Fast and Facile Synthesis of 4-Nitrophenyl 2-Azidoethylcarbamate Derivatives from N-Fmoc-Protected α-Amino Acids as Activated Building Blocks for Urea Moiety-Containing Compound Library

Article abstract of DOI:10.1021/acscombsci.6b00160

A fast and facile synthesis of a series of 4-nitrophenyl 2-azidoethylcarbamate derivatives as activated urea building blocks was developed. The N-Fmoc-protected 2-aminoethyl mesylates derived from various commercially available N-Fmoc-protected α-amino ac

Full text of DOI:10.1021/acscombsci.6b00160

Technology Note
pubs.acs.org/acscombsci
Fast and Facile Synthesis of 4‑Nitrophenyl 2‑Azidoethylcarbamate
Derivatives from N‑Fmoc-Protected α‑Amino Acids as Activated
Building Blocks for Urea Moiety-Containing Compound Library
Ying-Ying Chen,† Li-Te Chang,† Hung-Wei Chen,† Chia-Ying Yang,† and Ling-Wei Hsin*,†,‡,§
‡
§
†School of Pharmacy, College of Medicine, Molecular Probes Development Core, Molecular Imaging Center, and Center for
Innovative Therapeutics Discovery, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan
S
* Supporting Information
ABSTRACT: A fast and facile synthesis of a series of 4-nitrophenyl 2-azidoethylcarbamate derivatives as activated urea building
blocks was developed. The N-Fmoc-protected 2-aminoethyl mesylates derived from various commercially available N-Fmoc-
protected α-amino acids, including those having functionalized side chains with acid-labile protective groups, were directly
transformed into 4-nitrophenyl 2-azidoethylcarbamate derivatives in 1 h via a one-pot two-step reaction. These urea building
blocks were utilized for the preparation of a series of urea moiety-containing mitoxantrone-amino acid conjugates in 75−92%
yields and parallel solution-phase synthesis of a urea compound library consisted of 30 members in 38−70% total yields.
KEYWORDS: urea building block, one-pot synthesis, parallel synthesis, amino acid, microwave-assisted
methodology,10 the handling of highly toxic chemicals, such as
he urea functionality exists in a variety of biologically
Tactive compounds, and is an essential component in many azidic acid and triphosgene, and the harsh reaction conditions,
such as 60% N2H4·H2O in DMF to remove the phthaloyl
group, were avoided. In addition, those azido-substituted urea
monomers are versatile, which can serve as precursors to
amines and participate in the click reaction, Staudinger ligation,
and Curtius rearrangement, lending themselves to various
combinatorial libraries.
A series of mitoxantrone-amino acid conjugates (MAC)
demonstrated more potent anticancer activity and lower drug
resistance than mitoxantrone, which has been used in clinic for
many years (Figure 1).18−20 As a continued effort to develop
novel anticancer agents with higher metabolic stability, a
focused urea moiety-containing library, urea-MAC was
designed (Figure 1). To increase the diversity, the Schultz’s
urea monomers derived from various α-amino acids including
those with functional side chains protected by acid-labile
protective groups were chosen as the building blocks for the
construction of urea-MAC library.
