Direct synthesis of the arylboronic acid analogues of phenylglycine via microwave-assisted four-component Ugi reaction

Article abstract of DOI:10.1016/j.tet.2014.01.016

A four-component Ugi reaction (Ugi-4CR) utilizing formylphenyl boronic acids under mild condition was developed for the synthesis of arylboronic acid analogs. The reactions were performed in methanol and accelerated by microwave irradiation, which makes this strategy suitable for constructing boronic-containing chemical libraries. Two of the synthesized analogs were found to have cytotoxic activity against HepG2, MDA-MB231, and A549 cancer cell lines, demonstrating the potential application of this approach in developing novel boron-containing pharmaceuticals.

Full text of DOI:10.1016/j.tet.2014.01.016

Tetrahedron 70 (2014) 1800e1804
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct synthesis of the arylboronic acid analogues of phenylglycine
via microwave-assisted four-component Ugi reaction
Ru-Ching Lian a, Meng-Hsuan Lin a, Pin-Hsuan Liao a, Jia-Jie Fu a, Meng-Ju Wu a,
,
c
,
,
,
*
Yang-Chang Wu b d, Fang-Rong Chang e f, Chin-Chung Wu e, Po-Shen Pan a
a Department of Chemistry, Tamkang University, No. 151 Yingzhuan Rd., Tamsui Dist., New Taipei City 25137, Taiwan, ROC
b School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan, ROC
c Chinese Medicine Research and Development Center, China Medical University, Taichung 404, Taiwan, ROC
d Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, ROC
e Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
f Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A four-component Ugi reaction (Ugi-4CR) utilizing formylphenyl boronic acids under mild condition was
developed for the synthesis of arylboronic acid analogs. The reactions were performed in methanol and
accelerated by microwave irradiation, which makes this strategy suitable for constructing boronic-
containing chemical libraries. Two of the synthesized analogs were found to have cytotoxic activity
against HepG2, MDA-MB231, and A549 cancer cell lines, demonstrating the potential application of this
approach in developing novel boron-containing pharmaceuticals.
Received 21 November 2013
Received in revised form 8 January 2014
Accepted 9 January 2014
Available online 20 January 2014
Keywords:
Boronic acids
Ó 2014 Elsevier Ltd. All rights reserved.
Ugi-4CR
Multicomponent reaction
Microwave-assisted synthesis
Acid/base extraction
1. Introduction
Organoboron compounds have been widely used as Lewis acid
catalysts in various organic transformations because the vacant p-
orbital of boron can accommodate a lone pair of electrons.1 Re-
cently, it has been found that the vacant boron p-orbital interacts
with the oxygen lone pair on the N-terminal threonine (or serine)
hydroxyl group of a proteasome (or protease) to generate a stable
tetrahedral complex (Scheme 1).2 This trigonaletetragonal con-
version is reversible, and hence, organoboron compounds are ideal
candidates for transition-state inhibitors of proteasome/proteases.
Bortezomib (VelcadeÔ) (Fig. 1), which has been approved by the
Food and Drug Administration (United States) for the treatment of
relapsed multiple myeloma and mantle cell lymphoma, is a notable
example for the successful incorporation of boron into the drug
scaffold.3 Hence, significant numbers of research programs have
been focused on the development of boron-containing molecules
as potential pharmaceutical agents, and promising drug candidates
that are currently under clinical trials have been produced (Fig. 1).4
Scheme 1. Boronic acid as the proteasome inhibitor.
Generally, because of its sensitivity to a wide spectrum of synthesis
conditions,5 the boronic acid moiety is often protected beforehand
and incorporated into the molecular scaffold in the last step of the
synthesis. However, the difficulty in identifying the appropriate
conditions for boron incorporation into a functionalized scaffold
and the additional deprotection operation involved are the main
bottlenecks in boron research.6 One possible alternative strategy
for the generation of boronic acid libraries includes the use of
a multicomponent reaction (MCR),7 a convergent synthetic ap-
proach in which three or more reagents are combined in one pot to
give the desired products. The MCR is an invaluable platform for the
development of therapeutic agents. One of the well-recognized
* Corresponding author. Tel.: þ886 2 26215656; fax: þ886 2 26209924; e-mail
address: popan@mail.tku.edu.tw (P.-S. Pan).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.016

R.-C. Lian et al. / Tetrahedron 70 (2014) 1800e1804
1801
obtained 30 min when the reaction was performed at 45 ꢀC under
microwave irradiation with increased concentration (1.0 M). This
finding is especially valuable for the library synthesis as the usage
of the solvent and the reaction time were both greatly reduced.
