Highly convenient gram-scale solution-phase peptoid synthesis and orthogonal side-chain post-modification

Article abstract of DOI:10.1055/s-0030-1258351

This paper describes the development of a highly convenient solution-phase methodology using volatile amines for the synthesis of β-,α ,β- and α-tetrapeptoids, as an alternative to solid-phase technologies. Column chromatographic purifications are reduced

Full text of DOI:10.1055/s-0030-1258351

PAPER
257
Highly Convenient Gram-Scale Solution-Phase Peptoid Synthesis and
Orthogonal Side-Chain Post-Modification
Solution-Phase
Pe
ptoid Synt
c
hese
s
ile Caumes,a Thomas Hjelmgaard,*a,b,1, Roland Remuson,a,b Sophie Faure,*a,b Claude Taillefumiera,b
a
Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, 63000 Clermont-Ferrand, France
CNRS, UMR 6504, Laboratoire SEESIB, 63177 Aubière Cedex, France
b
Fax +33(4)73407717; E-mail: claude.taillefumier@univ-bpclermont.fr; E-mail: sophie.faure@univ-bpclermont.fr
Received 1 September 2010; revised 25 October 2010
methodologies which are able to provide large quantities
of peptoids in a manner competitive with solid-phase syn-
thesis. Accordingly, our published methodology for itera-
tive solution-phase synthesis of peptoids (Scheme 1) has
Abstract: This paper describes the development of a highly conve-
nient solution-phase methodology using volatile amines for the syn-
thesis of b-, a,b- and a-tetrapeptoids, as an alternative to solid-phase
technologies. Column chromatographic purifications are reduced to
a minimum and the majority of the intermediates are purified by fil- provided improvements, in terms of cost and time, com-
pared to earlier techniques.5
tration and/or evaporation. The method is amenable to gram-scale
synthesis of peptoids, and post-modification of a model peptoid by
successive and selective ligations, using click thiol–ene coupling,
Briefly, the peptoid residues are created in two steps by
acylation of the N-terminus, followed by reaction of the
acylated intermediate with an appropriate amine. By using
tetrahydrofuran as the solvent for the acylation steps the
formed ammonium salts precipitate, allowing for easy re-
moval by filtration. Evaporation of the filtrate then fur-
nishes the acylated intermediates in sufficiently high
purity for direct use in the second step. Thus, only one
chromatography operation per synthesised peptoid resi-
due is needed. Nevertheless, further improvements are
necessary if this methodology is to emerge as a truly com-
petitive alternative to solid-phase technologies. In this pa-
per, we describe the development of a highly convenient
procedure for solution-phase synthesis of tetrapeptoids.
The potential of this method is shown by the facile gram-
scale synthesis of a multifunctional model peptoid. Suc-
cessive and selective ligations of this multifunctional tet-
rapeptoid, as a possible entry to more complex structures,
are also demonstrated.
and copper-catalysed azide–alkyne cycloaddition is demonstrated.
Key words: peptoids, oligomers, gram-scale synthesis, thiol–ene
coupling, cycloaddition, post-modifications
There has been considerable interest in developing
pseudopeptide oligomers with reduced complexity that
are able to fulfill the functions of their natural peptide
counterparts, without drawbacks such as low half-life and
limited bioavailability.2 Oligomers of N-substituted gly-
cines, or a-peptoids, were developed in the early 1990s as
a new type of simple peptidomimetic. They are character-
ised by resistance to proteases, rapid cellular uptake, a
large potential for diversity and straightforward synthe-
ses.3 The first synthesis of oligomers of N-substituted b-
alanines, or b-peptoids, followed later in the same de-
cade.4 In addition, we have recently communicated our
initial studies on a new family of a,b-alternating pep-
toids.5 Structurally, peptoids differ from peptides in that
the side chains are attached to the amide nitrogen rather
than to the a- or b-carbon. The peptoid backbone is there-
fore achiral and does not contain any amide protons. In
spite of this, peptoids can still be driven to form secondary
structures such as helices if a-chiral side chains are incor-
porated.6 Peptoids have attracted significant interest and
have been used in a number of important biological appli-
cations.7
O
O
(b)
HN
R
N
R
N
R
a)
c)
β-peptoid residue
intermediates purified
by filtrations only
HN
R
O
R
O
(d)
Br
HN
N
N
R
R
The structural simplicity of the peptoids allows for their
synthesis using a unique ‘submonomer’ protocol in which
the peptoid residues are created directly on a growing
chain, in an iterative manner. Highly efficient procedures
have been developed for solid-phase synthesis of pep-
toids. However, our research project aimed at using b- and
a,b-peptoids as scaffolds for multivalent ligand display8
necessitates the development of efficient solution-phase
α-peptoid residue
Scheme 1 Solution-phase submonomer synthesis of b- and a-pep-
toid residues. Reagents and conditions: (a) CH2=CHCOCl (1.2
equiv), Et3N (1.4 equiv), THF, 0 °C; (b) RNH2 (2.0 equiv), MeOH, 50
°C then chromatography; (c) BrCH2COBr (1.2 equiv), Et3N (1.2
equiv), THF, 0 °C; (d) RNH2 (2.0 equiv), Et3N (2.0 equiv), THF, 0 °C
to r.t. then chromatography.
The synthetic steps illustrated in Scheme 1 proceed with
high efficiency to give crude products which are essential-
ly mixtures of the desired peptoid and unreacted starting
amine; the pure peptoid can be isolated by flash chroma-
SYNTHESIS 2011, No. 2, pp 0257–0264
Advanced online publication: 03.12.2010
DOI: 10.1055/s-0030-1258351; Art ID: T17610SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

258
C. Caumes et al.
PAPER
tography. We envisaged that by utilising amines that used in the addition step only resulted in a slight increase
could be removed by evaporation on a standard rotary of the overall yield from 58% to 60% (Table 1, entry 2 vs.
evaporator, we could potentially optimise our solution- 1). The highest overall yield of 65% (HPLC
phase method such that flash chromatographic purifica- purity = 99%) was obtained by increasing the amount of
tion could be omitted. The peptoid products would be ex- triethylamine used in the acylation steps (Table 1, entry
pected to be sufficiently pure to be used directly in the 3), or by replacing tetrahydrofuran with ethyl acetate as
iterative peptoid synthesis. Initially, we needed to im- the solvent for the acylation (Table 1, entry 4). For com-
prove the filtration operations. In our previous method parison, when each intermediate was purified, tetramer 1
(Scheme 1) the ammonium salts were filtered from the re- was obtained in 72% overall yield.8 Hence, by using this
action mixtures in THF. This gave crude products that still new methodology we were able to synthesise the same
contained small amounts of ammonium salts which could product in a slightly lower overall yield, but with only one
potentially lead to the formation of undesired by-products final flash chromatographic purification required; this
if continuously returned into the iterative synthesis. We represents a clear improvement in terms of cost and time.
found that dilution of the reaction mixtures with ethyl Furthermore, the yield obtained via this methodology was
acetate following the acylation and substitution steps, af- superior to the reported yields for the solid-phase synthe-
forded intermediates of higher purity after filtration and sis of b-peptoids.9
evaporation. Dilution with cyclohexane was also tested,
but peptoids longer than two units showed limited solubil-
ity in cyclohexane–tetrahydrofuran mixtures which com-
plicated the filtration.
