenylalanine pepfides. Subsequent arylation through a Suzuki-Miyaura crosscoupling was carried out using a variety of aryl halides under conventional heating and under microwave irradiation. Microwaves greatly enhanced the arylation, shortening the reaction time and providing the biaryl peptides in higher purities.

Full text of DOI:10.1002/ejoc.200901350

FULL PAPER
DOI: 10.1002/ejoc.200901350
Biaryl Peptides from 4-Iodophenylalanine by Solid-Phase Borylation and
Suzuki–Miyaura Cross-Coupling
Ana Afonso,[a] Cristina Rosés,[a] Marta Planas,[a] and Lidia Feliu*[a]
Keywords: Borylation / Biaryl peptides / Microwave chemistry / Cross-coupling / Solid-phase synthesis
Resin-bound phenylalanine boronates were prepared by so-
lid-phase Miyaura borylation of 4-iodophenylalanine pep-
tides. Subsequent arylation through a Suzuki–Miyaura cross-
coupling was carried out using a variety of aryl halides under
conventional heating and under microwave irradiation. Mi-
crowaves greatly enhanced the arylation, shortening the
reaction time and providing the biaryl peptides in higher
purities.
larger than that of boronic acids, this approach would in-
crease the diversity of biaryl peptides.
Introduction
Based on these considerations and taking into account
that the borylation on solid support of phenylalanine and,
in general, of aromatic amino acids has not been disclosed,
we envisioned that the solid-phase borylation of phenyl-
alanine peptides would emerge as a successful approach for
the preparation of modified peptides in a highly flexible
manner. On the one hand, it would provide structurally di-
versified peptide boronic acids, for which there is a growing
interest as potential pharmaceutical agents.[7] In fact, pep-
tide boronic acids have been used as enzyme inhibitors, bor-
on neutron capture agents for cancer therapy, and drug-
delivery devices. Additionally, a Suzuki–Miyaura cross-cou-
pling between polymer-bound borylated peptides and aryl
or heteroaryl halides would provide a large variety of 4-
arylphenylalanine peptides. In the present study, we de-
scribe the effectiveness of the solid-phase borylation of 4-
iodophenylalanine peptides and their subsequent arylation
by a Suzuki–Miyaura cross-coupling.
Nonproteinogenic amino acids play an important role in
drug development. In particular, a great deal of research
has been invested in the preparation of biaryl amino acids,
such as arylphenylalanines. These moieties are widely pres-
ent in natural products and constitute important structural
elements for molecular recognition between pharmaceuti-
cals and target receptors.[1] Moreover, their incorporation
into biologically active peptides may lead to peptidomimet-
ics with restricted conformational flexibility, increased pro-
teolytic stability, and enhanced selectivity and biological ac-
tivity.[2]
Despite the interest in these compounds, only a few 4-aryl-
phenylalanines are commercially available. The synthesis of
these compounds in solution has been accomplished by a Su-
zuki–Miyaura cross-coupling of either a 4-bromo- (or iodo-
or triflyl-) phenylalanine with an aryl boronic acid[3] or a 4-
boronophenylalanine with an aryl halide (or triflate).[4]
Even though the Suzuki–Miyaura coupling has been
adapted to the solid phase and has found interesting appli-
cations in the discovery of novel compounds,[5] the modifi-
cation of phenylalanine peptides through a solid-phase Su-
zuki–Miyaura reaction has only been described in two re-
cent reports.[6] Moreover, these couplings are based on the
reaction between a polymer-bound halogenated aromatic
amino acid and an arylboron in solution. The alternative
approach involving a polymer-bound amino acid boronate
and an aryl halide has not been reported. Since the number
of commercially available aryl and heteroaryl halides is
Results and Discussion
Solid-Phase Synthesis of Boronophenylalanines
We investigated the feasibility of the borylation on solid
support of a 4-iodophenylalanine residue starting with the
synthesis of the tripeptidyl resin Boc-Phe[4-pinacolato-
boron (BPin)]-Leu-Leu-Rink-MBHA (1a) as a model sys-
tem (Scheme 1). Thus, we prepared the resin Boc-Phe(4-I)-
Leu-Leu-Rink-MBHA (2a) by coupling Boc-Phe(4-I)-OH[8]
to H-Leu-Leu-Rink-MBHA, which was constructed from
an Fmoc-Rink-MBHA resin (0.56 mmol/g) following an
Fmoc/tBu strategy of sequential coupling and deprotection
steps under standard conditions. Treatment of an aliquot of
the resulting resin 2a with TFA/TIS/H2O for 2 h at room
temperature afforded H-Phe(4-I)-Leu-Leu-NH2 (3a) in 95%
purity, which was characterised by mass spectrometry.
[a] Laboratori d’Innovació en Processos i Productes de Síntesi
Orgànica (LIPPSO), Departament de Química, Universitat de
Girona
Campus Montilivi, 17071 Girona, Spain
Fax: +34-972-418150
E-mail: lidia.feliu@udg.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901350.
Eur. J. Org. Chem. 2010, 1461–1468
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 1. Synthesis of boronopeptidyl resins 1a–c. B2Pin2 = bis(pinacolato)diboron.
Among the methods of preparation of arylborons, the Entry 2). In both cases, the cleavage of the resin afforded
Miyaura reaction[4b,9] involves mild reaction conditions three main compounds, as shown by HPLC. These com-
compatible with a variety of functional groups and, there- pounds were identified by mass spectrometry analysis of the
fore, we considered it suitable for the solid-phase synthesis HPLC sample as the peptide boronic acid 4a (32–43%),
of boronophenylalanines. We investigated the Miyaura bor- the iodinated tripeptide H-Phe(4-I)-Leu-Leu-NH2 (3a, 30–
ylation of resin 2a by treatment with B2Pin2, PdCl2(dppf), 43%), and H-Phe-Leu-Leu-NH2 (5a, 25%) resulting from
and KOAc at 80 °C (Scheme 1, Table 1). The reaction con- deiodination or protodeborylation. As previously reported,
ditions evaluated included the solvent, reaction time, the peptide boronic acid 4a could arise from the hydrolysis
amount of reagents, and the addition of 1,1Ј-bis(diphenyl- of the pinacol ester functionality of the corresponding bor-
phosphanyl)ferrocene (dppf). After each experiment, an ali- onate 6a during HPLC analysis.[10] In fact, when the crude
quot of resin was treated with TFA/TIS/H2O, and the crude reaction mixture was dissolved and immediately analysed
reaction mixture was analysed by HPLC and mass spec- by mass spectrometry, only the boronate 6a was observed.
trometry. The formation of the boronate was also assessed Increasing the amount of borylation reagents led to a de-
by IR analysis of the resin, which would show a characteris- crease in the formation of H-Phe-Leu-Leu-NH2 (5a, 8%),
tic B–O band at 1362 cm–1.
but it had only a marginal effect on the reaction efficiency
Firstly, we treated resin 2a (5–10 mg) with B2Pin2 (Table 1, Entry 3). An increase of the reaction time to 48 h
(2 equiv.), PdCl2(dppf) (0.09 equiv.), and KOAc (3 equiv.) in or the addition of dppf did not improve the results (data
DMF at 80 °C for 16 h (Table 1, Entry 1) and 24 h (Table 1, not shown). Next, we analysed the use of dioxane and
Table 1. Miyaura borylation of Boc-Phe(4-I)-Leu-Leu-Rink-MBHA (2a).