With the optimized condition in hand, array of reagents were
employed to synthesize series of boronic acid analogs, and the re-
sults were reported in Table 2. Although flash column chromatog-
raphy is often required to remove the most of the excess reactants
or byproducts before the HPLC purification, we’ve found a simple
liquideliquid acid/base extraction protocol to be sufficient to give
the desired products in 72e98% purity. This extraction protocol
not only provides an efficient purification approach but also
avoid the generation of silica gel waste, making this strategy
ideal for chemical library synthesis. All desired products 5e16 were
obtained in moderate-to-good yields ranging from 52 to 81%
(Table 2).
(a)
(c)
(b)
(d)
(e)
Fig. 1. (a) Velcade; (b) TR150c; (c) PHX1149; (d) PT100; (e) AN2690.
MCRs is the isocyanide-based Ugi reaction, where an isocyanide, an
aldehyde, an amine, and a carboxylic acid are condensed to afford
the desired product.8 The Ugi reaction is an ideal strategy for
constructing chemical libraries, but to the best of our knowledge,
there is no report on the use of this strategy to generate boronic
acid compounds. The present report is the first to discuss the
synthesis of boronic acid analogs via a four-component Ugi reaction
(Ugi-4CR).
Table 2
Synthesis of boronic acid Ugi analogs
Entry
R1
R2
R3
Product
Purity (%)a
Yield (%)b
1
2
3
4
5
6
7
8
4-B(OH)2ePh
3-B(OH)2ePh
4-B(OH)2ePh
3-B(OH)2ePh
4-B(OH)2ePh
3-B(OH)2ePh
4-B(OH)2ePh
3-B(OH)2ePh
4-B(OH)2ePh
3-B(OH)2ePh
4-B(OH)2ePh
3-B(OH)2ePh
i-Pr
i-Pr
Me
Me
Me
Me
Et
Et
i-Bu
i-Bu
c-Hex
c-Hex
Bn
Bn
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
5
6
7
8
94
96
98
72
88
85
92
98
89
85
89
91
78
81
57
76
68
77
60
79
76
80
52
64
2. Results and discussion
A series of experiments were carried out to determine the op-
timal conditions for the Ugi-4CR; the results are summarized in
Table 1. First, a range of solvents were screened for the synthesis. 4-
Formylphenyl boronic acid 1, isobutyric acid 2, benzylamine 3, and
cyclohexylisocyanide 4 were dissolved in the chosen solvent, and
the mixture was stirred at room temperature for 1 h to obtain the
product (entries 1e5). Among the aforementioned solvents, MeOH
gave favorable results; hence further optimization was performed
by carrying out the reaction in MeOH. Although sequential addition
of the starting materials is not strictly required in the Ugi reaction,
pre-formation of the imine intermediate seemed beneficial, as the
yield was improved from 55% (entry 4) to 73% (entry 5). Prolonging
the reaction slightly increased the yield from 73% to 76% (entry 6),
although increasing the reaction temperature from room temper-
ature to 45 ꢀC by using a regular heating plate did not contribute to
an increase in the yield (entry 7). The best yield (78%, entry 8) was
9
10
11
12
13
14
15
16
9
10
11
12
a
Percentage determined by HPLC at 241 nm after acid/base extraction.
Isolated yield after HPLC purification.
b
The twelve boron-containing analogs synthesized in this study
were subsequently screened for cytotoxic activity against human
hepatocellular carcinoma (HepG2), human breast carcinoma (MDA-
MB231), and human lung carcinoma (A549) cancer cell lines using
the MTT cell viability assay.9 Compounds 15 and 16 were active
against the HepG2 (IC50¼32.7
m
M, 32.2
m
M), MDA-MB231
M, 21.9 M) cell
(IC50¼36.8
mM, 32.7
m
M), and A549 (IC50¼32.6
m
m
lines.
Table 1
Optimization of Ugi-4CR
3. Conclusion
A convenient and efficient microwave-assisted Ugi-4CR that
operates under mild conditions was developed, and a series of
boronic acid analogs were synthesized in moderate-to-good yields.