While working on optimising the two-step iterative pro-
cess for synthesising b-peptoid units, we were also able to
optimise the synthesis of a-peptoid residues. The a,b-al-
ternating tetrapeptoid 2 (Table 2) was chosen as a model
With an improved technique in hand, we next investigated target for this study. Thus, while using the initial condi-
the solution-phase iterative synthesis of b-peptoids with- tions for chain elongation with a b-peptoid residue (see
out any intermediate chromatographic purifications Table 1, entry 1) the synthetic conditions for a-peptoid
(Table 1). The synthesis started from tert-butyl acrylate residue incorporation were varied (Table 2). Using the
and propargylamine was used as a model amine. Using initial unoptimised conditions, a,b-tetrapeptoid 2 was iso-
our previously developed reaction conditions for b-pep- lated in 29% overall yield after seven steps and one final
toid synthesis (Scheme 1), the synthetic cycle shown in purification (Table 2, entry 1). The lower yield of a,b-
Table 1 was repeated until the tetrapeptoid stage, at which peptoid 2, compared to that of b-peptoid 1, was anticipat-
point thin layer chromatography showed the presence of ed since the solution-phase synthesis of a-peptoid resi-
non-negligible amounts of impurities.
dues proceeds less cleanly than that of b-peptoid
residues.5 Replacing triethylamine in the substitution re-
action with a further two equivalents of propargylamine
gave reaction mixtures that proved difficult to filter, and
consequently, a slightly decreased overall yield was ob-
tained (Table 2, entry 2). A significant improvement in
the overall yield to 42% was observed when maintaining
the use of triethylamine in the substitution steps, and at the
We were satisfied to find that b-tetrapeptoid 1 could be
isolated in 58% overall yield, and in high purity (Table 1,
entry 1), after seven steps and a single final flash chroma-
tography.
Encouraged by this initial result we sought to improve the
overall yield. Increasing the amount of propargylamine
Table 1 Optimisation of the Iterative Synthesis of b-Tetrapeptoid 1
O
O
(b)
1 n = 4
H
Ot-Bu
N
Ot-Bu
n = 1
n = 1–4
aza-Michael (b)
acylation (a)
O
N
Entry Acylation (step a)a
Aza-Michael (step b)a
Yield (%)
1
2
3
4
H2C=CHCOCl (1.2), Et3N (1.4), THF, 0 °C, 1 h
H2C=CHCOCl (1.2), Et3N (1.4), THF, 0 °C, 1 h
H2C=CHCOCl (1.2), Et3N (2.2), THF, 0 °C, 1 h
H2C=CHCOCl (1.2), Et3N (1.4), EtOAc, 0 °C, 1 h
propargylamine (2.0), MeOH, 50 °C, overnight
propargylamine (4.0), MeOH, 50 °C, overnight
propargylamine (2.0), MeOH, 50 °C, overnight
propargylamine (2.0), MeOH, 50 °C, overnight
58
60
65
65
a Numbers in parentheses are the equivalents used.
Synthesis 2011, No. 2, 257–264 © Thieme Stuttgart · New York

PAPER
Solution-Phase Peptoid Syntheses
259
same time, increasing the amount of propargylamine from (entry 3) are not the best in terms of yield (see entry 4), but
two to four equivalents (Table 2, entry 3). Increasing the they were considered the best compromise in terms of
amount of propargylamine to six equivalents raised the both the yield and the number of equivalents of propargyl-
overall yield to 46% (Table 2, entry 4). However, the use amine used. The a,b-tetrapeptoid 2 was isolated in 45%
of eight equivalents of propargylamine did not improve overall yield (HPLC purity = 95%) after one final flash
the yield further (Table 2, entry 5). Likewise, other modi- chromatographic purification. For comparison we synthe-
fications such as decreasing or increasing the temperature sised a,b-tetrapeptoid 2 where each amine intermediate
of the substitution step (Table 2, entries 6 and 7), replac- was purified; an overall yield of 40% was obtained which
ing tetrahydrofuran with ethyl acetate as the solvent demonstrates clearly the efficiency of our methodology.
(Table 2, entries 8 and 9), and increasing the amount of
Using the optimised conditions for a-peptoid residue syn-
triethylamine in the acylation step (Table 2, entry 10) or
thesis we also prepared a-tetrapeptoid 3 in seven steps and
the use of microwave irradiation10 (Table 2, entry 11) did
41% overall yield (Scheme 2). Due to difficulties in puri-
not improve the overall yield. As expected, the use of
fying the final tetramer an additional chromatographic pu-
chloroacetyl chloride instead of bromoacetyl bromide in
rification of the final bromoacetate intermediate (step six)
the acylation (step c) gave less reactive intermediates, and
was necessary in order to obtain the desired product in
heating or microwave activation was necessary for the
pure form (HPLC purity = 97%).
substitution reactions to proceed (Table 2, entry 12).
In order to demonstrate the potential of our methodology
Next, we resynthesised the alternating peptoid 2 by com-
we easily synthesised 2.5 grams of b-tetrapeptoid 4
bining the optimised conditions for incorporation of both
(Scheme 3). The product was obtained in high purity
the a- and b-peptoid residues (Table 1, entry 3 and
(HPLC purity = 98%) and 74% overall yield in seven
Table 2, entry 3). The reaction conditions listed in Table 2
Table 2 Optimisation of a-Peptoid Residue Formation for the Synthesis of a,b-Alternating Tetrapeptoid 2
step (b)
(entry 1, Table 1)
O
O
O
HN
N
Ot-Bu
N
Ot-Bu
n = 0–1
(c)
O
O
β-peptoid unit
2 steps (a), (b)
(entry 1, Table 1)
synthesis
Br
N
O
O
(d)
N
H
N
Ot-Bu
n = 1–2
2 n = 2
Entry Acylation (step c)a
Substitution (step d)a
Yield (%)
1
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), EtOAc, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.3), THF, 0 °C, 1 h
BrCOCH2Br (1.2), Et3N (1.2), THF, 0 °C, 1 h
ClCOCH2Cl (1.2), Et3N (1.2), THF, 0 °C, 1 h
propargylamine (2.0), Et3N (2.0), THF, r.t., overnight
propargylamine (4.0), THF, r.t., overnight
29
27
42
46
45
41
40
39
41
44
37
44
2
3
propargylamine (4.0), Et3N (2.0), THF, r.t., overnight
propargylamine (6.0), Et3N (2.0), THF, r.t., overnight
propargylamine (8.0), Et3N (2.0), THF, r.t., overnight
propargylamine (6.0), Et3N (2.0), THF, 0 °C, overnight
propargylamine (6.0), Et3N (2.0), THF, 40 °C, overnight
propargylamine (6.0), Et3N (2.0), EtOAc, r.t., overnight
propargylamine (6.0), Et3N (2.0), THF, r.t., overnight
propargylamine (6.0), Et3N (2.0), THF, r.t., overnight
propargylamine (4.0), Et3N (2.0), THF, 50 °C, MW, 5 min
propargylamine (4.0), Et3N (2.0), THF, 50 °C, overnight
4
5
6
7
8
9
10
11
12
a Numbers in parentheses are the equivalents used.
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260
C. Caumes et al.
PAPER
O
O
O
O
O
O
4 R = H
RN
Me
N
N
N
Ot-Bu
(d)
a)
b)
Br
N
5 R = Ac
3 n = 4
Ot-Bu
H
Ot-Bu
n = 1
n = 1–4
N
Me
substitution (d)
acylation (c)
O
O
O
O
O
AcN
Me
N
N
N
Ot-Bu
Ph
Br
N
N
N
N
N
Me
c)
6
Scheme 2 Synthesis of a-tetrapeptoid 3. Reagents and conditions:
(c) BrCH2COBr (1.2 equiv), Et3N (1.2 equiv), THF, 0 °C, 1 h; (d) pro-
pargylamine (4.0 equiv), Et3N (2.0 equiv), THF, 0 °C to r.t., over-
night, 41% (over 7 steps).
