Microwave-mediated synthesis of a cyclic heptapeptoid through consecutive Ugi reactions

Article abstract of DOI:10.1016/j.tet.2018.10.018

The combination of consecutive Isocyanide-based Multicomponent Reactions (IMCRs) allowed the synthesis of a cyclic heptapeptoid in a reduced number of steps. Herein, we describe this efficient approach using four consecutive Ugi reactions, being three Ugi

Full text of DOI:10.1016/j.tet.2018.10.018

Accepted Manuscript
Microwave-mediated synthesis of a cyclic heptapeptoid through consecutive Ugi
reactions
Angélica de Fátima S. Barreto, Carlos Kleber Z. Andrade
PII:
S0040-4020(18)31212-2
10.1016/j.tet.2018.10.018
TET 29851
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 August 2018
Revised Date: 6 October 2018
Accepted Date: 10 October 2018
Please cite this article as: Barreto AngéFáS, Andrade CKZ, Microwave-mediated synthesis of a cyclic
heptapeptoid through consecutive Ugi reactions, Tetrahedron (2018), doi: https://doi.org/10.1016/
j.tet.2018.10.018.
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ACCEPTED MANUSCRIPT
Graphical Abstract
O
(CH2O)n
H
N
N
O
OH
3 Consecutive
Ugi reactions
O
O
+
O
NHCbz
NC
O
O
O
MeO
HO
H
NH2
HN
N
NH2
MW-mediated
synthesis
N
N
O
Final Ugi
reaction
H
N
N
N
O
O
O
O
N
H
O
NH
O
O
O
N
N
N
H

ACCEPTED MANUSCRIPT
Microwave-mediated synthesis of a cyclic
heptapeptoid through consecutive Ugi Reactions
Angélica de Fátima S. Barreto and Carlos Kleber Z. Andrade
*
Laboratório de Química Metodológica e Orgânica Sintética, Instituto de Química,
Universidade de Brasília, 70910-970, Brasília-DF, Brazil.
Email: angelfsb@gmail.com
ckleber@unb.br
*Corresponding author
Abstract
The combination of consecutive Isocyanide-based Multicomponent Reactions
(IMCRs) allowed the synthesis of a cyclic heptapeptoid in a reduced number of
steps. Herein, we describe this efficient approach using four consecutive Ugi
reactions, being three Ugi four-center, four-component reactions, and one Ugi
four-center, three-component reaction. Our strategy involved eight steps of
which seven in a row were microwave-assisted with reaction times of 3-5
minutes and yields ranging from 88-98%.
1

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Keywords
Cyclic peptoids, consecutive Ugi reactions, Isocyanide-based Multicomponent
Reactions (IMCRs), microwave-mediated reactions, macroheterocycles.
1. Introduction
Natural products are an excellent source of new bioactive molecules [1,2,3].
Cyclic peptides occur naturally and exhibit diverse biological activities, such as
antitumor, antibacterial and immunosuppressive, among others, and usually
show better biological activities than linear peptides due to conformational
rigidity. Examples of cyclic peptide drugs are the natural antibiotic Vancomycin
and the neuropeptide Vasopressin. Figure 1 shows some structures of cyclic
peptides, including the heptapeptides Cupolamide A that is active against P388
murine leukemia cells (IC50 = 7.5 ꢀg/mL) [4], Axinellin A, which shows antitumor
activity against a human bronchopulmonary carcinoma (IC50 = 3.0 ꢀg/mL) [5],
and Argyrin B that is a potent inhibitor of T-cell independent antibody formation
[6], along with the octadepsipeptoid Verticilide, a potential insecticide with a
different mode of action since it acts by inhibiting the binding of ryanodine to
ryanodine receptors (RyR) [7,8]. Other important cyclic heptapeptides from
natural origin include Cateritins A and B [9], poly-proline Euryjanicins E−G [10],
Reniochalistatins A−E [11] and Stylissatins B–D [12], all of them isolated from
marine sponges.
2

