Dimeric building blocks for solid-phase synthesis of α-peptide- β-peptoid chimeras

Article abstract of DOI:10.1055/s-2008-1067171

Recently, a novel type of antimicrobial and proteolytically stable peptidomimetic oligomers having an α-peptide-β-peptoid chimeric backbone was reported. The present paper describes efficient protocols for the preparation of a wide range of dimeric buildi

Full text of DOI:10.1055/s-2008-1067171

PAPER
2381
Dimeric Building Blocks for Solid-Phase Synthesis of a-Peptide–b-Peptoid
Chimeras
B
a
uilding
B
locks fo
i
r
SPS
t
a
-
Pe
t
–
b
e
-Peptoid Chimera
B
s
onke,a Line Vedel,a Matthias Witt,b Jerzy W. Jaroszewski,a Christian A. Olsen,*a Henrik Franzyk*a
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark
Fax +45(3533)6040; E-mail: hf@farma.ku.dk
Bruker Daltonik GmbH, Fahrenheitstraße 4, 28359 Bremen, Germany
b
Received 11 December 2007; revised 22 April 2008
for the preparation of different types of such dimeric a-
peptide–b-peptoid building blocks are reported. In addi-
tion, conditions for efficient solid-phase synthesis (SPS)
oligomerization to afford a-peptide–b-peptoid chimeras
Abstract: Recently, a novel type of antimicrobial and proteolytical-
ly stable peptidomimetic oligomers having an a-peptide–b-peptoid
chimeric backbone was reported. The present paper describes effi-
cient protocols for the preparation of a wide range of dimeric build-
ing blocks, displaying different types of side-chains, for use in are described.
solid-phase synthesis (SPS) of libraries of this type of oligomers.
The b-peptoid monomers were obtained by microwave-assisted
O
R'
R
N
O
aza-Michael additions to acrylic esters. Subsequent solution-phase
peptide coupling with suitably protected a-amino acids afforded
dimeric intermediates. Even sluggish peptide couplings, involving
sterically hindered N-alkyl-b-alanines or amino acids with bulky
side-chains, gave high yields on multigram-scale when using micro-
wave (MW) irradiation. Protecting group and side-chain manipula-
tions were performed as one-pot solution-phase procedures to
afford ten different building blocks in good to excellent yields. Fi-
nally, the efficiency of SPS oligomerization of a representative
dimer was demonstrated by preparing 10- to 16-residue homomers
and by the assembly of four different building blocks to give a di-
versely functionalized octamer.
H
N
OH
OH
N
N
R'
n
H
R
O
O
n
1 peptide
3 peptoid
R
O
R'
O
O
N
O
N
N
OH
N
R
OH
H
H
R'
n
n
2 β3-peptide
4 β-peptoid
Key words: peptides, peptoids, Michael addition, solid-phase syn-
thesis, microwave irradiation
Figure 1 Structures of homomeric foldamer backbones
A general synthetic strategy involving coupling of com-
mercial Na-Fmoc-protected amino acids with an N-alky-
lated b-alanine ester was considered the most versatile
and straightforward. Thus, a microwave (MW)-assisted
aza-Michael addition protocol was developed for the
preparation of N-alkylated b-alanine esters. The optimal
conditions for the nucleophilic addition of (S)-1-pheneth-
ylamine (5) to tert-butyl acrylate (6) to give 7 (93%) were
found to be two hours at 150 °C using a two-fold excess
of the acrylate to ensure full conversion of the more ex-
pensive chiral amine component. This procedure also
gave satisfactory results for the more sterically hindered
(S)-1-naphthylethylamine and (S)-1-cyclohexylethyl-
amine, as well as for the less nucleophilic benzylamine
(Scheme 1). By contrast, only about 50% yield of 7 was
obtained after conventional heating to 70 °C for several
days. Furthermore, the purity of the aza-Michael adducts
Peptidomimetic backbone constructs are of broad interest
due to their new structural features and possible biological
activities.1–3 Distinct folding properties of oligomeric
mimics of peptides (1) have been observed for several un-
natural backbones constructed from, for example, b-ami-
no acids (2),4 N-alkylglycine moieties (peptoids; 3),5 g-
amino acids,6 or heterocycles.7 Combining the structural
features of b-peptides and peptoids to give b-peptoids
(4)8,9 results in a potentially valuable extension to the ex-
isting ensemble of peptidomimetic structures (see
Figure 1). Inspired by earlier heterogeneous backbones,10
a chimeric design with alternating chiral b-peptoid and a-
amino acid residues was probed.11 Biological evaluation
of the initial array of oligomers confirmed that this back-
bone design has potential in the development of non-
hemolytic antibacterial peptidomimetics that resist pro-
teolysis.11 An advantage of such novel heteromers over b-
peptoid homomers is the possibility of convenient diver-
sification of the side-chain functionalities via the inclu-
sion of a wide range of commercially available a-amino
acids. In the present paper, optimized synthetic protocols
1
7 and 10–11 were satisfactory (as judged by H and 13C
NMR, and analytical RP-HPLC) after a simple work-up,
followed by removal of excess alkyl acrylate under re-
duced pressure. Due to incomplete conversion of the
amine component, adducts 8 and 9 required chromato-
graphic purification.
A recently reported alternative to these conditions is an
aza-Michael addition performed in a heterogeneous mix-
ture containing water,12 which parallels previous SPS of
SYNTHESIS 2008, No. 15, pp 2381–2390
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067171; Art ID: T19207SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2382
G. Bonke et al.
PAPER
DMSO,
MW,
150 °C
compound 16 appeared to be an extreme case, as standard
TBTU conditions resulted in less than 10% conversion.
An attempted improvement by changing the coupling re-
agent to TFFH was equally unsuccessful. Again, use of
MW irradiation was an obvious choice to enhance the
coupling efficiency, in analogy with a recently reported
MW-assisted SPS assembly of peptoid monomers.14
O
+
O
NH2
HN
7 (93%)
COOtBu
5
6
However, application of MW irradiation at 60, 80 or
100 °C did not improve the conversion to any acceptable
degree when performing the reactions in DMF. On the
other hand, the use of less polar solvents [MeCN or
dichloroethane (DCE)] gave rise to significantly higher
conversions, and further optimization was performed as
shown in Table 1. In addition to TFFH, (tris)pyrrolidino-
phosphonium hexafluorophosphate (PyBOP) was investi-
gated as a coupling reagent in DCE, as high yields of
MW-assisted peptide formation were previously reported
with this reagent,16 but only an inferior conversion into
compound 16 was observed (entry 3, Table 1).
HN
O
O
HN
O
O
8 (65%)
9 (66%)
HN
O
HN
11 (99%)
O
O
O
10 (99%)
NHBoc
Scheme 1 Microwave-assisted aza-Michael addition of amines to
alkyl acrylates
homomeric b-peptoids.9a Even though the ‘on-water’ re-
action concept allows considerable rate accelerations of
various transformations,13 only insignificant formation of
compound 9 was observed under such conditions even af-
ter 16 hours.
i
Fmoc-Lys(Boc)-OH
+
7
N
OtBu
FmocHN
NHBoc
12
O
O
13 (67%)
The required dimeric intermediates (13–20) comprise
combinations of non-chiral (Bn) as well as chiral N-alkyl
side-chains in b-peptoid units with neutral, basic, and
acidic amino acid moieties. The gram-scale preparation of
dimers 13 and 17–19 in 64–88% yield using standard cou-
pling conditions with 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU) was con-
sidered satisfactory, since SPPS assembly of a-chiral pep-
toids proved difficult (Scheme 2).14 By contrast,
preparation of sterically congested building blocks led to
lowered yields [e.g., 28% of 14 using TBTU and 46% of
15 using tetramethylfluoroformamidinium hexafluoro-
phosphate (TFFH)15]. The peptide coupling leading to
R
N
OtBu
FmocHN
N
OtBu
FmocHN
O
O
14 (R = iPr, 28%)
15 (R = tBu, 66%)
O
O
16 (61%)
NHBoc
O
OtBu
OtBu
N
OMe
N
FmocHN
FmocHN
NHBoc
Table 1 Optimization of the Formation of 16 from 9 and 12
O
O
O
O
18 (64%)
17 (88%)
Entry Reagent
9
Solvent
Time
(h)
Temp
(°C)
16:9a
(equiv)
1
2
3
4
5
6
7
TFFH
TFFH
PyBOP
TFFH
TFFH
TFFH
TFFH
1
1
1
1
2
2
2
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
0.5
0.5
0.5
1
60
60
60
60
60
60
80
0.19
0.38
0.05
0.38
0.47
1.46
2.12
N
OtBu
N
O
OtBu
FmocHN
FmocHN
O
O
O
19 (65%)
20 (76%)
0.5
2
Scheme 2 Peptide couplings to afford dimeric intermediates 13–20.
Reagents and conditions: (i) For the synthesis of 13, 14 and 17–19:
corresponding Fmoc-protected amino acid, TBTU, DIPEA, CH2Cl2,
r.t., 16 h. For the synthesis of 15 and 20: TFFH, DIPEA, DCE, MW
60 °C, 0.5 h. For the synthesis of 16: TFFH, DIPEA, DCE, MW
80 °C, 2 h.
2
a Estimated by HPLC (220 nm).
