Synthetic and Biological Studies on New Urea and Triazole Containing Cystobactamid Derivatives

Article abstract of DOI:10.1002/chem.201904073

Cystobactamids belong to the group of arene-based oligoamides that effectively inhibit bacterial type IIa topoisomerases. Cystobactamid 861-2 is the most active member of these antibiotics. Most amide bonds present in the cystobactamids link benzoic acids

Full text of DOI:10.1002/chem.201904073

A Journal of
Accepted Article
Title: Synthetic and Biologic Studies on New Urea and Triazole
Containing Cystobactamid Derivatives
Authors: Andreas Kirschning, Therese Planke, Katarina Cirnski,
Jennifer Herrmann, and Rolf Müller
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To be cited as: Chem. Eur. J. 10.1002/chem.201904073
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10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
█ Antibiotics
Synthetic and Biologic Studies on New Urea and Triazole Containing
Cystobactamid Derivatives
Therese Planke,[a] Katarina Cirnski,[b], Jennifer Herrmann,[b] Rolf Müller,[b] and Andreas
Kirschning*[a]
Abstract: The cystobactamids belong to the group of arene- However, we exchanged selected amide bonds either by the
based oligoamides that effectively inhibit bacterial type IIa urea or the triazole groups and modified ring A in the latter
topoisomerases. Cystobactamid 861-2 is the most active case. While hydrolytic stability could be improved with these
member of these antibiotics. Most amide bonds present in structural substitutes, the high antibacterial potency of
the cystobactamids link benzoic acids with anilines and it cystobactamid 861-2 could only be preserved in selected
was found that some of these amide bonds undergo cases. This includes derivatives, in which the urea group is
chemical and enzymatic hydrolysis, especially the one linking positioned between rings A and B and where the triazole is
ring C with ring D. This work reports on the chemical found between rings C and D.
synthesis and biological evaluation of thirteen new
cystobactamids that still contain the methoxyaspartate hinge
[a]
T. Planke, Prof. Dr. A. Kirschning
Institut für Organische Chemie und Biomolekulares
Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax: (+49) 511-762-3011
E-mail: andreas.kirschning@oci.uni-hannover.de and
gerald.draeger@oci.uni-hannover.de
[b]
Prof. Dr. R. Müller, Dr. J. Herrmann, K. Cirnski
Abteilung Mikrobielle Naturstoffe, Helmholtz Institut für
Pharmazeutische Forschung Saarland, Helmholtz Zentrum für
Infektionsforschung und Universität des Saarlandes, Campus E8.1,
66123 Saarbrücken, Germany
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
1
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DOI: 10.1002/chem.201xxxxxx
Introduction
the amide bond that links rings C and D being the most labile
one.
The cystobactamids, an unusual group of oligoamides from
Cystobacter sp. Cbv34, were first reported in 2014.[1] The extracts
inhibited the growth of several Gram-negative and Gram-positive
bacteria and HPLC-assisted bioactivity-guided screening
provided cystobactamids 919-1 (1) and 919-2 (2) as active
compounds (Figure 1). These oligoamides contain p-
aminobenzoic acid building blocks and either an iso-β-
As part of a medicinal chemistry programme on cystobactamids,
we therefore envisaged to prepare a library of methoxyaspartate
containing cystobactamids. One aspect of this programme covers
the substitution of the amide group by supposedly chemically
more stable functional elements such as urea and triazole (figure
1). Besides 1,2,4-triazoles, a cis amide bond surrogate,[6] the
1,2,3-triazole ring has recently been found to be a prominant
amide bond bioisostere.[7,8]
Here, we report on our recent total synthetic endeavours towards
new cystobactamide derivatives with improved chemical stability
and the determination of their antibacterial properties. This
includes the direct comparison with ciprofloxacin (CP).
methoxyasparagine or
a β-methoxyasparagine unit. Later,
additional derivatives such as the cystobactamids 920-1 (3), 920-
2 (4) and 862-1 (5) were reported that structurally differ in the E-
ring and the asparate hinge region. [2a]
Cystobactamid 862-1 (5) was found to be the most active natural
member. It inhibits several clinically relevant Gram-positive and
Gram-negative strains (Acinetobacter baumannii: MIC = 0.5
µg/mL, Citrobacter freundii: MIC = 0.06 µg/mL, carbapenem-
Chemical Syntheses
General considerations: The cystobactamids are natural
products with a modular architecture. The key structural elements
are amide bonds, that are composed of combinations of benzoic
acids, anilines and carboxylate and amino group in the
methoxyasparate unit. In addition, protecting groups for the
carboxylates, amines and phenols have to be chosen. Substantial
search and optimisation led to a toolbox of reactions listed in
Scheme 1 (cases I-VI), that also repeatedly served to prepare the
new cystobactamids reported here. Three principal types of
amide forming processes have been developed, that combine two
aromatic building blocks (case I), a benzoic acid with an amine
(case II), and an aniline with a carboxylate (case III).
resistant E. coli WT-III marRΔ74bp: MIC
= 0.5 µg/mL,
fluoroquinolone-resistant P. aeruginosa CRE: MIC = 1.0 µg/mL,
and Proteus vulgaris: MIC = 0.25 µg/mL)[2] by inhibiting bacterial
type IIa topoisomerases. It has to be stressed, that the
cystobactamids are structurally related to albicidin with similar
antibacterial properties, which has extensively been studied by
Süssmuth et al.[3]
Scheme 1. Reagents employed for principal reaction for
Figure 1. Structures of selected cystobactamids 919-1 (1),
919-2 (2), 920-1 (3), 920-2 (4) and 861-2 (5) and the urea as well
as triazole groups as structural substitutes for amide group (rings
are labelled with letters A-E).
constructing cystobactamids (COMU
= (1-cyano-2-ethoxy-2-
oxoethylidene-aminooxy)dimethylaminomorpholinocarbenium-
hexa-fluorophosphate; EEDQ = N-ethoxycarbonyl-2-ethoxy-1,2-
dihydroquinoline; HATU = [O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-
tetramethyluronium-hexa-fluorophosphate]; DIPEA = diisopropyl-
ethylamine, DMF = dimethylformamide, TFA = trifluoroacetic acid).
Several total syntheses of cystobactamids 861-2, 919-2 and 920-
1 have been published by the Trauner group and by us.[2a,4,5]
These endeavours were essential to revise and prove the
constitutions as well as the 2S, 3R configurations of
cystobactamids.[5] Both, the synthetic programmes and the
cystobactamid isolation protocols revealed, that the amide bonds
between benzoic acids and anilines are prone to hydrolysis with
Boc-deprotection of the methoxyaspartate hinge region was
achieved under mildly acidic conditions (case IV), avoiding the
hydrolysis of the tert-butyl ester in ring E. This ester was
commonly cleaved under stronger acidic conditions in neat TFA,
routinely the final step of our chemical syntheses (case V). Finally,
2
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Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
the allyl deprotection of the phenol function was achieved under
Pd(0)-catalised conditions (case VI).
Diamide 9 was coupled with 1-isocyanato-4-nitrobenzene 10
followed by reduction of the nitro group yielded urea derivative 11
in which the urea group is located between rings C and D. We
first prepared cyano derivative 16 in which the urea group is
located between the A and B rings (Scheme 3). The cyano
derivative was chosen, because it has been established that
exchange of the nitro group by cyanide leads to improved
antibacterial properties.[8]
The synthesis commenced with the coupling of amide 9 with 4-
nitrobenzoic acid and reduction of the resulting nitroarene to yield
the aniline 12. Next the aniline was linked to the (2S,3R)-
methoxyasparate derivative 13.[2a] Then, the Boc group was
hydrolised under mildly acidic conditions circumventing cleavage
of the tert-butyl ester. Next, the resulting tetramide 14 was
coupled with the urea derivative 8 and the resulting product 15
was transformed into the cystobactamid derivative 16 after O-
deallylation and ester hydrolysis.
Syntheses of urea-modified cystobactamids: For exchanging
the amide group by urea one of the coupling partners was chosen
to contain the isocyanate group as in 4-isocyanato-benzonitrile 6
and 1-isocyanato-4-nitrobenzene 10 (Scheme 2). These building
blocks were flexibly used to prepare cystobactamid derivatives
containing an urea bridge between rings A and B as well as rings
C and D. Several coupling partners 9, 19 and 20 were at hand
from our previously published syntheses of cystobactamids 861-2
(5) and 920-1 (3).[2a,5]
4-Isocyanato-benzonitrile (6) was efficiently coupled with 4-
aminobenzoic acid 7 to yield disubstituted urea 8 resembling the
linkages between rings A and B.
Scheme 2. Synthesis of urea-containing building blocks 8 and 11.
Scheme 3. Synthesis of cystobactamid derivative 16 bearing an
urea group between rings A and B.
Scheme 4. Synthesis of cystobactamid derivatives 23 - 25
bearing an urea group between rings C and D.
3
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DOI: 10.1002/chem.201xxxxxx
Next, we installed the urea group between rings C and D
(Scheme 4). For that, urea derivative 11 was coupled with
methoxyasparate derivative 13 to yield Boc-amide 17, which was
transformed into amine 18 under mildly acidic conditions. Amide
formation with diamides 19 and 20, respectively, yielded
cystobactamid precursors 21 and 22, that underwent the common
two-step protocol for removing the allyl- and tert-butyl groups.
The two urea-bearing cystobactamid derivatives 23 and 24 were
purified by RP-HPLC. The truncated derivative 25 was prepared
from Boc-protected tetramide 17 under harsher acidic conditions,
that led to hydrolysis of both the Boc-group as well as the tert-
butyl ester. This was followed by cleavage of the allylether group.
In order to remove any traces of the transition metal the crude
product was also purified by RP-HPLC.
Finally, urea derivative 18 also served as starting point to
prepare cystobactamid 27 with two urea groups between rings
A/B and C/D (Scheme 6). Coupling with urea derivative 8
yielded compound 26 which was transformed into the
cystobactamid derivative 27 in two steps under our standard
conditions.
Scheme 6. Synthesis of the central triazole derivative 31.
Having installed the triazole ring between rings C and D, we
turned our attention to prepare several A/B-ring fragments that
vary in ring A (Table 1).
Table 1. Preparation of diamides 39-44 (COMU= 1-cyano-2-
ethoxy-2-oxoethylideneaminooxy) di-methylamino-morpholino-
carbenium-hexafluorophosphate).
Scheme 5. Synthesis of cystobactamid derivative 27 that
contains two urea linkages between rings A/B and C/D.
building block
ring A
building block
conditions
yields (%)
ring B
With a set of new urea-modified cystobactamids in hand we
tested the chemical stability of derivative 24 representing the
group of urea cystobactamids prepared here. It was dissolved in
33
7
Na2CO3, THF,
H2O, rt, 3 h
39 (98)
34
35
36
37
38
32
32
32
32
32
40 (75)
41 (66)
42 (94)
43 (83)
44 (79)
1
DMSO-d6, triethyl amine (12 eq.) was added and a series of H-
for 34-38:
COMU, DIPEA,
DMF, rt, 16 h,
then TFA, rt, 30
min
NMR spectra were recorded over a period of 27 h. Careful
inspection revealed no degradation products derived from urea
derivative 24. As expected exchange of the amide group by urea
leads to enhanced stability under basic conditions.
We mainly focussed on modifications in the 4-position and
exchange of the benzene by the pyridine ring (Table 1; building
blocks 33-37). In one case, we used a benzoyl chloride (33)
which was directly reacted with the aminobenzoic acid (7). In
most cases, however, the tert-butyl ester 32 which was coupled
with A-ring derivatives 34-37 by in situ activation of their
carboxylic function. Finally, also 3-(4-isocyanophenyl)propanoic
acid (38) was chosen as elongated bishomo analogue of 4-
cyanobenzoic acid. Consequently, we had a small library of A/B-
ring fragments (39-44) at hand that was used to access triazole-
bearing cystobactamids 45-52 in a three step sequence (coupling
of A/B fragments to triazole-containing aspartate building block 31,
de-O-allylation and tert-butyl ester hydrolysis) (Scehem 8).
Syntheses of triazole-modified cystobactamids: A second
structural element for amide substitution is the triazole ring that is
straifgthforwardly been prepared from an alkyne and an azide.[7,8]
We pursued to substitute the most labile amide group between
rings C and D. Thus, we chose 4-ethynylaniline 29 as alkyne
building block and consequently arylazide 28 as second
component. The latter was prepared from aniline 9 and reacted
under classical Sharpless conditions to yield triazole 30. Amide
coupling with methoxyasparate 13 provided amine 31 after Boc-
deprotection under mildly acidic conditions (Scheme 6).
4
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10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
not lead to loss of antibacterial activity, so that this modification
can be regarded to be a successful strategy to generate
cystobactamid derivatives with enhanced chemical and biological
stabilities between rings C and D.[9] Furthermore, this set of new
analogues reveals finetuning of antibacterial activities by
structural changes in ring A. Interestingly, when ring A represents
a pyridine ring with N positioned in the para and meta positions
relative to ring B as in compounds 50 and 51 substantial
reduction of antibacterial activity against S. aureus and P.
aeruginosa is observed. This is not the case for pyridine
derivative 48, in which the nitrogen atom is located in the ortho
position. When extending the length between rings A and B by
insertion of an ethylene unit as in derivative 52 reduced antibiotic
activity is also observed. On the other hand triazole derivatives
45-47 as well as fluoro derivative 49 bearing a cyanide group in
the para position are still highly active in a comparable range to
cystobactamid 861-2 (5). Importantly, the activity spans across all
four strains tested. The important finding of this study is, that the
triazole group is a good substitute for the amide linkage between
rings C and D.