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OSO3Na
H
O
HN
OH
N
N
HN
H
H
HO
N
O
N
O
N
O
O
Ph
HN
O
O
O
O
O
O
O
O
HN
NH
O
NH
H
HN
NH
NH2
N
NH2
O
HN
Ph
N
H
N
O
HO
Cupolamide A
Axinellin A
Me
S
H
N
O
N
N
O
N
O
O
O
O
HN
O
Me
O
O
N
O
NH
O
O
HN
O
N
Me
O
H
HN
N
O
O
N
H
OMe
O
O
O
N
Me
HN
Argyrin B
Verticilide
Figure 1. Examples of some bioactive cyclic peptides.
Oligomers of N-substituted glycine (peptoids) are versatile mimics of peptides
with several advantages such as proteolytic stability and increased cell
permeability [13,14]. These mimetics have the ability to link their natural targets
in the same way as the natural sequence of peptides [14,15,16]. Cyclic
peptoides [17,18,19] show several advantages over their acyclic counterparts
such as high conformational stability and resistance to degradation by the
action of proteases [20,21]. Furthermore, chirality is removed from the α-carbon
atom, so as their H-bonding donor ability [22]. Currently, the Ugi four-
component reaction (U-4CR) has proved to be a powerful synthetic strategy for
the preparation of a peptoid backbone [23,24,25]. The advantages of this
3

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versatile reaction include the use of commercial or readily available reagents,
the avoidance of usually expensive coupling agents for the amide bond
formation and the incredible variety of products that can be obtained by simply
modifying the structures of the starting materials. Indeed, several works in the
literature have shown that the combination of multicomponent reactions
produces a plethora of macroheterocycles in a reduced number of steps
[26,27,28,29].
In continuing our efforts in using consecutive multicomponent reactions to
efficiently obtain novel heterocycles [28,29,30,31,32], herein we describe a
concise and efficient strategy for the synthesis of a cyclic heptapeptoid that
possesses the core of the molecules represented in Figure 1 with the N-pentyl
side chains of Verticilide attached to three of its nitrogen atoms. Whereas
heptapeptoids have already been described [19,33], to the best of our
knowledge, there is only one previous example of a cyclic heptapeptoid in the
literature [34]. Furthermore, this is the first example in which four consecutive
Ugi reactions were employed in the synthesis of a particular molecule.
The retrosynthetic analysis (Scheme 1) shows that the target cyclic
heptapeptoid 1 can be synthesized by three consecutive Ugi four-center, four-
component
reactions
(Ugi-4CR),
followed
by
the
respective
deprotections/hydrolysis, forming an acyclic intermediate (amino acid 2) which
is then cyclized by an intramolecular Ugi four-center, three-component reaction
(Ugi-4C3CR). The use of methyl isocyanoacetate 6 as the isocyanide
component is a widely used strategy and allows the obtention of the carboxylic
acid component for the subsequent Ugi reactions [35]. Based on previous
experience within our research group [26,27,36,37,38], microwave heating was
4

ACCEPTED MANUSCRIPT
used in all steps of the synthesis except for the final cyclization step, which
greatly speeded up the methodology as will be further discussed.
Scheme 1. Retrosynthetic analysis for the synthesis of cyclic heptapeptoid 1.
2. Results and Discussions
The synthesis of compound 1 was initiated by an Ugi 4-component reaction (U-
4CR) between methyl isocyanoacetate 6, paraformaldehyde 5, pentylamine 8
and N-Cbz-glycine 7 in methanol (80 ºC, 3 min, MW) to obtain peptoid 9 in 88%
yield that was subjected to hydrolysis reaction with LiOH (60 ºC, 5 min,
THF/H2O, MW) followed by treatment with 2 mol/L NaHSO4 providing the
corresponding acid 4 in 98% yield (Scheme 2). Acid 4 was then employed in
another Ugi reaction using paraformaldehyde 5, pentylamine 8 and methyl
5