O
O
O
O
AcN
N
N
N
Ot-Bu
Ph
Br–
Me N+ Me
steps, requiring only a single final flash chromatographic
purification. Although our method is limited to the use of
volatile amines, it was still possible to install side chains
that may serve as entries to more complex structures. In-
deed, the model peptoid 4 contains different and useful
side chains; an a-chiral sec-butyl that can, for example, be
used to induce secondary structures, and a dimethylami-
noethyl moiety which can be exploited to form an ammo-
nium salt in order to increase the water solubility of the
peptoid. Furthermore, the allyl and propargyl side chains
can be derivatised successively by click thiol–ene cou-
pling (TEC)11 and copper-catalysed azide–alkyne cy-
cloaddition (CuAAC).12 The latter has already been used
widely for click ligation on peptoid scaffolds,8,13 whereas
the century-old thiol–ene coupling reaction14 remains un-
exploited in this research domain. Recently, thiol–ene
coupling and copper-catalysed azide–alkyne cycloaddi-
tion have been combined for successive and selective
chemical ligations.15 In order to demonstrate this principle
the copper-catalysed azide–alkyne cycloaddition ligation
should be carried out first, since otherwise the alkyne
would also react with the thiol during irradiation. We then
planned to perform the thiol–ene coupling ligation and
complete the selective ligations by forming the ammoni-
um salt. However, preliminary studies showed that the thi-
ol underwent rapid deprotonatation by the tertiary amine
under the thiol–ene coupling conditions making it inac-
tive. We therefore opted to form the ammonium salt by
nucleophilic substitution prior to the thiol–ene coupling
ligation. Thus, N-acetylated peptoid 5, obtained in excel-
lent yield from model peptoid 4, was subjected to copper-
catalysed azide–alkyne cycloaddition with benzyl azide in
the presence of copper(II) sulfate (8 mol%) and ascorbic
acid (24 mol%) in tert-butyl alcohol–water to give 6 in
86% yield. Next, the peptoid ammonium salt 7 was ob-
tained in 87% yield by reaction of 6 with 4-methylbenzyl
bromide. Finally, peptoid 7 was subjected to a photoclick
thiol–ene reaction in water with N-acetyl-L-cysteine in the
N
N
N
7
d)
O
O
O
O
AcN
N
O
N
N
Ot-Bu
Ph
N
Me N+ Me
–O
N
N
S
8
NHAc
Scheme 3 Structure of model b-tetrapeptoid 4 and successive post-
modifications. Reagents and conditions: (a) AcCl, Et3N, EtOAc, 0 °C,
30 min, 94%; (b) BnN3, CuSO4, ascorbic acid, t-BuOH–H2O (3:1),
r.t., 4 h, 86%; (c) 4-methylbenzyl bromide, CH2Cl2, r.t., 2 h, 87%; (d)
N(Ac)-L-cysteine, DPAP, H2O, hn, Pyrex reactor, 6 h, 86%.
In conclusion, we have developed a highly convenient
methodology for the solution-phase synthesis of multi-
functional peptoids. Thus, b- and a,b-tetrapeptoids have
been synthesised in seven steps and in high purity where
only the final products were purified by flash chromatog-
raphy. All reaction intermediates were isolated by filtra-
tion and/or evaporation. The methodology is also
applicable to the synthesis of a-tetrapeptoids, in which
case, additional purification of the final intermediate by
flash chromatography was necessary in order to obtain the
pure product. This method is highly suitable for gram-
scale synthesis, and although limited to the use of volatile
amines, we have shown that various functional groups can
be incorporated for further selective transformations. The
fully post-modified peptoid 8 was prepared in 45% overall
yield in 11 steps starting from tert-butyl acrylate. This ex-
cellent overall yield demonstrates the efficiency of both
the peptoid synthesis and successive post-modifications
using click ligation methods. Overall, this methodology
should be useful for gram-scale synthesis of relatively
short multifunctional peptoids, and is a valuable alterna-
tive to solid-phase methods.
presence
of
2,2-dimethoxy-2-phenylacetophenone
(DPAP) as the photoinitiator.16 The fully functionalised b-
tetrapeptoid 8 was isolated in an excellent 86% yield
(HPLC purity = 93%) by simple extraction from the aque-
ous layer.
Synthesis 2011, No. 2, 257–264 © Thieme Stuttgart · New York

PAPER
Solution-Phase Peptoid Syntheses
261
b-Tetrapeptoid 1
THF was distilled from potassium/benzophenone under N2, and
stored over 4 Å molecular sieves. CH2Cl2 and MeOH were distilled
from CaH2 under N2, and stored over 4 Å molecular sieves. EtOAc,
CH2Cl2, cyclohexane and MeOH for column chromatography were
distilled before use. Et3N was distilled from KOH and stored over 4
Å molecular sieves. (S)-(+)-sec-Butylamine was obtained by optical
resolution of ( )-sec-butylamine following a literature proce-
dure.17All other solvents and chemicals were obtained from com-
mercial sources and used as supplied. TLC was performed on
Merck TLC aluminum sheets, silica gel 60, F254. The extent of reac-
tions was, when applicable, followed by TLC and/or HPLC. Com-
ponents were made visual with UV light and/or ninhydrin in EtOH/
AcOH. Flash chromatography was performed with Merck silica gel
60, 40-63 mm. Unless otherwise stated, flash chromatography was
performed using the eluent system for which the Rf values are given.
Specific rotations were measured on a Jasco DIP-370 polarimeter
using a 10 cm cell. IR spectra were recorded on a Shimadzu FTIR-
8400S spectrometer equipped with a Pike Technologies MIRacleTM
ATR, or on a Perkin-Elmer 881 spectrometer, and wavenumbers (n)
are expressed in cm–1. NMR spectra were recorded on a 400 MHz
Bruker AC 400 spectrometer. Chemical shifts are referenced to the
residual solvent peak. The following multiplicity abbreviations are
used: (s) singlet, (m) multiplet, and (br) broad. All NMR spectral
data are of rotameric mixtures. Where applicable, assignments were
based on COSY, HMBC, HSQC and J-mod-experiments. HRMS
were recorded on a Micromass Q-Tof Micro (3000V) apparatus.
HPLC analysis was performed on a Waters 590 instrument
equipped with an Acclaim® 120 column (C18, 5 mm, 120 Å, 4.6 ×
250 mm) and a Waters 484 UV detector.
Linear b-tetrapeptoid 1 was prepared starting from tert-butyl acry-
late (384 mg, 3.00 mmol) by application of the appropriate general
procedures and using propargylamine as the amine reagent. Flash
chromatography of the crude product (EtOAc to EtOAc–MeOH,
90:10) yielded peptoid 1 as a pale-yellowish oil.
Yield: 1.01 g (65%); Rf = 0.22 (EtOAc–MeOH, 95:5).