Scheme 8. Synthesis of triazole-modified cystobactamids 45-
52 (yields refer to the three step sequence).
Table 3. Biological activity of triazole derivatives 45-52 compared
to cystobactamid 861-2 (5) and CP (MIC values in µg/ml).
Evaluation of antibacterial properties
strain
E. coli BW25113tolC
E. coli ΔacrB
S. aureus Newmann
P. aeruginosa Pa14
Pa14ΔmexAB
45
<0.03
<0.03
1
4
4
46
<0.03
<0.03
1
4
4
47
<0.03
<0.03
8
8
8
48
0.125
<0.03
4
8
4
The new urea-modified cystobactamids 16, 23-25 and 27 were
tested against a panel of different Gram-negative and Gram-
positive pathogens, including intrinsically multidrug-resistant
P. aeruginosa (Table 2) and directly compared with
cystobactamid 861-2 (5). Incorporation of the urea group
between rings C and D as in derivatives 23-25 and 27 leads to
substantial and even complete loss of antibacterial activity.
This also includes truncation that is represented by
cystobactamid derivative 25. In essence, although chemical
stabilisation of the cystobactamids can be achieved by
exchanging the amide group with urea, this approach fails for
connecting rings C and D due to loss of antibacterial activity.
However, when the urea group is positioned between rings A
and B as in cystobactamid derivative 16, biological activity is
almost completely preserved compared to cystobactamid 861-
2 (5) and even considerably higher for strain E. coli BW25113.
49
<0.03
<0.03
1
4
4
50
1
0.25
>64
>64
>64
51
52
5
CP
<0.03
0.25
64
32
32
0.25
0.125
>64
>64
>64
<0.03
0.06
0.125
1
0.03
<0.003
0.2
0.2
0.01
0.125
Conclusions
In summary, we report on the chemical synthesis of thirteen new
analogues derived from cystobactamid 861-2 (5). These
derivatives differ from the most potent natural member of the
cystobactamids by exchange of the amide groups by either the
urea group or by a triazole ring. These first structure activity
Table 2. Biological activity of urea derivatives 16, 23-25 and 27
compared to cystobactamid 861-2 (5) (MIC values in µg/ml; nd =
not determined).a
studies
(SAR)
for
natural
methoxyaspartate
bearing
strain
S. aureus
Newmann
E. coli
16
16
23
> 64
24
> 64
25
> 64
27
> 64
5
1
cystobactamids reveal, that the urea function can be introduced
between rings A and B but not rings D and E for preserving
antibacterial activity. We also show, that the triazole ring can
serve as a substitute for the amide group in cystobactamids.
Finally, ring A can be modified in various manners without
substantial loss of acticvity. This work provides a first information
on future directions of medicinal chemistry programmes on the
cystobactamids and matches recent findings on the albicidines.[10]
≤ 0.03
nd
1
nd
> 64
0.25
BW25113
E. coli ΔacrB
E. coli ΔtolC
≤ 0.03
nd
nd
> 64
≤ 0.03
nd
nd
> 64
>64
nd
≤ 0.003
≤0.003
E. coli DSM-
nd
> 64
nd
> 64
nd
0.2
1116
P. aeruginosa
Pa14
Pa14ΔmexAB
1
1
>64
>64
>64
>64
>64
>64
>64
>64
1
0.25
a Values for ciprofloxacin (CP) are listed in table 3.
Experimental Section
The experimental section below covers synthetic key protocols for preparing
cystobactamids, lists of analytic and spectroscopic data and protocols to
Likewise, antibacterial properties of triazole-modified
cystobactamid derivatives 45-52 were evaluated (Table 3).
Principally, exchange of the amide group by a triazole ring does
5
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10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
evaluate their biological properties.General experimental information as well as
copies of NMR spectra are found in the supporting information.
m, H-25, H-25‘), 7.42 (1H, d, J = 8.7 Hz, H-12), 6.08 – 5.98 (1H, m, H-19), 5.40
(1H, dq, J = 1.6, 17.2 Hz, H-20trans), 5.22 (1H, dq, J = 1.4, 10.4 Hz, H-20cis), 4.66
– 4.59 (3H, m, H-16, H-18), 1.54 (9H, s, H-1), 1.33 (6H, d, J = 6.2 Hz, H-17)
ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 164.6 (q, C-3), 164.3 (q, C-9), 151.6
(q, C-22), 149.3 (q, C-15), 146.0 (q, C-27), 143.0 (q, C-7), 141.3 (q, C-24),
138.9 (q, C-13), 136.8 (q, C-10), 133.6 (t, C-19), 130.1 (2C, t, C-5, C-5’), 126.0
(q, C-4), 125.3 (2C, t, C-26, C-26’), 124.4 (t, C-12), 124.1 (q, C-14), 118.8 (2C, t,
C-6, C-6’), 117.9 (s, C-20), 117.6 (2C, t, C-25, C-25’), 114.0 (t, C-11), 80.3 (q,
C-2), 76.2 (t, C-16), 74.2 (s, C-18), 27.9 (3C, p, C-1), 22.0 (2C, p, C-17) ppm;
HRMS (ESI): m/z calc. for C31H34N4O8Na [M + Na]+: 613.2274; found 613.2278.
General procedure I for amide formation (according to Scheme 1)
DIPEA (4.0 eq) was added to a stirred solution of acid (2.0 eq), amine (1.0 eq)
and COMU (2.0 eq) in DMF (0.15 M) at 0 °C. The mixture was stirred at rt for
15 h. The reaction was terminated by diluting with EtOAc, washed with sat.
NaHCO3 solution (4x), brine, dried over Na2SO4, filtered and concentrated
under reduced pressure.
General procedure II for amide formation (according to Scheme 1)
DIPEA (12.7 eq) was added dropwise to a stirred solution of acid (2.5 eq) and
HATU (2.5 eq) in DMF (0.11 M) at rt and stirring was continued at rt for five
minutes. The mixture was transferred dropwise to a stirred solution of amine
(1.0 eq) in DMF (0.07 M) at rt and the mixture was stirred at rt for 15 h. The
reaction was concentrated under reduced pressure.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-aminophenyl)ureido)-3-isopropoxy-
benzamido)benzoate (11): Zinc (78.5 mg, 1.20 mmol, 2.0 eq) was added in
one portion at rt to a stirred solution of nitro compound S1 (352 mg, 0.60 mmol,
1.0 eq) in THF (1 mL), EtOH (1 mL) and glacial acetic acid (0.2 mL). After
stirring vigorously at rt for 30 min, a 3rd and 4th equivalent of zinc were added
and the mixture was stirred at rt for another 30 min. This step was repeated
twice, after which time the reaction mixture was heated at 70 °C for a period of
30 min and the 9th and 10th equivalent of zinc were added and the mixture was
stirred at 70 °C for additional 30 min. The reaction mixture was cooled to rt,
diluted with Et2O and terminated by addition of a sat. aq. NaHCO3 solution. The
precipitate was filtered and washed with an excess of Et2O, the layers were
separated, the aq. layer was extracted with Et2O (3x), washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. Column chromatography
(PE/EtOAc= 3:1) yielded the title compound 11 (234 mg, 0.42 mmol, 70%) as a
yellow solid. TM = 134 °C; 1H-NMR (400 MHz, DMSO-d6): δ = 10.4 (1H, s, H-8),
9.05 (1H, s, H-21), 8.10 (1H, s, H-23), 8.08 (1H, s, H-11), 7.88 (2H, m, H-5, H-
5‘), 7.80 (2H, m, H-6, H-6‘), 7.39 (1H, d, J = 8.8 Hz, H-12), 7.10 (2H, m, H-25,
H-25‘), 6.53 (2H, m, H-26, H-26‘), 6.07 – 5.98 (1H, m, H-19), 5.40 (1H, dq,
J = 1.6, 17.2 Hz, H-20trans), 5.22 (1H, dq, J = 1.4, 9.3 Hz, H-20cis), 4.83 (2H, br.
S, NH2), 4.62 – 4.57 (3H, m, H-16, H-18), 1.54 (9H, s, H-1), 1.29 (6H, d,
J = 6.1 Hz, H-17) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 174.7 (q, C-3),
164.6 (q, C-9), 164.3 (q, C-22), 152.5 (q, C-13), 149.3 (q, C-15), 144.3 (q, C-27),
143.1 (q, C-7), 138.5 (q, C-10), 138.2 (q, C-14), 133.6 (t, C-19), 130.1 (2C, t, C-
5, C-5’), 128.4 (q, C-24) 125.9 (q, C-4), 124.4 (t, C-12), 122.2 (2C, t, C-25, C-
25’), 118.8 (2C, t, C-6, C-6’), 117.9 (s, C-20), 114.2 (2C, t, C-26, C-26’), 113.6 (t,
C-11), 80.3 (q, C-2), 75.7 (t, C-16), 74.0 (s, C-18), 27.9 (3C, p, C-1), 21.9 (2C, p,
C-17) ppm; HRMS (ESI): m/z calc. for C31H37N4O6 [M + H]+: 561.2713; found
561.2705.
General procedure III for amide formation (according to Scheme 1)
Precooled chlouroform (0.33 M) was added to amine (1.0 eq) and acid (1.7 eq).
A solution of EEDQ (1.6 eq) in precooled chloroform (0.75 M) was added
dropwise to the acid-amine-mixture at 0 °C. After the mixture was warmed up to
rt stirring was continued at rt for 16 h, it was dry loaded onto silica and purified
by column chromatography (PE/EtOAc = 2:1  1:4).
General procedure IV for Boc deprotection (according to Scheme 1)
Ester (1.0 eq) was added in small portions to 4 N HCl in 1,4-dioxane (100 eq) at
0 °C over five minutes, then the mixture was warmed up to rt over a period of 15
min. The mixture was slowly transferred to a mixture of EtOAc and a 80 % sat.
aq. NaHCO3 solution (400 mL, 1:1), the layers were separated, the aq. layer
was extracted with EtOAc (3x 100 mL), the combined organic phases were
washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in
vacuo.
General procedure V for tert-Bu ester hydrolysis (according to Scheme 1)
Precooled TFA (0.02 M) was added slowly to ester (1.0 eq) at 0 °C. The mixture
was warmed up to rt over a period 30 min, then it was stirred between 30 min
and 6 h. The reaction was terminated by addition of Et2O. The precipitate was
filtered, washed with an excess of Et2O and dried under high vacuum.
General procedure VI for de-O-allylation (according to Scheme 1)
Pd(PPh3)4 (0.25 eq) was added in one portion to a stirred mixture of allyl
ether (1.0 eq) and aniline (2.0 eq) in THF (0.04 M) and stirring was continued at
rt for 2.5 h. The mixture was terminated by addition of HCl. The reaction was
concentrated under reduced pressure.
tert-Butyl-4-(2-(allyloxy)-3-isopropoxy-4-(4-nitrobenzamido)-benzamido)-
benzoate (S2): 4-Nitrobenzoyl chloride (3.48 g, 18.7 mmol, 1.6 eq) was added
in small portions to a solution of amine 9 (5.00 g, 11.7 mmol, 1.0 eq) and
pyridine (3.78 mL, 46.8 mmol, 4.0 eq) in CH2Cl2 (80 mL). The reaction was
terminated after stirring 1.5 h at rt by addition of an aq. NaHSO4 solution (1 M).
The layers were separated and the aq. layer was extracted with CH2Cl2 (3x).
The combined organic phases were dried over Na2SO4, filtered and
concentrated in vacuo to yield crude nitro compound S2 (6.66 g, 11.6 mmol,
99%) as a brown oil which was used without further purification in the next step.
Chemical Syntheses
4-(3-(4-Cyanophenyl)ureido)-benzoic acid (8): DIPEA (3.50 mL, 20.8 mmol,
3.0 eq) was added to a solution of 4-aminobenzoic acid (7, 952 mg, 6.94 mmol,
1.0 eq) and 4-cyanophenyl isocyanate (6, 1.00 g, 6.94 mmol, 1.0 eq) in THF
(30 mL). The reaction was stirred at 55 °C for 16 h. The precipitate was filtered
tert-Butyl-4-(2-(allyloxy)-4-(4-aminobenzamido)-3-isopropoxybenzamido)-
benzoate (12): Zinc (757 mg, 11.6 mmol, 2.0 eq) was added in one portion at rt
to a stirred solution of nitro compound S2 (3.33 g, 5.79 mmol, 1.0 eq) in THF
(9.7 mL), EtOH (9.7 mL) and glacial acetic acid (2.0 mL). After stirring
vigorously at rt for 30 min, a 3rd and 4th equivalent of zinc were added and the
mixture was stirred at rt for another 30 min. This step was repeated twice, after
which time the reaction was heated to 70 °C for a period of 30 min and the 9th
and 10th equivalent of zinc were added. The mixture was stirred at 70 °C for
additional 30 min. The reaction mixture was cooled to rt, diluted with Et2O and
terminated by addition of a sat. aq. NaHCO3 solution. The precipitate was
filtered and washed with an excess of Et2O, the layers were separated, the aq.
layer was extracted with Et2O (3x), washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. Column chromatography (PE/EtOAc= 3:1)
yielded the title compound 12 (2.59 g, 4.75 mmol, 82% over two steps) as a
yellow solid. TM = 90 °C; 1H-NMR (400 MHz, CDCl3): δ = 10.2 (1H, s, H-8), 8.65
(1H, s, H-21), 8.49 (1H, d, J = 8.9 Hz, H-11), 8.05 (1H, d, J = 8.9 Hz, H-12),
7.98 (2H, m, H-5, H-5‘), 7.74 (2H, m, H-24, H-24‘), 7.73 (2H, m, H-6, H-6‘),
6.73 (2H, m, H-25, H-25‘), 6.19 – 6.09 (1H, m, H-19), 5.49 (1H, dq, J = 1.4,
17.1 Hz, H-20trans), 5.40 (1H, dq, J = 1.1, 10.4 Hz, H-20cis), 4.73 (1H, hept, J =
6.2 Hz, H-16), 4.69 (2H, dt, J = 1.2, 5.9 Hz, H-18), 4.11 (2H, br. s, NH2), 1.60
(9H, s, H-1), 1.38 (6H, d, J = 6.2 Hz, H-17) ppm; 13C-NMR (100 MHz, CDCl3): δ
= 165.6 (q, C-3), 164.8 (q, C-22), 162.9 (q, C-9), 150.5 (q, C-26), 149.4 (q, C-
15), 142.4 (q, C-7), 138.9 (q, C-14), 138.2 (q, C-4), 132.4 (t, C-19), 130.8 (2C, t,
C-5, C-5’), 129.1 (2C, t, C-24, C-24’), 127.6 (q, C-13), 127.3 (t, C-12), 123.8 (q,
C-23), 121.1 (q, C-10), 120.1 (s, C-20), 119.1 (2C, t, C-6, C-6’), 115.7 (t, C-11),
and
washed
with
Et2O
(200 mL).