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isocyanoacetate 6 in methanol under the same conditions as the first Ugi
reaction affording the acyclic tetrapeptoid 10 in 88% yield. Basic hydrolysis as
described for compound 9 led to acid 3 in 90% yield.
(CH2O)n
O
O
O
O
5
H
N
NHCbz
NC
NHCbz
+
1. 80 ºC, 3 min, MW
MeOH, 88%
MeO
N
MeO
HO
7
6
O
NH2
9
8
LiOH, THF/H2O
60 ºC, 5 min, MW
2 mol/L NaHSO4
98%
O
O
H
N
O
O
O
H
N
H
N
NHCbz
N
NHCbz
HO
O
N
MeO
N
O
80 ºC, 3 min, MW
MeOH, 88%
O
O
4
10
+
(CH2O)n
NC
MeO
5
NH2
6
LiOH,
THF/H2O, MW
60 ºC, 5 min
8
2 mol/L NaHSO4
90%
O
O
O
H
N
H
N
NHCbz
N
HO
N
O
O
3
Scheme 2. Synthesis of acid 3.
Subsequent use of acid 3 in the Ugi reaction with the same components as
before (5, 6 and 8) provided the acyclic hexapeptoid 11 in 88% yield (Scheme
3). Ester hydrolysis using lithium hydroxide under microwave irradiation (60 ºC,
5 min, 93%) and removal of the Cbz protecting group with Pd/C (10%) and
6

ACCEPTED MANUSCRIPT
cyclohexene (80 ºC, 3 min, MeOH, MW) furnished the corresponding amino
acid 12 in 92% yield. Up to this point, the acyclic hexapeptoid 2 was remarkably
prepared in seven consecutive MW-mediated steps in a total reaction time of
only 27 minutes (purification times not included).
In the last step, 2 was subjected to cyclization via an Ugi four-center, three-
component reaction (head-to-tail macrocyclization of 2 using normal coupling
agents was not the goal of this work, although the yields are usually better)
[39,40,41]. Amino acid 2 was added under pseudo-high dilution conditions (in
an attempt to avoid oligomerization) to a suspension of paraformaldehyde 5 and
butyl isocyanide 12 in methanol to furnish cyclic heptapeptoid 1 in a non-
optimized yield of 12%. The observed low yield in this last step may appear
frustrating considering that all other steps were high-yielding but it cannot be
considered a surprise. Despite the difficulties we encountered in the purification
process, it is known that small linear peptides, especially from three to eight
amino acids are tough to cyclize due to oligomerization [42,43]. As usual, the
presence of rotamers complicated the spectroscopic analysis of the peptoids.
Nevertheless, all compounds were fully and unequivocally characterized by 1H-
and 13C-NMR spectra and HRMS.
7

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O
H
N
O
+
O
O
N
OMe
H
H
N
N
NHCbz
80 ºC, 3 min, MW
O
N
HO
N
O
O
O
MeOH, 88%
HN
O
H
O
N
NHCbz
N
N
10
O
O
11
NH2
O
NC
(CH2O)n
MeO
6
5
8
1. LiOH, THF/H2O,
60 ºC, 5 min, MW
2 mol/L NaHSO4, 93%
2. Pd/C (10%), cyclohexene
80 ºC, 3 min, MeOH, 92%
O
H
N
N
N
O
OH
NH
O
HN
N
O
O
O
O
O
NH
O
O
H
N
(CH2O)n
+ CN
O
HN
NH2
N
3
12
N
N
O
O
O
O
pseudo-high dilution
N
MeOH, rt, 5 days, 12%
2
N
H
1
Scheme 3. Final steps in the synthesis of the target cyclic heptapeptoid 1.
3. Conclusion
In conclusion, the strategy of consecutive isocyanide-based multicomponent
reactions employed herein allowed the fast and efficient obtention of a cyclic
heptapeptoid and may be used to access other compounds of this type. It offers
several advantages, such as easy access to macroheterocycles, simple
synthetic procedures, and high atom-economy, which coupled with microwave
irradiation is even more powerful allowing a fast synthesis of more complex
molecules. Furthermore, it may also allow the obtention of larger cyclic peptoids
by increasing the number of consecutive Ugi reactions.
4. Experimental Section
8