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

PAPER
Building Blocks for SPS of a-Peptide–b-Peptoid Chimeras
2383
In order to detect possible instability of the reaction com- building blocks in moderate to high yields after purifica-
ponents under MW conditions, the individual components tion by vacuum liquid chromatography (VLC; Scheme 4).
were subjected to irradiation and the resulting mixtures The use of milder conditions (10% TFA–CH2Cl2 at 0 °C)
were analyzed by RP-HPLC. Only the acid was prone to and a prolonged reaction time, followed by a simple wash-
degradation, thus it was decided to use a two-fold excess ing procedure, allowed chromatography-free preparation
of the acid and TFFH. Comparison of entries 4 and 5 in of 25 and 26 in 99% and 95% yield, respectively. The di-
Table 1 shows that this resulted in a slight increase in con- amino-functionalized compounds 16, 17 and 20 were con-
version within a shorter time. Finally, the coupling was verted into the corresponding guanidinylated building
optimized with respect to reaction time and temperature blocks as described above for compound 22 (Scheme 4).
(entries 5–7). Thus, the use of TFFH in DCE with MW
R'
heating at 80 °C for two hours provided a satisfactory
61% yield of compound 16.
R
i
14
15
19
N
OH
FmocHN
Synthesis of tert-butylglycine intermediate 15 in DCE us-
ing TFFH as the coupling reagent at room temperature af-
forded 46% yield, but MW irradiation at 60 °C for 30
minutes raised the yield to 66%. Similarly, MW-assisted
coupling gave 76% yield of 20, showing that MW condi-
tions allowed sterically congested a-peptide–b-peptoid
building blocks (i.e., 15, 16, and 20) to be obtainable in
good yields on a gram-scale (Scheme 2).
O
O
24 (89%); R = iPr, R' = Ph
25 (99%); R = tBu, R' = Ph
26 (95%); R = Me, R' = c-Hex
NBoc
BocHN
NH
Cleavage of the tert-butyl ester group in 13 with concom-
itant cleavage of the Boc group using TFA–CH2Cl2, al-
lowed for 2-(trimethylsilyl)ethoxycarbonyl (Teoc)17
protection of the side-chain amino group to give 21, while
R''
N
16
17
20
i, ii
OH
FmocHN
O
O
guanidinylation
with
N,N¢-bis-Boc-1H-pyrazole-1-
27 (58%); R'' = (S)-1-(1-naphthyl)ethyl
28 (89%); R'' = Bn
29 (50%); R'' = (S)-1-cyclohexylethyl
carboxamidine18 gave 22. Furthermore, the Boc group
could be re-installed (one-pot from 13) to give 23
(Scheme 3), which was considered more straightforward
than applying an orthogonal three-dimensional protecting
group strategy, which would require the synthesis of an
additional dipeptide intermediate.
COOtBu
Ph'
iii
18
N
OH
FmocHN
Cleavage of the tert-butyl ester group in 14, 15 and 19 was
similarly accomplished with 40% TFA–CH2Cl2 at room
temperature, to give the corresponding Fmoc-protected
O
O
30 (55%)
Scheme 4 Conversion of intermediates 14–17 and 20 into building
blocks 24–29. Reagents and conditions: (i) For the synthesis of 24 and
27–29: 40% TFA–CH2Cl2, r.t., 0.5–1 h. For the synthesis of 25 and
26: 10% TFA–CH2Cl2, 0 °C, 7–10 h; (ii) N,N¢-bis-Boc-1H-pyrazole-
1-carboxamidine, DIPEA, CH2Cl2 (solvent used for 29: CH2Cl2–
DMF, 1:1), r.t., 16 h; (iii) (a) 1 M NaOH, EtOH, r.t., 3 h; (b) Fmoc-Cl
in 10% aq Na2CO3–dioxane, r.t., 2 h.
NHBoc
NHBoc
i, iv
N
OtBu
N
OH
FmocHN
FmocHN
O
O
O
O
After several unsuccessful attempts to achieve selective
hydrolysis of the methyl ester group in 18 without affect-
ing the Fmoc group, as reported in other cases,19 it was
found more convenient to remove both groups under alka-
line conditions and then re-install the Fmoc group. This
furnished the dipeptide building block 30 in 55% overall
yield in a one-pot procedure (Scheme 4). A truly orthogo-
nal three-dimensional protecting group strategy could
also be envisioned for this building block using an allyl
ester instead of the methyl ester.20 However, the allyl ester
would require cleavage with Pd(PPh3)4, raising the cost of
a large-scale synthesis of this building block considerably.
13
23 (80%)
i, iii
i, ii
NHBoc
NHTeoc
HN
NBoc
N
OH
N
OH
FmocHN
FmocHN
O
O
O
O
21 (74%)
22 (77%)
Scheme 3 Conversion of intermediate 13 into building blocks 21–
23. Reagents and conditions: (i) 40% TFA–CH2Cl2, r.t., 0.5 h; (ii) 2-
(trimethylsilyl)ethyl p-nitrophenyl carbonate, DIPEA, CH2Cl2, r.t., 16
h; (iii) N,N¢-bis-Boc-1H-pyrazole-1-carboxamidine, DIPEA, CH2Cl2,
r.t., 16 h; (iv) Boc2O, DIPEA, THF, r.t., 16 h.
To demonstrate the utility of the prepared building blocks,
compound 23 was submitted to SPS in order to generate a
series of chimeric oligomers up to the hexadecamer length
(Scheme 5 and Table 2). By using only two equivalents of
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

2384
G. Bonke et al.
PAPER
23 in each coupling step, good yields of the oligomers
were obtained. In addition to the standard Fmoc depro-
tection, subsequent treatment with DBU–piperidine–
N-methylpyrrolidinone (2:2:96) proved beneficial, as also
described for the SPS of b-peptides.21
NH2
i–iii
iv, v
H2N
O
N
NH2
n
Rink resin
(0.65 mmol/g)
n cycles
N
H
O
O
31a (n = 5)
31b (n = 6)
31c (n = 7)
31d (n = 8)
Figure 2 Structure and RP-HPLC traces (215 nm) of compound 32;
crude (left) and purified (right)
peptide couplings involving sterically hindered amines,
may also prove generally useful for other applications in
organic synthesis.
Scheme 5 SPS oligomerization of building block 23. Reagents and
conditions: (i) 23, PyBOP, DIPEA, DMF, r.t., 1.5 h; (ii) 20% piperi-
dine–DMF (2 × 10 min); (iii) 2% DBU and 2% piperidine in NMP (10
min, and then repeated for 5 min); (iv) Ac2O–DIPEA–DMF (1:2:3),
r.t., 0.5 h; (v) 95% TFA–CH2Cl2, r.t., 1 h.
Starting materials were obtained from commercial suppliers and
used without further purification. Water for HPLC was filtered
through a 0.22 mm membrane filter. Vacuum liquid chromatography
(VLC) was performed using silica gel 60H, 5–40 mm (average size
15 mm). The preparative HPLC system consisted of two preparative
pump units, a UV detector, and a Phenomenex Luna C18(2) (5 mm)
column (25 × 2.12 cm). Linear elution gradients were composed by
mixing solvent A (MeCN–H2O–TFA, 5:95:0.1) and B (MeCN–
H2O–TFA, 95:5:0.1) at a flow rate of 20 mL/min. Analytical HPLC
separations were performed using a Phenomenex Luna C18(2) (3
mm) column (150 × 4.6 mm). Linear elution gradients were com-
posed by mixing solvent C (MeCN–H2O–HCO2H, 5:95:0.1) and D
(MeCN–H2O–HCO2H, 95:5:0.1) at a flow rate of 0.8 mL/min. A
gradient with eluent D rising linearly from 0% to 80% during 5 min,
followed by a linear rise to 100% D during 25 min was applied for
the dimeric intermediates and final building blocks, whereas a gra-
dient with eluent D rising linearly from 10% to 60% during 30 min
followed by a linear rise to 100% D during 10 min was applied for
the oligomers. 1H and 13C NMR spectra were recorded at 300 MHz
and 75 MHz, respectively, using CDCl3 or CD3OD as solvents.
Coupling constants (J values) are given in hertz (Hz). Multiplicities
of the 1H NMR signals are reported as follows: singlet (s), doublet
(d), triplet (t), quartet (q), pentet (pent), multiplet (m) and broad
(br). HRMS were recorded using a Fourier-transform mass spec-
trometer equipped with a 9.4 tesla superconducting cryomagnet and
an external electrospray ion source. The spectra were externally cal-
ibrated with arginine clusters and measured in positive ion mode.
The samples were dissolved in MeOH, further diluted with 50%
MeOH containing 0.2% HCO2H, and introduced using a syringe
pump with a flow of 2 mL/min. A Biotage Initiator microwave reac-
tor system was operated in the single mode using Emrys™ Process
Vials (0.5–2.0 mL or 10–20 mL). The experiments were carried out
using a fixed hold time with variable power to reach and maintain
the set temperature in the vessel for the programmed period of time.
Table 2 Synthesis, Yield, Purity and MS Data of Oligomers 31a–d
Oligomer Yield (%)a Purity (%)b [M + nH]n+ calcdc Found (m/e)c
31a
31b
31c
31d
56
47
32
30
99
99
96
99
526.01078
627.07567
546.35724
622.15591
526.01066
627.07536
546.35734
622.15589
a Upon purification by preparative HPLC (79, 79, 62 and 67 mg, re-
spectively, were obtained).
b As judged by analytical HPLC.
c n = 3 for compounds 31a–b; n = 4 for compounds 31c–d.
Finally, we demonstrated that diversely functionalized
chimeras may also be obtained, as four different building
blocks (24–27) were efficiently coupled to give the a-pep-
tide–b-peptoid chimera 32 in excellent yield (69% i.e.,
>96% per SPS step; Figure 2). Thus, the building blocks
described here enable SPS of a wide variety of a-peptide–
b-peptoid chimeras for future structural as well as biolog-
ical investigations, which are in progress in our laborato-
ries.