IR (ATR): 3293, 3249, 2978, 2934, 1722, 1641, 1466, 1442, 1437,
1420, 1209, 1153, 754, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 9 H, t-Bu), 2.07–2.12 (br
s, 1 H, NH), 2.15–2.37 (m, 4 H, 4 × CH2C≡CH), 2.45–2.83 (m, 8 H,
4 × NCH2CH2C=O), 2.88–2.94 (m, 2 H, HNCH2CH2C=O), 3.35–
3.39 (m,
2 H, HNCH2C≡CH), 3.55–3.77 (m, 6 H, 3 ×
NCH2CH2C=O), 4.03–4.19 (m, 6 H, 3 × CH2C≡CH).
13C NMR (100 MHz, CDCl3): d = 27.9 (3 CH3, t-Bu), 31.4, 31.6,
31.7, 31.9, 32.0 (2 CH2, 2 × NCH2CH2C=O), 32.8, 32.9, 33.1 (CH2,
NCH2CH2C=O), 33.9, 34.0, 34.1, 34.3, 34.4, 34.5, 34.6 (2 CH2,
CH2C≡CH, NCH2CH2C=O), 38.2, 38.3, 38.4, 38.7, 38.9 (3 CH2, 2
× CH2C≡CH, HNCH2C≡CH), 42.6, 42.8, 43.0, 43.1, 43.3, 43.4,
43.5, 43.6, 43.7 (3 CH2, 3 × NCH2CH2C=O), 44.0, 44.1 (CH2,
HNCH2CH2C=O), 71.4, 71.6, 71.7, 71.9, 72.0, 72.5, 72.7, 73.1 (4
CH, 4 × CH2C≡CH), 78.4, 78.7, 78.8, 78.9, 79.1, 79.2, 81.8 (4 C, 4
× CH2C≡CH), 80.6, 80.7, 80.8, 81.2, 81.4 (C, t-Bu), 169.6, 169.7,
169.8, 169.9, 170.0, 170.1, 170.3, 170.7, 170.9, 171.0, 171.3, 171.5,
171.9, 171.9 (4 C, 4 × C=O).
HRMS–ESI: m/z [M + H]+ calcd for C28H38N4O5: 511.2920; found:
511.2917.
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 10.33 min, purity = 99%.
Acylation (b-Peptoid Residues, Step a); General Procedure
To a soln of the crude secondary amine (1.0 equiv, 0.2 M) in THF
at 0 °C under Ar, were added Et3N (2.2 equiv) and acryloyl chloride
(1.2 equiv). After stirring for 1 h at 0 °C, the resulting mixture was
diluted with EtOAc (10 mL per mmol of starting material) and fil-
tered. The solids were rinsed with EtOAc and the filtrate concd and
dried in vacuo to yield the crude acrylamide.
a,b-Tetrapeptoid 2
Linear a,b-tetrapeptoid 2 was prepared starting from tert-butyl
acrylate (384 mg, 3.00 mmol) by application of the appropriate gen-
eral procedures and using propargylamine as the amine reagent.
Flash chromatography of the crude product (EtOAc to EtOAc–
MeOH, 90:10) yielded peptoid 2 as a yellowish oil.
Aza-Michael Addition (b-Peptoid Residues, Step b); General
Procedure
Yield: 658 mg (45%); Rf = 0.40 (EtOAc–MeOH, 90:10).
To a soln of tert-butyl acrylate or the crude acrylamide (1.0 equiv,
0.4 M) in MeOH at r.t. under Ar, was added the appropriate primary
amine (2.0 equiv). After stirring overnight at 50 °C, the mixture was
concd under reduced pressure. EtOAc was added to the residue
which was then concd under reduced pressure. This was repeated
twice and the residue dried in vacuo to yield the desired crude sec-
ondary amine.
IR (ATR): 3291, 3256, 2979, 2931, 2360, 2342, 1723, 1719, 1653,
1648, 1472, 1465, 1457, 1436, 1420, 1369, 1249, 1211, 1196, 1152,
846, 734, 720 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40–1.41 (2 × s, 9 H, t-Bu), 2.15–
2.46 (m, 5 H, 4 × CH2C≡CH, NH), 2.46–2.91 (m, 4 H, 2 ×
NCH2CH2C=O), 3.37–3.51 (m, 2 H, HNCH2C≡CH), 3.51–3.60 (m,
2 H, HNCH2C=O), 3.60–3.81 (m, 4 H, NCH2CH2C=O), 4.05–4.30
(m, 6 H, NCH2C≡CH), 4.31–4.54 (m, 2 H, NCH2C=O).
13C NMR (100 MHz, CDCl3): d = 28.0 (3 CH3, t-Bu), 31.5, 31.6,
31.7, 32.6, 33.3, 33.7, 33.9, 34.0, 34.1 (2 CH2, 2 × NCH2CH2C=O),
34.3, 34.4, 34.6, 34.7, 35.3, 35.4, 37.6, 37.7, 37.8, 38.0, 38.1, 38.3
(4 CH2, 3 × NCH2C≡CH, HNCH2C≡CH), 41.7, 41.8, 42.2, 42.4,
42.7, 43.4, 43.5, 43.8, 43.9, 44.1 (2 CH2, 2 × NCH2CH2C=O), 45.9,
46.0, 46.2, 47.5, 47.6 (CH2, NCH2C=O), 48.6, 48.9, 49.1 (CH2,
NHCH2C=O), 71.8, 72.0, 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.9,
73.2, 73.4, 73.5, 73.8 (4 CH, 4 × CH2C≡CH), 78.1, 78.4, 78.7 (4 C,
4 × CH2C≡CH), 81.0, 81.4 (C, t-Bu), 167.0, 167.4, 167.7, 170.1,
170.4, 170.9, 171.3, 171.4, 171.8 (4 C, 4 × C=O).
Acylation (a-Peptoid Residues, Step c); General Procedure
To a soln of the crude secondary amine (1.0 equiv, 0.2 M) in THF
at 0 °C under Ar, were added Et3N (1.2 equiv) and bromoacetyl bro-
mide (1.2 equiv). After stirring for 1 h at 0 °C, the resulting mixture
was diluted with EtOAc (10 mL per mmol of starting material) and
filtered. The solids were rinsed with EtOAc and the filtrate concd
and dried in vacuo to yield the crude bromoacetyl amide.
Substitution (a-Peptoid Residues, Step d); General Procedure
To a soln of tert-butyl bromoacetate or the crude bromoacetyl
amide (1.0 equiv, 0.2 M) in THF at 0 °C under Ar, was added Et3N
(2.0 equiv) followed by the appropriate primary amine (4.0 equiv).
After stirring overnight at r.t., the resulting mixture was diluted with
EtOAc (10 mL per mmol of starting material) and filtered. The sol-
ids were rinsed with EtOAc and the filtrate concd under reduced
pressure. EtOAc was added to the residue which was then concd un-
der reduced pressure. This was repeated twice and the residue was
dried in vacuo to yield the desired crude secondary amine.
HRMS–ESI: m/z [M + H]+ calcd for C26H35N4O5: 483.2607; found:
483.2603.
HPLC [H2O (0.1% TFA)–MeOH, 40:60, flow = 0.50 mL/min]:
tR = 8.89 min, purity = 95%.
a-Tetrapeptoid 3
Linear a-tetrapeptoid 3 was prepared starting from tert-butyl bro-
moacetate (585 mg, 3.00 mmol) by application of the appropriate
Synthesis 2011, No. 2, 257–264 © Thieme Stuttgart · New York

262
C. Caumes et al.
PAPER
general procedures and using propargylamine as the amine reagent.