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4.1. General remarks
NMR spectra were recorded on a Varian Mercury Plus 300 spectrometer at 300
1
MHz for H and 75.46 MHz for 13C in the presence of TMS as an internal
standard. High-resolution ESI mass spectra were obtained on a Micro TOF-
Bruker Daltonics instrument. Reactions were performed on a CEM Co.,
Discover microwave reactor using sealed vessels, dynamic program,
temperature detection by internal fiber optic probe, simultaneous cooling, and
media stirring. TLC plates were revealed by treatment with a 10% solution of
phosphomolybdic acid in ethanol, followed by heating. Commercially available
reagents and solvents were analytical grade or were purified by standard
procedures prior to use.
4.2. Methyl N-(((benzyloxy)carbonyl)glycyl)-N-pentylglycylglycinate (9)
A sealed 10 mL glass tube containing a mixture of pentylamine (8, 0.044 g, 0.50
mmol), methanol (0.25 mL), anhydrous sodium sulfate (0.150 g),
paraformaldehyde (5, 0.015 g, 0.50 mmol), Cbz-glycine (7, 0.052 g, 0.25 mmol)
and methyl isocyanoacetate (6, 0.023 mL, 0.25 mmol) was introduced in the
cavity of a microwave reactor (CEM Co., Discover) and irradiated at 80 ºC for 3
min (ramp time: 98 s) under magnetic stirring. The residue was filtered,
concentrated in vacuum and purified by column chromatography (CH2Cl2→ 1%
MeOH/CH2Cl2) to yield peptoid 7 (0.090 g, 0.22 mmol, 88%) as a viscous yellow
oil.
Rf (4% MeOH/CH2Cl2)= 0.30
1H NMR (300 MHz, CDCl3, presence of rotamers): δ 7.37-7.29 (m, 5H, Ar), 6.89
(br t, J = 5.2 Hz, 1H), 5.82 (br t, J = 4.7 Hz, 1H), 5.12 and 5.09 (2s, 2H), 4.10 (d,
9

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J = 4.7 Hz, 2H), 4.05 (s, 2H), 3.98 (d, J = 5.3 Hz, 2H), 3.72 (s, 3H), 3.41 and
3.31 (2t, J = 7.6 and 7.9 Hz, 2H), 1.66-1.48 (m, 2H), 1.37-1.22 (m, 4H), 0.90 (t,
J = 6.7 Hz, 3H).
13C NMR (75.46 MHz, CDCl3, presence of rotamers): δ 170.1, 169.2, 168.9,
156.3, 136.2, 128.4, 128.1, 127.9, 66.9, 52.3, 50.1, 48.7, 42.3, 40.9, 28.7, 27.9,
22.3, 13.9.
HRMS (ESI): m/z: calc. for [M+H]+ C20H30N3O6: 408.2135; found: 408.2127.
4.3. N-(((Benzyloxy)carbonyl)glycyl)-N-pentylglycylglycine (9)
A sealed 10 mL glass tube containing a solution of peptoid 7 (0.442 mmol,
0.180 g) in THF/H2O (2:1, 6.6 mL) and LiOH (1.1 mmol, 0.026 g) at room
temperature was introduced in the cavity of a microwave reactor (CEM Co.,
Discover) and irradiated at 60 ºC for 5 min under magnetic stirring. The reaction
mixture was then acidified with a 2 M solution of NaHSO4 to pH 2 and extracted
twice with ethyl acetate (2 x 30 mL). The organic phase was dried over sodium
sulfate, filtered and concentrated to yield acid 9 (0.432 mmol, 0.170 g, 98%),
which was used without further purification.
1H NMR (300 MHz, CD3OD, presence of rotamers): δ 7.47-7.26 (m, 5H), 5.09
(s, 2H), 4.12-3.90 (m, 6H), 3.39-3.34 (m, 2H), 1.67-1.46 (m, 2H), 1.37-1.19 (m,
4H), 0.95-0.87 (m, 3H).
13C NMR (75.46 MHz, CD3OD, presence of rotamers): δ 173.0, 171.7, 171.2,
159.0, 138.0, 129.5, 129.0, 128.8, 67.8, 50.8, 49.5, 43.3, 41.8, 30.1, 28.9, 23.4,
14.4.
10