In conclusion, practical synthetic protocols for the prepa-
ration of a variety of dimeric a-peptide–b-peptoid build-
ing blocks for SPPS oligomerization have been
developed. Importantly, only readily available starting
materials were employed and the procedures allowed
multigram-scale preparations. The utility of these build-
ing blocks for the preparation of a-peptide–b-peptoid chi-
meras of various lengths and diverse compositions using
standard Fmoc SPPS conditions was also demonstrated.
The biological evaluation of compounds 31a–d have fur-
nished the first non-hemolytic, antiplasmodial peptidomi-
metics with an unnatural backbone construct.22 The
described MW-assisted aza-Michael additions, as well as
Aza Michael Addition; Typical Procedure
tert-Butyl acrylate (9.0 mL, 62 mmol) and (S)-1-phenethylamine
(4.0 mL, 31 mmol) were dissolved in DMSO (7 mL) and stirred in
a sealed vessel under MW irradiation at 150 °C for 2 h. The mixture
was cooled to r.t., diluted with EtOAc (300 mL) and washed with
H2O (4 × 100 mL) and brine (100 mL). The organic layer was dried
(Na2SO4), filtered, concentrated and lyophilized. The crude adduct
711 was used without further purification (as was the case for the
other Michael adducts unless otherwise stated below).
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Building Blocks for SPS of a-Peptide–b-Peptoid Chimeras
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7
mixture was stirred for 10 min then the Michael adduct was added
in a minimum amount of CH2Cl2. The mixture was stirred at r.t. un-
der N2 for 16 h, after which the solvent was removed in vacuo. The
residue was dissolved in EtOAc (20–40 mL/mmol) and washed
with H2O (10–20 mL), 1 M HCl (2 × 10–20 mL), sat. NaHCO3 (10–
20 mL), and brine (10–20 mL). Drying (Na2SO4), filtration and
evaporation afforded the crude product, which was dissolved in
CH2Cl2 and purified by VLC.
Yield: 14.5 g (93%); RP-HPLC: 95.5% at 267 nm (tR = 10.4 min).
1H NMR (300 MHz, CD3OD): d = 1.34 (d, J = 6.6 Hz, 3 H, CH3),
1.42 [s, 9 H, C(CH3)3], 2.31–2.46 (m, 2 H, COCH2), 2.56–2.67 (m,
2 H, NCH2), 3.73 (q, J = 6.6 Hz, 1 H, CH), 7.19–7.35 (m, 5 H, Ph).
13C NMR (75 MHz, CD3OD): d = 24.4, 28.4, 36.1, 43.9, 59.2, 81.6,
127.6, 128.0, 129.4, 145.7, 173.2.
HRMS: m/z [M + H]+ calcd for C15H24NO2: 250.18016; found:
250.18016.
1311
Prepared using general procedure A (1.1 equiv TBTU) and purified
by VLC (6 × 6 cm; hexane–EtOAc, 10:1 → 3:1).
8
Purified by VLC (6 × 6 cm; CH2Cl2–MeOH, 60:1 → 40:1).
Yield: 2.45 g (67%); RP-HPLC: 99.8% at 267 nm (tR = 21.2 min).
1H NMR (300 MHz, CD3OD): d = 1.30–1.57 (br m, 4 H, g-CH2, d-
CH2), 1.37 [s, 9 H, C(CH3)3], 1.40* [s, 9 H, C(CH3)3], 1.41 [s, 9 H,
C(CH3)3], 1.53* (d, J = 7.0 Hz, 3 H, CH3), 1.60–1.78 (br m, 2 H, b-
CH2), 1.67 (d, J = 6.8 Hz, 3 H, CH3), 2.05 (ddd, J = 15.5, 10.0, 5.3
Hz, 1 H, COCHAHB), 2.37 (ddd, J = 15.5, 10.6, 5.8 Hz, 1 H, CO-
CHAHB), 2.50* (m, 2 H, COCH2), 2.98–3.09 (br m, 2 H, e-CH2),
3.10–3.40 (br m, 2 H, NCH2), 3.45* (br t, J = 7.6 Hz, 2 H, NCH2),
4.15–4.27 (br m, 1 H, Fmoc-CH), 4.32–4.40 (br m, 2 H, Fmoc-
CH2), 4.45* (dd, J = 7.9, 5.3 Hz, 1 H, H-a), 4.79 (dd, J = 7.9, 5.3
Hz, 1 H, H-a), 5.42 (q, J = 6.8 Hz, 1 H, NCH), 5.81* (q, J = 7.0 Hz,
1 H, NCH), 7.20–7.45 (m, 9 H, Ph and Fmoc ArH), 7.68 (m, 2 H,
Fmoc ArH), 7.80 (d, J = 7.6 Hz, 2 H, Fmoc ArH). Signals desig-
nated with * correspond to additional peaks due to the presence of
a minor rotamer.
Yield: 4.25 g (65%); RP-HPLC: 97.6% at 267 nm (tR = 10.2 min).
1H NMR (300 MHz, CD3OD): d = 1.44 [s, 9 H, C(CH3)3], 2.46 (t,
J = 6.8 Hz, 2 H, COCH2), 2.79 (t, J = 6.8 Hz, 2 H, NCH2), 3.74 (s,
2 H, PhCH2), 7.21–7.36 (m, 5 H, Ph).
13C NMR (75 MHz, CD3OD): d = 28.4, 35.8, 45.2, 54.2, 81.8, 128.2,
129.4, 139.9, 173.1.
HRMS: m/z [M + H]+ calcd for C14H22NO2: 236.16451; found:
236.16450.
9
Purified by VLC (6 × 6 cm; CH2Cl2–MeOH, 50:1 to CH2Cl2–
MeOH–NH3 (concd), 300:10:1).
Yield: 6.89 g (66%); RP-HPLC: 97.1% at 267 nm (tR = 10.6 min).
13C NMR (75 MHz, CD3OD): d = 17.1*, 18.2, 24.1, 24.2*, 28.3,
28.8, 30.5*, 30.6, 32.9, 35.2, 37.6*, 40.2, 40.3*, 40.9, 41.0*, 48.4,
52.8, 53.1*, 53.4*, 56.0, 67.9, 79.7, 81.6, 82.1*, 120.8, 126.1,
128.0, 128.2, 128.3*, 128.5, 128.6, 128.7*, 129.6, 140.7, 141.6*,
142.4, 145.0, 145.1*, 158.2 (2 × C), 171.6*, 172.3, 173.9, 174.8*.
Signals designated with * correspond to additional peaks due to the
presence of a minor rotamer.
1H NMR (300 MHz, CD3OD): d = 1.40 [s, 9 H, C(CH3)3], 1.47 (d,
J = 6.5 Hz, 3 H, CH3), 2.42 (br t, J = 6.5 Hz, 2 H, COCH2), 2.67–
2.80 (m, 2 H, NCH2), 4.67 (q, J = 6.5 Hz, 1 H, NCH), 7.43–7.55 (m,
3 H, 3 × ArH), 7.62 (br d, J = 7.1 Hz, 1 H, ArH), 7.76 (br d, J = 8.2
Hz, 1 H, ArH), 7.87 (br d, J = 8.0 Hz, 1 H, ArH), 8.16 (br d, J = 8.5
Hz, 1 H, ArH).
13C NMR (75 MHz, CD3OD): d = 23.5, 28.4, 36.3, 44.0, 53.9, 81.8,
123.4, 123.6, 126.4, 127.0, 128.3, 129.9, 132.5, 135.3, 141.3, 173.4.
HRMS: m/z [M + H]+ calcd for C19H26NO2: 300.19581; found:
HRMS: m/z [M + H]+ calcd for C41H54N3O7: 700.39563; found:
700.39541.
300.19596.
14
Prepared using general procedure A (1.5 equiv TBTU) and purified
by VLC (6 × 6 cm; hexane–EtOAc, 15:1 → 6:1).
10
Yield: 5.96 g (99%).
Yield: 0.51 g (28%); RP-HPLC: 95.6% at 267 nm (tR = 21.9 min).
1H NMR (300 MHz, CD3OD): d = 0.90–1.50 (m, 6 H, c-Hex), 1.00
(d, J = 6.5 Hz, 3 H, CH3), 1.45 [s, 9 H, C(CH3)3], 1.64–1.83 (m,
5 H, c-Hex), 2.38–2.50 (m, 3 H, COCH2 and NCH), 2.69–2.87 (m,
2 H, NCH2).
13C NMR (75 MHz, CD3OD): d = 16.4, 27.6, 27.7, 27.8, 28.4, 29.0,
31.1, 35.9, 43.5, 43.8, 58.7, 81.7, 173.5.
1H NMR (300 MHz, CD3OD): d = 0.93* (d, J = 6.9 Hz, 6 H, g-
CH3), 0.98 (d, J = 6.6 Hz, 6 H, g-CH3), 1.37 [s, 9 H, C(CH3)3],
1.38* [s, 9 H, C(CH3)3], 1.51* (d, J = 7.1 Hz, 3 H, CH3), 1.64 (d,
J = 6.9 Hz, 3 H, CH3), 1.98–2.22 (br m, 3 H, COCHAHB, b-CH2),
2.30–2.46 (br m, 1 H, COCHAHB), 3.14 (ddd, J = 15.9, 10.2, 5.6 Hz,
1 H, NCH2), 3.34 (m, 1 H, NCH2), 3.52* (m, 2 H, NCH2), 4.16–
4.24 (br m, 1 H, Fmoc-CH), 4.27* (d, J = 8.2 Hz, 1 H, H-a), 4.32–
4.40 (br m, 2 H, Fmoc-CH2), 4.62 (d, J = 8.2 Hz, 1 H, H-a), 5.52 (q,
J = 6.9 Hz, 1 H, NCH), 5.80* (q, J = 7.1 Hz, 1 H, NCH), 7.20–7.50
(m, 9 H, Ph and Fmoc ArH), 7.66 (m, 2 H, Fmoc ArH), 7.80 (d,
J = 7.4 Hz, 2 H, Fmoc ArH). Signals designated with * correspond
to additional peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.1*, 18.2, 18.4, 18.7*, 20.0*,
20.3, 28.3, 32.2, 32.5*, 35.1, 37.7*, 40.0, 40.4*, 48.4, 53.7*, 56.2,
58.0, 58.4*, 67.8*, 68.0, 81.7, 82.0*, 120.8, 126.1, 128.0, 128.1,
128.3, 128.5*, 128.6 (2 × C), 128.7*, 129.5, 140.7, 141.5*, 142.4,
145.0, 145.1*, 158.3,* 158.4, 171.5*, 172.3, 173.6, 174.1*. Signals
designated with * correspond to additional peaks due to the pres-
ence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C15H30NO2: 256.22711; found:
256.22718.