Entry B2Pin2 KOAc PdCl2(dppf)
dppf
Solvent Time [h] Purity of 4a [%][a] Purity of 6a [%] Purity of 3a[b] [%] Purity of 5a[c] [%]
(equiv.) (equiv.)
(equiv.)
(equiv.)
1
2
3
4
5
6
7
2
2
4
4
4
4
4
8
4
3
3
6
6
6
6
6
12
6
0.09
0.09
0.18
0.18
0.18
0.18
0.18
0.36
0.18
0
0
0
0
0
DMF
DMF
DMF
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
16
24
24
24
24
48
24
12
24
32
43
48
7
38
24
21
22
28
0
0
3
4
0
54
63
24
71
43
30
26
76
55
17
0
25
25
8
3
7
0
4
4
0
0
0.09
0.18
0.09
8
5
0
9[d]
[a] Percentage determined by HPLC at 220 nm from the crude reaction mixture. [b] 3a corresponds to H-Phe(4-I)-Leu-Leu-NH2. [c] 5a
corresponds to H-Phe-Leu-Leu-NH2. [d] This experiment was performed using 600 mg of resin 2a.
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Biaryl Peptides from 4-Iodophenylalanine
DMSO as solvents (Table 1, Entries 4 and 5, respectively). to the appropriate reaction conditions, and, after acidic
While dioxane was inefficient, DMSO afforded 4a in 38% cleavage, the crude product mixture was analysed by HPLC
purity. With DMSO, the borylation was significantly fav- and mass spectrometry.
oured by either increasing the reaction time to 48 h (78%,
4a + 6a, Table 1, Entry 6) or by adding dppf (84%, 4a +
6a, Table 1, Entry 7). Moreover, the latter conditions af-
forded only 4% of 5a. Further increases in the amount of
reagents failed to improve the results (Table 1, Entry 8).
Interestingly, when the reaction conditions of Entry 7 were
scaled up to 600 mg of resin 2a, the borylated products were
obtained in 99% purity (4a + 6a, Table 1, Entry 9). The
We initially screened the arylation under conventional
heating using iodobenzene as the aryl halide for the survey
of the reaction conditions. These results are summarised in
Table 2. Treatment of resin 1a with iodobenzene (5 equiv.),
Pd(PPh3)4 (0.05 equiv.), and aq K3PO4 (2 , 5 equiv.) in de-
gassed DMF at 80 °C for 24 h provided H-Phe(4-Ph)-Leu-
Leu-NH2 (7a) but in low purity, and we also detected a
large amount of boronic acid 4a (Table 2, Entry 1). Using
a degassed mixture of DME/EtOH/H2O (9:9:2), the percen-
tage of 7a increased to 49% (Table 2, Entry 2). To avoid the
evaporation of the solvent due to the high temperature, the
long reaction time, and the low volume used (0.3 mL), we
performed the cross-coupling at 60 °C for 48 h (Table 2, En-
try 3). This experiment led to the best result, affording 7a
in 70% purity. It should be noted that these crude product
mixtures proved to contain the homocoupling product 8
and the phenol 9 (6–14%), which are common side-prod-
ucts of the Suzuki–Miyaura cross-couplings (Figure 1).[11]
We next explored the scope of these conditions with dif-
ferent aryl halides including 4-iodotoluene, 2- and 4-
iodoanisole, 1-iodo-4-nitrobenzene, 2-iodophenol, and [2-
(trimethylsilyl)ethoxy]methyl (SEM) protected bromoimid-
azoles g (Table 2, Entries 4–9). All reactions afforded the
desired 4-arylphenylalanine peptides 7b–g in purities rang-
ing from 35% to 87%. All arylpeptides were obtained with
concurrent formation of the homocoupling product 8 and
the phenol 9. The couplings with 4-iodotoluene and the
1
boronate 6a was characterized by H and 13C NMR spec-
troscopy and mass spectrometry.
We next explored the compatibility of this reaction with
common protecting groups used in solid-phase peptide syn-
thesis. The iodophenylalanine peptidyl resins 2b,c contain-
ing lysine (2b) and serine (2c) protected with Boc and tBu,
respectively, were prepared and subjected to the above opti-
mal reaction conditions (Scheme 1). Thus, the resins 2b,c
were treated with B2Pin2 (4 equiv.), PdCl2(dppf)
(0.18 equiv.), and KOAc (6 equiv.) in DMSO at 80 °C for
24 h. Acidic cleavage yielded the corresponding boronopep-
tides (4b + 6b) and (4c + 6c) in 99% purity. These results
clearly support the efficiency of our methodology.
Solid-Phase Synthesis of Biaryl Peptides
We then studied the arylation of Boc-Phe(4-BPin)-Leu-
Leu-Rink-MBHA (1a) by a Suzuki–Miyaura cross-cou-
pling. For each experiment, aliquots of resin were subjected
Table 2. Arylation of Boc-Phe(4-BPin)-Leu-Leu-Rink-MBHA (1a) under conventional heating.[a]
Entry ArX
Solvent[b]
Time [h]
T [°C]
Purity of 4a[c] [%][d]
Purity of 8+9[e] [%][d]
Peptide
Purity [%][d]
1
2
3
4
5
6
7
8
9
a
a
a
b
c
d
e
f
A
B
B
B
B
B
B
B
B
24
24
48
48
48
48
48
48
48
80
80
60
60
60
60
60
60
60
58
14
13
43
4
0
0
6
14
8
14
12
20
3
26
20
7a
7a
7a
7b
7c
7d
7e
7f
26
49
70
35
83
54
87
52
36
0
0
g
7g
[a] Reaction conditions: ArX (5 equiv.), Pd(PPh3)4 (0.05 equiv.), aq K3PO4 (2 , 5 equiv.). [b] A: DMF; B: DME/EtOH/H2O (9:9:2). [c]
Its structure is shown in Scheme 1. [d] Percentage determined by HPLC at 220 nm from the crude reaction mixture. [e] These compounds
coeluted during HPLC analysis and are depicted in Figure 1.
