Solid-phase synthesis of (ω-Aminoalkyl)peptoids using azide chemistry

Article abstract of DOI:10.1055/s-0029-1219925

Functionalized (ω-aminoalkyl)peptoids - useful molecular transporters for drugs and probes into cells - have been synthesized by a combined microwave-assisted sub-monomer peptoid synthesis with 1-amino ω- azidoalkanes and a subsequent reduction of the azide moiety on solid supports. This method enables the preparation of unprecedented chiral amino-functionalized and PEG-type peptoids. Both the scope and limitations of this process are presented herein. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219925

1544
LETTER
Solid-Phase Synthesis of (w-Aminoalkyl)peptoids Using Azide Chemistry
Solid-Phase
Synth
a
esis of
(
w
-A
n
minoalkyl)p
i
eptoidsel Fritz, Stefan Bräse*
Karlsruhe Institute of Technology, Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@kit.edu
Received 7 March 2010
alkane 3a is commercially available, it can easily be pre-
Abstract: Functionalized (w-aminoalkyl)peptoids – useful molecu-
lar transporters for drugs and probes into cells – have been synthe-
sized by a combined microwave-assisted sub-monomer peptoid
synthesis with 1-amino-w-azidoalkanes and a subsequent reduction
pared by selective Staudinger reduction of 1,6-
diazidohexane prepared in situ (46% overall yield).12 Oth-
er amino azides 3b–d were synthesized similarly. The
of the azide moiety on solid supports. This method enables the prep- chiral aminoazides 3b and 3c were prepared through a se-
aration of unprecedented chiral amino-functionalized and PEG-type
quence of the Sonogashira coupling of enantiomerically
peptoids. Both the scope and limitations of this process are present-
ed herein.
pure 3-bromophenylethylamine (obtained from BASF)
with 5-chloro-1-pentyne (9), subsequent optional reduc-
tion of the alkyne function, substitution of the chloride,
and protecting group chemistry (54–55% overall yields).
Key words: peptoid, amines, azides, peptidomimetic transporters,
solid-phase synthesis, microwave synthesis, protecting groups
The PEG-type azide15 3d was prepared from triethylene
glycol 10 via tosylation, double nucleophilic displace-
Peptoids – oligo(N-substituted glycines) – belong to an
ment with sodium azide and subsequent mono-Staudinger
emerging class of functionalized peptidomimetics.1 Pio-
reduction (22% overall yield). The aminoazides 3a–d are
neered by the Zuckermann group,2 the Bradley group,3
stable molecules that can be stored at 0 °C over a pro-
our group4 and others, it has been demonstrated that (w-
longed period of time.
aminoalkyl)peptoids are useful carriers for drugs and
probes into cells.5,6 Functionalized peptoids are often pre-
pared through classical peptide-like synthesis. Thus, a so-
called sub-monomer method7 is more easily accessible,
since the synthesis of the building blocks delivers the sub-
monomers in fewer overall steps. In this manuscript, we
exploit the sub-monomer method with 1-amino-w-
azidoalkanes (see safety note8), followed by the reduction
of the azide moieties on the bead (Scheme 1).9
With the aminoazides 3a–d in hand, various peptoids
4{a}2, 4{b}3, 4{c}3, 4{d}1, 4{d}6 were assembled using the
microwave-assisted protocol described by Gorske et
al.:16b Rink-amide resin 1 (loading: 0.63 mmol/g), acyla-
tion with bromoacetic acid [N,N¢-diisopropylcarbodi-
imide, N,N-dimethylformamide (DMF), MW] and
subsequent amination with the amines 3a–d (DMF,
MW).1,6 Microwave irradiation was used to accelerate the
heating and reaction times and thus to improve the cou-
pling efficiency of the more hindered a-branched amines
3b and 3c.16 This sequence was repeated until the desired
backbone length was reached. The efficiency of the cou-
pling was monitored through cleavage of the azidopep-
toids 4{x}n directly from the solid supports and
subsequent analysis by MALDI-TOF mass-spectrometry.
The use of azides in peptoid chemistry has been exten-
sively demonstrated by the Kirshenbaum group10 and,
more recently, by Kodadek et al.11 Despite the fact that re-
duction of azides into amines is well established in the lit-
erature,9 to the best of our knowledge the conversion into
amines has not been performed for the synthesis of pep-
toids.