11
Yield: 6.35 g (99%); RP-HPLC: 99.5% at 267 nm (tR = 9.5 min).
1H NMR (300 MHz, CD3OD): d = 1.35 (d, J = 6.8 Hz, 3 H, CH3),
2.48 (br t, J = 6.5 Hz, 2 H, COCH2), 2.58–2.72 (m, 2 H, NCH2),
3.64 (s, 3 H, OCH3), 3.75 (q, J = 6.8 Hz, 1 H, NCH), 7.20–7.33 (m,
5 H, Ph).
13C NMR (75 MHz, CD3OD): d = 24.0, 34.7, 43.7, 52.1, 59.2, 127.6,
128.0, 129.4, 145.6, 174.2.
HRMS: m/z [M + H]+ calcd for C12H18NO2: 208.13321; found:
208.13324.
HRMS: m/z [M + H]+ calcd for C35H43N2O5: 571.31665; found:
571.31659.
Solution-Phase Peptide Coupling; General Procedure (A)
The amino acid derivative (1.1 equiv), TBTU (1.1 or 1.5 equiv), and
DIPEA (2.5 equiv) were dissolved in CH2Cl2 (~10 mL/mmol). The
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

2386
17
G. Bonke et al.
PAPER
13C NMR (75 MHz, CD3OD): d = 17.1*, 17.8, 18.3*, 18.8, 27.0*,
27.1, 27.2 (2 × C), 27.3, 27.4*, 28.4, 31.0*, 31.3 (2 × C), 31.6*,
35.3, 37.5*, 38.9, 41.9*, 42.8, 48.3 (2 × C), 48.6* (2 × C), 59.4,
67.9, 81.8, 82.1*, 120.8, 126.1, 126.2*, 128.0, 128.6*, 142.4, 145.0,
145.1*, 157.6, 157.9*, 171.9*, 172.5, 174.6, 175.4*. Signals desig-
nated with * correspond to additional peaks due to the presence of
a minor rotamer.
Prepared using general procedure A (1.5 equiv TBTU) and purified
by VLC (6 × 6 cm; hexane–EtOAc, 10:1 → 2:1).
Yield: 6.30 g (88%); RP-HPLC: 96.7% at 267 nm (tR = 20.3 min).
1H NMR (300 MHz, CD3OD): d = 1.28–1.77 (br m, 6 H, b-CH2, g-
CH2, d-CH2), 1.37 [s, 9 H, C(CH3)3], 1.40 [s, 9 H, C(CH3)3], 1.42 [s,
9 H, C(CH3)3], 2.30–2.71 (br m, 2 H, COCH2), 2.96 (m, 1 H, HA-e),
3.04 (m, 1 H, HB-e), 3.45–3.72 (br m, 2 H, NCH2), 4.15–4.25 (br m,
1 H, Fmoc-CH), 4.30–4.44 (br m, 2 H, Fmoc-CH2), 4.50–4.82 (br
m, 3 H, H-a and PhCH2), 7.21–7.41 (br m, 9 H, Ph and Fmoc ArH),
7.66 (m, 2 H, Fmoc ArH), 7.79 (d, J = 7.4 Hz, 2 H, Fmoc ArH).
13C NMR (75 MHz, CD3OD): d = 24.0, 24.1*, 26.9, 28.4, 30.6, 32.9,
35.6, 40.9, 41.0*, 44.2, 44.3*, 48.4, 52.6, 52.8, 67.9, 79.7, 81.8,
120.8, 126.1, 128.0, 128.3*, 128.6, 129.5, 129.8 (2 × C), 138.1,
138.4*, 142.4, 145.0, 145.1*, 158.3 (2 × C), 172.4, 174.6, 174.7*.
Signals designated with * correspond to additional peaks due to the
presence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C33H45N2O5: 549.33230; found:
549.33240.
Solution-Phase Peptide Coupling with Microwave Irradiation;
General Procedure (B)
The amino acid derivative (2–4 mmol; 1.1 or 2.0 equiv), TFFH (1.1
or 2.0 equiv), and DIPEA (1.5 or 2.5 equiv) were dissolved in DCE
(5–10 mL) and stirred for 10 min in an Emrys Process Vial (20 mL)
for use in the Biotage Initiator MW reactor. The Michael adduct in
DCE (3–4 mL) was added, the vessel was sealed, and the mixture
was heated (MW) to 60 °C or 80 °C for 0.5–2 h applying the power
necessary to reach and maintain the set temperature. Upon cooling
to r.t., the reaction mixture was diluted with EtOAc (150 mL) and
washed successively with 1 M HCl (3 × 75 mL), H2O (1 × 75 mL),
0.1 M NaOH (3 × 75 mL) and brine (1 × 75 mL), dried (Na2SO4),
and evaporated in vacuo. The residue was dissolved in CH2Cl2 (10–
15 mL) and purified by VLC.
HRMS: m/z [M + H]+ calcd for C40H52N3O7: 686.37998; found:
686.37981.
18
Prepared using general procedure A (1.1 equiv TBTU) and purified
by VLC (5 × 5 cm; hexane–EtOAc, 10:1 → 5:1).
Yield: 1.31 g (64%); RP-HPLC: 99.8% at 267 nm (tR = 18.8 min).
15
1H NMR (300 MHz, CDCl3): d = 1.46* [s, 9 H, C(CH3)3], 1.47 [s,
9 H, C(CH3)3], 1.58* (d, J = 7.0 Hz, 3 H, CH3), 1.73 (d, J = 6.8 Hz,
3 H, CH3), 1.88 (br m, 1 H, HA-b), 1.96–2.20 (br m, 1 H, HB-b),
2.28–2.46 (br m, 2 H, g-CH2), 2.47–2.79 (br m, 2 H, COCH2), 3.28
(ddd, J = 15.9, 10.6, 5.3 Hz, 1 H, NCHAHB), 3.39* (ddd, J = 15.9,
10.6, 5.3 Hz, 2 H, NCH2), 3.49–3.70 (br m, 1 H, NCHAHB), 3.63 (s,
3 H, OCH3), 3.66* (s, 3 H, OCH3), 4.34 (br t, J = 7.2 Hz, 1 H,
Fmoc-CH), 4.35–4.46 (br m, 2 H, Fmoc-CH2), 4.66* (m, 1 H, H-a),
5.04 (m, 1 H, H-a), 5.41 (q, J = 6.8 Hz, 1 H, NCH), 6.00* (q, J = 7.0
Hz, 1 H, NCH), 5.76* (d, J = 8.8 Hz, 1 H, NH), 5.88 (d, J = 8.2 Hz,
1 H, NH), 7.28–7.38 (br m, 7 H, Ph, Fmoc ArH), 7.43 (br t, J = 7.3
Hz, 2 H, Fmoc Ar-H), 7.64 (m, 2 H, Fmoc ArH), 7.79 (d, J = 7.3
Hz, 2 H, Fmoc ArH). Signals designated with * correspond to addi-
tional peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CDCl3): d = 16.9*, 17.9, 28.2, 28.6*, 28.8, 30.8,
31.1*, 33.1, 35.6*, 39.1, 47.2, 50.6, 51.1*, 51.7, 51.9*, 54.7, 67.1,
80.8, 120.0, 125.2, 126.9, 127.1, 127.2*, 127.7*, 127.9*, 128.7,
128.8, 139.2, 140.2*, 141.2, 143.7, 143.9*, 156.1, 156.2*, 171.1*,
171.5, 172.0 (2 × C), 172.5*. Signals designated with * correspond
to additional peaks due to the presence of a minor rotamer.
Prepared using general procedure B (1.1 equiv TFFH, and MW to
60 °C for 0.5 h) and purified by VLC (5 × 5 cm; hexane–EtOAc,
15:1 → 9:1).
Yield: 0.77 g (66%); RP-HPLC: 99.3% at 267 nm (tR = 23.9 min).