Column
chromatography
(CH2Cl2/MeOH, 5-10% MeOH) yielded the title compound 8 (1.87 g, 6.66 mmol,
96%) as colourless solid.TM = 290 °C (decomposition); 1H-NMR (400 MHz,
DMSO-d6): δ = 12.7 (1H, br. s, CO2H), 9.31 (1H, s, H-6/H-8), 9.23 (1H, s,
H-6/H-8), 7.88 (2H, m, H-3, H-3‘), 7.74 (2H, m, H-10, H-10‘), 7.64 (2H, m, H-11,
H-11‘), 7.57 (2H, m, H-4, H-4‘) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 167.0
(q, C-1), 151.9 (q, C-7), 143.9 (q, C-9), 143.4 (q, C-5), 133.3 (2C, t, C-11,
C-11‘), 130.5 (2C, t, C-3, C-3‘), 124.2 (q, C-2), 119.2 (q, CN), 118.2 (2C, t,
C-10, C-10‘), 117.6 (2C, t, C-4, C-4‘), 103.6 (q, C-12) ppm; HRMS (ESI): m/z
calc. for C15H10N3O3 [M – H]-: 280.0722; found 280.0723.
tert-Butyl-4-(2-(allyloxy)-3-isopropoxy-4-(3-(4-nitrophenyl)ureido)-benz-
amido)benzoate (S1): DIPEA (36 µL, 211 µmol, 2.0 eq) was added to
a
solution of amine 9 (45 mg, 106 µmol, 1.0 eq) and 4-nitrophenyl isocyanate (10,
52 mg, 317 µmol, 3.0 eq) in THF (2 mL). The reaction mixture was stirred at
55 °C for 6 h. Additional 4-nitrophenyl isocyanate (9, 52 mg, 317 µmol, 3.0 eq)
was added and the reaction was stirred at 55 °C for another 14 h. The reaction
mixture was concentrated in vacuo and the residue was purified by preparative
HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 : 100 in 80 min; tr =
53 min) which provided compound S1 as
a colourless solid (44.7 mg,
76.4 mmol, 72%). TM = 202 °C; 1H-NMR (400 MHz, DMSO-d6): δ = 10.4 (1H, s,
H-8), 10.3 (1H, s, H-23), 8.55 (1H, s, H-21), 8.22 (2H, m, H-26, H-26‘), 8.09 (1H,
d, J = 8.7 Hz, H-11), 7.88 (2H, m, H-5, H-5‘), 7.81 (2H, m, H-6, H-6‘), 7.73 (2H,
6
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
114.5 (2C, t, C-25, C-25’), 80.9 (q, C-2), 76.7 (t, C-16), 75.0 (s, C-18), 28.4 (3C,
p, C-1), 23.0 (2C, p, C-17) ppm; HRMS (ESI): m/z calc. for C31H36N3O6 [M + H]+:
546.2604; found 546.2600.
tert-Butyl-4-(4-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)ureido)-benz-
amido)-3-methoxy-4-oxobutanamido)benzamido)-2-hydroxy-3-isopropoxy-
benzamido)benzoate (S4): Following to the general procedure VI compound
15 (42.0 mg, 44.1 µmol, 1.0 eq) was used. Preparative HPLC (RP-18; run time
80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 56 min) provided Phenol
S4 as a colourless amorphous solid (29.8 mg, 32.6 µmol, 74%). [α]D21 = +29.3°
(c 1.2, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.4 (1H, br. s, OH), 10.8
(1H, br. s, NH), 10.6 (1H, s, NH), 9.40 (1H, s, NH), 9.38 (1H, s, NHUrea), 9.28
(1H, s, NHUrea), 8.38 (1H, d, J = 8.1 Hz, NHCH), 7.96 (2H, m, ArH), 7.92 (2H, m,
ArH), 7.86 – 7.82 (7H, m, ArH), 7.74 (2H, m, ArH), 7.70 (1H, d, J = 8.9 Hz, ArH),
7.66 (2H, m, ArH), 7.59 (2H, m, ArH), 7.51 (2H, d, J = 26.5 Hz, CONH2), 4.91
(1H, t, J = 8.1 Hz, CHNH), 4.56 (1H, hept, J = 6.2 Hz, CHMe2), 4.09 (1H, d,
J = 8.1 Hz, CHOMe), 3.31 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.27 (6H, d,
J = 6.2 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 170.9 (q,
CONH2), 168.8 (q, CONH), 168.4 (q, CONH), 165.5 (q, CONH), 164.6 (q,
CO2tBu), 164.2 (q, CONH), 154.5 (q, C-Ar), 152.0 (q, NHCONH), 144.0 (q,
C-Ar), 142.4 (q, C-Ar), 142.3 (q, C-Ar), 142.1 (q, C-Ar), 137.0 (q, C-Ar), 136.3 (q,
C-Ar), 133.3 (2C, t, C-Ar), 129.9 (2C, t, C-Ar), 128.5 (2C, t, C-Ar), 128.3 (2C, t,
C-Ar), 127.1 (q, C-Ar), 126.7 (q, C-Ar), 122.9 (t, C-Ar), 120.6 (2C, t, C-Ar), 119.3
(q, CN), 119.0 (2C, t, C-Ar), 118.2 (2C, t, C-Ar), 117.5 (2C, t, C-Ar), 112.5 (t,
C-Ar), 111.8 (q, C-Ar), 103.5 (q, C-Ar), 80.5 (q, C(CH3)3), 80.0 (t, CHOMe), 74.7
(t, CH(CH3)2), 57.7 (p, OCH3), 55.8 (t, CHNH), 27.9 (3C, p, C(CH3)3), 22.3 (2C,
p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C48H48N8O11Na [M + Na]+:
935.3340; found 935.3342.
tert-Butyl-4-(2-(allyloxy)-4-(4-((2S,3R)-4-amino-2-((tert-butoxycarbonyl)-
amino)-3-methoxy-4-oxobutanamido)benzamido)-3-isopropoxybenz-
amido)benzoate (S3): Following to the general procedure III using amine 12
(1.50 g, 2.75 mmol, 1.0 eq) and acid 13 (1.23 g, 4.68 mmol, 1.7 eq) compound
S3 (1.37 g, 1.73 mmol, 63%) was obtained as a yellow amorphous solid.
[α]D22 = -0.9° (c 1.3, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.5 (1H, s,
NH), 10.4 (1H, s, NH), 9.51 (1H, s, NH), 7.98 (2H, m, ArH), 7.90 (2H, m, ArH),
7.84 – 7.80 (5H, m, ArH), 7.45 – 7.40 (3H, m, ArH, NH2), 6.80 (1H, d, J = 8.4 Hz,
NHBoc), 6.07 – 5.97 (1H, m, CHallyl), 5.37 (1H, dd, J = 1.6, 17.1 Hz, CHallyl-trans),
5.20 (1H, dd, J = 1.4, 9.8 Hz, CHallyl-cis), 4.61 (2H, d, J = 5.4 Hz, OCH2allyl), 4.50
(1H, hept, J = 6.1 Hz, CHMe2), 4.41 (1H, t, J = 7.9 Hz, CHNH), 3.86 (1H, d,
J = 7.4 Hz, CHOMe), 3.26 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.38 (9H, s,
C(CH3)3), 1.26 (6H, d, J = 6.2 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ = 170.6 (q, CONH2), 168.9 (q, CONH), 164.6 (q, CONH), 164.5 (q,
CONH), 164.3 (q, CO2tBu), 154.8 (q, CO2tBu), 149.5 (q, C-Ar), 143.0 (q, C-Ar),
142.5 (q, C-Ar), 142.2 (q, C-Ar), 135.7 (q, C-Ar), 133.6 (t, CHallyl), 130.1 (2C, t,
C-Ar), 128.4 (2C, t, C-Ar), 127.0 (q, C-Ar), 126.0 (q, C-Ar), 123.6 (t, C-Ar), 118.9
(t, C-Ar), 118.8 (4C, t, C-Ar), 117.8 (s, CH2allyl), 80.3 (t, CHOMe), 80.1 (q,
C(CH3)3), 78.7 (q, C(CH3)3), 76.3 (t, CH(CH3)2), 74.3 (s, OCH2allyl), 57.6 (p,
OCH3), 56.6 (t, CHNH), 28.1 (3C, p, C(CH3)3), 27.8 (3C, p, C(CH3)3), 22.3 (2C,
p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C41H51N5O11Na [M + Na]+:
812.3483; found 812.3480.
4-(4-(4-((2S,3R)-4-Amino-2-(4-(3-(4-cyanophenyl)ureido)benzamido)-3-
methoxy-4-oxo-butanamido)benzamido)-2-hydroxy-3-isopropoxybenz-
amido)benzoic acid (16): Following to the general procedure V phenol S4
(29.8 mg, 32.6 µmol, 1.0 eq) was stirred for 5.5 h. Acid 16 was obtained as a
colourless amorphous solid (22.5 mg, 26.3 µmol, 81%). [α]D22 = +23.1° (c 1.1,
MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.3 (1H, br. s, OH), 10.6 (1H, br. s,
NH), 10.6 (1H, s, NH), 9.40 (1H, s, NH), 9.38 (1H, s, NHUrea), 9.26 (1H, s,
NHUrea), 8.37 (1H, d, J = 8.1 Hz, NHCH), 7.98 – 7.95 (4H, m, ArH), 7.88 – 7.82
(7H, m, ArH), 7.76 – 7.70 (3H, m, ArH), 7.66 (2H, m, ArH), 7.58 (2H, m, ArH),
7.51 (2H, d, J = 26.7 Hz, CONH2), 4.90 (1H, t, J = 8.1 Hz, CHNH), 4.55 (1H,
hept, J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.31 (3H, s, OCH3),
1.27 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ =
170.9 (q, CONH2), 168.8 (q, CONH), 168.5 (q, CONH), 166.9 (q, CO2H), 165.5
(q, CONH), 164.2 (q, CONH), 154.1 (q, C-Ar), 151.9 (q, NHCONH), 144.0 (q, C-
Ar), 142.4 (q, C-Ar), 142.3 (q, C-Ar), 142.0 (q, C-Ar), 137.0 (q, C-Ar), 136.3 (q,
C-Ar), 133.3 (2C, t, C-Ar), 130.2 (2C, t, C-Ar), 128.5 (2C, t, C-Ar), 128.5 (q, C-
Ar), 128.3 (2C, t, C-Ar), 127.1 (q, C-Ar), 126.3 (q, C-Ar), 122.8 (t, C-Ar), 120.7
(2C, t, C-Ar), 119.3 (q, CN), 119.0 (2C, t, C-Ar), 118.2 (2C, t, C-Ar), 117.5 (2C, t,
C-Ar), 112.4 (t, C-Ar), 112.2 (q, C-Ar), 103.5 (q, C-Ar), 80.0 (t, CHOMe), 74.9 (t,
CH(CH3)2), 57.7 (p, OCH3), 55.7 (t, CHNH), 22.3 (2C, p, CH(CH3)2) ppm; HRMS
(ESI): m/z calc. for C44H41N8O11 [M + H]+: 857.2895; found 857.2896.
tert-Butyl-4-(2-(allyloxy)-4-(4-((2S,3R)-2,4-diamino-3-methoxy-4-oxobutan-
amido)-benzamido)-3-isopropoxybenzamido)benzoate (14): Following the
general procedure IV with S3 (200 mg, 0.25 mmol, 1.0 eq) preparative HPLC
(RP-18; run time 100 min; H2O/MeCN = 80 : 20 → 0 : 100 in 80 min; tr = 32 min)
provided amine 14 as a yellow amorphous solid (83 mg, 0.12 mmol, 48%).