In our case, Staudinger reduction conditions9 [a) 1–2 M
R3P, THF, 3 h; b) H2O–THF (1:8), r.t., 60 min] for the
The syntheses of the different 1-amino-w-azidoalkanes
3a–d are outlined in Scheme 2. Although 1-amino-6-azido-
N3
NH2
O
H2N
N3
O
O
O
R
N
1) functionalization
2) reduction
3) cleavage
R
N
R
Br
Br
NH2
3a–d
HO
HN
HN
H
H2N
FG
n
n
DMF,
MW, 60 °C,
10 min
DIC, DMF,
MW, 35 °C,
30 s
(ω-aminoalkyl)peptoid
FG = H: 5{x}n
4{a}n
1
2
FG = rhodaminyl + spacer: 6{x}n
4{b}n
4{c}n
4{d}n
repeat n–1 times
Scheme 1 Generic synthesis of aminoalkylpeptoids 5{x}n and 6{x}n (MW = microwave); for details, see Scheme 2
SYNLETT 2010, No. 10, pp 1544–1548
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219925; Art ID: G08110ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Solid-Phase Synthesis of (w-Aminoalkyl)peptoids
1545
Table 1 Reduction of Azido Peptoids 4{a}1{a¢-Boc}1 as Shown in
1) NaN3, DMF
2) 5% HCl, EtOAc, Et2O,
Ph3P, 0 °C to r.t.
Scheme 4
NH2
3a
N3
Br
Br
6
6
Entry Reduction conditions
Temp Time Com-
46%
(°C)
(h)
menta
7
NH2
1
2
a) Bu3P, THF
b) H2O–THF (1:8)
r.t.
r.t.
3
0.5
Cl
A
NHBoc
9
1) (Ph3P)4Pd, CuI,
a) Bu3P, THF
b) H2O–THF (1:8), MW
r.t.
60
3
0.5
i-Pr2NH, THF, 80 °C
2) NaN3, DMF, 60 °C
3) 95% TFA–H2O, r.t.
A
3
a) Ph3P, THF
b) H2O–THF (1:8)
r.t.
r.t.
3
0.5
Br
55%
A
8
3b
N3
4
a) Ph3P, THF
b) H2O–THF (1:8), MW
r.t.
60
3
0.5
A
NH2
Cl
5
a) Bu3P, THF
b) H2O–THF (1:8)
r.t.
r.t.
4
12
9
A
NHBoc
1) (Ph3P)4Pd, CuI,
i-Pr2NH, THF, 80 °C
2) H2, Pd/C 5%, EtOAc, r.t.
3) NaN3, DMF, 60 °C
4) 95% TFA–H2O, r.t.
6
a) Bu3P, THF
b) H2O–THF (1:8), MW
r.t.
60
4
1
A
7
a) Bu3P, THF
b) H2O–DMF (1:4)
r.t.
r.t.
4
12
Br
54%
A
8
3c
N3
8
a) Bu3P, THF
b) H2O–DMF (1:4), MW
r.t.
60
4
1
A
5% HCl, EtOAc, Et2O,
Ph3P, 0 °C to r.t.
N3
H2N
9
a) Bu3P, THF
b) concd NH4OH–DMF (1:4)
r.t.
r.t.
4
12
X
X
O
O
A
22%
2
2
3d
10
a) Bu3P, THF
b) H2O–AcOH–DMF (1:2:8), MW 60
r.t.
4
1
10 X = OH
11 X = OTs
12 X = N3
TsCl, NaOH, dioxane–H2O
NaN3, DMF, 60 °C
A
B
B
C
11
12
13
1 M SnCl2 in DMF, MW
1 M SnCl2 in DMF
60
1
Scheme 2 Synthesis of functionalized 1-amino-w-azidoalkanes 3a–d13
r.t.
12
1
0.1 M SnCl2, 0.4 M PhSH, 0.5 M r.t.
Et3N in THF
H
H2N
H
N
O
H
N
N
1) Ph3P, THF, 3 h
2) H2O–THF (1:8),
MW, 60 °C, 1 h
14
0.1 M SnCl2, 0.4 M PhSH, 0.5 M 60
Et3N in THF, MW
1
C
O
O
6
6
O
O
3) 95% TFA–H2O
a According to MALDI-TOF analysis. A: No product or low content:
Starting material and intermediate iminophosphoranes were strongly
detected. B: Product visible but starting material strongly detected. C:
Quantitative conversion; no starting material detected.