This strategy allows the direct use of unprotected boronic acid
building blocks to generate desired products, and hence would be
suitable for boron-containing chemical library synthesis. In addi-
tion, two of the synthesized analogs were active against HepG2,
MDA-MB231, and A549 cell lines. Extension of this study to the
preparation of a library of boron-containing analogs and their bi-
ologic evaluation is in progress and will be reported in due course.
Entry
Solvent
Temp
Time
Concn
Yield (%)c
1a
2a
3a
4a
5b
6b
7b
8b
9b
H2O
Ether
DCM
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
rt
rt
rt
rt
rt
rt
45 ꢀC
1 h
1 h
1 h
1 h
1 h
5 h
1 h
0.5 h
0.25 h
0.25 M
0.25 M
0.25 M
0.25 M
0.25 M
0.25 M
0.25 M
1.0 M
20
49
30
55
73
76
70
78
41
4. Experimental section
4.1. General
m
m
W, 45 ꢀC
W, 45 ꢀC
1.0 M
a
Aldehyde, amine, isocyanide, and acid were added at once.
b
Aldehyde and amine were stirred for 5 min prior the addition of isocyanide and
acid.
All starting materials were obtained from commercial suppliers
and used without further purification unless otherwise noted.
c
Yield after HPLC purification.

1802
R.-C. Lian et al. / Tetrahedron 70 (2014) 1800e1804
Reactions were performed on a CEM Co., Discover microwave re-
actor with sealed vessels. Unless otherwise specified 1H , 13C NMR
spectra were recorded on a Bruker AC-300 FT-NMR spectrometer at
300, 75.5 MHz, respectively. 11B NMR spectra were recorded on
a Bruker Avance 600 FT-NMR spectrometer at 192.5 MHz. All 11B
chemical shifts were referenced to external BF3$OEt2 (0.0 ppm).
Data are represented as follows: chemical shifts (ppm), multiplicity
(s¼singlet, d¼doublet, t¼triplet, m¼multiplet, br¼broad), coupling
constant J (Hertz). Melting points were determined by using a Fargo
MP-2D melting point apparatus and were uncorrected. High-
resolution ESI mass spectra were obtained by Finnigan MAT 95S
instrument. The desired products 5e16 were purified by RP-HPLC
4.4. (4-(2-(Cyclohexylamino)-2-oxo-1-(N-phenylacetamido)
ethyl)phenyl)boronic acid (7)
Following the General Procedure, the desired compound was
synthesized utilizing aniline (0.10 mL,1.10 mmol), (4-formylphenyl)
boronic acid (150 mg, 1.00 mmol), acetic acid (0.06 mL, 1.10 mmol),
and cyclohexylisocyanide (0.14 mL, 1.10 mmol) giving compound 7
as a white solid (mp¼183 ꢀC) in 57% yield (272 mg); 1H NMR
(CD3OD-d4) d: 7.92 (OH), 7.49e7.34 (m, 3H), 7.14e7.07 (m, 6H), 6.05
(s, 1H), 3.70 (br, 1H), 1.82e1.58 (m, 7H), 1.38e1.03 (m, 6H). 13C NMR
(CD3OD-d4) : 179.01, 178.31, 150.04, 147.26, 147.03, 143.20, 142.99,
140.30, 138.74, 137.84, 137.00, 72.93, 57.50, 41.80, 34.81, 34.23,
d
using ODS-A C18 reverse phase column (5
m
m, 10 mmꢁ250 mm)
34.09, 32.69. 11B NMR (CD3OD-d4)
d: 28.12. HRMS (ESI, positive ion)
and following gradient elutions with solvent A: 0.1% TFA/water,
solvent B: 0.1% TFA/acetonitrile; For compounds 3, 4, from 0% to
90% of B over 60 min, for compounds 2, 7, 8, 80% of B over 60 min,
for compounds 1, 5, 6, 9, 10e12, from 50% to 100% of B over 60 min;
a flow rate 2.0 mL/min; detection: UV, 241 and 254 nm.
(m/z): [MþH]þ, calcd for C22H27BN2O4, 395.2140; found, 395.2153.