clinically useful drugs with various indications, such as
anticancer,1 antiviral,2 antibacterial,3 antiepileptic,4 neuroleptic,5
antiarrhythmic,6 etc., approved by U.S. FDA in last two
decades. Incorporation of the urea group into peptides as a
bioisosteric replacement for the amide group provided
oligoureas as unnatural biopolymers with different physico-
chemical and biological activity from the natural peptides. For
example, an oligourea derived from HIV-1 Tat protein was
resistant to proteinase K degradation and retained the high
affinity and selectivity to the trans-activation responsive region
(TAR) RNA.7
Several synthetic approaches provide activated urea building
blocks derived from α-amino acids for the preparation of N,N′-
linked oligoureas. Burgess and co-workers first demonstrated
the synthesis of N-phthalimide-protected isocyanates in situ
with phosgene as urea monomers for the solid-phase synthesis
of oligoureas.8,9 Later, Schultz et al. described a series of 4-
nitrophenyl 2-azidoethylcarbamates prepared from either N-
Boc- or N-2-(trimethylsilyl)ethoxycarbonyl (Teoc)-protected
α-amino acids as urea monomers.10 Liskamp and co-workers
developed methods for the preparation of N-Boc- and N-Fmoc-
protected 4-nitrophenyl carbamates as urea monomers from the
corresponding N-Boc- and N-Fmoc-protected α-amino
acids.11,12 Guichard et al. described the synthesis of N-Boc-
and N-Fmoc-protected O-succinimidyl-carbamates as activated
urea building blocks from the corresponding N-Boc- and N-
Fmoc-protected α- and β-amino acids.13−17 In the Schultz’s
Based on previous structure−activity relationships of MAC,
the urea building blocks derived from the arginine, lysine, and
tyrosine are the most promising members in the focused
library. Therefore, N-Teoc-protected α-amino acid derivatives
are needed for the synthesis of these urea monomers with acid-
labile side-chain protective groups in Schultz’s methodology.
Received: October 20, 2016
Revised: December 27, 2016
Published: January 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.6b00160
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ACS Combinatorial Science
Technology Note
Figure 1. Structures of mitoxantrone-amino acid conjugate (MAC).
Scheme 1. Synthesis of 4-Nitrophenyl 2-Azidoethylcarbamates 4 and Urea-MAC 5
The necessity of additional protection and deprotection steps
for the N-Teoc protective group resulted in tedious purification
processes and difficulties to prepare the activated urea building
blocks in parallel way. In addition, the isolation and purification
of highly polar, water-soluble, and volatile low-molecular weight
azido amine intermediates (i.e., 3a−c and 3e) were trouble-
some. Thus, here we report a concise, fast, and feasible
methodology for parallel synthesis of various 4-nitrophenyl 2-
azidoethylcarbamate derivatives 4 as activated urea building
blocks via a one-pot, two-step synthesis from the N-Fmoc-
protected amino mesylates 2. Utilization of these activated urea
building blocks 4 for the preparation of urea-MAC 5 and a
urea-moiety containing compound library 7-9 by parallel
solution-phase synthesis was demonstrated.
The N-Fmoc-protected amino alcohols 1a−j were prepared
using the corresponding N-Fmoc-protected α-amino acids by a
method described by Rodriguez et al.21 Alcohols 1a−j were
obtained as solids in high yields and directly used without
further purification for the following steps. Treatment of the
crude alcohols 1a−j with methanesulfonyl chloride provided
the N-Fmoc-protected amino mesylates 2a−j in high yields and
purity as shown in Scheme 1.22
Teoc-protected amino mesylates using NaN3 followed by
deprotection reactions. We envisioned that if the N-Fmoc-
protected amino mesylates 2a−j were used in the same reaction
condition, the Fmoc-protective group could be removed
simultaneously by the excess amount of NaN3 in the
nucleophilic reaction condition, and therefore the instability
of the Fmoc group can be utilized to shorten the route for the
preparation of urea building blocks. The model study was
conducted by treatment of compound 2d with 5 eq of NaN3 in
DMF at 60−70 °C for 8 h. The reaction provided a complicate
mixture containing the desired product 3d, but the yield was
low and time-consuming column chromatography was
necessary to obtain 3d in high purity. In addition, the high
polarity and water solubility of azido amines 3 and the high
volatility of low-molecular weight azido amines (i.e., 3a−c, and
3e) significantly increased the difficulty in purification and
resulted in lower yields.