[α]D23 = +3.8° (c 1.1, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.5 (1H, s,
NH), 9.53 (1H, s, NH), 7.98 (2H, m, ArH), 7.89 (2H, m, ArH), 7.84 – 7.80 (5H, m,
ArH), 7.47 (2H, d, J = 70 Hz, NH2), 7.41 (1H, d, J = 8.5 Hz, ArH), 6.07 –
5.97 (1H, m, CHallyl), 5.38 (1H, dd, J = 1.7, 17.1 Hz, CHallyl-trans), 5.20 (1H, dd,
J = 1.5, 9.8 Hz, CHallyl-cis), 4.61 (2H, d, J = 5.5 Hz, OCH2allyl), 4.50 (1H, hept,
J = 6.1 Hz, CHMe2), 3.86 (1H, d, J = 6.6 Hz, CHOMe), 3.79 (1H, d, J = 6.6 Hz,
CHNH2), 3.31 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.26 (6H, d, J = 6.1 Hz,
CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.1 (q, CONH2), 164.6
(q, CONH), 164.5 (q, CONH), 164.3 (q, CONH), 163.0 (q, CO2tBu), 149.5 (q,
C-Ar), 143.0 (q, C-Ar), 142.5 (q, C-Ar), 142.0 (q, C-Ar), 135.6 (q, C-Ar), 133.6 (t,
CHallyl), 130.1 (2C, t, C-Ar), 128.5 (q, C-Ar), 128.4 (2C, t, C-Ar), 127.1 (q, C-Ar),
126.0 (q, C-Ar), 123.6 (t, C-Ar), 119.0 (t, C-Ar), 118.8 (2C, t, C-Ar), 118.8 (2C, t,
C-Ar), 117.8 (s, CH2allyl), 82.1 (t, CHOMe), 80.3 (q, C(CH3)3), 76.2 (t,
CH(CH3)2), 74.3 (s, OCH2allyl), 58.0 (p, OCH3), 56.6 (t, CHNH2), 27.9 (3C, p,
C(CH3)3), 22.3 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C36H43N5O9Na
[M + Na]+: 712.2958; found 712.2960.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-((2S,3R)-4-amino-2-((tert-butoxycarbonyl)-
amino)-3-methoxy-4-oxobutanamido)phenyl)ureido)-3-isopropoxybenz-
amido)benzoate (17): Following the general procedure III using amine 11
(234 mg, 417 µmol, 1.0 eq) and acid 13 (186 mg, 710 µmol, 1.7 eq) compound
17 (229 mg, 284 mmol, 68%) was obtained as a yellow solid. TM = 168 °C;
[α]D21 = -7.0° (c 0.9, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.4 (1H, s,
NH), 9.94 (1H, s, NH), 9.52 (1H, s, NHUrea), 8.30 (1H, s, NHUrea), 8.11 (1H, d,
J = 8.8 Hz, ArH), 7.88 (2H, m, ArH), 7.81 (2H, m, ArH), 7.57 (2H, m, ArH),
7.42 – 7.38 (5H, m, ArH, NH2), 6.70 (1H, d, J = 8.3 Hz, NHBoc), 6.05 – 5.98 (1H,
m, CHallyl), 5.40 (1H, dd, J = 1.6, 17.2 Hz, CHallyl-trans), 5.22 (1H, dd, J = 1.4,
9.3 Hz, CHallyl-cis), 4.64 – 4.58 (3H, m, OCH2allyl, CHMe2), 4.35 (1H, t,
J = 8.5 Hz, CHNH), 3.83 (1H, d, J = 7.4 Hz, CHOMe), 3.25 (3H, s, OCH3), 1.54
(9H, s, C(CH3)3), 1.38 (9H, s, C(CH3)3), 1.33 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm;
13C-NMR (100 MHz, DMSO-d6): δ = 170.8 (q, CONH2), 167.8 (q, CONH), 164.6
(2C, q, CONH), 164.3 (q, CO2tBu), 152.0 (q, NHCONH), 149.3 (q, C-Ar), 143.1
(q, C-Ar), 138.4 (q, C-Ar), 137.8 (q, C-Ar), 135.0 (q, C-Ar), 133.6 (t, CHallyl),
130.1 (2C, t, C-Ar), 125.9 (q, C-Ar), 124.5 (t, C-Ar), 124.4 (q, C-Ar), 123.0 (q,
C-Ar), 120.1 (2C, t, C-Ar), 118.8 (2C, t, C-Ar), 118.6 (2C, t, C-Ar), 117.9 (s,
CH2allyl), 113.7 (t, C-Ar), 80.3 (t, CHOMe), 78.6 (2C, q, C(CH3)3), 75.9 (t,
CH(CH3)2), 74.1 (s, OCH2allyl), 57.6 (p, OCH3), 56.5 (t, CHNH), 28.1 (3C, p,
C(CH3)3), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C41H53N6O11 [M + H]+: 805.3772; found 805.3772.
tert-Butyl-4-(2-(allyloxy)-4-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)-
ureido)-benz-amido)-3-methoxy-4-oxobutanamido)benzamido)-3-iso-
propoxybenzamido)benzoate (15): Following the general procedure II acid 8
(41.8 mg, 149 µmol, 2.5 eq) and amine 14 (41.0 mg, 59.4 µmol, 1.0 eq).
provided compound 15 as a colourless solid after preparative HPLC (RP-18; run
time 100 min; H2O/MeCN = 60 : 40 → 0 : 100 in 80 min; tr = 67 min) (42.7 mg,
44.8 µmol, 75%).TM = 226 °C (decomposition); [α]D22 = +34.0° (c 4.2, MeOH);
1H-NMR (400 MHz, DMSO-d6): δ = 10.5 (1H, s, NH), 10.5 (1H, s, NH), 9.52 (1H,
s, NH), 9.51 (1H, s, NHUrea), 9.38 (1H, s, NHUrea), 8.37 (1H, d, J = 8.1 Hz,
NHCH), 7.98 (2H, m, ArH), 7.89 (2H, m, ArH), 7.84 – 7.82 (7H, m, ArH), 7.74
(2H, m, ArH), 7.66 (2H, m, ArH), 7.59 (2H, m, ArH), 7.51 (2H, d, J = 27.1 Hz,
CONH2), 7.41 (1H, d, J = 8.5 Hz, ArH), 6.07 – 5.97 (1H, m, CHallyl), 5.38 (1H,
dq, J = 1.6, 17.2 Hz, CHallyl-trans), 5.20 (1H, dq, J = 1.3, 10.5 Hz, CHallyl-cis), 4.90
(1H, t, J = 8.1 Hz, CHNH), 4.61 (2H, d, J = 5.4 Hz, OCH2allyl), 4.50 (1H, hept,
J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.01 (3H, s, OCH3), 1.54
(9H, s, C(CH3)3), 1.26 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ = 170.9 (q, CONH2), 168.8 (q, CONH), 165.5 (q, CONH), 164.6 (q,
CONH), 164.5 (q, CO2tBu), 164.3 (q, CONH), 152.0 (q, NHCONH), 149.5 (q, C-
Ar), 144.0 (q, C-Ar), 143.0 (q, C-Ar), 142.5 (q, C-Ar), 142.5 (q, C-Ar), 142.2 (q,
C-Ar), 135.7 (q, C-Ar), 133.6 (t, CHallyl), 133.3 (2C, t, C-Ar), 130.1 (2C, t, C-Ar),
128.5 (2C, t, C-Ar), 128.5 (t, C-Ar), 128.4 (2C, t, C-Ar), 127.1 (q, C-Ar), 126.0 (q,
C-Ar), 123.6 (t, C-Ar), 119.3 (q, CN), 118.9 (2C, t, C-Ar), 118.8 (2C, t, C-Ar),
118.2 (2C, t, C-Ar), 117.8 (s, CH2allyl), 117.5 (2C, t, C-Ar), 103.5 (q, C-Ar), 80.3
(q, C(CH3)3), 80.0 (t, CHOMe), 76.3 (t, CH(CH3)2), 74.3 (s, OCH2allyl), 57.7 (p,
OCH3), 55.7 (t, CHNH), 27.9 (3C, p, C(CH3)3), 22.3 (2C, p, CH(CH3)2) ppm;
HRMS (ESI): m/z calc. for C51H52N8O11Na [M + Na]+: 975.3653; found 975.3633.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-((2S,3R)-2,4-diamino-3-methoxy-4-
oxobutanamido)-phenyl)ureido)-3-isopropoxybenzamido)benzoate
(18):
Following to the general procedure IV compound 17 (178 mg, 0.22 mmol,
1.0 eq) was used. Preparative HPLC (RP-18; run time 100 min; H2O/MeCN =
7
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
70 : 30 → 0 : 100 in 80 min; tr = 26 min) provided amine 18 as a yellow
amorphous solid (76.2 mg, 0.11 mmol, 49%). [α]D21 = +4.1° (c 1.1, MeOH);
1H-NMR (400 MHz, DMSO-d6): δ = 10.4 (1H, s, NH), 9.87 (1H, br. s, NH), 9.59
(1H, s, NHUrea), 8.33 (1H, s, NHUrea), 8.11 (1H, d, J = 8.8 Hz, ArH), 7.88 (2H, m,
ArH), 7.81 (2H, m, ArH), 7.58 (2H, m, ArH), 7.43 – 7.41 (3H, m, ArH), 7.36 (2H,
d, J = 80.3 Hz, CONH2), 6.07 – 5.98 (1H, m, CHallyl), 5.40 (1H, dd, J = 1.6,
17.2 Hz, CHallyl-trans), 5.22 (1H, dd, J = 1.4, 9.3 Hz, CHallyl-cis), 4.65 – 4.59 (3H,
m, OCH2allyl, CHMe2), 3.76 (1H, d, J = 6.8 Hz, CHOMe), 3.59 (1H, d,
J = 6.8 Hz, CHNH2), 3.37 (2H, br. s, NH2), 3.28 (3H, s, OCH3), 1.54 (9H, s,
C(CH3)3), 1.33 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ = 171.7 (q, CONH2), 170.7 (q, CONH), 164.6 (q, CO2tBu), 164.3
(q, CONH), 152.1 (q, NHCONH), 149.3 (q, C-Ar), 143.1 (q, C-Ar), 138.4 (q,
C-Ar), 137.8 (q, C-Ar), 134.9 (q, C-Ar), 133.7 (q, C-Ar), 133.6 (t, CHallyl), 130.1
(2C, t, C-Ar), 125.9 (q, C-Ar), 124.5 (t, C-Ar), 122.9 (q, C-Ar), 119.9 (2C, t, C-Ar),
118.8 (2C, t, C-Ar), 118.7 (2C, t, C-Ar), 117.9 (s, CH2allyl), 113.7 (t, C-Ar), 83.2
(t, CHOMe), 80.3 (q, C(CH3)3), 75.9 (t, CH(CH3)2), 74.1 (s, OCH2allyl), 57.8 (p,
OCH3), 57.1 (t, CHNH2), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm;
HRMS (ESI): m/z calc. for C36H45N6O9 [M + H]+: 705.3248; found 705.3242.
NHUrea), 8.43 – 8.35 (4H, m, ArH, NHUrea, NHCH), 8.22 (2H, m, ArH), 8.11 (1H, d,
J = 8.7 Hz, ArH), 7.91 – 7.87 (6H, m, ArH), 7.81 (2H, m, ArH), 7.61 – 7.55 (3H,
m, ArH, CONH2), 7.44 – 7.40 (4H, m, ArH, CONH2), 6.06 – 5.98 (1H, m, CHallyl),
5.40 (1H, dd, J = 1.4, 17.3 Hz, CHallyl-trans), 5.22 (1H, dd, J = 1.1, 9.2 Hz, CHallyl-
cis), 4.89 (1H, t, J = 8.1 Hz, CHNH), 4.63 – 4.59 (3H, m, OCH2allyl, CHMe2),
4.09 (1H, d, J = 7.9 Hz, CHOMe), 3.31 (3H, s, OCH3), 1.54 (9H, s, C(CH3)3),
1.33 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ =
171.1 (q, CONH2), 167.6 (q, CONH), 165.3 (q, CONH), 164.6 (q, CO2tBu),
164.3 (q, CONH), 164.2 (q, CONH), 152.1 (q, NHCONH), 149.3 (q, C-Ar), 143.1
(q, C-Ar), 141.7 (q, C-Ar), 140.7 (q, C-Ar), 138.4 (q, C-Ar), 137.9 (q, C-Ar),
135.1 (q, C-Ar), 133.6 (t, CHallyl), 130.1 (2C, t, C-Ar), 129.4 (2C, t, C-Ar), 129.1
(q, C-Ar), 128.3 (2C, t, C-Ar), 125.9 (q, C-Ar), 124.5 (t, C-Ar), 123.6 (2C, t, C-Ar),
122.9 (q, C-Ar), 120.1 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.8 (2C, t, C-Ar),
118.6 (2C, t, C-Ar), 117.9 (s, CH2allyl), 113.7 (t, C-Ar), 80.3 (q, C(CH3)3), 80.1 (t,
CHOMe), 75.9 (t, CH(CH3)2), 74.1 (s, OCH2allyl), 57.7 (p, OCH3), 55.6 (t,
CHNH), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C50H52N8O13Na [M + Na]+: 995.3552; found 995.3553.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-((2S,3R)-4-amino-2-(4-(4-cyanobenzamido)-
benzamido)-3-methoxy-4-oxobutanamido)phenyl)ureido)-3-isopropoxy-
benzamido)benzoate (22): Following the general procedure II acid 20 (34.5 mg,
129 µmol, 2.5 eq) and amine 18 (36.5 mg, 51.8 µmol, 1.0 eq) provided
compound 22 as a colourless solid (26.6 mg, 27.9 µmol, 54%). Preparative
HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 : 100 in 80 min; tr =
56 min). TM = 239 °C (decomposition); [α]D23 = +24.4° (c 1.2, MeOH); 1H-NMR
(600 MHz, DMSO-d6): δ = 10.7 (1H, s, NH), 10.4 (1H, s, NH), 10.1 (1H, s, NH),
9.54 (1H, s, NHUrea), 8.39 (1H, d, J = 8.1 Hz, NHCH), 8.31 (1H, s, NHUrea),
8.13 – 8.10 (3H, m, ArH), 8.04 (2H, m, ArH), 7.94 – 7.81 (6H, m, ArH), 7.81 (2H,
m, ArH), 7.60 (2H, m, ArH), 7.53 (1H, s, CONH2), 7.44 – 7.40 (4H, m, ArH,
CONH2), 6.05 – 6.00 (1H, m, CHallyl), 5.40 (1H, dq, J = 1.6, 17.1 Hz, CHallyl-trans),
5.22 (1H, dq, J = 1.3, 10.4 Hz, CHallyl-cis), 4.88 (1H, t, J = 8.1 Hz, CHNH), 4.63 –
4.59 (3H, m, OCH2allyl, CHMe2), 4.07 (1H, d, J = 8.1 Hz, CHOMe), 3.30 (3H, s,
OCH3), 1.54 (9H, s, C(CH3)3), 1.33 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR
(125 MHz, DMSO-d6): δ = 171.1 (q, CONH2), 167.6 (q, CONH), 165.3 (q,
CONH), 164.6 (q, CO2tBu), 164.5 (q, CONH), 164.3 (q, CONH), 152.0 (q,
NHCONH), 149.3 (q, C-Ar), 143.1 (q, C-Ar), 141.7 (q, C-Ar), 138.7 (q, C-Ar),
138.4 (q, C-Ar), 137.8 (q, C-Ar), 135.0 (q, C-Ar), 133.6 (t, CHallyl), 132.5 (2C, t,
C-Ar), 130.1 (2C, t, C-Ar), 129.0 (q, C-Ar), 128.6 (2C, t, C-Ar), 128.2 (2C, t, C-
Ar), 125.9 (q, C-Ar), 124.5 (t, C-Ar), 123.0 (q, C-Ar), 120.1 (2C, t, C-Ar), 119.6
(2C, t, C-Ar), 118.8 (2C, t, C-Ar), 118.6 (2C, t, C-Ar), 118.3 (q, C-Ar), 117.9 (s,
CH2allyl), 117.3 (q, CN), 114.0 (q, C-Ar), 113.7 (t, C-Ar), 80.3 (q, C(CH3)3), 80.1
(t, CHOMe), 75.9 (t, CH(CH3)2), 74.1 (s, OCH2allyl), 57.7 (p, OCH3), 55.5 (t,
CHNH), 27.9 (3C, p, C(CH3)3), 22.0 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C51H53N8O11 [M + H]+: 953.3834; found 953.3840.