O
NH2
a
N3
5{d}6
4{d}6
N3
NH2
(CH2)6
(CH2)6
O
O
Scheme 3 Example of
a
synthesis of
functionalized
1) reduction
2) 95%TFA–H2O
aminopeptoid14
N
N
O
HN
NH
H2N
NH
(CH2)6
(CH2)6
O
reduction of the azido moiety were only successful with
hydrophilic and water-soluble azidopeptoids 4{d}n
(Scheme 3). Peptoids having sidechains other than the
ethyleneoxy unit, such as the more hydrophobic alkyl or
aromatic groups, did not deliver the anticipated amines in
acceptable yields. Unreacted starting material and the for-
mation of the corresponding iminophosphorane were de-
tected, but subsequent hydrolysis with water was limited,
even after cleavage from the resin. In order to optimize the
reduction in a Boc-orthogonal fashion, we screened for
optimized reduction conditions, using the dipeptoid sys-
tem 4{a}1{a¢-Boc}1 with an azido and a Boc-protected
amine moiety (Scheme 4, Table 1).
NHBoc
NH2
4{a}1{a'-Boc}1
5{a}2
Scheme 4 Reduction of the (w-azido)peptoid 4{a}1{a¢-Boc}1 for
screening of conditions as described in Table 114
After this screening, SnCl2 indisputably generated the best
results. Standard Staudinger reduction conditions primari-
ly yielded the corresponding iminophosphorane, which
could not be hydrolyzed in satisfactory quantities. Chang-
ing the solvent system from THF to DMF, heating under
microwave irradiation (60 °C), prolonging hydrolysis
time, use of alkyl or aryl phosphines and application of
Synlett 2010, No. 10, 1544–1548 © Thieme Stuttgart · New York

1546
D. Fritz, S. Bräse
LETTER
Table 2 Analytical Data of the Synthesized (w-Aminoalkyl)pep-
toids
basic or acidic conditions did not significantly improve
the hydrolysis.
Entry
Peptoid
Amine used in m/z [M]+
m/z [M + H]+
Better results were achieved by using SnCl2 in DMF.
Moreover, more satisfactory results were obtained
through the addition of thiophenol and base (Et3N), lead-
ing to the formation of the highly selective Bartra
reagent17 [Sn(SPh)3]–, which gave good and selective con-
version into the amines.
synthesis
calcd
founda
1
2
3
4
5
6
5{a}2
5{b}3
5{c}3
5{d}1
5{d}6
6{d}6
3a
3b
3c
3d
3d
3d
329
330
755
756
743
744
Cleavage from the solid support yielded the (w-ami-
noalkyl)peptoids 5{x}n in generally good purities, accord-
ing to MALDI-TOF analysis (Table 2, Figure 1).
233
234
1145
1684
1146
1684b
NH2
a According to MALDI-TOF analysis.
b Found mass: [M]+.
(CH2)6
NH
O
H2N
H
H2N
H2N
H
N
N
N
(CH2)6
O
O
O
3
3
The peptoids 5{b}n and 5{c}n represent a new class of
chiral amino-functionalized peptoids, which might have
an impact in their secondary structure18 and therewith dif-
fer in their properties as molecular transporters.4 The ami-
no-PEG-type peptoids 5{d}n, which are unprecedented in
structure,19,20 will be explored for their delivery abilities.
NH2
5{a}2
(CH2)5
NH2
5{b}3
(CH2)3
NH2
5{c}3
After exploration of the reducing methods, we attached
functionalized cargo, such as a rhodamine B dye, to the
azidopeptoids. Subsequent reduction [a) Ph3P, THF, 4 h;
b) H2O–THF (1:8), MW, 60 °C, 30 min] and cleavage
from the solid support (95% TFA–H2O) furnished novel
rhodaminyl molecular transporters, for example 6{d}6, in
good purities and overall yields up to 70% (Figure 2).
H2N
H
H2N
H
N
N
O
O
6
O
O
O
O
The sub-monomer method is particularly useful for the
generation of highly functionalized side chains. In the
case of the chiral protected sub-monomers 3b and 3c, at
least two steps can be saved and therewith the overall
yield is up to 35% higher compared to the synthesis of the
corresponding monomers (data not shown).
NH2
NH2
5{d}1
5{d}6
Figure 1 Synthesized peptoids 5{x}n.14
Figure 2 (A) Example of a synthesized aminopeptoid functionalized with the fluorescent dye rhodamine B. Only one rhodamine isomer is
shown.21 (B) HPLC-Chromatogram (A/B = H2O/MeCN 0.1% TFA; 2 min at 37% B, then 37 to 77% B in 40 min) of crude 6{d}6 at 256 nm.