The large excess amount of NaN3 and the long reaction time
were responsible for the undesired intramolecular cyclization,
decomposition, and rearrangement. In Govindaraju’s study, N-
Boc- and N-Cbz-protected amino azides were synthesized from
corresponding mesylates in the presence of 1.5−2.0 equiv of
NaN3 in 2−12 min using microwave-assisted heating, in which
both the reaction time and the amount of NaN3 used were
In original Schultz’s methodology, the (2-azidoethyl)amines
3 were prepared via nucleophilic substitution of N-Boc- or N-
B
DOI: 10.1021/acscombsci.6b00160
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ACS Combinatorial Science
Technology Note
substantially reduced in comparison with conventional
heating.23 Moreover, if only a stoichiometric amount of NaN3
is used, then the potential interaction between the excess NaN3
and 4-nitrophenyl chloroformate, which is the reagent used in
the following reaction step, would be prevented. Therefore, the
tedious and time-consuming isolation and purification steps for
azido amines 3 may be eliminated and the 4-nitrophenyl 2-
azidoethylcarbamate derivatives 4 can be obtained directly from
the N-Fmoc-protected mesylates 2 by this one-pot two-step
synthesis strategy.
Table 2. Structures, Melting Points, and Yields of Urea-MAC
5
Amino mesylate 2d was used to explore the reaction
parameters for the microwave-assisted nucleophilic substitution
(Table 1). Initially, a mixture of NaN3 (1.5 equiv) and 2d (0.1
a
Table 1. Microwave-Assisted Heating Reaction Conditions
entry
NaN3 (equiv)
temp (°C)
time (min)
results
1
2
3
4
5
6
1.5
1.5
1.3
1.2
1.2
1.1
80
100
100
100
120
100
20
10
20
30
10
40
complete reaction
complete reaction
complete reaction
complete reaction
bad mixture
complete reaction
a
A solution of 2d (0.1 M, 3 mL) in anhydrous DMF in a sealed tube
was used.
M) in DMF (3 mL) was heated in a sealed heavy-duty glass
tube using microwave synthesizer at 80 °C for 20 min (entry
1). The reaction was complete and only the azido amine 3d and
the dibenzofulvene derivatives were observed by TLC
monitoring. When the reaction temperature increased to 100
°C, the reaction was finished in 10 min (entry 2). When the
amount of NaN3 was reduced, the rate of reaction was
significantly decreased. Using 1.3 equiv and 1.2 equiv of NaN3
at 100 °C, the reaction was complete in 20 and 30 min,
respectively (entries 3 and 4). Attempt to further accelerate the
reaction by increasing the reaction temperature to 120 °C
resulted in unknown products (entry 5). When the amount of
NaN3 was reduced to 1.1 equiv, 40 min at 100 °C was needed
for complete reaction (entry 6).
Therefore, the N-Fmoc-protected amino mesylates 2a−j and
1.3 equiv of NaN3 were heated at 100 °C using microwave for
30 min and then cooled in an ice bath. A solution of 4-
nitrophenyl chloroformate (1.6 equiv) in CH2Cl2 and pyridine
(1.8 equiv) were added to the cooled reaction mixture
containing the azido amine intermediates 3a−j and then the
solution was stirred at room temperature for 30 min to obtain
4-nitrophenyl 2-azidoethylcarbamates 4a−j (Scheme 1). The
yields were acceptable for our need, and therefore no attempt
was made to optimize the chemical yields for individual
product. Carbamates 4a−j were afforded as white to pale-
yellow solids which are stable for months when stored in the
refrigerator. Treatment of anthraquinone 6 with the activated
urea building blocks 4 at room temperature in the presence of
N,N-diisopropylethylamine yielded the urea-MAC 5 in the
yields of 75−92% (Table 2). The cytotoxicity of urea-MAC 5
against different human cancer cell lines is currently under
investigation and will be published in due course.
a
Isolated yields.
of a variety of 4-nitrophenyl 2-azidoethylcarbamates by only
three reaction steps from N-Fmoc-protected α-amino acids.
Furthermore, this methodology is efficient and economic, since
it significantly diminished the tedious purification processes,
which were necessary in the previous methods.