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HRMS (ESI): m/z: calc. for [M+Na]+ C19H27N3O6Na: 416.1798; found: 416.1810.
4.4. Methyl
N-N-(((benzyloxy)carbonyl)glycyl)-N-pentylglycylglycyl-N-
pentylglycylglycinate (10)
A sealed 10 mL glass tube containing a mixture of pentylamine (8, 0.052 g, 0.60
mmol), methanol (0.30 mL), anhydrous sodium sulfate (0.180 g),
paraformaldehyde (5, 0.018 g, 0.60 mmol), acid (9, 0.118 g, 0.30 mmol) and
methyl isocyanoacetate (6, 0.027 mL, 0.30 mmol) was introduced in the cavity
of a microwave reactor (CEM Co., Discover) and irradiated at 80 ºC for 3 min
(ramp time: 103 s) under magnetic stirring. The residue was filtered,
concentrated in vacuum and purified by column chromatography (CH2Cl2→ 3%
MeOH/CH2Cl2) to yield peptoid 10 (0.157 g, 0.266 mmol, 88%) as a viscous
yellow oil.
Rf (8% MeOH/CH2Cl2)= 0.25
1H NMR (300 MHz, CDCl3, presence of rotamers): δ 7.36-7.24 (m, 5H), 7.13 (br
t, J = 5.3 Hz, 1H), 5.93 (br t, J = 4.5 Hz, 1H), 5.11 and 5.08 (2s, 2H), 4.14-3.96
(m, 10H), 3.70 (s, 3H), 3.42-3.24 (m, 4H), 1.64-1.45 (m, 4H), 1.37-1.19 (m, 8H),
0.92-0.85 (m, 6H).
13C NMR (75.46 MHz, CDCl3, presence of rotamers): δ 170.2, 169.1, 168.9,
168.7, 168.3, 156.3, 136.3, 128.4, 128.0, 127.9, 66.8, 52.2, 49.9, 49.7, 49.6,
48.6, 47.8, 42.4, 40.9, 28.9, 28.7, 27.9, 27.9 (2C), 26.9, 26.8, 22.3, 13.9.
HRMS (ESI): m/z: calc. for [M+Na]+ C29H45N5O8Na: 614.3166; found: 614.3166.
11

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4.5. N-N-(((Benzyloxy)carbonyl)glycyl)-N-pentylglycylglycyl-N-
pentylglycylglycine (3)
A sealed 10 mL glass tube containing a solution of peptoid 10 (0.282 mmol,
0.167 g) in THF/H2O (2:1, 4.2 mL) and LiOH (0.71 mmol, 0.017 g) at room
temperature was introduced in the cavity of a microwave reactor (CEM Co.,
Discover) and irradiated at 60 ºC for 5 min under magnetic stirring. The reaction
mixture was then acidified with a 2 M solution of NaHSO4 to pH 2 and extracted
twice with ethyl acetate (4 x 30 mL). The organic phase was dried over sodium
sulfate, filtered and concentrated to yield acid 3 (0.255 mmol, 0.147 g, 90%),
which was used without further purification.
HRMS (ESI): m/z: calc. for [M+Na]+ C28H43N5O8Na: 600.3009; found: 600.3010.
4.6. Methyl
N-N-N-(((benzyloxy)carbonyl)glycyl)-N-pentylglycylglycyl-N-
pentylglycylglycyl-N-pentylglycylglycinate (12)
A sealed 10 mL glass tube containing a mixture of pentylamine (8, 0.044 g,
0.50 mmol), methanol (1.50 mL), anhydrous sodium sulfate (0.151 g),
paraformaldehyde (5, 0.015 g, 0.50 mmol), acid (3, 0.145 g, 0.25 mmol) and
methyl isocyanoacetate (6, 0.023 mL, 0.25 mmol) was introduced in the cavity
of a microwave reactor (CEM Co., Discover) and irradiated at 80 ºC for 3 min
(ramp time: 59 s) under magnetic stirring. The residue was filtered,
concentrated in vacuum and purified by column chromatography (CH2Cl2→ 4%
MeOH/CH2Cl2) to yield peptoid 12 (0.172 g, 0.222 mmol, 88%) as a viscous
brown oil.
Rf
(5% MeOH/CH
2
Cl )= 0.20
2
12