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A. Afonso, C. Rosés, M. Planas, L. Feliu
FULL PAPER
zene yielded the expected arylated products 7c and 7e,
respectively, in significantly higher purities (≈ 85%, Table 2,
Entries 5 and 7).
Taking into account that microwave heating has been
employed to accelerate the rate of solid-phase Suzuki–
Miyaura reactions,[12] the arylation of Boc-Phe(4-BPin)-
Leu-Leu-Rink-MBHA (1a) was attempted under micro-
wave irradiation (Table 3). As before, we first surveyed reac-
tion conditions using iodobenzene. Thus, resin 1a was
treated with iodobenzene (5 equiv.), Pd(PPh3)4 (0.05 equiv.),
and aq K3PO4 (2 , 5 equiv.) in degassed DME/EtOH/H2O
(9:9:2) at different temperatures and for different reaction
times (Table 3, Entries 1–5). Reactions carried out either at
80 °C or 120 °C for 30 min of irradiation afforded the best
results, yielding the arylated peptide H-Phe(4-Ph)-Leu-Leu-
NH2 (7a) in 62–63% purity together with the homocou-
pling product 8 and the phenol 9 (8–9%, Table 3, Entries 3
and 4). Since the boronic acid 4a was not detected at
Figure 1. Structures of 8 and 9.
bromoimidazoles g were the most difficult, affording the 120 °C, we selected this temperature for the following as-
lowest purity percentages of the corresponding biaryl pep- says. It should also be noted that, in order to minimise the
tide 7b and 7g (≈ 35%, Table 2, Entries 4 and 9). In con- formation of phenol 9, solvents must be thoroughly de-
trast, arylation with 2-iodoanisole and 1-iodo-4-nitroben- gassed before carrying out the reactions.
Table 3. Arylation of Boc-Phe(4-BPin)-Leu-Leu-Rink-MBHA (1a) under microwave irradiation.
Entry
ArX
Time [min]
T [°C]
Purity of 4a[b] [%][c]
Purity of 8+9[d] [%][c]
Peptide
Purity [%][c]
1[a]
a
a
a
a
a
b
c
d
e
f
15
15
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
60
80
80
15
12
9
0
2
0
0
0
4
0
0
0
0
0
8
5
0
10
11
8
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
51
47
63
62
59
69
91
73
80
2[a]
3[a]
4[a]
120
140
120
120
120
120
120
120
120
120
120
120
120
120
120
9
5[a]
15
15
5
14
6
4
49
8
6
0
8
6
6[a]
7[a]
8[a]
9[a]
10[a]
11[a]
12[e]
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
88
22
g
a
b
c
d
e
f
7g
7a
7b
7c
7d
7e
7f
73 (27)[f]
79 (26)[f]
91 (63)[f]
77 (35)[f]
86 (49)[f]
60 (37)[f]
57 (10)[f]
12
5
g
0
7g
[a] Reaction conditions (Entries 1–11): ArX (5 equiv.), Pd(PPh3)4 (0.05 equiv.), aq K3PO4 (2 , 5 equiv.). [b] Its structure is shown in
Scheme 1. [c] Percentage determined by HPLC at 220 nm from the crude reaction mixture. [d] These compounds coeluted during HPLC
analysis and are depicted in Figure 1. [e] Reaction conditions (Entries 12–18): ArX (5 equiv.), Pd2(dba)3 (0.2 equiv.), P(o-tolyl)3
(0.4 equiv.), KF (4 equiv.). [f] Isolated yield.
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Biaryl Peptides from 4-Iodophenylalanine
We then extended the selected conditions for the aryl- modification and are likely to have an impact on the gener-
ation under microwave irradiation to the reaction of resin ation of combinatorial libraries containing biaryl motifs.
1a with the aryl halides mentioned above (Table 3, Entries
6–11). This reaction yielded the biaryl peptides 7b–f in
moderate to good purities (69–91%). Homocoupling prod-
Experimental Section
uct 8 and phenol 9 were also formed as minor byproducts
General Methods: Commercially available reagents were used
(4–15%). Compared to conventional heating, microwave ir-
throughout without purification. Solvents were purified and dried
radiation significantly favoured the coupling of resin 1a
by passing them through an activated alumina purification system
(MBraun SPS-800) or by conventional distillation techniques. IR
with 4-iodotoluene, 4-iodoanisole, and 2-iodophenol (35–
54% vs. 69–88%). In contrast, arylation of resin 1a with
bromoimidazoles g yielded the biaryl peptide 7g in only
22% purity (Table 3, Entry 11).
spectra were recorded with a Mattson-Galaxy Satellite FT-IR spec-
trometer using a single-reflection ATR system as a sampling access-
ory.
To improve the result obtained for the cross-coupling of
resin 1a with bromoimidazoles g, we assayed the conditions
previously described for the solid-phase arylation of 5-bro-
mohistidines.[13] Thus, this reaction was conducted by using
Pd2(dba)3 (0.2 equiv.), P(o-tolyl)3 (0.4 equiv.), and KF
(4 equiv.) in degassed DME/EtOH/H2O (9:9:2) yielding 7g
in 57% purity (Table 3, Entry 18). This finding is especially
noteworthy because, to the best of our knowledge, this is
the first example of the solid-phase synthesis of a 4-imid-
azol-4(5)-ylphenylalanine peptide. In view of this result, the
arylation of resin 1a was also performed with the aryl ha-
lides a–f under these conditions. Except for the reaction
with 2-iodophenol (f, 60%, Table 3, Entry 17), all the cross-
couplings yielded the biaryl peptides with comparable or
better purities than those using Pd(PPh3)4 (73–91%,
Table 3, Entries 12–16). Purification of the crude reaction
mixtures by column chromatography afforded the corre-
sponding biaryl peptides in 10–63% yield, and these prod-
Flash chromatography (FC) purifications were performed on C18-
reverse-phase silica gel 100 (Ͼ400 mesh, Fluka).
All compounds were analysed under standard analytical HPLC
conditions with a Dionex liquid chromatography instrument com-
posed of an UV/Vis Dionex UVD170U detector, a P680 Dionex
bomb, an ASI-100 Dionex automatic injector, and
CHROMELEON 6.60 software. Detection was performed at
220 nm. Method A: Analysis was carried out with a Kromasil 100
C18 (250 mmϫ4.6 mm, 3.5 µm) column with a 2–100% B linear
gradient over 28 min at a flow rate of 1 mL/min. Solvent A was
0.1% aq TFA, and solvent B was 0.1% TFA in CH3CN. Method
B: Analysis was carried out with
a Kromasil 100 C18
(40 mmϫ4.6 mm, 3.5 µm) column with a 2–100% B linear gradient
over 7 min at a flow rate of 1 mL/min.