4-(2-(Allyloxy)-4-(3-(4-((2S,3R)-2,4-diamino-3-methoxy-4-oxobutanamido)-
phenyl)-ureido)-3-isopropoxybenzamido)benzoic acid (S5): Ester 17 (80 mg,
99.4 µmol, 1.0 eq) was added in small portions to 4 N HCl in 1,4-dioxane
(2.48 mL, 9.94 mmol, 100 eq) and stirred for 30 min at rt. The mixture was
slowly transferred to a mixture of EtOAc and a 80 % sat. aq. NaHCO3 solution
(400 mL, 1:1). The layers were separated, the aq. layer was extracted with
EtOAc (3x 100 mL), the combined organic phases were washed with brine
(150 mL), dried over Na2SO4, filtered and concentrated in vacuo. Preparative
HPLC (RP-18; run time 100 min; H2O/MeCN = 95 : 05 → 0 : 100 in 90 min; tr =
30 min) provided acid S5 as a yellow amorphous solid (57.3 mg, 88.4 µmol,
89%). [α]D22 = +7.0° (c 0.9, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.4 (1H,
s, NH), 9.87 (1H, br. s, NH), 9.56 (1H, s, NHUrea), 8.31 (1H, s, NHUrea), 8.11 (1H,
d, J = 8.8 Hz, ArH), 7.92 (2H, m, ArH), 7.81 (2H, m, ArH), 7.58 (2H, m, ArH),
7.42 – 7.40 (3H, m, ArH), 7.37 (2H, d, J = 80.7 Hz, CONH2), 6.08 – 5.99 (1H, m,
CHallyl), 5.40 (1H, dd, J = 1.7, 17.2 Hz, CHallyl-trans), 5.23 (1H, dd, J = 1.4,
10.4 Hz, CHallyl-cis), 4.64 – 4.59 (3H, m, OCH2allyl, CHMe2), 3.76 (1H, d,
J = 6.8 Hz, CHOMe), 3.60 (1H, d, J = 6.8 Hz, CHNH2), 3.27 (3H, s, OCH3), 1.33
(6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.7
(q, CONH2), 170.7 (q, CONH), 167.1 (q, CO2H), 164.3 (q, CONH), 152.1 (q,
NHCONH), 149.3 (q, C-Ar), 142.9 (q, C-Ar), 138.5 (q, C-Ar), 137.8 (q, C-Ar),
134.9 (q, C-Ar), 133.7 (q, C-Ar), 133.6 (t, CHallyl), 130.4 (2C, t, C-Ar), 125.8 (q,
C-Ar), 124.5 (t, C-Ar), 123.1 (q, C-Ar), 119.9 (2C, t, C-Ar), 118.9 (2C, t, C-Ar),
118.7 (2C, t, C-Ar), 117.9 (s, CH2allyl), 113.7 (t, C-Ar), 83.2 (t, CHOMe), 76.0 (t,
CH(CH3)2), 74.1 (s, OCH2allyl), 57.8 (p, OCH3), 57.1 (t, CHNH2), 22.0 (2C, p,
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C32H37N6O9 [M + H]+: 649.2622;
found 649.2624.
tert-Butyl-4-(4-(3-(4-((2S,3R)-4-amino-3-methoxy-2-(4-(4-nitrobenzamido)-
benzamido)-4-oxobutanamido)phenyl)ureido)-2-hydroxy-3-isopropoxy-
benzamido)benzoate (S6): Following the general procedure VI compound 21
(25.0 mg, 25.7 µmol, 1.0 eq) provided phenol S6 as a yellow amorphous solid
(11.5 mg, 12.3 µmol, 48%). Preparative HPLC (RP-18; run time 80 min;
H2O/MeCN = 90 : 10 → 0 : 100 in 70 min; tr = 61 min). [α]D24 = +130.6° (c 0.9,
MeCN); 1H-NMR (400 MHz, DMSO-d6): δ = 12.5 (1H, s, OH), 10.8 (1H, s, NH),
10.6 (1H, s, NH), 10.2 (1H, s, NH), 9.61 (1H, s, NHurea), 8.39 – 8.37 (3H, m, ArH,
NHCH), 8.33 (1H, s, NHurea), 8.21 (2H, m, ArH), 7.92 – 7.79 (10H, m, ArH), 7.60
(2H, m, ArH), 7.53 (1H, s, CONH2), 7.44 – 7.41 (3H, m, ArH, CONH2), 4.89 (1H,
t, J = 8.0 Hz, CHNH), 4.63 (1H, hept, J = 6.1 Hz, CHMe2), 4.07 (1H, d,
J = 8.0 Hz, CHOMe), 3.31 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.30 (6H, d,
J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.1 (q,
CONH2), 169.0 (q, CONH), 167.6 (q, CONH), 165.4 (q, CONH), 164.6 (q,
CO2tBu), 164.2 (q, CONH), 151.9 (q, NHCONH), 149.3 (q, C-Ar), 142.1 (q,
C-Ar), 141.7 (q, C-Ar), 140.3 (q, C-Ar), 139.0 (q, C-Ar), 135.0 (q, C-Ar), 133.6 (q,
C-Ar), 132.9 (q, C-Ar), 129.9 (2C, t, C-Ar), 129.4 (2C, t, C-Ar), 129.1 (q, C-Ar),
128.3 (2C, t, C-Ar), 126.7 (q, C-Ar), 123.6 (2C, t, C-Ar), 123.0 (t, C-Ar), 120.7
(2C, t, C-Ar), 120.2 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.7 (2C, t, C-Ar), 109.3
(t, C-Ar), 80.5 (q, C(CH3)3), 80.1 (t, CHOMe), 74.2 (t, CH(CH3)2), 57.7 (p, OCH3),
55.5 (t, CHNH), 27.9 (3C, p, C(CH3)3), 22.0 (2C, p, CH(CH3)2) ppm; HRMS
(ESI): m/z calc. for C47H47N8O13 [M – H]-: 931.3268; found 931.3262.
4-(4-(3-(4-((2S,3R)-2,4-diamino-3-methoxy-4-oxobutanamido)phenyl)-
ureido)-2-hydroxy-3-isopropoxybenzamido)benzoic acid (25): Following to
the general procedure VI compound S5 (10.0 mg, 15.4 µmol, 1.0 eq) provided
phenol 25 as
a colourless amorphous solid (6.5 mg, 10.7 µmol, 69%).
Preparative HPLC (RP-18; run time 80 min; H2O/MeCN = 95 : 05 → 0 : 100 in
60 min; tr = 21 min). [α]D23 = +24.1° (c 0.7, MeOH); 1H-NMR (500 MHz, DMSO-
d6): δ = 9.83 (1H, br. s, CO2H), 9.55 (1H, s, NH), 8.34 (2H, br. s, NHUrea), 8.09
(1H, s, NH), 7.87 (2H, m, ArH), 7.76 (2H, m, ArH), 7.57 – 7.54 (3H, m, ArH),
7.46 – 7.43 (2H, m, ArH, CONH2), 7.40 (2H, m, ArH), 7.24 (1H, s, CONH2), 4.79
(1H, hept, J = 6.5 Hz, CHMe2), 3.74 (1H, d, J = 7.0 Hz, CHOMe), 3.57 (1H, d,
J = 7.0 Hz, CHNH2), 3.27 (3H, s, OCH3), 1.25 (6H, d, J = 6.5 Hz, CH(CH3)2)
ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.8 (q, CONH2), 170.8 (q, CONH),
168.0 (q, CO2H), 164.8 (q, CONH), 152.2 (q, NHCONH), 143.5 (q, C-Ar), 137.4
(q, C-Ar), 135.3 (q, C-Ar), 134.5 (q, C-Ar), 133.9 (q, C-Ar), 133.9 (q, C-Ar),
130.4 (q, C-Ar), 130.2 (2C, t, C-Ar), 123.4 (t, C-Ar), 119.8 (2C, t, C-Ar), 119.2
(2C, t, C-Ar), 118.5 (2C, t, C-Ar), 112.0 (q, C-Ar), 104.0 (t, C-Ar), 83.3 (t,
CHOMe), 72.0 (t, CH(CH3)2), 57.7 (p, OCH3), 57.1 (t, CHNH2), 22.1 (2C, p,
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C29H32N6O9Na [M + Na]+: 631.2128;
found 631.2127.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-((2S,3R)-4-amino-3-methoxy-2-(4-(4-nitro-
benzamido)-benzamido)-4-oxobutanamido)phenyl)ureido)-3-isopropoxy-
benzamido)benzoate (21): Following the general procedure II acid 19 (31.0 mg,
108 µmol, 2.5 eq) and amine 18 (31.0 mg, 44.0 µmol, 1.0 eq) provided phenol
S7 as a grey amorphous solid (15.8 mg, 17.3 µmol, 61%). Preparative HPLC
(RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 : 100 in 80 min; tr = 57 min)
tert-Butyl-4-(4-(3-(4-((2S,3R)-4-amino-2-(4-(4-cyanobenzamido)benzamido)-
3-methoxy-4-oxobutanamido)phenyl)ureido)-2-hydroxy-3-isopropoxybenz-
amido)benzoate (S7): Following the general procedure VI compound 22 (26.0
mg, 27.3 µmol, 1.0 eq) was used. Preparative HPLC (RP-18; run time 80 min;
H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 26 min) [α]D25 = +66.7° (c 0.8,
MeOH); 1H-NMR (600 MHz, DMSO-d6): δ = 12.5 (1H, br. s, OH), 10.7 (1H, s,
NH), 10.5 (1H, s, NH), 10.1 (1H, s, NH), 9.62 (1H, s, NHurea), 8.39 (1H, d,
provided compound 21 as a colourless solid (25.2 mg, 25.9 µmol, 59%). TM
=
230 °C (decomposition); [α]D21 = +46.1° (c 0.9, MeOH); 1H-NMR (400 MHz,
DMSO-d6): δ = 10.8 (1H, s, NH), 10.4 (1H, s, NH), 10.2 (1H, s, NH), 9.67 (1H, s,
8
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
J = 8.1 Hz, NHCH), 8.34 (1H, s, NHurea), 8.13 (2H, m, ArH), 8.04 (2H, m, ArH),
7.93 – 7.87 (7H, m, ArH), 7.84 (2H, m, ArH), 7.81 (1H, d, J = 9.3 Hz, ArH), 7.60
(2H, m, ArH), 7.53 (1H, s, CONH2), 7.44 – 7.42 (3H, m, ArH, CONH2), 4.89 (1H,
t, J = 8.1 Hz, CHNH), 4.63 (1H, hept, J = 6.2 Hz, CHMe2), 4.07 (1H, d,
J = 8.1 Hz, CHOMe), 3.31 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.30 (6H, d,
J = 6.2 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.1 (q,
CONH2), 169.0 (q, CONH), 167.6 (q, CONH), 165.3 (q, CONH), 164.6 (q,
CO2tBu), 164.5 (q, CONH), 154.4 (q, C-Ar), 151.9 (q, NHCONH), 142.1 (q,
C-Ar), 141.7 (q, C-Ar), 139.1 (q, C-Ar), 138.7 (q, C-Ar), 135.0 (q, C-Ar), 133.6 (q,
C-Ar), 132.8 (q, C-Ar), 132.5 (2C, t, C-Ar), 129.9 (2C, t, C-Ar), 129.0 (q, C-Ar),
128.6 (2C, t, C-Ar), 128.2 (2C, t, C-Ar), 126.7 (q, C-Ar), 123.0 (t, C-Ar), 120.7
(2C, t, C-Ar), 120.1 (2C, t, C-Ar), 119.6 (2C, t, C-Ar), 118.6 (2C, t, C-Ar), 118.3
(q, CN), 114.0 (q, C-Ar), 109.2 (q, C-Ar), 108.1 (t, C-Ar), 80.5 (q, C(CH3)3), 80.1
(t, CHOMe), 74.2 (t, CH(CH3)2), 57.7 (p, OCH3), 55.5 (t, CHNH), 27.8 (3C, p,
C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C48H48N8O11Na [M + Na]+: 935.3340; found 935.3339.