1H NMR (300 MHz, CD3OD): d = 0.98* (s, 9 H, g-CH3), 1.05 (s,
9 H, g-CH3), 1.39 [s, 9 H, C(CH3)3], 1.49* (d, J = 7.1 Hz, 3 H,
CH3), 1.63 (d, J = 6.8 Hz, 3 H, CH3), 2.15 (ddd, J = 16.1, 10.0, 5.3
Hz, 1 H, COCHAHB), 2.32–2.60* (br m, 2 H, COCH2), 2.38 (ddd,
J = 16.1, 10.3, 5.6 Hz, 1 H, COCHAHB), 3.10 (ddd, J = 15.3, 10.0,
5.6 Hz, 1 H, NCHAHB), 3.19–3.47 (br m, 1 H, NCHAHB), 3.60*
(ddd, J = 15.6, 10.3, 5.0 Hz, 1 H, NCHAHB), 4.15–4.24 (br m, 1 H,
Fmoc-CH), 4.26–4.49 (br m, 3 H, H-a, Fmoc-CH2), 5.52 (q, J = 6.8
Hz, 1 H, NCH), 5.81* (q, J = 7.1 Hz, 1 H, NCH), 7.13–7.41 (m,
9 H, Ph, Fmoc ArH), 7.64 (d, J = 7.4 Hz, 2 H, Fmoc ArH), 7.78 (m,
2 H, Fmoc ArH). Signals designated with * correspond to additional
peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.1*, 17.9, 27.1*, 27.2, 28.3,
35.2, 36.7, 36.9*, 37.8*, 39.8, 40.8*, 48.4, 48.5*, 53.5*, 56.8, 58.3,
59.1*, 67.6*, 68.1, 81.7, 82.0*, 120.8, 126.0*, 126.1, 128.0, 128.1,
128.5*, 128.6, 128.7, 129.5, 141.0, 141.6*, 142.4, 145.0, 145.1*,
158.1*, 158.2, 171.6*, 172.3, 173.0, 173.2*. Signals designated
with * correspond to additional peaks due to the presence of a minor
rotamer.
HRMS: m/z [M + H]+ calcd for C36H43N2O7: 615.30643; found:
615.30649.
19
HRMS: m/z [M + H]+ calcd for C36H45N2O5: 585.33230; found:
585.33246.
Prepared using general procedure A (1.1 equiv TBTU) and purified
by VLC (5 × 5 cm; hexane–EtOAc, 10:1 → 4:1).
Yield: 1.39 g (65%); RP-HPLC: 99.7% at 267 nm (tR = 24.0 min).
16
1H NMR (300 MHz, CD3OD): d = 0.80–1.50 (br m, 5 H, c-Hex),
1.15* (d, J = 7.0 Hz, 3 H, CH3), 1.22 (d, J = 6.5 Hz, 3 H, CH3), 1.25
(d, J = 7.0 Hz, 3 H, b-CH3), 1.28* (d, J = 6.9 Hz, 3 H, b-CH3), 1.44
[s, 9 H, C(CH3)3], 1.50–1.83 (br m, 6 H, c-Hex), 2.42 (ddd, J = 15.9,
10.0, 5.9 Hz, 1 H, COCHAHB), 2.52–2.67 (br m, 1 H, COCHAHB),
2.91* (m, 2 H, COCH2), 3.24 (m, 1 H, NCHAHB), 3.45–3.62 (br m,
2 H, NCH, NCHAHB), 4.18 (br t, J = 6.9 Hz, 1 H, Fmoc-CH), 4.23–
4.37 (br m, 2 H, Fmoc-CH2), 4.50* (q, J = 6.9 Hz, 1 H, H-a), 4.69
(q, J = 7.0 Hz, 1 H, H-a), 7.28 (br t, J = 7.3 Hz, 2 H, Fmoc ArH),
7.36 (br t, J = 7.3 Hz, 2 H, Fmoc ArH), 7.65 (m, 2 H, Fmoc ArH),
7.77 (d, J = 7.3 Hz, 2 H, Fmoc ArH). Signals designated with * cor-
respond to additional peaks due to the presence of a minor rotamer.
Prepared using general procedure B (2.0 equiv TFFH, and MW at
80 °C for 2 h) and purified by VLC (7 × 8 cm; heptane–EtOAc, 5:1
→ 4:1 then heptane–acetone, 10:1 → 4:1).
Yield: 3.04 g (61%); RP-HPLC: 99.1% at 267 nm (tR = 23.7 min).
1H NMR (300 MHz, CD3OD): d = 1.20–1.68 (br m, 6 H, b-CH2, g-
CH2, d-CH2), 1.30 [s, 9 H, C(CH3)3], 1.39 [s, 9 H, C(CH3)3], 1.63 (d,
J = 7.1 Hz, 3 H, CH3), 1.76 (m, 1 H, COCHAHB), 2.06 (m, 1 H, CO-
CHAHB), 2.91–3.02 (br m, 2 H, e-CH2), 3.27 (m, 1 H, NCHAHB),
3.48 (m, 1 H, NCHAHB), 4.23 (br t, J = 6.8 Hz, 1 H, Fmoc-CH),
4.32–4.45 (br m, 3 H, H-a, Fmoc-CH2), 6.48 (q, J = 7.1 Hz, 1 H,
NCH), 7.33 (br t, J = 7.3 Hz, 2 H, Fmoc ArH), 7.35 (br t, J = 7.3 Hz,
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

PAPER
Building Blocks for SPS of a-Peptide–b-Peptoid Chimeras
2387
2 H, Fmoc ArH), 7.47 (m, 3 H, ArH), 7.70 (m, 3 H, ArH), 7.79–7.83
(m, 3 H, ArH, Fmoc ArH), 7.90 (m, 2 H, ArH).
Anal. Calcd for C38H49N3O7Si: C, 66.35; H, 7.18; N, 6.11. Found:
C, 66.29; H, 7.31; N, 6.03.
13C NMR (75 MHz, CD3OD): d = 17.0, 24.3, 28.3, 28.8, 30.6, 33.3,
37.3, 39.6, 41.1, 48.4, 50.0, 53.2, 67.8, 79.7, 81.9, 120.8, 124.1,
126.1, 126.2, 127.0, 127.6, 128.0, 128.6, 129.9, 133.0, 135.0, 136.1,
142.4, 145.1, 158.3 (2 × C), 171.2, 174.4.
2211
The crude product obtained from deprotection of 13 was dissolved
in CH2Cl2 (5 mL/mmol), and DIPEA (5 equiv) was added followed
by N,N¢-bis-Boc-1H-pyrazole-1-carboxamidine (1.2 equiv) in
CH2Cl2 (5 mL/mmol). The mixture was stirred at r.t. for 16 h then
concentrated and purified by VLC (6 × 8 cm; hexane–EtOAc, 5:1 to
hexane–EtOAc–AcOH, 66:33:0.1).
HRMS: m/z [M + H]+ calcd for C45H56N3O7: 750.41128; found:
750.41131.
20
Yield: 5.70 g (77%); RP-HPLC: 96.0% at 267 nm (tR = 18.9 min).
1H NMR as reported.11
Prepared using general procedure B (2.0 equiv TFFH, and MW to
60 °C for 0.5 h) and purified by VLC (5 × 5 cm; hexane–EtOAc,
10:1 → 5:1).
13C NMR (75 MHz, CD3OD): d = 17.1*, 18.1, 24.1, 24.3*, 28.3,
28.6, 29.8, 33.0*, 33.2, 33.8, 36.3*, 40.4, 40.5*, 41.5, 41.6*, 48.4,
52.7, 53.1*, 53.5*, 56.0, 67.9, 80.3, 84.3, 120.8, 126.1, 128.0,
128.2, 128.3*, 128.5*, 128.6, 128.7, 129.6, 140.7, 141.6*, 142.4,
144.9*, 145.1, 154.0, 157.3, 158.2, 158.3*, 164.3, 173.9, 174.1*,
174.8*, 174.9. Signals designated with * correspond to additional
peaks due to the presence of a minor rotamer.
Yield: 1.05 g (76%); RP-HPLC: 98.7% at 267 nm (tR = 25.7 min).
1H NMR (300 MHz, CD3OD): d = 0.80–1.50 (br m, 5 H, c-Hex),
1.16* (d, J = 6.8 Hz, 3 H, CH3), 1.25 (d, J = 6.5 Hz, 3 H, CH3),
1.30–1.86 (br m, 6 H, b-CH2, g-CH2, d-CH2), 1.41 [s, 9 H,
C(CH3)3], 1.45 [s, 9 H, C(CH3)3], 1.50–1.86 (br m, 6 H, c-Hex),
2.41 (ddd, J = 16.1, 10.3, 5.6 Hz, 1 H, COCHAHB), 2.53–2.67 (br m,
1 H, COCHAHB), 2.88* (m, 2 H, COCH2), 3.03 (m, 2 H, e-CH2),
3.23 (m, 1 H, NCHAHB), 3.48–3.66 (br m, 2 H, NCH, NCHAHB),
4.20 (br t, J = 6.8 Hz, 1 H, Fmoc-CH), 4.27–4.38 (br m, 2 H, Fmoc-
CH2), 4.45* (br t, J = 6.5 Hz, 1 H, H-a), 4.65 (dd, J = 8.2, 4.6 Hz,
1 H, H-a), 7.29 (br t, J = 7.6 Hz, 2 H, Fmoc ArH), 7.38 (br t, J = 7.3
Hz, 2 H, Fmoc ArH), 7.66 (m, 2 H, Fmoc ArH), 7.78 (d, J = 7.6 Hz,
2 H, Fmoc ArH). Signals designated with * correspond to additional
peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.2*, 17.9, 23.8, 24.2*, 27.0*,
27.1, 27.2, 27.3, 27.4*, 28.4, 28.9, 30.6, 31.1*, 31.2, 31.4, 31.7*,
33.0*, 33.4, 35.3, 37.6*, 39.0, 40.9*, 41.1, 41.8*, 42.8, 48.4, 52.6,
53.3*, 59.5, 67.8, 67.9*, 79.7, 81.8, 82.2*, 120.8, 126.1, 126.2*,
128.0, 128.6*, 142.4, 144.9*, 145.1, 158.0, 158.3, 171.9*, 172.5,
174.0, 174.7*. Signals designated with * correspond to additional
peaks due to the presence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C43H56N5O9: 786.40725; found:
786.40687.