Previously, carbamates 4 have been used for the preparation
of oligoureas by solid-phase synthesis.7,10 In this study, the
parallel synthesis of a urea-moiety containing compound library
using activated monomers 4 via solution-phase strategy was
investigated as shown in Scheme 2. Treatment of carbamates 4
with linear or cyclic amines at room temperature obtained azido
ureas 7 in quantitative yields. In previous solid-phase synthesis
of oligoureas, SnCl2 was used for reduction of azido groups.
However, it is not convenient to remove the Sn-related
substances after reduction reaction in parallel solution-phase
synthesis as in the solid-phase synthesis. Therefore, catalytic
hydrogenation of compounds 7 using Pd/C under atmospheric
hydrogen provided amino ureas 8, which were then coupled
with acyl chlorides at 0 °C to afford amido ureas 9 in 38−70%
total yields. The crude products 7 and 8 were used directly for
the following reactions without purification. Only compounds 9
were isolated to determine the total yields of these reactions.
Most reactions produced the expected compounds as the major
products except the benzoylation reaction of compound 8a,
which gave dibenzoyl-substituted imide 9b as the major
product.
In summary, a fast and facile synthesis of various 4-
nitrophenyl 2-azidoethylcarbamate derivatives 4 as activated
urea building blocks from the commercially available N-Fmoc-
protected α-amino acids including those having functionalized
side chains was demonstrated. The key reaction was a one-pot
two-step reaction which provided the desired urea building
blocks 4 starting from the N-Fmoc-protected amino mesylates
2 in 1 h with acceptable yields. The utility of these urea building
In comparison to the N-Boc- and N-Teoc-protected
strategies, in which five and seven reaction steps, respectively
were needed to prepare 4-nitrophenyl 2-azidoethylcarbamates 4
from commercially available protected α-amino acids, this N-
Fmoc-protected one-pot strategy enabled the parallel synthesis
C
DOI: 10.1021/acscombsci.6b00160
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ACS Combinatorial Science
Technology Note
Scheme 2. Solution-Phase Parallel Synthesis of Ureas 7−9
Table 3. Structures and Yields of Urea Compound Library
single mode cavity Discover Microwave Synthesizer (CEM
Corporation, P.O. Box 200, Matthews, NC 28106, USA),
producing continuous irradiation at 2.45 GHz. The reaction
temperature was measured and feedback controlled with an
Infrared device under the reaction vessel.
General Procedure for the Preparation of N-Fmoc-
Protected Amino Mesylates 2. To a stirred solution of N-
Fmoc-protected amino alcohol (2.0 mmol) and Et3N (0.36 mL,
2.6 mmol) in THF (10 mL) was added methanesulfonyl
chloride (MsCl, 0.20 mL, 2.6 mmol) dropwise at 0 °C. After it
was stirred for 30 min at room temperature, the reaction
mixture was filtered, and then the filtrate was evaporated. The
residue was purified by flash column chromatography to afford
N-Fmoc-protected amino mesylate. Mesylates 2a−2d are
known compounds and were prepared according to the
literature procedures.22
General Procedure for the Microwave-Assisted One-
Pot Synthesis of 1-Azidoalkyl 4-Nitrophenyl Carba-
mates 4. A mixture of N-Fmoc-protected amino mesylate
(0.50 mmol) and sodium azide (42.3 mg, 0.65 mmol) in DMF
(5 mL) was heated by microwave (ramp time = 1 min, hold
time = 30 min, temperature = 100 °C). The reaction mixture
was cooled in an ice bath and then was added a solution of 4-
nitrophenyl chloroformate (161 mg, 0.80 mmol) in CH2Cl2 (5
mL) followed by pyridine (70 μL, 0.90 mmol). The mixture
was stirred at rt for 30 min and then diluted with diethyl ether
(50 mL). The solution was washed with 1 N KHSO4, water,
and brine. The organic layer was dried (MgSO4), filtered, and
evaporated. The residue was purified by flash column
chromatography to afford 4-nitrophenyl (2-azidoethyl)-
carbamate 4.