4.5. (3-(2-(Cyclohexylamino)-2-oxo-1-(N-phenylacetamido)
ethyl)phenyl)boronic acid (8)
Following the General Procedure, the desired compound was
synthesized utilizing aniline (0.10 mL, 1.1 mmol), (3-formylphenyl)
boronic acid (150 mg, 1.00 mmol), acetic acid (0.06 mL, 1.10 mmol),
and cyclohexylisocyanide (0.14 mL; 1.10 mmol) giving compound 8
as a white solid (mp¼144 ꢀC) in 76% yield (362 mg); 1H NMR
4.2. General procedure for (4-(1-(N-benzylisobutyramido)-2-
(cyclohexylamino)-2-oxoethyl)phenyl)boronic acid (5)
A 10 mL glass tube containing benzylamine (0.12 mL; 1.1 mmol),
(4-formylphenyl)boronic acid (150 mg; 1 mmol), and methanol
(1.00 mL) was first stirring for 5 min under room temperature.
Isobutric acid (0.1 mL; 1.1 mmol) and cyclohexylisocyanide
(0.14 mL; 1.1 mmol) was then added to the reaction mixture. The
microwave irradiation was applied for 45 min (45 ꢀC, 150 W) under
medium speed magnetic stirring. After the reaction was com-
pleted, the crude material was concentrated and re-dissolved in
dichloromethane. The resulting organic solution was then washed
with 1 M HCl(aq). This was followed by adding a saturated aqueous
solution of NaHCO3(aq) combined with brine. The resulting organic
layer was collected, dried by MgSO4, and then concentrated in
vacuo at 40 ꢀC for 8 h to afford the crude material. The crude
material was purified by High Performance Liquid Chromatogra-
phy (HPLC) to give the desired product 5 as a white solid
(CD3OD-d4) d: 7.55e7.26 (m, 3H), 7.13e7.04 (m, 6H), 6.06 (s, 1H),
3.70 (br, 1H), 1.81e1.58 (m, 7H), 1.38e1.03 (m, 6H). 13C NMR
(CD3OD-d4) : 173.57, 171.72, 141.62, 133.21, 132.06, 129.84, 129.15,
d
65.35, 33.72, 33.60, 26.76, 26.28, 26.20, 23.40. 11B NMR (CD3OD-d4)
d
: 28.50. HRMS (ESI, positive ion) (m/z): [MþH]þ, calcd for
C22H27BN2O4, 395.2140; found 395.2142.
4.6. (4-(1-(N-Benzylacetamido)-2-(cyclohexylamino)-2-
oxoethyl)phenyl)boronic acid (9)
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (4-
formylphenyl)boronic acid (150 mg, 1.00 mmol), acetic acid
(0.06 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 9 as a white solid (mp¼166 ꢀC) in 68%
(mp¼156 ꢀC) in 78% yield (406 mg); 1H NMR (CD3OD-d4)
d: 8.09
(br, OH), 7.97 (br, OH), 7.61 (br, OH), 7.44 (br, OH), 7.26e7.05 (m,
7H), 6.93e6.86 (m, 2H), 6.13 (s, 0.82H), 5.78 (s, 0.18H), 4.69 (q,
J¼54.0, 18.0, 2H), 3.66 (m, 1H), 2.73 (m, 1H), 1.81e1.58 (m, 6H),
1.35e1.02 (m, 12H). 13C NMR (Bruker AC-600 FT-NMR spectrome-
yield (336 mg); 1H NMR (CD3OD-d4)
d: 8.10e7.98 (OH), 7.61e7.45
(m, 2H), 7.26 (d, J¼7.8 Hz, 2H), 7.20e7.06 (m, 3H), 6.93e6.91 (d,
J¼6.8 Hz, 5H), 6.10 (s, 0.80H), 5.66 (s, 0.20H), 4.66 (dd, J¼47.9, 18.5,
2H), 3.66 (br, 1H), 2.06 (s, 1H), 1.85e1.58 (m, 4H), 1.39e1.05 (m, 6H).
ter at 150.9 MHz, CD3OD-d4)
d: 175.80, 168.96, 137.85, 136.74,
13C NMR (CD3OD-d4)
d: 175.43, 171.54, 139.42, 135.23, 134.75,
134.45, 132.24, 128.22, 126.69, 126.05, 83.87, 62.83, 49.88, 48.51,
32.73, 27.30, 25.49, 24.90, 9.38. 11B NMR (CD3OD-d4)
d: 28.19.