23
The crude product obtained from deprotection of 13 was dissolved
in THF (4 mL/mmol) and then Boc2O (1.2 equiv) in THF (1 mL/
mmol) and DIPEA (6 equiv) were added. The mixture was stirred
for 16 h then diluted with EtOAc (200 mL) and washed successively
with 1 M HCl (3 × 100 mL), H2O (8 × 100 mL until pH 7) and brine
(1 × 100 mL), dried (Na2SO4), and evaporated in vacuo. The residue
was purified on a VLC column (7 × 5.5 cm; hexane–EtOAc, 10:1 to
hexane–EtOAc–AcOH, 50:50:0.1).
Yield: 2.92 g (80%); RP-HPLC: 96.0% at 267 nm (tR = 15.5 min).
1H NMR (300 MHz, CD3OD): d = 1.32–1.53 (br m, 4 H, g-CH2, d-
CH2), 1.41 [s, 9 H, C(CH3)3], 1.55* (d, J = 7.0 Hz, 3 H, CH3), 1.61–
1.78 (br m, 2 H, b-CH2), 1.67 (d, J = 7.0 Hz, 3 H, CH3), 2.14 (ddd,
J = 15.8, 10.1, 5.3 Hz, 1 H, COCHAHB), 2.44 (ddd, J = 15.8, 10.1,
5.3 Hz, 1 H, COCHAHB), 2.48–2.70* (br m, 2 H, COCH2), 2.97–
3.09 (br m, 2 H, e-CH2), 3.19 (m, 1 H, NCHAHB), 3.38 (m, 1 H,
NCHAHB), 3.48* (br t, J = 8.1 Hz, 2 H NCH2), 4.16–4.25 (br m,
1 H, Fmoc-CH), 4.33–4.38 (m, 2 H, Fmoc-CH2), 4.46* (dd, J = 8.4,
5.3 Hz, 1 H, H-a), 4.81 (dd, J = 8.4, 5.3 Hz, 1 H, H-a), 5.43 (q,
J = 7.0 Hz, 1 H, NCH), 5.82* (q, J = 7.0 Hz, 1 H, NCH), 7.23–7.44
(br m, 9 H, Ph, Fmoc ArH), 7.68 (m, 2 H, Fmoc ArH), 7.80 (d,
J = 7.9 Hz, 2 H, Fmoc ArH). Signals designated with * correspond
to additional peaks due to the presence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C41H60N3O7: 706.44258; found:
706.44223.
Conversion of Compound 13 into Building Blocks 21–23
The ester 13 (3.5–9.5 mmol) was dissolved in 40% TFA–CH2Cl2
(5–15 mL/mmol) and stirred at r.t. for 0.5 h. The mixture was con-
centrated and the residue was co-concentrated with Et2O or toluene.
The crude intermediate was treated with the respective reagents at
r.t. in CH2Cl2 or THF.
2111
The above crude intermediate was dissolved in CH2Cl2 (10 mL/
mmol), and DIPEA (5 equiv) was added followed by (2-trimethyl-
silyl)ethyl p-nitrophenyl carbonate (1.2 equiv) in CH2Cl2 (5 mL/
mmol). The mixture was stirred for 16 h then evaporated and the
residue was purified on a VLC column (5.5 × 6 cm; hexane–EtOAc,
10:1 to hexane–EtOAc–AcOH, 50:50:0.1).
13C NMR (75 MHz, CD3OD): d = 17.1*, 18.1, 24.0, 24.2*, 28.8,
30.5*, 30.6, 33.1, 33.7, 36.2*, 40.3, 40.4*, 40.9, 48.4, 52.8, 53.2*,
53.4*, 56.0, 67.9, 79.7, 120.8, 126.1, 128.0, 128.2, 128.3*, 128.5,
128.6, 128.7*, 129.6, 140.7, 141.6*, 142.4, 144.9*, 145.1, 158.2,
158.8, 174.0, 174.9. Signals designated with * correspond to addi-
tional peaks due to the presence of a minor rotamer.
Yield: 1.77 g (74%); RP-HPLC: 98.8% at 267 nm (tR = 17.3 min).
1H NMR as reported.11
HRMS: m/z [M + H]+ calcd for C37H46N3O7: 644.33303; found:
644.33300.
13C NMR (75 MHz, CD3OD): d = –1.3, 17.1*, 18.1, 18.7, 24.0,
24.1*, 30.5*, 30.6, 33.0*, 33.1, 33.7, 36.2*, 40.3, 40.4*, 41.2, 48.4,
52.8, 53.2*, 53.4*, 56.0, 63.7, 67.9*, 68.0, 120.8, 126.1, 128.0,
128.2, 128.3*, 128.5, 128.6*, 128.7*, 129.6, 140.7, 141.6*, 142.4,
145.0*, 145.1, 158.2, 158.3*, 159.0, 174.0, 174.1*, 174.9. Signals
designated with * correspond to additional peaks due to the pres-
ence of a minor rotamer.
Anal. Calcd for C37H45N3O7: C, 69.03; H, 7.05; N, 6.53. Found: C,
68.71; H, 7.13; N, 6.48.
Conversion of Compounds 14, 15 and 19 into Building Blocks
24–26
Hydrolysis Procedure I
The ester was dissolved in 40% TFA–CH2Cl2 (5 mL/mmol) and the
mixture was stirred at r.t. for 0.5–1 h. The solvents were evaporated
and the residue was co-concentrated with Et2O or toluene.
HRMS: m/z [M + H]+ calcd for C38H50N3O7Si: 688.34125; found:
688.34121.
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

2388
G. Bonke et al.
PAPER
Hydrolysis Procedure II
26
Compound 19 was hydrolyzed using procedure I and purified by
VLC (5 × 5 cm; hexane–EtOAc, 10:1 to hexane–EtOAc–AcOH,
75:25:0.1).
The ester was dissolved in 10% TFA–CH2Cl2 (10 mL/mmol) and
the mixture was stirred at 0 °C for 7–10 h, whilst following the re-
action by analytical HPLC. Upon completion of the reaction, the
mixture was diluted with CH2Cl2 (30 mL/mmol), washed with H2O
(4 × 30 mL/mmol), dried (Na2SO4), and evaporated in vacuo to give
the acid.
Yield: 0.85 g (86%).
Hydrolysis by procedure II afforded a yield of 95%. RP-HPLC:
98.8% at 267 nm (tR = 15.5 min).
1H NMR (300 MHz, CD3OD): d = 0.80–1.50 (br m, 5 H, c-Hex),
1.16* (d, J = 6.9 Hz, 3 H, CH3), 1.23 (d, J = 6.9 Hz, 3 H, CH3), 1.25
(d, J = 6.9 Hz, 3 H, b-CH3), 1.30* (d, J = 6.9 Hz, 3 H, b-CH3),
1.51–1.84 (br m, 6 H, c-Hex), 2.49 (ddd, J = 15.8, 9.9, 5.5 Hz, 1 H,
COCHAHB), 2.61–2.73 (br m, 1 H, COCHAHB), 3.00* (m, 2 H,
COCH2), 3.50–3.64 (m, 2 H, NCH, NCHAHB), 3.28 (m, 1 H,
NCHAHB), 4.18 (m, 1 H, Fmoc-CH), 4.24–4.36 (br m, 2 H, Fmoc-
CH2), 4.51* (q, J = 6.9 Hz, 1 H, H-a), 4.69 (q, J = 6.9 Hz, 1 H, H-
a), 7.28 (br t, J = 7.4 Hz, 2 H, Fmoc ArH), 7.36 (br t, J = 7.4 Hz,
2 H, Fmoc ArH), 7.65 (m, 2 H, Fmoc ArH), 7.77 (d, J = 7.4 Hz,
2 H, Fmoc ArH). Signals designated with * correspond to additional
peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.1*, 17.7, 18.3*, 18.8, 27.0*,
27.1, 27.2 (2 × C), 27.3, 27.4*, 31.0*, 31.3 (2 × C), 31.6*, 33.9,
36.1*, 38.9, 41.9*, 42.8, 48.3 (2 × C), 48.6* (2 × C), 59.4, 67.9,
120.8, 126.1, 128.0, 128.6, 142.4, 145.0, 145.1*, 157.7, 158.0*,
174.4*, 174.7, 175.1, 175.6*. Signals designated with * correspond
to additional peaks due to the presence of a minor rotamer.
24
Compound 14 was hydrolyzed using procedure I and purified by
VLC (4 × 4 cm; hexane–EtOAc, 10:1 to hexane–EtOAc–AcOH,
80:20:0.1).
Yield: 0.37 g (89%); RP-HPLC: 97.7% at 267 nm (tR = 15.2 min).
1H NMR (300 MHz, CD3OD): d = 0.93* (d, J = 6.8 Hz, 3 H, g-
CH3), 0.97* (d, J = 6.8 Hz, 3 H, g-CH3), 0.98 (d, J = 6.5 Hz, 6 H, g-
CH3), 1.53* (d, J = 7.3 Hz, 3 H, CH3), 1.64 (d, J = 7.0 Hz, 3 H,
CH3), 1.99–2.22 (br m, 2 H, COCHAHB, b-CH), 2.37–2.51 (br m,
1 H, COCHAHB), 3.17 (ddd, J = 15.6, 10.3, 5.0 Hz, 1 H, NCHAHB),
3.38 (m, 1 H, NCHAHB), 3.54* (m, 2 H, NCH2), 4.17–4.24 (br m,
1 H, Fmoc-CH), 4.28* (d, J = 8.2 Hz, 1 H, H-a), 4.32 (d, J = 7.1 Hz,
2 H, Fmoc-CH2), 4.38* (d, J = 6.8 Hz, 2 H, Fmoc-CH2), 4.62 (d,
J = 8.2 Hz, 1 H, H-a), 5.53 (q, J = 7.0 Hz, 1 H, NCH), 5.82* (q,
J = 7.3 Hz, 1 H, NCH), 7.20–7.49 (m, 9 H, Ph, Fmoc ArH), 7.68 (m,
2 H, Fmoc ArH), 7.80 (m, 2 H, Fmoc ArH). Signals designated with
* correspond to additional peaks due to the presence of a minor rot-
amer.