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1H NMR (300 MHz, CDCl3, presence of rotamers): δ 7.49 (br s, 1H), 7.43-7.28
(m, 6H), 6.04 and 5.96 (br 2s, 1H), 5.11 and 5.09 (2s, 2H), 4.18-3.95 (m, 14H),
3.70 (s, 3H), 3.43-3.24 (m, 6H), 1.66-1.39 (m, 6H), 1.37-1.21 (m, 12H), 0.92-
0.85 (m, 9H).
13C NMR (75.46 MHz, CDCl3, presence of rotamers): δ 169.2, 169.1 (2C), 169.0
(2C), 168.7 (2C), 156.4, 136.3, 128.4, 128.0, 127.9, 66.8, 52.2, 49.8, 49.6 (2C),
48.6, 48.5, 42.4, 41.1, 40.9, 28.9, 28.7, 27.9, 22.3 (2C), 13.9.
HRMS (ESI): m/z: calc. for [M+Na]+ C38H61N7O10Na: 798.4378; found:
798.4369.
4.7. N-N-N-Glycyl-N-pentylglycylglycyl-N-pentylglycylglycyl-N-
pentylglycylglycine (2)
A sealed 10 mL glass tube containing a solution of peptoid 12 (0.222 mmol,
0.172 g) in THF/H2O (2:1, 3.3 mL) and LiOH (0.55 mmol, 0.013 g) at room
temperature was introduced in the cavity of a microwave reactor (CEM Co.,
Discover) and irradiated at 60 ºC for 5 min under magnetic stirring. The reaction
mixture was then acidified with a 2 M solution of NaHSO4 to pH 2 and extracted
twice with ethyl acetate (4 x 30 mL). The organic phase was dried over sodium
sulfate, filtered and concentrated to yield acid 13 (0.206 mmol, 0.157 g, 93%),
which was used without further purification. A sealed 10 mL glass tube
containing a solution of acid 13 (0.126 mmol, 0.096 g) in methanol, cyclohexene
(1:1. 3.2 mL) and 10% Pd-C (0.0096 g) was introduced in the cavity of a
microwave reactor (CEM Co., Discover) and irradiated at 80 ºC for 3 min (ramp
time: 125 s, 150 W) under magnetic stirring. After filtration under Celite®, the
solvent was concentrated, and amino acid 2 (0.116 mmol, 0.073 g) was
13

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obtained in 92% yield and was used in the subsequent reaction without prior
purification.
HRMS (ESI): m/z: calc. for [M+Na]+ C29H53N7O8Na: 650.3853; found: 650.3872.
4.8. N-Butyl-2-(2,5,8,11,14,17,20-heptaoxo-7,13,19-tripentyl-
1,4,7,10,13,16,19-heptaazacyclohenicosan-1-yl)acetamide (1)
A solution of the amino acid 2 (0.143 mmol, 0.090 g) in 60 mL of methanol at
room temperature was added via a syringe pump to a solution of
paraformaldehyde (5, 0.143 mmol, 0.004 g), anhydrous sodium sulfate (2.25 g),
butyl isocyanide (14, 0.572 mmol, 0.060 mL) in methanol (200 mL) at a rate of
0.6 mL/h (addition time: 100 h). After the addition was complete (~ 4 days), the
reaction mixture was stirred for further 24 h, filtered and concentrated under
vacuum. The cyclic heptapeptoid 1 (0.071 mmol, 0.051 g) was purified by
preparative TLC plate (CH2Cl2/MeOH 5% [2x]) to furnish the pure product
(0.008 mmol, 0.006 g) in 12% yield.
1H NMR (300 MHz, CDCl3, presence of rotamers): δ 7.94 (br s, 2H), 4.23-3.63
(m, 16H), 3.41-3.15 (m, 8H), 1.73-1.41 (m, 8H), 1.39-1.18 (m, 14H), 0.96-0.77
(m, 12H).
HRMS (ESI): m/z: calc. for [M+Na]+ C35H62N8O8Na: 745.4588; found: 745.4593.
Acknowledgments
14

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The authors thank the Instituto de Química, Universidade de Brasília and CNPq
for financial support.
Appendix A. Supplementary data
Detailed experimental procedures, NMR and mass spectra of all compounds.
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