ESI-MS analyses were performed with an Esquire 6000 ESI ion
Trap LC/MS (Bruker Daltonics) instrument equipped with an elec-
trospray ion source. The instrument was operated in the positive
ESI(+) ion mode. Samples (5 µL) were introduced into the mass
spectrometer ion source directly through an HPLC autosampler.
1
ucts were characterised by H and 13C NMR spectroscopy
The mobile phase (80:20 CH3CN/H2O at
a flowrate of
and mass spectrometry. In agreement with previous re-
sults,[13] the NMR spectra showed the presence of one
stereoisomer, revealing that no epimerisation occurred dur-
ing the borylation and Suzuki–Miyaura cross-coupling
steps.
Comparing the arylation of resin 1a under conventional
heating and microwave irradiation, the latter dramatically
shortened the reaction time and facilitated the Suzuki–Mi-
yaura cross-coupling, giving superior results. Moreover, in
agreement with previous reports, this study revealed that,
under both heating conditions, the electronic properties of
the substituents on the aromatic ring cannot explain the
reactivity of the aryl halide and, generally, the reaction pro-
ceeded smoothly for both electron-rich and -poor aryl ha-
lides.[6b]
100 µLmin–1) was delivered by a 1100 Series HPLC pump (Ag-
ilent). Nitrogen was employed as both the drying and nebulising
gas. HRMS were recorded under conditions of ESI with a Bruker
MicroTof-Q instrument using a hybrid quadrupole time-of-flight
mass spectrometer (University of Zaragoza). Samples were intro-
duced into the mass spectrometer ion source directly through a
1100 Series Agilent HPLC autosampler and were externally cal-
ibrated using sodium formate. The instrument was operated in the
positive ESI(+) ion mode.
1H and 13C NMR spectra were measured with a Bruker 300 or
400 MHz NMR spectrometer. Chemical shifts were reported as δ
values (ppm) directly referenced to the solvent signal.
The microwave-assisted reactions were performed with an Ethos
SEL labstation microwave (Milestone) equipped with a dual mag-
netron (1600 W). The time, temperature, and power were controlled
with the EasyControl software. The temperature was monitored
through the ATC-400FO Automatic Fiber Optic Temperature Con-
trol System immersed in a standard Milestone reference vessel. This
equipment regulates the power to achieve and maintain the selected
temperature.
Conclusions
In summary, we have developed a convenient strategy for
the modification of phenylalanine peptides through solid-
phase borylation and subsequent cross-coupling. This
methodology yielded resin-bound phenylalanine boronates
in good purities. Additionally, the cross-coupling between a
polymer-bound phenylalanine boronate and different aryl
halides led to a set of 4-arylphenylalanine tripeptides. These
Boc-Phe(4-I)-Leu-Leu-Rink-MBHA (2a): This peptidyl resin was
synthesised manually by the solid-phase method using standard
Fmoc chemistry. Fmoc-Rink-MBHA resin (0.56 mmol/g) was used
as solid support. Couplings of Fmoc-Leu-OH (4 equiv.) and N-tert-
butoxycarbonyl-4-iodo--phenylalanine[8] were performed using
HBTU (3.8 equiv.), HOBt (4 equiv.), and DIEA (3 equiv.) in DMF
at room temperature for 1 h. The completion of the reactions was
results constitute a new tool for post-synthesis peptide monitored by the Kaiser test.[14] Fmoc group removal was achieved
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A. Afonso, C. Rosés, M. Planas, L. Feliu
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with piperidine/DMF (3:7, 2 + 8 min). After each coupling and
deprotection step, the resin was washed with DMF (3ϫ1 min) and
CH2Cl2 (3ϫ1 min) and air-dried. An aliquot of Boc-Phe(4-I)-Leu-
Leu-Rink-MBHA (2a) was cleaved with TFA/H2O/TIS (95:2.5:2.5)
whilst being stirred for 2 h at room temperature. After the reaction
time, TFA evaporation and diethyl ether extraction afforded H-
Phe(4-I)-Leu-Leu-NH2 (3a, 95% purity). tR = 6.93 min (Method
B). HRMS (ESI): calcd. for C21H34IN4O3 517.1670; found
517.1693; calcd. for C21H34IN4NaO3 539.1490; found 539.1512.
(s, 1 H, CONH), 7.62 (d, J = 7.0 Hz, 2 H, 3-Harom, 5-Harom), 8.27
(d, J = 8.0 Hz, 1 H, CONH) ppm. 13C NMR (100 MHz, CD3CN):
δ = 21.95 [2 CH3(δ)-Leu], 23.36 [CH2(γ)-Lys], 25.19 [(CH3)BPin],
25.65 [CH(γ)-Leu], 32.58 [CH2(β)-Lys, CH2(δ)-Lys], 37.97 [CH2(β)-
Phe], 40.47 [CH2(ε)-Lys], 41.54 [CH2(β)-Leu], 52.96, 53.58, 55.18
[3 CH(α)], 84.88 (CBPin), 129.81 (Carom-4), 130.20 (Carom-2,
Carom-6), 135.90 (Carom-3, Carom-5), 138.53 (Carom-1), 172.73,
175.02, 176.35 (3 CO) ppm. MS (ESI): m/z = 532.3 [M + H]+.
HRMS (ESI): calcd. for C27H47BN5O5 532.3669; found 532.3664;
calcd. for C27H46BN5NaO5 554.3489; found 554.3500. During
HPLC analysis, the pinacol boronic ester 6b was partially hydro-
lysed to the boronic acid 4b. tR = 5.50 min (Method B).
Boc-Phe(4-I)-Lys(Boc)-Leu-Rink-MBHA (2b): This peptidyl resin
was prepared following the procedure described for resin 2a. Acidic
cleavage of an aliquot of Boc-Phe(4-I)-Lys(Boc)-Leu-Rink-MBHA
(2b) afforded H-Phe(4-I)-Lys-Leu-NH2 (3b, 94% purity). tR
6.33 min (Method B).