13C NMR (75 MHz, CD3OD): d = 17.0*, 18.1, 18.3, 18.7*, 19.9*,
20.2, 32.2, 32.6*, 33.7, 36.2*, 40.1, 40.4*, 48.4, 53.7*, 56.2, 58.0,
58.4*, 67.8*, 68.0, 120.8, 126.1, 128.0, 128.1*, 128.3, 128.4*,
128.6, 128.7, 129.5, 140.7, 141.5*, 142.4, 145.0, 145.1*, 158.4,
173.6, 174.0*, 174.2*, 174.9. Signals designated with * correspond
to additional peaks due to the presence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C29H37N2O5: 493.26970; found:
493.26993.
Conversion of Compounds 16, 17 and 20 into Building Blocks
27–29
The N-Boc-protected tert-butyl ester derivative was treated with
40% TFA–CH2Cl2 under stirring for 0.5–1 h. The reaction mixture
was concentrated, and the residue was co-evaporated with Et2O.
HRMS: m/z [M + H]+ calcd for C31H35N2O5: 515.25406; found:
515.25422.
27
Anal. Calcd for C31H34N2O5: C, 72.35; H, 6.66; N, 5.44. Found: C,
72.70; H, 6.82; N, 5.52.
The residue (from 0.53 mmol of 16) was dissolved in CH2Cl2 (10
mL) and DIPEA (10 equiv) and N,N¢-bis-Boc-1H-pyrazole-1-car-
boxamidine (1.2 equiv) in CH2Cl2 (2 mL) were added successively.
The mixture was stirred at r.t. for 16 h, diluted with EtOAc (100
mL), washed with 0.1 M HCl (2 × 50 mL), H2O (3 × 50 mL), brine
(1 × 50 mL), and then the organic phase was dried (Na2SO4) and
concentrated. The residue was purified on a VLC column (4 × 4 cm;
hexane–EtOAc, 10:1 to hexane–EtOAc–AcOH, 66:33:0.1).
25
Compound 15 was hydrolyzed using procedure II.
Yield: 0.34 g (99%); RP-HPLC: 95.0% at 267 nm (tR = 16.0 min).
1H NMR (300 MHz, CD3OD): d = 0.98* (s, 9 H, g-CH3), 1.05 (s,
9 H, g-CH3), 1.50* (d, J = 7.3 Hz, 3 H, CH3), 1.64 (d, J = 7.0 Hz,
3 H, CH3), 2.26 (ddd, J = 15.9, 10.3, 5.6 Hz, 1 H, COCHAHB), 2.44
(ddd, J = 15.9, 10.2, 5.3 Hz, 1 H, COCHAHB), 2.51* (ddd, J = 15.9,
11.0, 5.6 Hz, 1 H, COCHAHB), 2.69* (ddd, J = 15.9, 10.8, 5.5 Hz,
1 H, COCHAHB), 3.14 (ddd, J = 15.6, 10.3, 5.3 Hz, 1 H, NCHAHB),
3.26–3.49 (br m, 1 H, NCHAHB), 3.63* (ddd, J = 15.9, 11.0, 5.5 Hz,
1 H, NCHAHB), 4.19 (br t, J = 6.8 Hz, 1 H, Fmoc-CH), 4.28–4.41
(br m, 3 H, H-a, Fmoc-CH2), 5.53 (q, J = 7.0 Hz, 1 H, NCH), 5.85*
(q, J = 7.3Hz, 1 H, NCH), 7.15–7.40 (br m, 9 H, Ph, Fmoc ArH),
7.65 (d, J = 7.3 Hz, 2 H, Fmoc ArH), 7.78 (m, 2 H, Fmoc ArH). Sig-
nals designated with * correspond to additional peaks due to the
presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.2*, 17.8, 27.1*, 27.2, 33.8,
36.2*, 36.7, 37.0*, 39.9, 40.8*, 48.4, 48.5*, 53.4*, 56.8, 58.3,
59.1*, 67.7*, 68.1, 120.8, 126.1, 127.9, 128.0, 128.1*, 128.5*,
128.6, 128.7, 129.5, 141.0, 141.6*, 142.4, 145.0, 158.2, 172.2*,
173.0, 174.1*, 174.9. Signals designated with * correspond to addi-
tional peaks due to the presence of a minor rotamer.
Yield: 0.26 g (58%); RP-HPLC: 96.7% at 267 nm (tR = 20.9 min).
1H NMR (300 MHz, CD3OD): d = 1.20–1.68 (br m, 4 H, g-CH2, d-
CH2), 1.42 [s, 9 H, C(CH3)3], 1.45 [s, 9 H, C(CH3)3], 1.62 (d, J = 6.9
Hz, 3 H, CH3), 1.68–1.85 (br m, 3 H, COCHAHB, b-CH2), 2.07–
2.24 (br m, 1 H, COCHAHB), 3.24 (m, 2 H, e-CH2), 3.28–3.40 (br
m, 1 H, NCHAHB), 3.49 (m, 1 H, NCHAHB), 4.18 (br t, J = 6.8 Hz,
1 H, Fmoc-CH), 4.32 (br d, J = 6.8 Hz, 2 H, Fmoc-CH2), 4.41 (dd,
J = 8.2, 4.7 Hz, 1 H, H-a), 6.48 (q, J = 6.9 Hz, 1 H, NCH), 7.28 (br
t, J = 7.4 Hz, 2 H, Fmoc ArH), 7.36 (br t, J = 7.1 Hz, 2 H, Fmoc
ArH), 7.44–7.56 (br m, 3 H, ArH), 7.65 (m, 3 H, ArH, Fmoc ArH),
7.76 (d, J = 7.4 Hz, 2 H, Fmoc ArH), 7.78–7.90 (m, 3 H, ArH).
13C NMR (75 MHz, CD3OD): d = 17.1, 24.3, 28.2, 28.6, 29.8, 33.3,
35.8, 39.7, 41.5, 48.4, 50.0, 53.3, 67.9, 80.3, 84.3, 120.8, 124.2,
126.1, 126.2 (2 × C), 127.6, 127.9, 128.0, 128.6, 129.9, 130.0,
133.0, 135.0, 136.1, 142.4, 145.0, 153.9, 157.3, 158.3, 164.3, 173.7,
174.4.
HRMS: m/z [M + H]+ calcd for C47H58N5O9: 836.42290; found:
836.42255.
HRMS: m/z [M + H]+ calcd for C32H37N2O5: 529.26970; found:
529.26983.
Anal. Calcd for C47H57N5O9: C, 67.53; H, 6.87; N, 8.38. Found: C,
67.61; H, 7.10; N, 8.27.
Anal. Calcd for C32H36N2O5: C, 72.70; H, 6.86; N, 5.30. Found: C,
72.37; H, 6.99; N, 5.20.
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

PAPER
Building Blocks for SPS of a-Peptide–b-Peptoid Chimeras
2389
2811
Yield: 0.33 g (55%); RP-HPLC: 95.4% at 267 nm (tR = 16.2 min).
The residue (from 4.08 mmol of 17) was dissolved in CH2Cl2 (25
mL) and DIPEA (8 equiv) was added, followed by N,N¢-bis-Boc-
1H-pyrazole-1-carboxamidine (1.2 equiv) in CH2Cl2 (5 mL). The
mixture was stirred at r.t. for 16 h, then concentrated and purified by
VLC (6 × 7 cm; hexane–EtOAc, 10:1 to hexane–EtOAc–AcOH,
50:50:0.1).
1H NMR (300 MHz, CDCl3): d = 1.43* [s, 9 H, C(CH3)3], 1.44 [s,
9 H, C(CH3)3], 1.55* (d, J = 7.0 Hz, 3 H, CH3), 1.70 (d, J = 6.8 Hz,
3 H, CH3), 1.84 (m, 1 H, HA-b), 1.92–2.14 (br m, 1 H, HB-b), 2.23–
2.76 (br m, 2 H, COCH2), 2.36 (m, 2 H, g-CH2), 3.26 (ddd, J = 15.1,
10.2, 5.5 Hz, 1 H, NCHAHB), 3.32–3.54 (br m, 1 H, NCHAHB),
3.60* (ddd, J = 16.2, 10.7, 5.5 Hz, 1 H, NCHAHB), 4.22 (br t,
J = 6.9 Hz, 1 H, Fmoc-CH), 4.32–4.44 (br m, 2 H, Fmoc-CH2),
4.60* (dd, J = 9.8, 3.4 Hz, 1 H, H-a), 4.99 (dd, J = 8.9, 3.4 Hz, 1 H,
H-a), 5.39 (q, J = 6.8 Hz, 1 H, NCH), 5.94* (q, J = 7.0 Hz, NCH),
7.24–7.36 (br m, 7 H, Ph, Fmoc ArH), 7.40 (br t, J = 7.4 Hz, 2 H,
Fmoc ArH), 7.62 (d, J = 7.2 Hz, 1 H, Fmoc ArH), 7.63 (d, J = 7.2
Hz, 1 H, Fmoc ArH), 7.76 (d, J = 7.4 Hz, 2 H, Fmoc ArH). Signals
designated with * correspond to additional peaks due to the pres-
ence of a minor rotamer.