General Procedure for the Preparation of 1,4-Bis-
[(azidoalkyl)ureido]anthracene-9,10-diones 5. To a sol-
ution of diamine 6 (24.9 mg, 0.070 mmol) in 10% DMF/
CH2Cl2 (4 mL) was added a solution of urea monomer 4f (60
mg, 0.18 mmol) in 10% DMF/CH2Cl2 (1 mL) at room
temperature. DIPEA (60 μL, 0.34 mmol) was added dropwise
to the mixture, and stirred for 3 h. The resulting solution was
diluted with CH2Cl2 (30 mL) and then washed with 10%
NH4OH(aq) (6 × 30 mL). The organic fraction was evaporated,
and then treated with diethyl ether. The precipitate was
collected by filtration to afford 5f (38.3 mg, 75%) as a blue
solid.
General Procedure for the Parallel Synthesis of Azido
Urea 7. To a solution of urea monomer 4 (1.00 mmol) in 10%
DMF/CH2Cl2 (4 mL) was added n-butylamine or piperidine
(5.00 mmol) at room temperature and stirred for 16 h. After
evaporation, the residue was dissolved in 2-propanol/CHCl3
(1/9; 30 mL), washed with a mixture of water (20 mL) and 10
N NaOH (0.3 mL), followed by brine (20 mL), and evaporated
to afford the crude azido urea 7 in quantitative yield, which was
used in the following reaction without further purification. The
ab
,
compd
R1
R
R2
N3
total yield (%)
c
7a
7b
7c
7d
7e
7f
BuNH
M
M
P
>99
piperidinyl
BuNH
N3
ND
N3
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
piperidinyl
BuNH
P
N3
A
A
L
N3
piperidinyl
BuNH
N3
7g
7h
8a
8b
8c
8d
8e
8f
N3
piperidinyl
BuNH
L
N3
M
M
P
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
AcNH
Bz2N
BzNH
BsNH
BzNH
BsNH
BzNH
AcNH
BzNH
BzNH
BzNH
BsNH
BzNH
BsNH
piperidinyl
BuNH
piperidinyl
BuNH
P
A
A
L
piperidinyl
BuNH
8g
8h
9a
9b
9c
9d
9e
9f
piperidinyl
BuNH
L
M
M
M
M
P
66
38
BuNH
piperidinyl
piperidinyl
BuNH
66
c
>99
70
BuNH
P
70
9g
9h
9i
piperidinyl
BuNH
P
44
A
A
A
L
56
c
BuNH
>99
78
9j
piperidinyl
BuNH
9k
9l
58
BuNH
L
63
9m
9n
piperidinyl
piperidinyl
L
64
L
46
b
a
ND: Not determined. Bz: Benzoyl. Bs: Benzenesulfonyl. Isolated
c
yield. Crude yield.
blocks was demonstrated by the efficient preparation of a series
of urea-MAC 5 under mild reaction conditions, and the parallel
synthesis of a urea-moiety containing library consisted of 30
compounds in solution-phase. Thus, these methods are
practical and could be suitable for the construction of various
compound libraries for medicinal and combinatorial chemistry
purposes.
EXPERIMENTAL PROCEDURES
■
Microwave Experimental Procedure. The reactions
under microwave irradiation were conducted in sealed heavy-
walled Pyrex tubes. Microwave heating was carried out with a
D
DOI: 10.1021/acscombsci.6b00160
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ACS Combinatorial Science
Technology Note
1H NMR spectrum of crude 7a is shown in Figure 43
(Supporting Information), as a representative.
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General Procedure for the Parallel Synthesis of
Amino Urea 8. A mixture of azido urea 7 (1.00 mmol) and
10% Pd/C (50 mg) in 20% HOAc/MeOH (3 mL) was stirred
at room temperature under H2 (1 atm) for 3 h. The reaction
mixture was filtered and evaporated. The residue was dissolved
in CH2Cl2 (25 mL), and then anhydrous K2CO3 was added and
stirred for 10 min to remove the trace of HOAc. The mixture
was filtered and evaporated to obtain the crude amino urea 8,
which was used in the following reaction without further
purification. Analytical samples of amino urea 8 were obtained
by column chromatography using a solution of NH4OH/
MeOH/CH2Cl2 (1/9/90).