=
Boc-Phe(4-BPin)-Ser-Leu-Rink-MBHA (1c): Starting from Boc-
Phe(4-I)-Ser(tBu)-Leu-Rink-MBHA (2c, 100 mg), the procedure
described for 1a afforded boronate 1c. IR (neat): ν = 3309, 2927,
˜
Boc-Phe(4-I)-Ser(tBu)-Leu-Rink-MBHA (2c): This peptidyl resin
was prepared following the procedure described for resin 2a. Acidic
cleavage of an aliquot of Boc-Phe(4-I)-Ser(tBu)-Leu-Rink-MBHA
1664, 1644, 1504, 1452, 1363, 1209, 1160 cm–1. The corresponding
acidic cleavage afforded H-Phe(4-BPin)-Ser-Leu-NH2 (6c, 99% pu-
1
rity). tR = 6.81 min (Method B). H NMR (400 MHz, CD3CN): δ
(2c) afforded H-Phe(4-I)-Ser-Leu-NH2 (3c, 96% purity). tR
=
= 0.85–0.99 [m, 6 H, 2 CH3(δ)-Leu], 1.31 [s, 12 H, 4 (CH3)BPin],
1.58–1.70 [m, 3 H, CH(γ)-Leu, CH2(β)-Leu], 3.09–3.11 [m, 1 H,
CH2(β)-Phe], 3.26–3.28 [m, 1 H, CH2(β)-Phe], 3.68–3.79 [m, 2 H,
CH2(β)-Ser], 4.28–4.42 [m, 3 H, CH(α)-Phe, CH(α)-Leu, CH(α)-
Ser], 5.86 (s, 1 H, CONH2), 6.71 (s, 1 H, CONH2), 7.04 (s, 1 H,
CONH), 7.31 (d, J = 6.8 Hz, 2 H, 2-Harom, 6-Harom), 7.67 (d, J =
6.8 Hz, 2 H, 3-Harom, 5-Harom), 7.75 (s, 1 H, CONH) ppm. 13C
NMR (75 MHz, CD3CN): δ = 22.47 [2 CH3(δ)-Leu], 24.62
[(CH3)BPin], 24.65 [CH(γ)-Leu], 36.79 [CH2(β)-Phe], 40.28 [CH2(β)-
Leu], 54.37, 54.88, 55.45 [3 CH(α)], 40.39 [CH2(β)-Ser], 83.93
(CBPin), 128.91 (Carom-4), 129.19 (Carom-2, Carom-6), 134.98
(Carom-3, Carom-5), 137.52 (Carom-1) ppm. MS (ESI): m/z = 491.2
[M + H]+. HRMS (ESI): calcd. for C24H40BN4O6 491.3040; found
491.3035; calcd. for C24H39BN4NaO6 513.2859; found 513.2854.
During HPLC analysis, the pinacol boronic ester 6c was partially
hydrolysed to the boronic acid 4c. tR = 5.53 min (Method B).
6.51 min (Method B).
Boc-Phe(4-BPin)-Leu-Leu-Rink-MBHA (1a): A 25 mL round-bot-
tomed flask was charged with Boc-Phe(4-I)-Leu-Leu-Rink-MBHA
(2a, 600 mg), B2Pin2 (4 equiv.), PdCl2(dppf) (0.18 equiv.), and dppf
(0.09 equiv.). A thoroughly sonicated solution of KOAc (6 equiv.)
in anhydrous DMSO (12 mL) was then added, and the mixture was
heated at 80 °C for 24 h. After the reaction time, the resin was
washed with DMSO (6ϫ1 min), MeOH (6ϫ1 min), CH2Cl2
(6ϫ1 min), and Et O (3ϫ1 min). IR (neat): ν = 3316, 2953, 2928,
˜
2
1650, 1505, 1453, 1362, 1209, 1159, 699 cm–1.
An aliquot of Boc-Phe(4-BPin)-Leu-Leu-Rink-MBHA (1a) was
cleaved with TFA/H2O/TIS (95:2.5:2.5) whilst being stirred for 2 h
at room temperature. After the reaction time, TFA evaporation and
diethyl ether extraction afforded H-Phe(4-BPin)-Leu-Leu-NH2 (6a,
99% purity). tR = 7.23 min (Method B). 1H NMR (400 MHz,
CD3CN): δ = 0.85–0.94 [m, 12 H, 4 CH3(δ)-Leu], 1.31 [s, 12 H, 4
(CH3)BPin], 1.55–1.65 [m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.09–
3.11 [m, 1 H, CH2(β)-Phe], 3.26–3.29 [m, 1 H, CH2(β)-Phe], 4.31–
4.35 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe], 5.90 (s, 1 H, CONH2),
6.64 (s, 1 H, CONH2), 7.24 (d, J = 8.0 Hz, 1 H, CONH), 7.28 (d,
J = 7.0 Hz, 2 H, 2-Harom, 6-Harom), 7.65 (d, J = 7.0 Hz, 2 H, 3-
Harom, 5-Harom), 7.97 (d, J = 8.0 Hz, 1 H, CONH) ppm. 13C NMR
(100 MHz, CD3CN): δ = 21.85 [2 CH3(δ)-Leu], 23.17 [2 CH3(δ)-
Leu], 25.09 [(CH3)BPin], 25.24, 25.49 [2 CH(γ)-Leu], 37.72 [CH2(β)-
Phe], 41.52, 41.67 [2 CH2(β)-Leu], 52.44, 53.36, 55.29 [3 CH(α)],
84.76 (CBPin), 129.72 (Carom-4), 130.08 (Carom-2, Carom-6), 135.81
(Carom-3, Carom-5), 138.59 (Carom-1), 169.46, 172.66, 175.42 (3 CO)
ppm. HRMS (ESI): calcd. for C27H46BN4O5 517.3556; found
517.3559; calcd. for C21H45BN4NaO5 539.3375; found 539.3375.
During HPLC analysis, the pinacol boronic ester 6a was partially
hydrolysed to the boronic acid 4a. tR = 6.07 min (Method B). MS
(ESI): m/z = 435.2 [M + H]+.
General Method for the Suzuki–Miyaura Reaction Under Conven-
tional Heating: A 1 mL round-bottomed flask was charged with
Boc-Phe(4-BPin)-Leu-Leu-Rink-MBHA (1a, 5–10 mg), and de-
gassed DME/EtOH/H2O (9:9:2, 0.3 mL) was added under nitrogen.
The corresponding aryl halide (5 equiv.), a solution of 0.017 mmol/
mL of Pd(PPh3)4 (0.05 equiv.) in DME/EtOH/H2O (9:9:2), and de-
gassed aq K3PO4 (2 , 5 equiv.) were then added. The reaction mix-
ture was heated at 60 °C for 48 h. After this time, the resin was
washed with DMF (6ϫ1 min), EtOH (6ϫ1 min), CH2Cl2
(6ϫ1 min), and diethyl ether (3ϫ1 min). The arylphenylalanine
peptides were released from the solid support by treatment with
TFA/H2O/TIS (95:2.5:2.5) with stirring for 2 h at room tempera-
ture. Following TFA evaporation and diethyl ether extraction, the
crude peptides were dissolved in H2O/CH3CN, analysed by HPLC
and characterised by mass spectrometry.
General Method for the Suzuki–Miyaura Reaction Under Microwave
Irradiation. Protocol A: A 5 mL vial was charged with Boc-Phe(4-
BPin)-Leu-Leu-Rink-MBHA (1a, 5–10 mg), and thoroughly de-
gassed DME/EtOH/H2O (9:9:2, 0.3 mL) was added under nitrogen.