CHallyl), 5.40 (1H, dd, J = 1.7, 17.2 Hz, CHallyl-trans), 5.22 (1H, dd, J = 1.5,
10.5 Hz, CHallyl-cis), 4.86 (1H, t, J = 8.1 Hz, CHNH), 4.64 – 4.59 (3H, m,
OCH2allyl, CHMe2), 4.06 (1H, d, J = 8.1 Hz, CHOMe), 3.30 (3H, s, OCH3), 1.54
(9H, s, C(CH3)3), 1.32 (6H, d, J = 6.2 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz,
DMSO-d6): δ = 171.1 (q, CONH2), 167.7 (q, CONH), 165.4 (q, CONH), 164.6 (q,
CONH), 164.3 (q, CO2tBu), 152.0 (q, NHCONH), 152.0 (q, NHCONH), 149.3 (q,
C-Ar), 144.0 (q, C-Ar), 143.1 (q, C-Ar), 142.4 (q, C-Ar), 138.4 (q, C-Ar), 137.8 (q,
C-Ar), 135.0 (q, C-Ar), 133.6 (q, C-Ar), 133.6 (t, CHallyl), 133.3 (2C, t, C-Ar),
130.1 (2C, t, C-Ar), 128.5 (2C, t, C-Ar), 127.2 (q, C-Ar), 125.9 (q, C-Ar), 124.4 (t,
C-Ar), 123.0 (q, C-Ar), 120.1 (2C, t, C-Ar), 119.3 (q, CN), 118.8 (2C, t, C-Ar),
118.6 (2C, t, C-Ar), 118.2 (2C, t, C-Ar), 117.9 (s, CH2allyl), 117.5 (2C, t, C-Ar),
113.7 (t, C-Ar), 103.5 (q, C-Ar), 80.3 (q, C(CH3)3), 80.1 (t, CHOMe), 75.9 (t,
CH(CH3)2), 74.1 (s, OCH2allyl), 57.7 (p, OCH3), 55.5 (t, CHNH), 27.9 (3C, p,
C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C51H53N9O11Na [M + Na]+: 990.3762; found 990.3769.
tert-Butyl-4-(4-(3-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)ureido)-benz-
amido)-3-methoxy-4-oxobutanamido)phenyl)ureido)-2-hydroxy-3-iso-
propoxybenzamido)benzoate (S8): Following the general procedure VI
compound 26 (26.0 mg, 26.8 µmol, 1.0 eq) was used. Preparative HPLC
(RP-18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 61 min)
provided phenol S8 as a colourless amorphous solid (9.3 mg, 10.0 µmol, 37%).
[α]D22 = +43.6° (c 0.9, MeOH); 1H-NMR (600 MHz, DMSO-d6): δ = 12.5 (1H, br.
s, OH), 10.6 (1H, br. s, NH), 10.1 (1H, s, NH), 9.61 (1H, s, NHurea), 9.50 (1H, s,
NHurea), 9.36 (1H, s, NHurea), 9.32 (1H, s, NHurea), 8.30 (1H, d, J = 8.1 Hz,
NHCH), 7.91 (2H, m, ArH), 7.88 – 7.79 (6H, m, ArH), 7.73 (2H, m, ArH), 7.66
(2H, m, ArH), 7.60 – 7.56 (4H, m, ArH), 7.52 – 7.38 (4H, m, ArH, CONH2), 4.86
(1H, t, J = 8.1 Hz, CHNH), 4.63 (1H, hept, J = 6.2 Hz, CHMe2), 4.06 (1H, d,
J = 8.1 Hz, CHOMe), 3.30 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.30 (6H, d,
J = 6.2 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.1 (q,
CONH2), 169.0 (q, CONH), 167.7 (q, CONH), 165.4 (q, CONH), 164.6 (q,
CO2tBu), 154.6 (q, C-Ar), 152.0 (q, NHCONH), 151.9 (q, NHCONH), 144.0 (q,
C-Ar), 142.4 (q, C-Ar), 142.2 (q, C-Ar), 139.0 (q, C-Ar), 135.0 (q, C-Ar), 133.6 (q,
C-Ar), 133.3 (2C, t, C-Ar), 132.9 (q, C-Ar), 129.9 (2C, t, C-Ar), 128.5 (2C, t, C-
Ar), 127.2 (q, C-Ar), 126.6 (q, C-Ar), 123.0 (t, C-Ar), 120.6 (2C, t, C-Ar), 120.1
(2C, t, C-Ar), 119.3 (q, CN), 118.6 (2C, t, C-Ar), 118.2 (2C, t, C-Ar), 117.5 (2C, t,
C-Ar), 109.3 (q, C-Ar), 107.9 (t, C-Ar), 103.5 (q, C-Ar), 80.4 (q, C(CH3)3), 80.1 (t,
CHOMe), 74.1 (t, CH(CH3)2), 57.7 (p, OCH3), 55.5 (t, CHNH), 27.8 (3C, p,
C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C48H49N9O11Na [M + Na]+: 950.3449; found 950.3447.
4-(4-(3-(4-((2S,3R)-4-Amino-3-methoxy-2-(4-(4-nitrobenzamido)benzamido)-
4-oxobutan-amido)phenyl)ureido)-2-hydroxy-3-isopropoxybenzamido)-
benzoic acid (23): Following the general procedure V phenol S6 (9.0 mg, 9.64
µmol, 1.0 eq) was stirred for 6 h. Acid 23 was obtained as a colourless
amorphous solid (5.8 mg, 6.62 µmol, 69%). [α]D24 = +38.7° (c 0.6, DMSO);
1H-NMR (500 MHz, DMSO-d6 +2 µL DCO2D): δ = 10.8 (1H, s, NH), 10.6 (1H, br.
s, NH), 10.2 (1H, s, NH), 9.61 (1H, s, NHUrea), 8.40 – 8.37 (3H, m, ArH, NHCH),
8.33 (1H, s, NHUrea), 8.20 (2H, m, ArH), 7.96 (2H, m, ArH), 7.92 – 7.84 (5H, m,
ArH), 7.84 (2H, m, ArH), 7.80 (1H, d, J = 8.5 Hz, ArH), 7.60 (2H, m, ArH), 7.49
(2H, d, J = 46.1 Hz, CONH2), 7.42 (2H, m, ArH), 4.89 (1H, t, J = 8.5 Hz, CHNH),
4.63 (1H, hept, J = 6.0 Hz, CHMe2), 4.07 (1H, d, J = 7.3 Hz, CHOMe), 3.30 (3H,
s, OCH3), 1.30 (6H, d, J = 6.0 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-
d6 +2 µL DCO2D): δ = 171.1 (q, CONH2), 169.0 (q, CONH), 167.6 (q, CONH),
167.0 (q, CO2H), 165.4 (q, CONH), 164.3 (q, CONH), 154.5 (q, C-Ar), 152.0 (q,
NHCONH), 149.3 (q, C-Ar), 142.1 (q, C-Ar), 141.7 (q, C-Ar), 140.4 (q, C-Ar),
139.1 (q, C-Ar), 135.0 (q, C-Ar), 133.7 (q, C-Ar), 132.9 (q, C-Ar), 130.2 (2C, t,
C-Ar), 129.4 (2C, t, C-Ar), 129.2 (q, C-Ar), 128.3 (2C, t, C-Ar), 126.2 (q, C-Ar),
123.6 (2C, t, C-Ar), 123.1 (t, C-Ar), 120.8 (2C, t, C-Ar), 120.2 (2C, t, C-Ar),
119.7 (2C, t, C-Ar), 118.7 (2C, t, C-Ar), 109.3 (q, C-Ar), 108.2 (t, C-Ar), 80.2 (t,
CHOMe), 74.2 (t, CH(CH3)2), 57.7 (p, OCH3), 55.6 (t, CHNH), 22.0 (2C, p,
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C43H40N8O13Na [M + Na]+: 899.2613;
found 899.2613.
4-(4-(3-(4-((2S,3R)-4-Amino-2-(4-(4-cyanobenzamido)benzamido)-3-
methoxy-4-oxo-butanamido)phenyl)ureido)-2-hydroxy-3-isopropoxybenz-
amido)benzoic acid (24): Following the general procedure V phenol S7 (14.0
mg, 15.3 µmol, 1.0 eq) was stirred for 30 min. Acid 24 was obtained as a yellow
amorphous solid (13.0 mg, 15.2 µmol, 99%). [α]D23 = +37.2° (c 0.3, DMSO); 1H-
NMR (500 MHz, DMSO-d6 +2 µL DCO2D): δ = 12.5 (1H, s, OH), 10.7 (1H, s,
NH), 10.5 (1H, s, NH), 10.1 (1H, s, NH), 9.61 (1H, s, NHUrea), 8.38 (1H, d,
J = 8.1 Hz, NHCH), 8.34 (1H, s, NHUrea), 8.13 (2H, m, ArH), 8.04 (2H, m, ArH),
7.96 (2H, m, ArH), 7.91 – 7.83 (7H, m, ArH), 7.81 (1H, d, J = 9.2 Hz, ArH), 7.60
(2H, m, ArH), 7.52 – 7.41 (4H, m, ArH, CONH2), 4.88 (1H, t, J = 8.1 Hz, CHNH),
4.62 (1H, hept, J = 6.1 Hz, CHMe2), 4.06 (1H, d, J = 8.1 Hz, CHOMe), 3.30 (3H,
s, OCH3), 1.30 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-
d6 +2 µL DCO2D): δ = 171.1 (q, CONH2), 169.0 (q, CONH), 167.6 (q, CONH),
166.9 (q, CO2H), 165.3 (q, CONH), 164.5 (q, CONH), 154.3 (q, C-Ar), 151.9 (q,
NHCONH), 142.0 (q, C-Ar), 141.7 (q, C-Ar), 139.1 (q, C-Ar), 138.7 (q, C-Ar),
134.9 (q, C-Ar), 133.7 (q, C-Ar), 132.5 (2C, t, C-Ar), 130.2 (2C, t, C-Ar), 129.0
(q, C-Ar), 128.6 (2C, t, C-Ar), 128.3 (2C, t, C-Ar), 126.1 (q, C-Ar), 123.0 (t, C-Ar),
120.8 (2C, t, C-Ar), 120.6 (q, C-Ar), 120.1 (2C, t, C-Ar), 119.6 (2C, t, C-Ar),
118.7 (2C, t, C-Ar), 118.3 (q, CN), 114.1 (q, C-Ar), 109.2 (q, C-Ar), 108.2 (t, C-
Ar), 80.1 (t, CHOMe), 74.3 (t, CH(CH3)2), 57.7 (p, OCH3), 55.5 (t, CHNH), 21.9
(2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C44H40N8O11Na [M + Na]+:
879.2714; found 879.2714.
4-(4-(3-(4-((2S,3R)-4-Amino-2-(4-(3-(4-cyanophenyl)ureido)benzamido)-3-
methoxy-4-oxobutanamido)phenyl)ureido)-2-hydroxy-3-isopropoxybenz-
amido)benzoic acid (27): Following the general procedure V phenol S8 (9.0
mg, 9.70 µmol, 1.0 eq) was stirred for 30 min. Acid 27 was obtained as a
colourless amorphous solid (8.4 mg, 9.70 µmol, 99%). [α]D23 = +12.7° (c 1.1,
MeOH); 1H-NMR (600 MHz, DMSO-d6 +2 µL DCO2D): δ = 12.5 (1H, br. s, OH),
10.5 (1H, br. s, NH), 10.1 (1H, s, NH), 9.61 (1H, s, NHUrea), 9.37 (1H, s, NHUrea),
9.25 (1H, s, NHUrea), 8.34 (1H, s, NHUrea),8.30 (1H, d, J = 8.1 Hz, NHCH), 7.96
(2H, m, ArH), 7.89 (1H, d, J = 9.0 Hz, ArH), 7.85 – 7.80 (5H, m, ArH), 7.74 (2H,
m, ArH), 7.65 (2H, m, ArH), 7.60 – 7.55 (4H, m, ArH), 7.52 – 7.41 (4H, m, ArH,
CONH2), 4.86 (1H, t, J = 8.1 Hz, CHNH), 4.62 (1H, hept, J = 6.2 Hz, CHMe2),
4.06 (1H, d, J = 8.1 Hz, CHOMe), 3.30 (3H, s, OCH3), 1.30 (6H, d, J = 6.2 Hz,
CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6 +2 µL DCO2D): δ = 171.1 (q,
CONH2), 169.0 (q, CONH), 167.7 (q, CONH), 166.9 (q, CO2H), 165.4 (q,
CONH), 154.3 (q, C-Ar), 152.0 (q, NHCONH), 151.9 (q, NHCONH), 144.0 (q, C-
Ar), 142.3 (q, C-Ar), 142.0 (q, C-Ar), 139.1 (q, C-Ar), 134.9 (q, C-Ar), 133.7 (q,
C-Ar), 133.3 (2C, t, C-Ar), 132.8 (q, C-Ar), 130.2 (2C, t, C-Ar), 128.5 (2C, t, C-
Ar), 127.3 (q, C-Ar), 126.2 (q, C-Ar), 123.0 (t, C-Ar), 120.8 (2C, t, C-Ar), 120.1
(2C, t, C-Ar), 119.3 (q, CN), 118.7 (2C, t, C-Ar), 118.2 (2C, t, C-Ar), 117.5 (2C, t,
C-Ar), 109.2 (q, C-Ar), 108.2 (t, C-Ar), 103.5 (q, C-Ar), 80.1 (t, CHOMe), 74.3 (t,
CH(CH3)2), 57.7 (p, OCH3), 55.5 (t, CHNH), 21.9 (2C, p, CH(CH3)2) ppm; HRMS
(ESI): m/z calc. for C44H42N9O11 [M + H]+: 872.3004; found 872.3004.
tert-Butyl-4-(2-(allyloxy)-4-(3-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)-
ureido)-benz-amido)-3-methoxy-4-oxobutanamido)phenyl)ureido)-3-iso-
propoxybenzamido)-benzoate (26): Following the general procedure II acid 8
(26.0 mg, 92.2 µmol, 2.5 eq) and amine 18 (26.0 mg, 36.9 µmol, 1.0 eq)
provided compound 26 as a colourless solid (27.0 mg, 27.9 µmol, 76%).