Flash chromatography of the crude product (EtOAc to EtOAc–
MeOH, 90:10) yielded peptoid 3 as a yellowish oil. In order to ob-
tain a pure product, the final bromoacetyl amide intermediate was
purified by flash chromatography (EtOAc–cyclohexane, 60:40) be-
fore being subjected to the final substitution step.
HRMS–ESI: m/z [M + H]+ calcd for C30H54N5O5: 564.4119; found:
564.4138.
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 7.09 min, purity = 98%.
b-Tetrapeptoid 5
Yield: 546 mg (41%); Rf = 0.40 (EtOAc–MeOH, 90:10).
To a soln of peptoid 4 (846 mg, 1.50 mmol) and Et3N (0.50 mL,
3.59 mmol) in EtOAc (30 mL), at 0 °C under Ar, was added AcCl
(0.117 mL, 1.65 mmol). After stirring for 30 min at 0 °C the mixture
was washed with sat. aq NaHCO3 soln (2 × 15 mL). The combined
aq layer was extracted with EtOAc (15 mL) and the combined or-
ganic layers dried over Na2SO4, filtered and concd under reduced
pressure. Flash chromatography (CH2Cl2–MeOH, 90:10 to 80:20)
of the residue yielded peptoid 5 as a colorless oil.
IR (ATR): 3287, 3256, 2979, 2936, 2360, 2343, 1734, 1663, 1653,
1472, 1465, 1457, 1437, 1420, 1369, 1349, 1213, 1153, 961, 750,
740, 668 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.23–1.41 (m, 9 H, t-Bu), 2.03 (br
s, 1 H, NH), 2.09–2.47 (m, 4 H, 4 × CH2C≡CH), 3.18–3.34 (m, 3 H,
0.5 × NHCH2C≡CH, NHCH2C=O), 3.45–3.55 (m, 1 H, 0.5 ×
NHCH2C=O), 3.89–4.20 (m, 10 H, 2 × NCH2C=O, 3 ×
NCH2C≡CH), 4.25–4.42 (m, 2 H, NCH2C=O).
21
Yield: 856 mg (94%); [a]D +1.1 (c 0.74, CHCl3); Rf = 0.38
(CH2Cl2–MeOH, 90:10).
13C NMR (100 MHz, CDCl3): d = 27.5, 27.6 (3 CH3, t-Bu), 35.1,
35.2, 35.4, 35.5, 35.6, 35.7, 35.9, 36.6, 36.7, 37.0, 37.3, 37.6 (4 CH2,
NHCH2C≡CH, 3 × NCH2C≡CH), 45.7, 45.8, 46.0, 46.2, 46.3, 46.4,
46.5, 46.6, 46.7, 47.5, 47.6, 47.7, 47.8, 48.0, 48.1, 48.6 (4 CH2,
NHCH2C=O, 3 × NCH2C=O), 71.0, 71.4, 71.5, 71.7, 72.4, 72.5,
72.8, 73.1, 73.2, 73.3, 73.4, 73.5, 73.7, 73.8, 74.0, 74.1, 74.2 (4 CH,
4 × CH2C≡CH), 76.8, 76.9, 77.1, 77.2, 77.3, 77.7, 77.8, 78.2, 78.3,
78.4 (4 C, 4 × CH2C≡CH), 81.2, 81.4, 81.6, 81.7, 82.5, 82.6, 82.8,
83.0 (C, t-Bu), 167.1, 167.3, 167.4, 167.5, 167.6, 168.0, 168.1,
168.2, 170.5, 170.6, 170.8, 171.1, 171.2 (4 C, 4 × C=O).
IR (ATR): 1724, 1635, 1446, 1419, 1368, 1325, 1308, 1289, 1256,
1210, 1153, 1022 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.75–0.85 [m,
3 H,
CH(CH3)CH2CH3], 1.04–1.16 [m, 3 H, CH(CH3)CH2CH3], 1.38 (s,
9 H, t-Bu), 1.40–1.57 [m, 2 H, CH(CH3)CH2CH3], 2.00–2.09 (m, 3
H, Ac), 2.14–2.30 [m, 7 H, N(CH3)2, CH2C≡CH], 2.33–2.79 [m, 10
H, 4 × NCH2CH2C=O, CH2CH2N(CH3)2], 3.10–3.79 [m, 11 H,
CH(CH3)CH2CH3, 4 × NCH2CH2C=O, CH2CH2N(CH3)2], 3.85–
4.00 (m, 2 H, CH2CH=CH2), 4.04–4.20 (m, 2 H, CH2C≡CH), 5.02–
5.19 (m, 2 H, CH2CH=CH2), 5.65–5.80 (m, 1 H, CH2CH=CH2).
HRMS–ESI: m/z [M + H]+ calcd for C24H31N4O5: 455.2294; found:
455.2301.
13C NMR (100 MHz, CDCl3): d = 11.0 [CH3, CH(CH3)CH2CH3],
18.3, 19.2 [CH3, CH(CH3)CH2CH3], 21.4 (CH3, Ac), 27.1, 27.6
[CH2, CH(CH3)CH2CH3], 27.9 (3 CH3, t-Bu), 31.3, 31.5, 32.0, 32.1,
32.5, 32.7, 33.6, 34.0, 34.1, 34.4 (4 CH2, 4 × NCH2CH2C=O), 33.9,
38.2 (CH2, CH2C≡CH), 37.4, 37.5, 39.3, 39.5 (CH2,
NCH2CH2C=O), 42.5, 42.6, 43.1, 43.2, 43.4, 43.5, 43.6, 43.8, 45.1,
47.9, 48.0 [4 CH2, 3 × NCH2CH2C=O, CH2CH2N(CH3)2], 45.3,
45.7 [2 CH3, N(CH3)2], 48.1, 48.3, 51.0, 51.1 (CH2, CH2CH=CH2),
54.5, 54.6 [CH, CH(CH3)CH2CH3], 56.6, 56.7, 58.0 [CH2,
CH2CH2N(CH3)2], 71.6, 71.9, 72.0, 72.5, 73.0 (CH, CH2C≡CH),
78.7, 78.8, 78.9 (C, CH2C≡CH), 80.6, 80.7, 81.1 (C, t-Bu), 116.3,
116.9, 117.1 (CH2, CH2CH=CH2), 132.8, 133.0, 133.1, 133.3 (CH,
CH2CH=CH2), 170.0, 170.1, 170.2, 170.3, 170.5, 170.7, 170.8,
170.9, 171.1, 171.2, 171.6 (5 C, 5 × C=O).
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 6.51 min, purity = 97%.
b-Tetrapeptoid 4
Linear b-tetrapeptoid 4 was prepared starting from tert-butyl acry-
late (768 mg, 5.99 mmol) by application of the appropriate general
procedures and using propargylamine, (S)-(+)-sec-butylamine,
allylamine and N,N-dimethylethylenediamine as the amine re-
agents. Flash chromatography of the crude product [EtOAc–
MeOH, 80:20 then EtOAc–MeOH–concd NH3 (aq), 80:20:5] yield-
ed peptoid 4 as a pale-yellowish oil.
Yield: 2.49 g (74%); [a]D21 +3.2 (c 0.71, CHCl3); Rf = 0.20 [EtOAc–
MeOH–concd NH3 (aq), 80:20:5].
HRMS–ESI: m/z [M + H]+ calcd for C32H56N5O6: 606.4225; found:
IR (ATR): 2974, 1726, 1636, 1456, 1445, 1418, 1368, 1287, 1252,
1217, 1153, 1098, 1063, 1030, 993, 924, 845, 754, 731 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.74–0.84 [m,
606.4233.