General Procedure for the Parallel Synthesis of
Amido Urea 9. A mixture of amino urea 8 (0.50 mmol)
and Et3N (0.75 mmol) in CH2Cl2 (3 mL) was cooled to 0 °C
under N2. Acyl chloride (0.55 mmol) in CH2Cl2 (0.5 mL) was
added and stirred at 0 °C for 30 min. The resulting mixture was
diluted with CH2Cl2 (25 mL), washed with 1 N HCl (20 mL ×
2), 1 N NaOH (20 mL), and brine (20 mL), dried with
MgSO4, filtered, and evaporated to yield the crude amido urea
9. Pure amido urea 9 was afforded by flash column
chromatography using EtOAc and n-hexane (1:1).
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ASSOCIATED CONTENT
* Supporting Information
■
(7) Tamilarasu, N.; Huq, I.; Rana, T. M. High affinity and specific
binding of HIV-1 TAR RNA by a Tat-derived oligourea. J. Am. Chem.
Soc. 1999, 121, 1597−1598.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00160.
(8) Burgess, K.; Linthicum, D. S.; Shin, H. Solid-phase syntheses of
unnatural biopolymers containing repeating urea units. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 907−909.
1
Detailed experimental procedures, the H and 13C NMR
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Shitangkoon, A.; Totani, R.; Zhang, A. J. Solid phase syntheses of
oligoureas. J. Am. Chem. Soc. 1997, 119, 1556−1564.
spectra, and HRMS data for compounds 2e−j, 4a−j, 5,
and 7−9 (PDF)
(10) Kim, J.-M.; Bi, Y.; Paikoff, S. J.; Schultz, P. G. The solid phase
synthesis of oligoureas. Tetrahedron Lett. 1996, 37, 5305−5308.
(11) Boeijen, A.; Liskamp, R. M. J. Solid-phase synthesis of oligourea
peptidomimetics. Eur. J. Org. Chem. 1999, 1999, 2127−2135.
(12) Boeijen, A.; van Ameijde, J.; Liskamp, R. M. J. Solid-phase
synthesis of oligourea peptidomimetics employing the Fmoc
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P.; Rodriguez, M. Effective preparation of O-succinimidyl-2(tert-
butoxycarbonylamino) ethylcarbamate derivatives from beta-amino
acids. Application to the synthesis of urea-containing pseudopeptides
and oligoureas. J. Org. Chem. 1999, 64, 8702−8705.
(14) Guichard, G.; Semetey, V.; Rodriguez, M.; Briand, J.-P. Solid
phase synthesis of oligoureas using O-succinimidyl-(9H-fluoren-9-
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(15) Hemmerlin, C.; Marraud, M.; Rognan, D.; Graff, R.; Semetey,
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AUTHOR INFORMATION
Corresponding Author
*Tel.: +886-2-3366-8696. Fax: +886-2-2351-2086. E-mail:
lwhsin@ntu.edu.tw.
■
ORCID
Ling-Wei Hsin: 0000-0001-5018-4491
Author Contributions
L.-W.H. conceived and designed the experiments and wrote the
manuscript and Supporting Information. Y.-Y.C., L.-T.C., H.-
W.C., and C.-Y.Y. performed the experiments.
Funding
This research was supported by the Ministry of Science and
Technology of the Republic of China (Grant No. MOST 103-
2320-B-002-012-MY3) and National Taiwan University (Grant
No. 101R7614-1, 102R7614-1, and 103R7614-1).
Notes
The authors declare no competing financial interest.
(16) Aisenbrey, C.; Pendem, N.; Guichard, G.; Bechinger, B. Solid
state NMR studies of oligourea foldamers: interaction of N-15-labelled
amphiphilic helices with oriented lipid membranes. Org. Biomol. Chem.
2012, 10, 1440−1447.
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