13C NMR (75 MHz, CDCl3): d = 16.8*, 17.8, 28.2,* 28.3, 28.5*,
28.6, 30.9, 31.1*, 33.3, 35.5*, 39.0, 47.2, 50.6, 51.1*, 52.0*, 54.9,
67.2, 67.3, 80.9, 120.0, 125.2, 127.0, 127.1, 127.2*, 127.7*, 127.9*,
128.7, 128.9, 138.9, 139.9*, 141.2, 143.7, 143.9*, 156.3, 156.5*,
172.1, 172.2*, 172.9, 174.5*, 175.8. Signals designated with * cor-
respond to additional peaks due to the presence of a minor rotamer.
Yield: 2.8 g (89%); RP-HPLC: 96.7% at 267 nm (tR = 18.8 min).
1H NMR as reported.11
13C NMR (75 MHz, CD3OD): d = 23.9, 24.2*, 28.3, 28.6, 29.6,
29.8*, 32.8*, 32.9, 34.3, 41.5, 41.6*, 44.1*, 44.5, 48.9, 52.4, 52.8,
67.8, 80.3, 84.4, 120.8, 125.6*, 126.1, 127.9, 128.6, 142.4, 144.9,
145.1*, 153.9, 157.3, 158.1, 164.3, 174.3, 174.6*, 174.7*, 174.9.
Signals designated with * correspond to additional peaks due to the
presence of a minor rotamer.
HRMS: m/z [M + H]+ calcd for C42H54N5O9: 772.39160; found:
772.39152.
Anal. Calcd for C42H53N5O9: C, 65.35; H, 6.92; N, 9.07. Found: C,
65.59; H, 7.04; N, 9.23.
HRMS: m/z [M + H]+ calcd for C35H41N2O7: 601.29083; found:
29
The residue (from 4.56 mmol of 20) was dissolved in CH2Cl2–DMF
(1:1, 80 mL), and DIPEA (7.5 equiv) and N,N¢-bis-Boc-1H-pyra-
zole-1-carboxamidine (1.2 equiv) in CH2Cl2 (5 mL) were added
successively. The mixture was stirred at r.t. for 16 h, diluted with
EtOAc (250 mL), then the organic phase was washed with 0.1 M
HCl (2 × 75 mL), H2O (3 × 75 mL), brine (1 × 75 mL), dried
(Na2SO4), and concentrated. The residue was purified on a VLC
column (4 × 4 cm; hexane–EtOAc, 10:1 to hexane–EtOAc–AcOH,
1:1:0.1%).
601.29065.
Anal. Calcd for C35H40N2O7: C, 69.98; H, 6.71; N, 4.66. Found: C,
69.97; H, 6.79; N, 4.63.
Solid-phase Synthesis and Purification of 31a–d
SPS were performed in Teflon filter vessels on a Scansys PLS 4 × 6
Organic Synthesizer equipped with a heating block. Fmoc-protect-
ed Rink amide resin (100 mg, 0.065 mmol) was treated with 20%
piperidine–DMF (4 mL, 2 × 10 min), and washed with DMF,
MeOH, and CH2Cl2 (3 × 5 mL, 5 min each). Oligomerization was
performed as previously described,11 using building block 23 for the
appropriate number of coupling/deprotection cycles. Terminal ami-
no groups were capped with Ac2O–DIPEA–DMF (1:2:3, 3 mL, 0.5
h) and the resins were washed with DMF, MeOH, and CH2Cl2
(3 × 5 mL, 5 min each). The crude products were cleaved from the
support with 95% TFA–CH2Cl2 (3 mL, 1 h). The compounds were
purified by preparative RP-HPLC. A gradient with eluent B rising
linearly from 5% to 40% during 25 min followed by a linear rise to
100% during 10 min was applied. The isolated peptidomimetics
were lyophilized from the HPLC solvents and stored at –20 °C. See
Table 2 for yields and HRMS data.
Yield: 1.80 g (50%); RP-HPLC: 95.2% at 267 nm (tR = 21.9 min).
1H NMR (300 MHz, CD3OD): d = 0.81–1.30 (br m, 5 H, c-Hex),
1.18* (d, J = 6.9 Hz, 3 H, CH3), 1.26 (d, J = 6.6 Hz, 3 H, CH3),
1.30–1.84 (br m, 12 H, b-CH2, g-CH2, d-CH2, c-Hex), 1.46 [s, 9 H,
C(CH3)3], 1.48 [s, 9 H, C(CH3)3], 2.47 (ddd, J = 15.7, 9.9, 5.5 Hz,
1 H, COCHAHB), 2.60–2.74 (br m, 1 H, COCHAHB), 2.95* (m, 2 H,
COCH2), 3.20–3.38 (m, 2 H, e-CH2), 3.54–3.67 (m, 3 H, NCH,
NCH2), 4.21 (br t, J = 7.0 Hz, 1 H, Fmoc-CH), 4.23–4.38 (br m,
2 H, Fmoc-CH2), 4.48* (br t, J = 7.1 Hz, 1 H, H-a), 4.66 (dd,
J = 6.9, 5.2 Hz, 1 H, H-a), 7.30 (br t, J = 7.4 Hz, 2 H, Fmoc ArH),
7.38 (br t, J = 7.3 Hz, 2 H, Fmoc ArH), 7.66 (m, 2 H, Fmoc ArH),
7.79 (d, J = 7.4 Hz, 2 H, Fmoc ArH). Signals designated with * cor-
respond to additional peaks due to the presence of a minor rotamer.
13C NMR (75 MHz, CD3OD): d = 17.2*, 17.9, 23.9, 24.3, 27.0, 27.2,
27.4, 28.3, 28.6, 29.7, 31.2, 31.4, 33.1*, 33.4, 34.0, 36.3*, 39.1*,
41.5, 41.6, 41.8*, 42.8, 48.4, 52.5, 53.3*, 59.6, 67.9, 80.3, 84.3,
120.8, 126.1, 128.0, 128.6, 142.4, 144.9*, 145.1, 154.0, 157.3,
157.9, 164.3, 173.9, 175.0. Signals designated with * correspond to
additional peaks due to the presence of a minor rotamer.
Solid-phase Synthesis and Purification of 32
SPS was performed as above agitating the resin (100 mg) with a pre-
incubated (10 min) mixture of compound 24 (67 mg, 0.13 mmol, 2
equiv), PyBOP (68 mg, 0.13 mmol, 2 equiv), and DIPEA (0.045
mL, 0.26 mmol, 4 equiv) in anhydrous DMF (1.5 mL) under N2 for
2 h, and washed with MeOH, DMF and CH2Cl2 (3 × 5 mL, 5 min
each). Fmoc-deprotection with 20% piperidine–DMF (4 mL, 2 × 10
min) followed by 2% DBU and 2% piperidine in NMP21 (3 mL, 10
+ 5 min) followed by the above washing procedure. This two-step
coupling/deprotection sequence was repeated with building blocks
26, 25 and 27, to give the resin-bound oligomer. The crude product
was cleaved from the support with 95% TFA–CH2Cl2 (3 mL, 1 h),
and purified by preparative RP-HPLC. A gradient with eluent B ris-
ing linearly from 5% to 55% during 25 min followed by a linear rise
to 100% B during 10 min was applied. The isolated oligomer was
lyophilized from the HPLC solvent and stored at –20 °C.
HRMS: m/z [M + H]+ calcd for C43H62N5O9: 792.45421; found:
792.45434.
Conversion of Compound 18 into Dipeptide Building Block 30
Compound 18 (0.98 mmol) was dissolved in EtOH (10 mL) and
then aq NaOH (1 M, 1.55 equiv) was added slowly (some precipi-
tation was observed). The mixture was stirred for 3 h then aq
Na2CO3 (10%, 10 mL) and Fmoc-Cl (1.5 equiv) in dioxane (10 mL)
were added successively. After stirring at r.t. for 2 h, the mixture
was acidified with 1 M HCl then extracted with EtOAc (4 × 50 mL).
The combined organic layers were washed with brine (1 × 50 mL),
dried (Na2SO4), and concentrated. The residue was dissolved in
EtOAc and coated onto Celite (10–15 mL), which was loaded onto
a VLC column (4 × 4 cm) and eluted with hexane–EtOAc, 10:1 to
hexane–EtOAc–AcOH, 66:33:0.1.
Yield: 66 mg (69%); RP-HPLC: >99.5% at 215 nm (tR = 24.8 min).
HRMS: m/z [M + 2H]2+ calcd for C69H102N12O8: 614.40446; found:
614.40439.
Synthesis 2008, No. 15, 2381–2390 © Thieme Stuttgart · New York

2390
G. Bonke et al.
PAPER
(9) (a) Norgren, A. S.; Zhang, S.; Arvidsson, P. I. Org. Lett.
Acknowledgment
2006, 8, 4533. (b) Olsen, C. A.; Lambert, M.; Witt, M.;
Franzyk, H.; Jaroszewski, J. W. Amino Acids 2008, 34, 465.
(c) Baldauf, C.; Günther, R.; Hofmann, H.-J. Phys. Biol.
2006, 3, 1.
We thank Ms. Birgitte Simonsen for technical assistance. This work
was supported by grants from the Danish Technical Research
Council (now Danish Research Council for Technology and
Production Sciences; Grant 26-04-0248) and the Danish Medical
Research Council (Grant 271-06-0126). C.A.O. thanks the Danish
Independent Research Council for a Young Researcher Award
(274-06-0317).
(10) (a) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O.
Angew. Chem. Int. Ed. 2004, 43, 511. (b) Hayen, A.;
Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.; Gellman,
S. H. Angew. Chem. Int. Ed. 2004, 43, 505. (c) Schmitt, M.
A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004,
126, 6848.
(11) Olsen, C. A.; Bonke, G.; Vedel, L.; Adsersen, A.; Witt, M.;
Franzyk, H.; Jaroszewski, J. W. Org. Lett. 2007, 9, 1549.
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