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 9.00 min, purity = 96%.
3 H,
CH(CH3)CH2CH3], 1.05–1.15 [m, 3 H, CH(CH3)CH2CH3], 1.37 (s,
9 H, t-Bu), 1.39–1.54 [m, 2 H, CH(CH3)CH2CH3], 2.13–2.26 [m, 7
H, N(CH3)2, CH2C≡CH], 2.30–2.92 [m, 14 H, HNCH2CH2C=O,
CH2N(CH3)2, CH2CH2N(CH3)2, 4 × NCH2CH2C=O], 3.24–3.78 [m,
7 H, CH(CH3)CH2CH3, 3 × NCH2CH2C=O], 3.85–3.98 (m, 2 H,
CH2CH=CH2), 4.03–4.19 (m, 2 H, CH2C≡CH), 5.02–5.15 (m, 2 H,
CH2CH=CH2), 5.64–5.77 (m, 1 H, CH2CH=CH2).
13C NMR (100 MHz, CDCl3): d = 11.0, 11.1 [CH3,
CH(CH3)CH2CH3], 18.3, 19.2 [CH3, CH(CH3)CH2CH3], 27.1, 27.6
[CH2, CH(CH3)CH2CH3], 27.9 (3 CH3, t-Bu), 32.1, 32.4, 32.7, 32.9,
33.7, 33.9, 34.1, 34.4 (4 CH2, 4 × NCH2CH2C=O), 33.9, 38.2 (CH2,
CH2C≡CH), 37.4, 39.3, 39.5 (CH2, NCH2CH2C=O), 42.5, 42.6,
43.1, 43.5, 43.6 (2 CH2, 2 × NCH2CH2C=O), 45.43 (CH2,
NCH2CH2C=O), 45.37, 45.6, 45.7, 45.8 [2 CH3, N(CH3)2], 47.2
[CH2, CH2CH2N(CH3)2], 48.0, 48.1, 51.0, 51.1 (CH2,
CH2CH=CH2), 54.4, 54.5 [CH, CH(CH3)CH2CH3], 58.5, 58.7
[CH2, CH2N(CH3)2], 71.6, 71.9, 72.5, 73.0 (CH, CH2C≡CH), 78.6,
78.7, 78.9 (C, CH2C≡CH), 80.6, 81.1 (C, t-Bu), 116.3, 116.4, 116.5,
116.9 (CH2, CH2CH=CH2), 132.8, 133.0, 133.3 (CH,
CH2CH=CH2), 170.0, 170.1, 170.3, 170.8, 170.9, 171.0, 171.1,
171.2, 172.1 (4 C, 4 × C=O).
b-Tetrapeptoid 6
To a soln of peptoid 5 (586 mg, 0.97 mmol) in t-BuOH (9 mL, 0.1
M) at r.t. under Ar, were added freshly prepared aq ascorbic acid
(0.1 M, 2.32 mL, 0.24 equiv), aq CuSO4 (0.1 M, 0.77 mL, 0.08
equiv) and BnN3 (258 mg, 2 equiv). After stirring for 4 h at r.t., H2O
(16 mL) was added and the product was extracted with CH2Cl2 (5 ×
10 mL). The combined organic layer was dried over MgSO4, fil-
tered and concd under reduced pressure. Flash chromatography
(CH2Cl2–MeOH, 90:10 to 80:20) yielded peptoid 6 as a pale-green-
ish oil.
21
Yield: 613 mg (86%); [a]D +1.0 (c 0.87, CHCl3); Rf = 0.50
(CH2Cl2–MeOH, 80:20).
IR (ATR): 2971, 2938, 2876, 2822, 2770, 1724, 1635, 1455, 1448,
1419, 1368, 1328, 1253, 1153, 1047, 1028, 1022, 923, 730 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.73–0.91 [m,
CH(CH3)CH2CH3], 1.01–1.17 [m, 3 H, CH(CH3)CH2CH3], 1.38 (s,
9 H, t-Bu), 1.36–1.58 [m, 2 H, CH(CH3)CH2CH3], 1.98–2.14 (m, 3
H, Ac), 2.24 [s, 3 H, CH2CH2N(CH3)2], 2.35–2.47 [m, 3 H,
CH2CH2N(CH3)2], 2.36–2.86 [m, 10 H, 4 × NCH2CH2C=O,
3 H,
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Solution-Phase Peptoid Syntheses
263
CH2CH2N(CH3)2], 3.25–3.71 [m, 10 H, 4 × NCH2CH2C=O,
CH2CH2N(CH3)2], 3.61–3.79 [m, 1 H, CH(CH3)CH2CH3], 3.90–
4.03 (m, 2 H, CH2CH=CH2), 4.45–4.67 (m, 2 H, NCH2-triazole),
5.04–5.21 (m, 2 H, CH2CH=CH2), 5.40–5.53 (m, 2 H, NCH2C6H5),
5.66–5.81 (m, 1 H, CH2CH=CH2), 7.18–7.38 (m, 5 H, CH2C6H5),
7.44–7.54 (m, 1 H, C=CHN).
b-Tetrapeptoid 8
To a soln of peptoid 7 (99 mg, 0.11 mmol, 1 equiv) in CH2Cl2 (1
mL, 0.1 M) in a Pyrex tube was added N(Ac)-L-cysteine (34 mg, 2
equiv), DPAP (8 mg, 0.3 equiv) and H2O (1 mL). The heteroge-
neous mixture was degassed with Ar until complete evaporation of
CH2Cl2. The resulting aq soln was irradiated for 6 h, at r.t. under Ar,
using a 400 W medium-pressure Hg lamp fitted with a Pyrex filter.
The mixture was diluted with aq NH4HCO3 soln (1 M, 20 mL) and
extracted with Et2O (20 mL) and EtOAc (20 mL). The aq layer was
then extracted with CH2Cl2 (4 × 15 mL). The combined organic lay-
er was dried over MgSO4, filtered and concd under reduced pressure
to yield peptoid 8 as an off-white foam.
13C NMR (100 MHz, CDCl3): d = 11.1 [CH3, CH(CH3)CH2CH3],
18.3, 19.3 [CH3, CH(CH3)CH2CH3], 21.5 (CH3, Ac), 27.2, 27.7
[CH2, CH(CH3)CH2CH3], 28.0 (3 CH3, t-Bu), 31.3, 31.5, 32.1, 32.4,
32.5, 32.6, 32.7, 33.6, 33.8, 33.9, 34.2, 34.3, 34.5 (4 CH2, 4 ×
NCH2CH2C=O), 37.5, 37.6, 39.6, 40.4, 40.5, 42.2, 42.4, 42.7, 42.8,
42.9, 43.4, 43.6, 43.8, 45.2, 47.9 [6 CH2, 4 × NCH2CH2C=O,
CH2CH2N(CH3)2, NCH2-triazole], 44.9, 45.7 [2 CH3,
CH2CH2N(CH3)2], 48.3, 48.4, 51.1, 51.2 (CH2, CH2CH=CH2), 54.1
(CH2, NCH2C6H5), 54.5 [CH, CH(CH3)CH2CH3], 56.3, 58.0 [CH2,
CH2CH2N(CH3)2], 80.6, 81.0 (C, t-Bu), 116.3, 117.0, 117.2 (CH2,
CH2CH=CH2), 121.7, 123.2 (CH, C=CHN), 128.0, 128.6, 128.7,
129.0 (5 CH, CH2C6H5), 133.0, 133.1, 133.2, 133.4 (CH,
CH2CH=CH2), 134.5 (C, CH2C6H5), 144.5, 144.6 (C, C=CHN),
170.0, 170.2, 170.6, 170.7, 170.9, 171.1, 171.2, 171.3, 171.6 (5 C,
5 × C=O).