Synlett 2010, No. 10, 1544–1548 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of (w-Aminoalkyl)peptoids
1547
(8) CAUTION: Short chained 1-halo-w-azidoalkanes might be
explosive. We recommend the use of alkanes with at least six
carbon atoms in case diazidoalkanes are formed. For a
discussion, see ref. 9
(9) For a review concerning azide chemistry, see: Bräse, S.; Gil,
C.; Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed.
2005, 44, 5188; Angew. Chem. 2005, 117, 5320.
(10) (a) Jang, H.; Fafarman, A.; Holub, J. M.; Kirshenbaum, K.
Org. Lett. 2005, 7, 1951. (b) Holub, J. M.; Jang, H.;
Kirshenbaum, K. Org. Biomol. Chem. 2006, 4, 1497.
(c) Shin, S. B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K.
J. Am. Chem. Soc. 2007, 129, 3218. (d) Holub, J. M.; Jang,
H.; Kirshenbaum, K. Org. Lett. 2007, 9, 3275. (e) Holub, J.
M.; Garabedian, M. J.; Kirshenbaum, K. QSAR Comb. Sci.
2007, 26, 1175. (f) Shah, N. H.; Kirshenbaum, K.
Introducing w-aminoalkyl chains into peptoids through
the reduction of the w-azidoalkyl species opens new pos-
sibilities for inserting protected amines. This method is
orthogonal to the frequently used Boc- and Nosyl-protect-
ing groups. Besides the useful Click reaction, this method
can also be an effective tool for creating new bioconju-
gates, with more than one active element bound through a
peptide bond in cell-penetrating transporter systems.
Compared to the Boc-, Fmoc- and Nosyl-protected
amines so far predominantly used,1–7 this method is
cheaper and, in various cases such as with the chiral pep-
toids 5{b,c}n, also leads to the desired product in fewer
reaction steps with better overall yields.
Macromol. Rapid Commun. 2008, 29, 1134.
In summary, azidopeptoids with hydrophilic side chains
can be readily reduced under standard Staudinger condi-
tions, while reduction of more hydrophobic peptoids only
generates high yields when using the Bartra reagent for
the reduction of the azido moiety. A new class of chiral
and amino-PEG-type peptoids has been synthesized
through an efficient, combined microwave-assisted sub-
monomer synthesis, starting from 1-amino-w-azido-
alkanes and using the aforementioned reduction condi-
tions on solid supports. Structural and biological studies
of these new chiral and achiral molecular transporters will
remain our focus in the near future.
(11) (a) Lim, H.-S.; Archer, C. T.; Kim, Y.-C.; Hutchens, T.;
Kodadek, T. Chem. Commun. 2008, 1064. (b) See also:
Disney, M. D. PCT Int. Appl. WO 20081034898, 2008.
(12) Lee, J. W.; Jun, S. I.; Kim, K. Tetrahedron Lett. 2001, 42,
2709.
(13) Analytical data for selected products: (S)-1-[3-(5-Azido-
pentyl)phenyl]ethylamine (3b): 1H NMR (400 MHz,
CDCl3): d = 1.41 (tt, J = 7.2, 7.2 Hz, 2 H, N3CH2CH2CH2),
1.44 (d, J = 6.4 Hz, 3 H, CHCH3), 1.62 (tt, J = 7.6, 7.2 Hz,
2 H, CH2CH2-Ar), 1.63 (tt, J = 7.2, 7.2 Hz, 2 H, CH2CH2N3),
2.60 (t, J = 7.6 Hz, 2 H, CH2-Ar), 3.25 (t, J = 7.2 Hz, 2 H,
N3CH2), 4.12 (q, J = 6.4 Hz, 2 H, CHCH3), 4.52 (br s, 2 H,
NH2), 7.08 (d, J = 7.2 Hz, 1 H, Ar6-H), 7.14 (s, 1 H, Ar2-H),
7.15 (d, J = 7.2 Hz, 1 H, Ar4-H), 7.24 (dd, J = 7.2, 7.2 Hz,
1 H, Ar5-H) ppm. 13C NMR (100 MHz, CDCl3): d = 23.4
(CHCH3), 26.4 (N3CH2CH2CH2), 28.7 (N3CH2CH2), 30.9
(CH2CH2-Ar), 35.7 (CH2-Ar), 51.3 (N3CH2), 51.4 (CH),
123.5 (C6-Ar-H), 126.2 (C4-Ar-H), 127.8 (C2-Ar-H), 128.7
(C5-Ar-H), 142.9 [Cq-Ar(CH2)], 143.5 [Cq-Ar(CH)] ppm.