Preparative HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 : 100 in
tert-Butyl-4-(2-(allyloxy)-4-azido-3-isopropoxybenzamido)benzoate
(28):
tert-Butylnitrite (1.13 mL, 9.50 mmol, 1.5 eq) and trimethylsilyl azide (1.26 mL,
9.50 mmol, 1.5 eq) were added dropwise to a solution of amine 9 (2.70 g,
6.34 mmol, 1.0 eq) in acetonitrile (127 mL) at 0 °C. After 2 h at rt all volatiles
were removed in vacuo. Column chromatography (PE/EtOAc = 20:1  10:1)
yielded azide 28 (2.86 g, 6.34 mmol, quant.) as a yellow solid. TM = 78 °C;
1H-NMR (400 MHz, CDCl3): δ = 10.2 (1H, s, H-8), 8.00 – 7.96 (3H, m, H-5, H-5‘,
H-11), 7.71 (2H, m, H-6, H-6‘), 6.95 (1H, d, J = 8.7 Hz, H-12), 6.17 – 6.08 (1H,
m, H-19), 5.48 (1H, dq, J = 1.4, 17.2 Hz, H-20trans), 5.40 (1H, dq, J = 1.2,
10.3 Hz, H-20cis), 4.73 (2H, dt, J = 1.2, 6.0 Hz, H-18), 4.60 (1H, hept, J = 6.2 Hz,
H-16), 1.60 (9H, s, H-1), 1.36 (6H, d, J = 6.2 Hz, H-17) ppm; 13C-NMR (100
80 min; tr
= 56 min). TM =
203 °C (decomposition); [α]D24 = +40.0° (c 0.8,
MeOH); 1H-NMR (500 MHz, DMSO-d6): δ = 10.4 (1H, s, NH), 10.1 (1H, s, NH),
9.52 (1H, s, NHurea), 9.43 (1H, s, NHurea), 9.30 (1H, s, NHurea), 8.31 – 8.30 (2H,
m, NHurea, NHCH), 8.11 (1H, d, J = 8.8 Hz, ArH), 7.88 (2H, m, ArH), 7.82 – 7.80
(4H, m, ArH), 7.74 (2H, m, ArH), 7.65 (2H, m, ArH), 7.60 – 7.57 (4H, m, ArH),
7.51 (1H, s, CONH2), 7.43 – 7.40 (4H, m, ArH, CONH2), 6.07 – 5.99 (1H, m,
9
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
MHz, CDCl3): δ = 165.5 (q, C-3), 162.5 (q, C-9), 151.4 (q, C-15), 143.1 (q, C-14),
142.2 (q, C-7), 139.2 (q, C-13), 132.3 (t, C-19), 130.8 (2C, t, C-5, C-5’), 127.6 (q,
C-4), 127.1 (t, C-11), 123.3 (q, C-10), 120.3 (s, C-20), 119.2 (2C, t, C-6, C-6’),
116.4 (t, C-12), 81.0 (q, C-2), 76.9 (t, C-16), 75.3 (s, C-18), 28.4 (3C, p, C-1),
126.0 (2C, t, C-Ar), 125.9 (q, C-Ar), 123.9 (t, C-Ar), 122.9 (t, C-HTriazol), 120.9 (t,
C-Ar), 120.0 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.0 (s, CH2allyl), 80.4 (q,
C(CH3)3), 78.7 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 58.6 (p,
OCH3), 54.3 (t, CHNH2), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm;
HRMS (ESI): m/z calc. for C37H44N7O8 [M + H]+: 714.3251; found 714.3250.
22.3 (2C, p, C-17) ppm; HRMS (ESI): m/z calc. for C24H28N4O5Na [M + Na]+:
~
475.1957; found 475.1959; IR (neat): = 3318, 2980, 2118, 1708, 1672, 1589,
v
1528, 1252, 1101, 978, 770 cm-1.
4-(4-Fluorobenzamido)-benzoic acid (39): 4-Fluorbenzoyl chloride (33,
3.5 mL, 29.2 mmol, 4.0 eq) was dropped to a solution of 4-aminobenzoic acid
(7, 1.0 g, 7.29 mmol, 1.0 eq) and Na2CO3 (1.55 g, 14.6 mmol, 2.0 eq) in
water/THF (47 mL, 1:1). After stirring vigorously at rt for 3 h, the filtrate was
filtered and washed with hot water (1.5 L). Acid 39 (1.85 g, 7.15 mmol, 98%)
was obtained after drying at high vacuum as colourless solid. TM = 301 °C; 1H-
NMR (400 MHz, DMSO-d6): δ = 12.8 (1H, s, CO2H), 10.5 (1H, s, H-6), 8.07 –
8.03 (2H, m, H-9, H-9‘), 7.95 – 7.89 (4H, m, H-3, H-3‘, H-4, H-4‘), 7.41 – 7.36
(2H, m, H-10, H-10‘) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 166.9 (q, C-1),
164.8 (q, C-7), 164.2 (d, J = 249.4 Hz, C-11), 143.2 (q, C-5), 131.1 (d,
J = 2.9 Hz, C-8), 130.6 (d, J = 9.2 Hz, C-9, C-9‘), 130.2 (2C, t, C-3, C-3‘), 125.5
(q, C-2), 119.5 (2C, t, C-4, C-4‘), 115.4 (d, J = 21.8 Hz, C-10, C-10‘) ppm;
HRMS (ESI): m/z calc. for C14H9NO3F [M – H]-: 258.0566; found 258.0564.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)-3-iso-
propoxy-benzamido)benzoate (30): Azide 28 (2.98 g, 6.58 mmol, 1.0 eq) and
4-ethynylaniline (29, 771 mg, 6.56 mmol, 1.0 eq) were dissolved in a mixture of
THF (55 mL) and DMSO (110 mL). Sodium ascorbate (782 mg, 3.95 mmol,
0.6 eq) was dissolved in water (5.5 mL) and added to the reaction mixture. After
addition of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (1.40 g, 2.63 mmol,
0.4 eq) and CuSO4 (105 mg, 0.66 mmol, 0.1 eq), the reaction was stirred at rt
for 2 h. Half of the solvent was removed under reduced pressure. The residue
was extracted with EtOAc (3x). The combined organic phases were washed
with NH4Cl-solution, water and brine, dried over Na2SO4, filtered and
concentrated in vacuo. Column chromatography (PE/EtOAc = 20:1) yielded the
desired product 30 (3.56 g, 6.25 mmol, 95%) as yellow solid. TM = 75 °C;
1H-NMR (400 MHz, CDCl3): δ = 10.2 (1H, s, H-8), 8.36 (1H, s, H-21), 8.16 (1H,
d, J = 8.7 Hz, H-11), 8.00 (2H, m, H-5, H-5‘), 7.80 (1H, d, J = 8.7 Hz, H-12),
7.76 – 7.72 (4H, m, H-6, H-6‘, H-24, H-24‘), 6.38 (2H, m, H-25, H-25‘), 6.22 –
6.12 (1H, m, H-19), 5.53 (1H, dq, J = 1.2, 17.1 Hz, H-20trans), 5.44 (1H, dq,
J = 1.0, 10.4 Hz, H-20cis), 4.83 (2H, d, J = 6.0 Hz, H-18), 4.36 (1H, hept,
J = 6.2 Hz, H-16), 1.60 (9H, s, H-1), 1.12 (6H, d, J = 6.2 Hz, H-17) ppm;
13C-NMR (100 MHz, CDCl3): δ = 165.4 (q, C-3), 162.0 (q, C-9), 151.4 (q, C-15),
148.1 (q, C-22), 146.0 (q, C-26), 142.9 (q, C-14), 141.9 (q, C-7), 135.8 (q, C-13),
132.1 (t, C-19), 130.8 (2C, t, C-5, C-5’), 127.8 (q, C-4/C-10), 127.3 (q,
C-4/C-10), 127.3 (t, C-11), 127.2 (2C, t, C-24, C-24’), 121.3 (q, C-23), 120.8 (t,
C-12), 120.6 (s, C-20), 120.3 (t, C-21), 119.3 (2C, t, C-6, C-6’), 115.9 (2C, t,
C-25, C-25’), 81.0 (q, C-2), 77.9 (t, C-16), 75.6 (s, C-18), 28.4 (3C, p, C-1), 22.3
(2C, p, C-17) ppm; HRMS (ESI): m/z calc. for C32H36N5O5 [M + H]+: 570.2716;
found 570.2714.
4-(5-Cyanopicolinamido)-benzoic acid (40): Following the general procedure
I
using amine 32 (32.6 mg, 0.17 mmol) and acid 34 (50 mg, 0.34 mmol)
intermediate was isolated and used directly for tBu-saponification following to
general procedure V. Acid 40 (33.7 mg, 0.13 mmol, 75%) was obtained as a
beige solid.TM = 354 °C; 1H-NMR (400 MHz, DMSO-d6): δ = 12.8 (1H, s, CO2H),
11.1 (1H, s, H-6), 9.22 (1H, d, J = 1.7 Hz, H-12), 8.60 (1H, dd, J = 1.7, 8.1 Hz,
H-10), 8.31 (1H, d, J = 8.1 Hz, H-9), 8.06 (2H, m, H-4, H-4‘), 7.95 (2H, m, H-3,
H-3‘) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 166.9 (q, C-1), 161.8 (q, C-7),
152.3 (q, C-8), 151.5 (t, C-10), 142.3 (t, C-12), 142.1 (q, C-5), 130.2 (2C, t, C-3,
C-3‘), 126.2 (q, C-2), 122.6 (t, C-9), 120.0 (2C, t, C-4, C-4‘), 116.6 (q, CN),
111.8 (q, C-11) ppm; HRMS (ESI): m/z calc. for C14H8N3O3 [M – H]-: 266.0566;
found 266.0564.
4-(4-Cyano-3-fluorobenzamido)-benzoic acid (41): Following the general
procedure
I using amine 32 (58.5 mg, 0.30 mmol) and acid 35 (100 mg,
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-((tert-butoxycarbonyl)-
amino)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-3-iso-
propoxybenzamido)-benzoate (S9): Following the general procedure III using
amine 30 (2.83 g, 4.97 mmol, 1.0 eq) and acid 13 (2.22 g, 8.45 mmol, 1.7 eq)
compound S9 (2.72 g, 3.34 mmol, 67%) was obtained as a yellow amorphous
solid. [α]D24 = -3.9° (c 2.0, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.7 (1H,
s, NH), 10.2 (1H, s, NH), 8.89 (1H, s, CHTriazol), 7.93 – 7.91 (4H, m, ArH), 7.84
(2H, m, ArH), 7.76 (2H, m, ArH), 7.61 (1H, d, J = 8.3 Hz, ArH), 7.54 (1H, d,
J = 8.3 Hz, ArH), 7.43 (2H, d, J = 17.8 Hz, NH2), 6.76 (1H, d, J = 8.4 Hz,
NHBoc), 6.07 – 5.97 (1H, m, CHallyl), 5.38 (1H, dq, J = 1.6, 17.3 Hz, CHallyl-trans),
5.20 (1H, dd, J = 1.4, 9.6 Hz, CHallyl-cis), 4.69 (2H, d, J = 5.5 Hz, OCH2allyl), 4.40
(1H, t, J = 7.5 Hz, CHNH), 4.28 (1H, hept, J = 6.1 Hz, CHMe2), 3.86 (1H, d,
J = 7.4 Hz, CHOMe), 3.26 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.39 (9H, s,
C(CH3)3), 1.01 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-
d6): δ = 170.7 (q, CONH2), 168.4 (q, CONH), 168.1 (q, CO2tBu), 164.6 (q,
CONH), 164.3 (q, CO2tBu), 150.3 (q, C-Ar), 146.3 (q, C-ArTriazol), 143.9 (q, C-Ar),
142.8 (q, C-Ar), 138.9 (q, C-Ar), 133.6 (q, C-Ar), 133.5 (t, CHallyl), 132.9 (q, C-
Ar), 130.1 (2C, t, C-Ar), 126.3 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.3 (q, C-Ar),
123.9 (t, C-Ar), 122.8 (t, C-HTriazol), 120.9 (t, C-Ar), 119.8 (2C, t, C-Ar), 118.9
(2C, t, C-Ar), 118.0 (s, CH2allyl), 80.4 (t, CHOMe), 80.2 (q, C(CH3)3), 78.6 (q,
C(CH3)3), 76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.6 (p, OCH3), 56.5 (t,
CHNH), 28.1 (3C, p, C(CH3)3), 27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2)
ppm; HRMS (ESI): m/z calc. for C42H51N7O10Na [M + Na]+: 836.33595; found
836.3596.