The corresponding aryl halide (5 equiv.), a solution of 0.017 mmol/
mL of Pd(PPh3)4 (0.05 equiv.) in DME/EtOH/H2O (9:9:2), and de-
gassed aq K3PO4 (2 , 5 equiv.) were then added. The reaction mix-
Boc-Phe(4-BPin)-Lys-Leu-Rink-MBHA (1b): Starting from Boc-
Phe(4-I)-Lys(Boc)-Leu-Rink-MBHA (2b, 100 mg), the procedure
described for 1a afforded boronate 1b. IR (neat): ν = 3298, 2925,
˜
1669, 1641, 1505, 1452, 1364, 1209, 1167 cm–1. The corresponding
acidic cleavage afforded H-Phe(4-BPin)-Lys-Leu-NH2 (6b, 99% pu-
rity). tR = 6.62 min (Method B). H NMR (400 MHz, CD3CN): δ
1
= 0.89–0.93 [m, 6 H, 2 CH3(δ)-Leu], 1.30 [s, 12 H, 4 (CH3)BPin], ture was heated at 120 °C under microwave irradiation for 30 min.
1.58–1.65 [m, 9 H, CH(γ)-Leu, CH2(β)-Leu, CH2(β)-Lys, CH2(γ)- After this time, the resin was washed with DMF (6ϫ1 min), EtOH
Lys, CH2(δ)-Lys], 2.88–2.92 [m, 2 H, CH2(ε)-Lys], 3.06–3.09 [m, 1
H, CH2(β)-Phe], 3.23–3.32 [m, 1 H, CH2(β)-Phe], 4.32–4.48 [m, 3
(6ϫ1 min), CH2Cl2 (6ϫ1 min), and diethyl ether (3ϫ1 min). The
arylphenylalanine peptides were released from the solid support by
H, CH(α)-Leu, CH(α)-Lys, CH(α)-Phe], 6.11 (s, 1 H, CONH2), 6.98 treatment with TFA/H2O/TIS (95:2.5:2.5) with stirring for 2 h at
(s, 1 H, CONH2), 7.24 (d, J = 7.0 Hz, 2 H, 2-Harom, 6-Harom), 7.56 room temperature. Following TFA evaporation and diethyl ether
1466
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1461–1468

Biaryl Peptides from 4-Iodophenylalanine
extraction, the crude peptides were dissolved in H2O/CH3CN and
analysed by HPLC.
2 H, 2-Harom, 6-Harom), 7.35 (dd, J = 1.7, 8.0 Hz, 1 H, 6Ј-Harom),
7.47 (d, J = 8.0 Hz, 2 H, 3-Harom, 5-Harom) ppm. 13C NMR
(100 MHz, CD3CN + D2O): δ = 21.66, 22.91 [4 CH3(δ)-Leu], 25.14,
25.33 [2 CH(γ)-Leu], 36.91 [CH2(β)-Phe], 41.26, 41.34 [2 CH2(β)-
Protocol B: A 5 mL vial was charged with Boc-Phe(4-BPin)-Leu-
Leu-Rink-MBHA (1a, 60–80 mg), the corresponding aryl halide
(5 equiv.), Pd2(dba)3 (0.2 equiv.), P(o-tolyl)3 (0.4 equiv.), and KF
(4 equiv.). Thoroughly degassed DME/EtOH/H2O (9:9:2, 1.2 mL)
was then added under nitrogen. The reaction mixture was heated
at 120 °C under microwave irradiation for 30 min. After this time,
the resin was washed with DMF (6ϫ1 min), EtOH (6ϫ1 min),
CH2Cl2 (6ϫ1 min), and diethyl ether (3ϫ1 min). The arylphenyl-
alanine peptides were released from the solid support by treatment
with TFA/H2O/TIS (95:2.5:2.5) with stirring for 2 h at room tem-
perature. Following TFA evaporation and diethyl ether extraction,
an aliquot of the crude peptides was dissolved in H2O/CH3CN and
analysed by HPLC. The pure biaryl peptides were obtained after
purification by reverse-phase column chromatography.
Leu], 52.21, 53.25, 55.03 [3 CH(α)], 55.91 (OCH3), 112.34 (Carom
3Ј), 121.61 (Carom-5Ј), 129.77 (Carom-4Ј), 130.06 (Carom-3, Carom
-
-
5), 130.46 (Carom-1Ј), 130.64 (Carom-2, Carom-6), 131.31 (Carom-6Ј),
133.55 (Carom-4), 138.71 (Carom-1), 157.19 (Carom-2Ј), 168.57,
172.59, 175.44 (3 CO) ppm. MS (ESI): m/z = 497.3 [M + H]+.
HRMS (ESI): calcd. for C28H41N4O4 497.3122; found 497.3125.
Biaryl Peptide 7d: Starting from resin 1a (80 mg), elution with H2O/
MeOH/TFA (60:40:0.2) afforded 7d (6.5 mg, 35% yield). tR
=
20.99 min (Method A), 7.20 min (Method B). 1H NMR (300 MHz,
CD3CN + D2O): δ = 0.85–0.90 [m, 12 H, 4 CH3(δ)-Leu], 1.51–1.55
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.08 [dd, J = 7.8, 14.1 Hz,
1 H, CH2(β)-Phe], 3.28 [dd, J = 9.0, 14.1 Hz, 1 H, CH2(β)-Phe],
3.80 (s, 3 H, OCH3), 4.19–4.32 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe],
7.01 (d, J = 8.9 Hz, 2 H, 3Ј-Harom, 5Ј-Harom), 7.32 (d, J = 8.1 Hz,
2 H, 2-Harom, 6-Harom), 7.56 (d, J = 8.1 Hz, 2 H, 3-Harom, 5-Harom),
7.58 (d, J = 8.9 Hz, 2 H, 2Ј-Harom, 6Ј-Harom) ppm. 13C NMR
(75 MHz, CD3CN + D2O): δ = 21.88, 21.91, 23.28, 23.36 [4
CH3(δ)-Leu], 25.38, 25.60 [2 CH(γ)-Leu], 37.07 [CH2(β)-Phe],
41.40, 41.52 [2 CH2(β)-Leu], 52.43, 53.57, 55.24 [3 CH(α)], 56.06
(OCH3), 115.36 (Carom-3Ј, Carom-5Ј), 127.86 (Carom-3, Carom-5),
128.93 (Carom-2, Carom-6), 129.10 (Carom-1Ј), 131.16 (Carom-2Ј,
Carom-6Ј), 133.58 (Carom-4), 140.79 (Carom-1), 160.49 (Carom-4Ј),
168.78, 172.89, 175.79 (3 CO) ppm. MS (ESI): m/z = 497.3 [M +
H]+. HRMS (ESI): calcd. for C28H41N4O4 497.3122; found
497.3101; calcd. for C28H40N4NaO4 519.2942; found 519.2927.