130.41, 129.52, 129.07, 128.60, 127.62, 63.90, 51.38, 33.70, 26.83,
26.28, 22.74. 11B NMR (CD3OD-d4)
d: 28.71. HRMS (ESI, positive ion)
HRMS (ESI, positive ion) (m/z): [MþH]þ, calcd for C25H33BN2O4,
(m/z): [MþH]þ, calcd for C23H29BN2O4, 409.2197; found 409.2307.
437.2610; found 437.2620.
4.3. (3-(1-(N-Benzylisobutyramido)-2-(cyclohexylamino)-2-
4.7. (3-(1-(N-Benzylacetamido)-2-(cyclohexylamino)-2-
oxoethyl)phenyl)boronic acid (6)
oxoethyl)phenyl)boronic acid (10)
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL; 1.10 mmol), (3-
formylphenyl)boronic acid (150 mg; 1.00 mmol), isobutric acid
(0.1 mL; 1.10 mmol), and cyclohexylisocyanide (0.14 mL;
1.10 mmol) giving compound 6 as a white solid (mp¼169 ꢀC) in
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (3-
formylphenyl)boronic acid (150 mg, 1.00 mmol), acetic acid
(0.06 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 10 as the white solid (mp¼150 ꢀC) in
81% yield (428 mg); 1H NMR (CD3OD-d4)
d
: 8.06 (br, OH), 7.94 (br,
77% yield (245 mg); 1H NMR (CD3OD-d4)
d: 7.93 (br, OH), 7.67e7.44
OH), 7.68e7.44 (m, OH), 7.32 (s, 1H), 7.19e7.02 (m, 6H), 6.89e6.82
(m, 1H), 6.3 (s, 0.84H), 5.79 (s, 0.16H), 4.67 (dd, J¼57.0, 18.0, 2H),
(m, 2H), 7.31 (d, J¼7.3 Hz, 1H), 7.21e7.05 (m, 4H), 6.94 (d,
J¼14.7 Hz), 6.10 (s, 0.87H), 5.67 (s, 0.13H), 4.65 (dd, J¼50.7,18.3, 2H),
3.67 (m, 1H), 2.73 (t, 1H), 1.81e1.57 (m, 6H), 1.38e1.00 (m, 10H). 13
C
3.67 (br, 1H), 2.07 (s, 3H), 1.82e1.58 (m, 4H), 1.39e1.09 (m, 6H). 13
C
NMR (CD3OD-d4)
d
: 182.95, 171.66, 139.95, 136.46, 135.84, 135.02,
NMR (CD3OD-d4)
d: 175.48, 171.83, 139.47, 136.59, 135.59, 134.85,
132.43, 129.45, 128.99, 127.98, 127.11, 65.90, 33.75, 33.08, 26.85,
129.52, 128.98, 128.59, 127.98, 127.20, 64.16, 51.30, 49.20, 33.75,
26.28, 20.18, 19.91. 11B NMR (CD3OD-d4)
d
: 28.58. HRMS (ESI,
26.86, 26.31, 22.76. 11B NMR (CD3OD-d4)
d: 27.75. HRMS (ESI, pos-
positive ion) (m/z): [MþH]þ, calcd for C25H33BN2O4, 437.2610;
itive ion) (m/z): [MþH]þ, calcd for C23H29BN2O4, 409.2197; found
found, 437.2623.
409.2300.

R.-C. Lian et al. / Tetrahedron 70 (2014) 1800e1804
1803
4.8. (4-(1-(N-Benzylpropionamido)-2-(cyclohexylamino)-2-
oxoethyl)phenyl)boronic acid (11)
(CD3OD-d4)
for C26H35BN2O4, 451.2766; found 451.2769.