21
Yield: 93 mg (86%); [a]D +21.7 (c 0.95, CHCl3); Rf = 0.33
(CH2Cl2–MeOH, 80:20).
IR (ATR): 3398, 2975, 2934, 2874, 1723, 1628, 1623, 1615, 1456,
1429, 1423, 1369, 1326, 1288, 1252, 1223, 1151, 1048, 843, 820,
795, 752, 725 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.73–0.95 [m,
3 H,
CH(CH3)CH2CH3], 1.04–1.23 [m, 3 H, CH(CH3)CH2CH3], 1.31,
1.41 (2 × s, 9 H, t-Bu), 1.48–1.66 [m, 2 H, CH(CH3)CH2CH3], 1.74–
1.93 (m, 2 H, CH2CH2CH2S), 2.00 (s, 3 H, NHAc), 2.07–2.26 (m, 3
H, Ac), 2.29–2.41 (m, 3 H, C6H4CH3), 2.41–2.98 (m, 12 H, 2 ×
CH2S, 4 × NCH2CH2C=O), 2.99–3.19 [m, 6 H, N+(CH3)2], 3.27–
HRMS–ESI: m/z [M + H]+ calcd for C39H63N8O6: 739.4871; found:
739.4876.
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 10.29 min, purity = 98%.
4.29 [m, 15 H, 4 × NCH2CH2C=O, CH(CH3)CH2CH3,
CH2CH2CH2S, CH2CH2N+), 4.35–4.45 (m, 1 H, SCH2CHNHAc),
4.49–4.77 (m, 4 H, NCH2-triazole and N+CH2C6H4], 5.52–5.63 (m,
2 H, NCH2C6H5), 7.22–7.56 (m, 9 H, CH2C6H5, N+CH2C6H4), 7.82–
8.05 (m, 1 H, C=CHN).
b-Tetrapeptoid 7
To a soln of peptoid 6 (613 mg, 0.83 mmol) in CH2Cl2 (5 mL, 0.2
M) at r.t. was added 4-methylbenzyl bromide (161 mg, 1.05 equiv).
The resulting mixture was stirred for 2 h and the solvent was evap-
orated under reduced pressure. Flash chromatography of the residue
(CH2Cl2–MeOH, 90:10 to 80:20) yielded peptoid 7 as a white foam.
13C NMR (100 MHz, CD3OD): d = 11.6, 11.7 [CH3,
CH(CH3)CH2CH3], 18.7, 19.6, 19.7 [CH3, CH(CH3)CH2CH3], 21.4,
21.6 (2 CH3, Ac, C6H4CH3), 23.0 (CH3, NHAc), 28.4 (3 CH3, t-Bu),
28.2, 28.6, 28.8, 29.6, 29.8, 30.0, 30.1, 30.4, 30.7, 30.8 [2 CH2,
CH(CH3)CH2CH3, NCH2CH2CH2S], 32.8, 32.9, 33.0, 33.3, 33.8,
33.9, 34.6, 34.7, 35.1, 35.2, 35.3, 35.9 (4 CH2, 4 × NCH2CH2C=O),
38.7, 38.8, 41.0, 41.2, 41.4, 41.5, 43.6, 43.8, 44.1, 44.2, 44.5, 44.6,
44.7, 45.0, 45.2, 45.4, 45.5, 46.5, 46.7 (9 CH2, 4 × NCH2CH2C=O,
CH2CH2N+, NCH2-triazole, CH2CH2CH2SCH2), 49.9, 50.5 [2 CH3,
N+(CH3)2], 53.7, 53.9 [CH, CH(CH3)CH2CH3], 54.9 (CH2,
NCH2C6H5), 55.8, 56.2 (CH, SCH2CHNHAc), 61.4, 62.1 (CH2,
CH2CH2N+), 69.4 (CH2, N+CH2C6H4), 81.9, 82.1 (C, t-Bu), 124.5,
125.0 (CH, C=CHN), 125.7 (C, p-N+CH2C6H4), 129.2, 129.6,
130.1, 131.0, 134.2 (9 CH, CH2C6H5, N+CH2C6H4), 136.8, 136.9
(C, CH2C6H5), 142.5 (C, ipso-N+CH2C6H4), 145.5, 145.7 (C,
C=CHN), 172.1, 172.4, 172.5, 172.7, 172.8, 173.0, 173.2, 173.3,
173.5, 173.6, 173.7, 174.0, 177.1, 177.3 (7 C, 7 × C=O).
21
Yield: 669 mg (87%); [a]D +0.6 (c 0.87, CHCl3); Rf = 0.68
(CH2Cl2–MeOH, 80:20).
IR (ATR): 3004, 2975, 2931, 2878, 1724, 1635, 1454, 1419, 1368,
1328, 1247, 1220, 1152, 1048, 846, 819, 789, 751 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.73–0.91 [m,
3 H,
CH(CH3)CH2CH3], 1.02–1.21 [m, 3 H, CH(CH3)CH2CH3], 1.40 (s,
9 H, t-Bu), 1.45–1.58 [m, 2 H, CH(CH3)CH2CH3], 2.07–2.20 (m, 3
H, Ac), 2.30–2.92 (m, 11 H, C6H4CH3, 4 × NCH2CH2C=O), 3.12–
4.43 [m, 21 H, N+(CH3)2, 4 × NCH2CH2C=O, CH(CH3)CH2CH3,
CH2CH=CH2, CH2CH2N+], 4.44–4.72 (m, 2 H, NCH2-triazole),
4.72–4.89 (m, 2 H, N+CH2C6H4), 4.96–5.24 (m, 2 H, CH2CH=CH2),
5.41–5.60 (m, 2 H, NCH2C6H5), 5.66–5.93 (m, 1 H, CH2CH=CH2),
7.15–7.73 (m, 10 H, CH2C6H5, C=CHN, N+CH2C6H4).
HRMS–ESI: m/z [M + H]2+ calcd for C52H81N9O9S: 503.7939;
13C NMR (100 MHz, CDCl3): d = 10.5, 10.6 [CH3,
CH(CH3)CH2CH3], 17.7, 18.7 [CH3, CH(CH3)CH2CH3], 20.7, 20.9
(2 CH3, Ac, C6H4CH3), 26.5, 27.1 [CH2, CH(CH3)CH2CH3], 27.4 (3
CH3, t-Bu), 31.3, 31.4, 31.8, 32.1, 33.2, 33.3, 33.7, 33.8, 33.9 (4
CH2, 4 × NCH2CH2C=O), 36.8, 37.0, 39.2, 39.5, 39.7, 39.9, 41.6,
43.0, 44.8 (6 CH2, 4 × NCH2CH2C=O, CH2CH2N+, NCH2-triazole),
47.4, 50.5 (CH2, CH2CH=CH2), 48.9, 49.1 [2 CH3, N+(CH3)2], 53.4
(CH2, NCH2C6H5), 53.8 [CH, CH(CH3)CH2CH3], 59.4 (CH2,
CH2CH2N+), 67.3 (CH2, N+CH2C6H4), 79.9, 80.4 (C, t-Bu), 115.5,
116.2 (CH2, CH2CH=CH2), 120.6, 123.1 (CH, C=CHN), 123.4 (C,
p-N+CH2C6H4), 127.4, 128.0, 128.4, 129.2 (9 CH, CH2C6H5,
N+CH2C6H4), 132.5, 132.8 (CH, CH2CH=CH2), 134.0 (C,
CH2C6H5), 140.3 (C, ipso-N+CH2C6H4), 169.5, 169.6, 169.7, 170.0,
170.3, 170.4, 170.5, 170.7, 170.9, 171.0 (5 C, 5 × C=O).
found: 503.7934.