FTIR (film on KBr): 2936, 2860, 2097, 1678, 1542, 1490,
1452, 1385, 1256, 1203, 1136, 897, 835, 799, 721, 706, 558,
461 cm–1; MS (FAB, matrix: mNBA): m/z (%) = 233(100)
[M + H]+, 205(6) [M – N2]+; HRMS: m/z calcd: 233.1766;
found: 233.1769. (S)-1-[3-(5-Azidopent-1-enyl)phenyl]-
ethylamine (3c): 1H NMR (400 MHz, CDCl3): d = 1.38 (d,
J = 6.8 Hz, 3 H, NCHCH3), 1.87 (tt, J = 6.8, 6.8 Hz, 2 H,
CH2CH2CH2), 2.44 (t, J = 6.8 Hz, 2 H, CH2C≡C), 3.91 (t,
J = 6.8 Hz, 2 H, N3CH2), 4.04 (q, J = 6.8 Hz, 1 H, CHCH3),
5.62 (br s, 2 H, NH2), 7.18 (dd, J = 4.0, 3.6 Hz, 1 H, Ar5-H),
7.18 (d, J = 4.0 Hz, 1 H, Ar6-H), 7.20–7.28 (m, 1 H, Ar4-H),
7.31 (s, 1 H, Ar2-H) ppm. 13C NMR (100 MHz, CDCl3): d =
16.7 (CH2C≡C), 21.9 (CHCH3), 27.8 (N3CH2), 50.2
(CH2CH2CH2), 51.2 (CH), 81.1 (C≡C-Ar), 88.8 (C≡C-Ar),
124.2 [Cq-Ar(C≡C)], 125.8 (C6-Ar-H), 128.9 (C5-Ar-H),
129.5 (C4-Ar-H), 131.4 (C2-Ar-H), 141.3 [Cq-Ar(CH)] ppm.
FTIR (film on KBr): 2932 (m), 2099, 1678, 1602, 1483,
1430, 1367, 1293, 1256, 1202, 1134, 897, 834, 798, 721,
700, 476; MS (FAB, matrix: mNBA): m/z (%) = 229(50)[M
+ H]+, 212(100) [M – NH2]+; HRMS: m/z calcd: 229.1453;
found: 229.1449. 2-[2-(2-Azidoethoxy)ethoxy]ethylamine
(3d): Analytical data are consistent with those reported by:
Klein, E.; DeBonis, S.; Thiede, B.; Skoufias, D. A.;
Kozielski, F.; Lebeau, L. Bioorg. Med. Chem. 2007, 6474.
(14) The final products were isolated as ammonium
trifluoroacetate salts.
Acknowledgment
We acknowledge the financial support of the Evangelisches
Studienwerk e.V. Villigst and the DFG-Centre for functionalized
nanostructures (CFN, project E1.1). The chiral phenylethylamines
were gifts from BASF (Prof. Dr. Ditrich, ChiPros). We greatly ap-
preciate the dedicated help received from Karolin Niessner and
Dr. Michael Gartner.
References and Notes
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(15) For a different approach, see: (a) Natarajan, A.; Du, W.;
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(6) For a different approach, see: Hahn, F.; Schmitz, K.;
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Synlett 2010, No. 10, 1544–1548 © Thieme Stuttgart · New York

1548
D. Fritz, S. Bräse
LETTER
(19) For the only report of PEG-type side chains in peptoids
(16) (a) Olivos, H. J.; Alluri, P. G.; Reddy, M. M.; Salony, D.;
Kodadek, T. Org. Lett. 2002, 4, 4057. (b) Gorske, B. C.;
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2005, 7, 1521.
(17) (a) Bartra, M.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 1987,
28, 5941. (b) For general scope and limitation of this
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Tetrahedron 1990, 46, 587. (c) For its application on solid
supports, see: Zimmermann, V.; Avemaria, F.; Bräse, S.
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according to CAS, see: Barron, A. E. PCT Int. Appl.
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(a) Kim, J. M.; Roy, R. Carbohydr. Lett. 1996, 1, 465.
(b) Huang, C.-Y.; Uno, T.; Murphy, J. E.; Lee, S.; Hamer,
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A. E.; Messersmith, P. B. Biofouling 2008, 24, 439.
(d) Statz, A. R.; Barron, A. E.; Messersmith, P. B. Soft
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