d
: 28.07. HRMS (ESI, positive ion) (m/z): [MþH]þ, calcd
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (4-
formylphenyl)boronic acid (150 mg, 1.00 mmol), propanoic
acid (0.08 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 11 as the white solid (mp¼146 ꢀC) in
4.12. (4-(1-(N-Benzylcyclohexanecarboxamido)-2-(cyclo-
hexylamino)-2-oxoethyl)phenyl)boronic acid (15)
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (4-
formylphenyl)boronic acid (150 mg, 1.00 mmol), cyclohexane
carboxylic acid (0.14 mL, 1.10 mmol), and cyclohexylisocyanide
(0.14 mg; 1.10 mmol) giving compound 15 as a white solid
60% yield (303 mg); 1H NMR (CD3OD-d4)
d: 7.96 (br, OH), 7.60 (br,
1H), 7.44 (br, 1H), 7.26 (br, 2H), 7.69e7.62 (m, 5H), 6.12 (s, 0.87H),
5.71 (br, 0.13H), 4.66 (dd, J¼54.0,18.0, 2H), 3.64 (s, 1H), 2.41 (m, 1H),
2.28 (m, 1H), 1.96e1.59 (m, 5H), 1.35e1.06 (m, 8H). 13C NMR
(mp¼179 ꢀC) in 52% yield (300 mg); 1H NMR (CD3OD-d4)
d: 8.15 (br,
(CD3OD-d4) d: 178.43, 171.68, 138.57, 135.24, 134.77, 130.39, 129.48,
OH), 7.95 (br, OH), 7.61 (br, OH), 7.45 (br, OH), 7.23 (d, 2H), 7.13 (m,
5H), 6.94 (d, 2H), 6.12 (s, 0.78H), 5.72 (br, 0.22NH), 4.70 (dd, J¼66.9,
18.2, 2H), 3.65 (m, 1H), 2.46 (m, 1H), 1.82e0.98 (m, 20H). 13C NMR
127.98, 127.16. 11B NMR (CD3OD-d4)
d: 28.24. HRMS (ESI, positive
ion) (m/z): [MþH]þ, calcd for C24H31BN2O4, 423.2453; found
423.2465.
(CD3OD-d4) d: 139.98, 135.13, 130.18, 129.34, 127.92, 127.09, 61.55,
43.55, 33.57, 30.68, 26.92, 26.67, 26.10. 11B NMR (CD3OD-d4)
d:
28.33. HRMS (ESI, positive ion) (m/z): [MþH]þ, calcd for
4.9. (3-(1-(N-Benzylpropionamido)-2-(cyclohexylamino)-2-
oxoethyl)phenyl)boronic acid (12)
C28H37BN2O4, 477.2923; found 477.2917.
4.13. (3-(1-(N-Benzylcyclohexanecarboxamido)-2-(cyclo-
hexylamino)-2-oxoethyl)phenyl)boronic acid (16)
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (3-
formylphenyl)boronic acid (150 mg, 1.00 mmol), propanoic acid
(0.08 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 12 as a white solid (mp¼160 ꢀC) in
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (3-
formylphenyl)boronic acid (150 mg, 1.00 mmol), cyclohexane
carboxylic acid (0.14 mL,1.10 mmol), cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 16 as a white solid (mp¼114 ꢀC) in
79% yield (401 mg); 1H NMR (CD3OD-d4)
d: 7.93 (br, OH), 7.68e7.45
(m, OH), 7.30e7.12 (m, 6H), 6.89 (d, J¼6 Hz), 6.12 (s, 0.90H), 5.70 (br,
0.10H), 4.65 (dd, J¼54.0,18.0, 2H), 3.66 (s,1H), 2.44 (m,1H), 2.26 (m,
64% yield (380 mg); 1H NMR (CD3OD-d4)
d: 7.95 (br, OH), 7.69e7.44
1H), 1.82e1.58 (m, 5H), 1.39e1.40 (m, 8H). 13C NMR (CD3OD-d4)
d:
(m, OH), 7.29e7.04 (m, 7H), 6.92 (d, 2H), 6.12 (s, 0.78H), 5.74 (br,
0.22H), 4.42 (dd, J¼51.3, 10.7, 2H), 3.63 (m, 1H), 2.46 (m, 1H),
178.44, 171.88, 138.06, 135.74, 135.08, 132.94, 129.46, 128.94, 127.93,
127.15, 64.21, 33.73, 33.73, 28.49, 26.84, 26.29, 9.94. 11B NMR
1.82e0.98 (m, 20H). 13C NMR (CD3OD-d4)
d: 180.75, 171.73, 140.15,
(CD3OD-d4)
for C24H31BN2O4, 423.2453; found 423.2464.
d
: 27.92. HRMS (ESI, positive ion) (m/z): [MþH]þ, calcd
136.97, 135.95, 135.05, 132.82, 132.40, 129.48, 128.47, 127.56, 127.24.