HPLC [H2O (0.1% TFA)–MeOH, 35:65, flow = 0.50 mL/min]:
tR = 15.91 min, purity = 93%.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are RP-HPLC data for all compounds and NMR spectra of products
1, 2, 3, 4 and 8.
Acknowledgment
This work was supported by funding from the French Ministry of
Higher Education and Research (MESR). We are grateful to the
Carlsberg Foundation for a grant to T.H., and to Aurélie Job and
Bertrand Légeret (Clermont-Université, Laboratoire SEESIB) for
HPLC and mass spectrometric analysis.
HRMS–ESI: m/z [M + H]+ calcd for C47H71N8O6: 843.5497; found:
843.5510.
HPLC [H2O (0.1% TFA)–MeOH, 30:70, flow = 0.50 mL/min]:
tR = 14.00 min, purity = 93%.
Synthesis 2011, No. 2, 257–264 © Thieme Stuttgart · New York

264
C. Caumes et al.
PAPER
(9) Norgren, A. S.; Zhang, S.; Arvidsson, P. I. Org. Lett. 2006,
8, 4533.
References
(1) Present address: Faculty of Life Sciences, IGM, Section for
Bioorganic Chemistry, University of Copenhagen,
Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
Email: thhj@life.ku.dk.
(2) (a) Pseudo-Peptides in Drug Discovery; Nielsen, P. E., Ed.;
Wiley-VCH: Weinheim, 2004. (b) Patch, J. A.; Barron, A.
E. Curr. Opin. Chem. Biol. 2002, 6, 872.
(3) (a) Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner,
V. D.; Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.;
Rosenberg, S.; Marlowe, C. K.; Spellmeyer, D. C.; Tan, R.;
Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P. A.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367. (b) Patch, J.
A.; Kirshenbaum, K.; Seurynck, S. L.; Zuckermann, R. N.;
Barron, A. E. In Pseudo-Peptides in Drug Discovery;
Nielsen, P. E., Ed.; Wiley-VCH: Weinheim, 2004, 1–31.
(4) Hamper, B. C.; Kolodziej, S. A.; Scates, A. M.; Smith, R. G.;
Cortez, E. J. Org. Chem. 1998, 63, 708.
(10) (a) Gorske, B. C.; Jewell, S. A.; Guerard, E. J.; Blackwell, H.
E. Org. Lett. 2005, 7, 1521. (b) Olivos, H. J.; Alluri, P. G.;
Reddy, M. M.; Salony, D.; Kodadek, T. Org. Lett. 2002, 4,
4057. (c) Fowler, S. A.; Stacy, D. M.; Blackwell, H. E. Org.
Lett. 2008, 10, 2329. (d) Messeguer, J.; Cortes, N.; García-
Sanz, N.; Navarro-Vendrell, G.; Ferrer-Montiel, A.;
Messeguer, A. J. Comb. Chem. 2008, 10, 974. (e) Fritz, D.;
Bräse, S. Synlett 2010, 1544.
(11) (a) Dondoni, A. Angew. Chem. Int. Ed. 2008, 47, 8995.
(b) Hoyle, C. E.; Bowman, C. N. Angew. Chem. Int. Ed.
2010, 49, 1540. (c) Lowe, A. B. Polym. Chem. 2010, 1, 17.
(12) (a) Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
(b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (c) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596. (d) Kolb, H. C.; Sharpless, K. B. Drug Discovery
Today 2003, 8, 1128.
(5) Hjelmgaard, T.; Faure, S.; Caumes, C.; De Santis, E.;
Edwards, A. A.; Taillefumier, C. Org. Lett. 2009, 11, 4100.
(6) (a) Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack, R.
L.; Dill, K. A.; Zuckermann, R. N.; Cohen, F. E. Folding
Des. 1997, 2, 369. (b) Kirschenbaum, K.; Barron, A. E.;
Goldsmith, R. A.; Armand, P.; Bradley, E. K.; Truong, K. T.
V.; Dill, K. A.; Cohen, F. E.; Zuckermann, R. N. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 4303. (c) Wu, C. W.; Sanborn,
T. J.; Huang, K.; Zuckermann, R. N.; Barron, A. E. J. Am.
Chem. Soc. 2001, 123, 6778. (d) Sanborn, T. J.; Wu, C. W.;
Zuckermann, R. N.; Barron, A. E. Biopolymers 2002, 63,
12. (e) Lee, B.-C.; Zuckermann, R. N.; Dill, K. A. J. Am.
Chem. Soc. 2005, 127, 10999. (f) Fowler, S. A.;
(13) (a) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39,
1325. (b) Schilling, C.; Jung, N.; Bräse, S. In Click
Chemistry for Biotechnology and Materials Science;
Lahann, J., Ed.; Wiley: Chichester, 2009, Chap. 2, 9.
(c) Jang, H.; Farfarman, A.; Holub, J. M.; Kirshenbaum, K.
Org. Lett. 2005, 7, 1951. (d) Holub, J. M.; Jang, H.;
Kirshenbaum, K. Org. Biomol. Chem. 2006, 4, 1497.
(e) Norgren, A. S.; Budke, C.; Majer, Z.; Heggemann, C.;
Koop, T.; Sewald, N. Synthesis 2009, 488.
(14) Posner, T. Chem. Ber. 1905, 38, 646.
(15) (a) Campos, L. M.; Killops, K. L.; Sakai, R.; Paulusse, J. M.
J.; Damiron, D.; Drockenmuller, D. E.; Messmore, B. M.;
Hawker, C. J. Macromolecules 2008, 41, 7063. (b) Fiore,
M.; Chambery, A.; Marra, A.; Dondoni, A. Org. Biomol.
Chem. 2009, 7, 3910. (c) Nurmi, L.; Lindqvist, J.; Randev,
R.; Syrett, J.; Haddleton, D. M. Chem. Commun. 2009,
2727. (d) Iehl, J.; Nierengarten, J.-F. Chem. Commun. 2010,
46, 4160.
Luechapanichkul, R.; Blackwell, H. E. J. Org. Chem. 2009,
74, 1440. (g) Seo, J.; Barron, A. E.; Zuckermann, R. N. Org.
Lett. 2010, 12, 492.
(7) (a) Fowler, S. A.; Blackwell, H. E. Org. Biomol. Chem.
2009, 7, 1508. (b) Zuckermann, R. N.; Kodadek, T. Curr.
Opin. Mol. Ther. 2009, 11, 299. (c) Yoo, B.; Kirshenbaum,
K. Curr. Opin. Chem. Biol. 2008, 12, 714.
(8) Roy, O.; Faure, S.; Thery, V.; Didierjean, C.; Taillefumier,
C. Org. Lett. 2008, 10, 921.
(16) Fiore, M.; Marra, A.; Dondoni, A. J. Org. Chem. 2009, 74,
4422.
(17) Cohen, S. G.; Chao, H. M. J. Am. Chem. Soc. 1968, 90, 165.
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