Biaryl Peptide 7a: Starting from resin 1a (50 mg), elution with H2O/
MeOH/TFA (50:50:0.2) afforded 7a (3 mg, 27% yield). tR
=
21.13 min (Method A), 7.25 min (Method B). 1H NMR (400 MHz,
CD3CN + D2O): δ = 0.87–0.92 [m, 12 H, 4 CH3(δ)-Leu], 1.52–1.64
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.11 [dd, J = 7.6, 14.4 Hz,
1 H, CH2(β)-Phe], 3.30 [dd, J = 6.0, 14.4 Hz, 1 H, CH2(β)-Phe],
4.23–4.34 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe], 7.35–7.39 (m, 3 H,
2-Harom, 6-Harom, 4Ј-Harom), 7.46 (t, J = 7.4 Hz, 2 H, 3Ј-Harom, 5Ј-
H
arom), 7.61 (d, J = 8.2 Hz, 2 H, 3-Harom, 5-Harom), 7.64 (dt, J =
1.2, 7.4 Hz, 2 H, 2Ј-Harom, 6Ј-Harom) ppm. 13C NMR (100 MHz,
CD3CN + D2O): δ = 21.60, 21.63, 23.03, 23.09 [4 CH3(δ)-Leu],
25.12, 25.32 [2 CH(γ)-Leu], 36.81 [CH2(β)-Phe], 41.21, 41.29 [2
CH2(β)-Leu], 52.12, 53.25, 54.97 [3 CH(α)], 127.56, 128.09 (Carom
-
2Ј, Carom-6Ј, Carom-3, Carom-5), 128.33 (Carom-4Ј), 129.72 (Carom-3Ј,
Carom-5Ј), 130.96 (Carom-2, Carom-6), 134.08 (Carom-4), 140.90,
140.97 (Carom-1, Carom-1Ј), 168.54, 172.61, 175.48 (3 CO) ppm. MS
(ESI): m/z = 467.2 [M + H]+. HRMS (ESI): calcd. for C27H39N4O3
467.3017; found 467.3016.
Biaryl Peptide 7e: Starting from resin 1a (60 mg), elution with H2O/
MeOH/TFA (60:40:0.2) afforded 7e (7 mg, 49% yield). tR
=
21.09 min (Method A), 7.22 min (Method B). 1H NMR (400 MHz,
CD3CN + D2O): δ = 0.81–0.88 [m, 12 H, 4 CH3(δ)-Leu], 1.49–1.58
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.09–3.14 [m, 1 H, CH2(β)-
Phe], 3.28–3.33 [m, 1 H, CH2(β)-Phe], 4.23–4.31 [m, 3 H, 2 CH(α)-
Leu, CH(α)-Phe], 7.39 (d, J = 7.8 Hz, 2 H, 2-Harom, 6-Harom), 7.65
(d, J = 7.8 Hz, 2 H, 3-Harom, 5-Harom), 7.82 (d, J = 8.8 Hz, 2 H,
Biaryl Peptide 7b: Starting from resin 1a (80 mg), elution with H2O/
MeOH/TFA (50:50:0.2) afforded 7b (5 mg, 26% yield). tR
=
22.07 min (Method A), 7.47 min (Method B). 1H NMR (400 MHz,
CD3CN + D2O): δ = 0.85–0.88 [m, 12 H, 4 CH3(δ)-Leu], 1.48–1.56
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 2.33 (s, 3 H, CH3), 3.07 [dd,
J = 8.0, 14.4 Hz, 1 H, CH2(β)-Phe], 3.26 [dd, J = 5.6, 14.4 Hz, 1
H, CH2(β)-Phe], 4.18–4.30 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe], 7.24
(d, J = 8.4 Hz, 2 H, 3Ј-Harom, 5Ј-Harom), 7.31 (d, J = 8.4 Hz, 2 H,
2-Harom, 6-Harom), 7.50 (d, J = 8.4 Hz, 2 H, 2Ј-Harom, 6Ј-Harom),
7.56 (d, J = 8.4 Hz, 2 H, 3-Harom, 5-Harom) ppm. 13C NMR
(100 MHz, CD3CN + D2O): δ = 20.71 (CH3), 21.47, 21.50, 22.89,
22.95 [4 CH3(δ)-Leu], 24.97, 25.18 [2 CH(γ)-Leu], 36.68 [CH2(β)-
Phe], 40.98, 41.11 [2 CH2(β)-Leu], 52.00, 53.13, 54.79 [3 CH(α)],
127.29 (Carom-2Ј, Carom-6Ј), 127.72 (Carom-3, Carom-5), 130.21
(Carom-2, Carom-6), 130.78 (Carom-3Ј, Carom-5Ј), 133.72, 137.91,
138.14, 140.68 (Carom-1, Carom-4, Carom-1Ј, Carom-4Ј), 168.62,
172.70 (3 CO) ppm. MS (ESI): m/z = 481.3 [M + H]+. HRMS
(ESI): calcd. for C28H41N4O3 481.3173; found 481.3155; calcd. for
C28H40N4NaO3 503.2993; found 503.2973.
2Ј-Harom, 6Ј-Harom), 8.25 (d, J = 8.8 Hz, 2 H, 3Ј-Harom, 5Ј-Harom
)
ppm. 13C NMR (100 MHz, CD3CN + D2O): δ = 21.87, 21.89,
23.28, 23.34 [4 CH3(δ)-Leu], 25.37, 25.57 [2 CH(γ)-Leu], 37.30
[CH2(β)-Phe], 41.35, 41.48 [2 CH2(β)-Leu], 52.41, 53.49, 55.11 [3
CH(α)], 125.12 (Carom-3Ј, Carom-5Ј), 128.85 (Carom-3, Carom-5,
Carom-2Ј, Carom-6Ј), 131.49 (Carom-2, Carom-6), 136.30 (Carom-4),
138.75 (Carom-1), 147.72 (Carom-1Ј), 148.30 (Carom-4Ј), 169.38,
172.92, 175.86 (3 CO) ppm. MS (ESI): m/z = 512.2 [M + H]+.
HRMS (ESI): calcd. for C27H38N5O5 512.2867; found 512.2846;
calcd. for C27H37N5NaO5 534.2687; found 534.2674.