11B NMR (CD3OD-d4)
d: 27.91. HRMS (ESI, positive ion) (m/z):
[MþH]þ, calcd for C28H37BN2O4, 476.2844; found 476.2852.
4.10. (4-(1-(N-Benzyl-3-methylbutanamido)-2-(cyclohexyl
amino)-2-oxoethyl)phenyl)boronic acid (13)
Conflict of interest
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.00 mmol), (4-
formylphenyl)boronic acid (150 mg, 1.00 mmol), isovalic acid
(0.12 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 13 as a white solid (mp¼144 ꢀC) in
The authors declare no conflict of interest.
Acknowledgements
89% yield (337 mg); 1H NMR (CD3OD-d4)
d: 7.98 (br, OH), 7.59 (br,
This research was supported by the National Science Council in
Taiwan (NSC-99-2113-032-002-MY2, NSC-101-2113-M-032-001-
MY2, NSC-102-2911-1-002-303, NSC-103-2911-1-002-303). We
thank Department of Chemistry of Tamkang University for the
equipment and financial support. We thank Ms. Shen-Shen Chen
for conducting 11B NMR experiments, we thank Shu-Li Chen for
conducting MTT experiments, and we thank Instrumentation
Center of National Taiwan University for conducting HRMS
experiments.
OH), 7.32 (d, 2H), 7.10 (m, 5H), 6.93 (m, 2H), 6.13 (s, 0.81H), 5.75 (br,
0.19H), 4.67 (dd, J¼57.5, 18.2, 2H), 3.64 (m, 1H), 2.34e2.10 (m, 3H),
1.81e1.57 (m, 6H), 1.34e1.07 (m, 4H), 0.96e0.84 (m, 6H). 13C NMR
(CD3OD-d4)
d: 176.95, 171.51, 139.65, 138.41, 135.08, 130.35, 129.41,
127.97, 127.22, 63.91, 50.62, 50.29, 44.06, 33.69, 27.08, 26.80, 26.23,
23.19. 11B NMR (CD3OD-d4)
d: 28.36. HRMS (ESI, positive ion) (m/z):
[MþH]þ, calcd for C26H35BN2O4, 451.2766; found 451.2771.
4.11. (3-(1-(N-Benzyl-3-methylbutanamido)-2-(cyclohexyl
amino)-2-oxoethyl)phenyl)boronic acid (14)
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.01.016.
Following the General Procedure, the desired compound was
synthesized utilizing benzylamine (0.12 mL, 1.10 mmol), (4-
formylphenyl)boronic acid (150 mg, 1.00 mmol), isovalic acid
(0.12 mL, 1.10 mmol), and cyclohexylisocyanide (0.14 mL,
1.10 mmol) giving compound 14 as a white solid (mp¼157 ꢀC) in
References and notes
80% yield (254 mg); 1H NMR (CD3OD-d4)
d: 7.69e7.44 (m, OH),
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€
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breast (MDA-MB231), and liver (HepG2) cancer cell lines were evaluated using
a microculture tetrazolium test (MTT, Sigma). Briefly, tumor cells or fibroblasts
(5000 cells in 100
m
L complete medium per well) were seeded into a 96-well
plate (Nunc, Denmark). After incubation at 37 ꢀC for 24 h, 100
mL of culture
medium with or without boron-containing analogs was added to each well in
triplicate for 48 h of consecutive incubation at 37 ꢀC. In the treatment of each
cell line, cells were incubated for another 24, 48, and 72 h. MTT solution 50
(Sigma) was added to each well. Following incubation at 37 ꢀC for an additional
4 h, supernatants were removed and 100 L DMSO was added to dissolve the
MTT-formazan product. The plate was read using a microplate reader (Labsys-
tems, Helsinki, Finland) at 550 nm. The cell inhibitions at 20, 10, 5, 2.5 g/mL of
mL
m
4. (a) Trigen Limited, US20080234228. (b) Trigen Limited, US20080287370. (c)
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m
boron-containing analogs were estimated and the IC50 for boron-containing
analogs calculated for the control group was set to 100% (Phillips et al., 1990).