Biaryl Peptide 7f: Starting from resin 1a (60 mg), elution with H2O/
MeOH/TFA (60:40:0.2) afforded 7f (5 mg, 37% yield). tR
=
19.84 min (Method A), 6.91 min (Method B). 1H NMR (300 MHz,
CD3CN + D2O): δ = 0.83–0.91 [m, 12 H, 4 CH3(δ)-Leu], 1.49–1.60
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.09 [dd, J = 7.8, 14.1 Hz,
1 H, CH2(β)-Phe], 3.21–3.28 [m, 1 H, CH2(β)-Phe], 4.16–4.35 [m,
3 H, 2 CH(α)-Leu, CH(α)-Phe], 6.91–6.95 (m, 2 H, 3Ј-Harom, 5Ј-
Harom), 7.17–7.35 (m, 4 H, 2-Harom, 6-Harom, 4Ј-Harom, 6Ј-Harom),
7.49 (d, J = 8.1 Hz, 2 H, 3-Harom, 5-Harom) ppm. 13C NMR
Biaryl Peptide 7c: Starting from resin 1a (60 mg), elution with H2O/
MeOH/TFA (60:40:0.2) afforded 7c (9 mg, 63% yield). tR
=
21.16 min (Method A), 7.19 min (Method B). 1H NMR (400 MHz,
CD3CN + D2O): δ = 0.86–0.92 [m, 12 H, 4 CH3(δ)-Leu], 1.51–1.66 (75 MHz, CD3CN + D2O): δ = 21.88, 23.25 [4 CH3(δ)-Leu], 25.32,
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 3.07–3.15 [m, 1 H, CH2(β)-
Phe], 3.32 [dd, J = 3.6, 12.4 Hz, 1 H, CH2(β)-Phe], 3.78 (s, 3 H,
OCH3), 4.30–4.39 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe], 7.03 (td, J
25.54 [2 CH(γ)-Leu], 37.27 [CH2(β)-Phe], 41.41 [2 CH2(β)-Leu],
52.37, 53.20, 55.21 [3 CH(α)], 117.13 (Carom-3Ј), 121.18 (Carom-5Ј),
128.27 (Carom-4Ј), 129.90, 130.41, 130.79, 131.47 (Carom-2, Carom-6,
= 0.8, 8.0 Hz, 1 H, 5Ј-Harom), 7.08 (dd, J = 0.8, 8.0 Hz, 1 H, 3Ј- Carom-3, Carom-5, Carom-1Ј, Carom-6Ј), 133.65 (Carom-4), 138.97
Harom), 7.30 (td, J = 1.7, 8.0 Hz, 1 H, 4Ј-Harom), 7.30 (d, J = 8.0 Hz, (Carom-1), 154.69 (Carom-2Ј), 168.72, 172.96, 180.39 (3 CO) ppm.
Eur. J. Org. Chem. 2010, 1461–1468
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1467

A. Afonso, C. Rosés, M. Planas, L. Feliu
FULL PAPER
MS (ESI): m/z = 483.3 [M + H]+. HRMS (ESI): calcd. for
C27H39N4O4 483.2966; found 483.2951; calcd. for C27H38N4NaO4
505.2785; found 505.2775.
Löweneck, J. V. Schreiber, J. Frackenpohl, D. Seebach, Helv.
Chim. Acta 2006, 89, 1427–1441; d) M. Vilaró, G. Arsequell,
G. Valencia, A. Ballesteros, J. Barluenga, Org. Lett. 2008, 10,
3243–3245.
Biaryl Peptide 7g: Starting from resin 1a (80 mg), elution with H2O/
[4]
a) F. Firooznia, C. Gude, K. Chan, N. Marcopulos, Y. Satoh,
Tetrahedron Lett. 1999, 40, 213–216; b) O. Skaff, K. A. Jolliffe,
C. A. Hutton, J. Org. Chem. 2005, 70, 7353–7363; c) Y. Gong,
J. K. Barbay, A. B. Dyatkin, T. A. Miskowski, E. S. Kimball,
S. M. Prouty, M. C. Fisher, R. J. Santulli, C. R. Schneider,
N. H. Wallace, S. A. Ballentine, W. E. Hageman, J. A. Masucci,
B. E. Maryanoff, B. P. Damiano, P. Andrade-Gordon, D. J.
Hlasta, P. J. Hornby, W. He, J. Med. Chem. 2006, 49, 3402–
MeOH/TFA (80:20:0.2) afforded 7g (2 mg, 10% yield). tR
=
15.70 min (Method A), 5.96 min (Method B). 1H NMR (400 MHz,
CD3CN + D2O): δ = 0.86–0.88 [m, 12 H, 4 CH3(δ)-Leu], 1.45–1.57
[m, 6 H, 2 CH(γ)-Leu, 2 CH2(β)-Leu], 2.40 (s, 3 H, CH3), 3.11 [dd,
J = 7.6, 14.6 Hz, 1 H, CH2(β)-Phe], 3.24 [dd, J = 6.8, 14.6 Hz, 1
H, CH2(β)-Phe], 4.16–4.21 [m, 3 H, 2 CH(α)-Leu, CH(α)-Phe], 7.37
(d, J = 8.4 Hz, 2 H, 2-Harom, 6-Harom), 7.47 (d, J = 8.4 Hz, 2 H, 3-
ˇ
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arom, 5-Harom), 8.50 (s, 1 H, CHimid) ppm. 13C NMR (100 MHz,
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CD3CN + D2O): δ = 10.44 (CH3), 21.82, 21.87, 23.21, 23.25 [4
CH3(δ)-Leu], 25.29, 25.51 [2 CH(γ)-Leu], 37.26 [CH2(β)-Phe],
[5]
[6]
41.33 [2 CH2(β)-Leu], 52.85, 53.49, 55.02 [3 CH(α)], 129.00 (Carom
-
3, Carom-5), 131.42 (Carom-2, Carom-6), 136.27 (CHimid) ppm. MS
(ESI): m/z = 471.3 [M + H]+. HRMS (ESI): calcd. for C25H39N6O3
471.3078; found 471.3073; calcd. for C25H38N6NaO3 493.2898;
found 493.2890.
[7]
Supporting Information (see also the footnote on the first page of
this article): Experimental details, copies of IR spectra of borono-
peptidyl resins 1a–c, copies of 1H and 13C NMR, IR, ESI-MS, and
HRMS spectra, and HPLC chromatograms of boronopeptides 6a–
c and biaryl peptides 7a–g.
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Acknowledgments
A. A. is the recipient of a predoctoral fellowship from the Spanish
Ministry of Education and Science (MEC). This work was sup-
ported by grant AGL2006-13564-C02-02/AGR from MEC of
Spain. We are also grateful to the Serveis Tècnics de Recerca of the
University of Girona.
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Received: November 23, 2009
Published Online: February 8, 2010
1468
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Eur. J. Org. Chem. 2010, 1461–1468