0.61 mmol) intermediate was isolated and used directly for tBu-saponification
following to general procedure V. Acid 41 (57.0 mg, 0.20 mmol, 66%) was
obtained as a colourless solid.TM = 298 °C; 1H-NMR (400 MHz, DMSO-d6):
δ = 12.8 (1H, s, CO2H), 10.8 (1H, s, H-6), 8.16 – 8.13 (1H, m, H-9), 8.08 – 8.05
(1H, m, H-13), 7.98 – 7.95 (3H, m, H-4, H-4‘, H-10), 7.91 – 7.88 (2H, m, H-3,
H-3‘) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 166.8 (q, C-1), 163.5 (q, C-7),
162.1 (d, J = 238.1 Hz, C-12), 142.6 (q, C-5), 141.5 (d, J = 7.3 Hz, C-8), 134.3
(t, C-9), 130.3 (2C, t, C-3, C-3‘), 126.1 (q, C-2), 124.7 (d, J = 3.5 Hz, C-10),
119.7 (2C, t, C-4, C-4‘), 115.8 (d, J = 21.4 Hz, C-13), 113.6 (q, CN), 102.9 (d,
J = 15.3 Hz, C-11) ppm; HRMS (ESI): m/z calc. for C15H8N2O3F [M – H]-:
283.0519; found 283.0516.
4-(Isonicotinamido)-benzoic acid (42): Following to general procedure I using
amine 32 (78.4 mg, 0.41 mmol) and acid 36 (100 mg, 0.81 mmol) the
intermediate was isolated and directly used for tBu-saponification following the
general procedure V. Acid 42 (92.3 mg, 0.38 mmol, 94%) was obtained as a
beige solid. TM = 381 °C; 1H-NMR (400 MHz, DMSO-d6): δ = 12.8 (1H, s, CO2H),
10.8 (1H, s, H-6), 8.82 (2H, m, H-10, H-10‘), 7.97 (2H, m, H-4, H-4‘), 7.92 – 7.91
(2H, m, H-3, H-3‘), 7.90 – 7.89 (2H, m, H-9, H-9‘) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ = 166.9 (q, C-1), 164.3 (q, C-7), 149.9 (2C, t, C-10, C-10‘), 142.6
(q, C-5), 142.1 (q, C-8), 130.3 (2C, t, C-4, C-4‘), 126.1 (q, C-2), 121.9 (2C, t,
C-9, C-9‘), 119.7 (2C, t, C-3, C-3‘) ppm; HRMS (ESI): m/z calc. for C13H9N2O3
[M – H]-: 241.0613; found 241.0608.
4-(6-Cyanonicotinamido)-benzoic acid (43): Following the general procedure
I using amine 32 (65.2 mg, 0.34 mmol) and acid 37 (100 mg, 0.68 mmol)
intermediate was isolated and used directly for tBu-saponification following the
general procedure V. Acid 43 (75.0 mg, 0.28 mmol, 83%) was obtained as a
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-2,4-diamino-3-methoxy-4-
oxobutanamido)-phenyl)-1H-1,2,3-triazol-1-yl)-3-isopropoxybenzamido)-
benzoate (31): Following the general procedure IV compound S9 (420 mg,
0.52 mmol, 1.0 eq) was used. Preparative HPLC (RP-18; run time 100 min;
H2O/MeCN = 80 : 20 → 0 : 100 in 80 min; tr = 31 min) provided amine 31 as a
yellow amorphous solid (131 mg, 0.18 mmol, 36%). [α]D24 = +27.7° (c 1.1,
MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.7 (1H, s, NH), 8.93 (1H, s,
CHTriazol), 8.14 – 7.73 (10H, m, NH, ArH), 7.66 – 7.53 (3H, m, ArH, NH2), 6.07 –
5.99 (1H, m, CHallyl), 5.39 (1H, d, J = 17.2 Hz, CHallyl-trans), 5.20 (1H, d,
J = 10.3 Hz, CHallyl-cis), 4.69 (2H, d, J = 5.5 Hz, OCH2allyl), 4.31 – 4.13 (3H, m,
CHNH2, CHOMe, CHMe2), 3.39 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.00 (6H,
d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 170.0 (q,
CONH2), 164.6 (q, CONH), 164.3 (q, CONH), 163.0 (q, CO2tBu), 150.3 (q, C-Ar),
146.2 (q, C-ArTriazol), 143.9 (q, C-Ar), 142.8 (q, C-Ar), 138.2 (q, C-Ar), 133.6 (q,
C-Ar), 133.5 (t, CHallyl), 133.0 (q, C-Ar), 130.1 (2C, t, C-Ar), 126.3 (q, C-Ar),
beige solid.TM
=
289 °C (decomposition); 1H-NMR (400 MHz, DMSO-d6):
δ = 12.7 (1H, s, CO2H), 10.9 (1H, s, H-6), 9.23 (1H, d, J = 1.9 Hz, H-12), 8.53
(1H, dd, J = 1.9, 8.0 Hz, H-9), 8.26 (1H, d, J = 8.0 Hz, H-10), 7.97 (2H, m, H-4,
H-4‘), 7.90 (2H, m, H-3, H-3‘) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 166.8
(q, C-1), 163.1 (q, C-7), 150.2 (t, C-12), 142.5 (q, C-5), 137.3 (t, C-9), 134.5 (q,
C-8), 133.4 (q, C-11), 130.4 (2C, t, C-4, C-4‘), 128.8 (t, C-10), 126.2 (q, C-2),
119.6 (2C, t, C-3, C-3‘), 117.1 (q, CN) ppm; HRMS (ESI): m/z calc. for
C14H8N3O3 [M – H]-: 266.0566; found 266.0565.
4-(3-(4-Cyanophenyl)-propanamido)-benzoic acid (44): Following the
general procedure I using amine 32 (55.1 mg, 0.29 mmol) and acid 38 (100 mg,
0.57 mmol) the intermediate was isolated and directly used for the next step,
10
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
the tBu-saponification following the general procedure V. Acid 44 (66.0 mg,
0.22 mmol, 79%) was obtained as a colourless solid. TM = 280 °C; 1H-NMR
(400 MHz, DMSO-d6): δ = 12.7 (1H, br. s, CO2H), 10.3 (1H, s, H-6), 7.87 (2H, m,
H-3, H-3‘), 7.76 (2H, m, H-12, H-12‘), 7.67 (2H, m, H-4, H-4‘), 7.47 (2H, m, H-11,
H-11‘), 3.00 (2H, t, J = 7.5 Hz, H-9), 2.71 (2H, t, J = 7.5 Hz, H-8) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ = 170.5 (q, C-7), 166.9 (q, C-1), 147.2 (q, C-10), 143.1
(q, C-5), 132.2 (2C, t, C-12, C-12‘), 130.4 (2C, t, C-3, C-3‘), 129.4 (2C, t, C-11,
C-11‘), 125.0 (q, C-2), 119,0 (q, CN), 118,3 (2C, t, C-4, C-4‘), 108.9 (q, C-13),
37.1 (s, C-8), 30.5 (s, C-9) ppm; HRMS (ESI): m/z calc. for C17H13N2O3 [M – H]-:
293.0926; found 293.0924.
10.4 (1H, s, NH), 8.90 (1H, s, CHTriazol), 8.45 (1H, d, J = 8.1 Hz, NHCH), 8.08 –
8.05 (2H, m, ArH), 7.94 – 7.88 (8H, m, ArH), 7.85 (2H, m, ArH), 7.80 (2H, m,
ArH), 7.62 – 7.47 (4H, m, ArH, CONH2), 7.41 – 7.32 (2H, m, ArH), 6.07 –
5.97 (1H, m, CHallyl), 5.38 (1H, dd, J = 1.5, 17.1 Hz, CHallyl-trans), 5.21 (1H, d,
J = 10.6 Hz, CHallyl-cis), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.69 (2H, d, J = 5.3 Hz,
OCH2allyl), 4.28 (1H, hept, J = 6.1 Hz, CHMe2), 4.10 (1H, d, J = 8.1 Hz,
CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.1 Hz,
CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2
(q, CONH), 165.4 (q, CONH), 164.7 (q, CO2tBu), 164.6 (q, CONH), 164.3 (q,
CONH), 164.2 (d, J = 254.2 Hz, C-F), 150.3 (q, C-Ar), 146.3 (q, C-ArTriazol),
143.9 (q, C-Ar), 142.8 (q, C-Ar), 142.1 (q, C-Ar), 138.9 (q, C-Ar), 133.6 (q, C-Ar),
133.5 (t, CHallyl), 132.9 (q, C-Ar), 131.1 (d, J = 2.8 Hz, C-Ar), 130.5 (2C, d,
J = 9.2 Hz, C-Ar), 130.1 (2C, t, C-Ar), 128.6 (q, C-Ar), 128.2 (2C, t, C-Ar), 126.3
(q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 123.9 (t, C-Ar), 122.8 (t,
C-ArTriazol), 120.9 (t, C-Ar), 119.8 (2C, t, C-Ar), 119.5 (2C, t, C-Ar), 118.9 (2C, t,
C-Ar), 118.0 (s, CH2allyl), 115.4 (2C, d, J = 21.9 Hz, C-Ar), 80.4 (q, C(CH3)3),
80.1 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.7 (p, OCH3), 55.7 (t,
CHNH), 27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C51H51N8O10FNa [M + Na]+: 977.3610; found 977.3611.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-3-methoxy-2-(4-(4-nitro-
benzamido)-benzamido)-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-3-
isopropoxybenzamido)-benzoate (S10): Following the general procedure II
acid 19 (32.0 mg, 112 µmol, 2.5 eq) and amine 31 (32.0 mg, 44.9 µmol, 1.0 eq)
provided compound S10 as a colourless amorphous solid (20.1 mg, 20.5 µmol,
45%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 :
100 in 80 min; tr = 58 min). [α]D24 = +48.6° (c 2.0, DMSO); 1H-NMR (400 MHz,
DMSO-d6): δ = 10.8 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.90 (1H, s,
CHTriazol), 8.50 (1H, d, J = 7.9 Hz, NHCH), 8.39 (2H, m, ArH), 8.21 (2H, m, ArH),
7.94 – 7.92 (8H, m, ArH), 7.84 (2H, m, ArH), 7.80 (2H, m, ArH), 7.62 – 7.60 (2H,
m, ArH, CONH2), 7.54 (1H, d, J = 8.4 Hz, ArH), 7.48 (1H, s, CONH2), 6.07 –
5.97 (1H, m, CHallyl), 5.38 (1H, d, J = 17.2 Hz, CHallyl-trans), 5.21 (1H, d,
J = 10.3 Hz, CHallyl-cis), 4.92 (1H, t, J = 7.9 Hz, CHNH), 4.69 (2H, d, J = 4.8 Hz,
OCH2allyl), 4.28 (1H, hept, J = 6.0 Hz, CHMe2), 4.11 (1H, d, J = 7.9 Hz,
CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.0 Hz,
CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.1 (q, CONH2), 168.2
(q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.3 (q, CONH), 164.3 (q,
CONH), 150.3 (q, C-Ar), 149.3 (q, C-Ar), 146.3 (q, C-ArTriazol), 144.0 (q, C-Ar),
142.9 (q, C-Ar), 141.7 (q, C-Ar), 140.3 (q, C-Ar), 138.9 (q, C-Ar), 133.7 (q, C-Ar),
133.5 (q, C-Ar), 133.0 (t, CHallyl), 130.2 (q, C-Ar), 129.4 (2C, t, C-Ar), 129.1 (q,
C-Ar), 128.3 (2C, t, C-Ar), 126.3 (2C, t, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (2C, t,
C-Ar), 123.9 (t, C-Ar), 123.6 (2C, t, C-Ar), 122.8 (t, C-ArTriazol), 120.9 (t, C-Ar),
119.8 (q, C-Ar), 119.7 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.0 (s, CH2allyl), 80.4
(q, C(CH3)3), 80.1 (t, CHOMe), 76.9 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.8 (p,
OCH3), 55.7 (t, CHNH), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm;
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(5-cyanopicolin-
amido)-benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-
1-yl)-3-isopropoxy-benzamido)benzoate (S13): Following the general
procedure II acid 40 (31.8 mg, 119 µmol, 2.5 eq) and amine 31 (34.0 mg,
47.6 µmol, 1.0 eq) provided compound S13 as a beige amorphous solid (23.0
mg, 23.9 µmol, 50%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN
= 70 : 30 → 0 : 100 in 80 min; tr = 56 min). [α]D22 = +27.7° (c 0.3, MeOH); 1H-
NMR (400 MHz, DMSO-d6): δ = 11.0 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s,
NH), 9.22 (1H, br. s, ArH), 8.90 (1H, s, CHTriazol), 8.60 (1H, dd, J = 1.7, 8.1 Hz,
ArH), 8.49 (1H, d, J = 8.1 Hz, NHCH), 8.31 (1H, d, J = 8.1 Hz, ArH), 8.06 (2H, m,
ArH), 7.94 – 7.89 (6H, m, ArH), 7.85 (2H, m, ArH), 7.80 (2H, m, ArH), 7.61 (1H,
d, J = 8.3 Hz, ArH), 7.54 (1H, d, J = 8.3 Hz, ArH), 7.53 (2H, d, J = 40.9 Hz,
CONH2), 6.07 – 5.97 (1H, m, CHallyl), 5.38 (1H, d, J = 17.2 Hz, CHallyl-trans), 5.20
(1H, d, J = 10.4 Hz, CHallyl-cis), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.69 (2H, d,
J = 5.1 Hz, OCH2allyl), 4.28 (1H, hept, J = 6.0 Hz, CHMe2), 4.11 (1H, d,
J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d,
J = 6.0 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q,
CONH2), 168.2 (q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.3 (q,
CONH), 161.7 (q, CONH), 152.3 (q, C-Ar), 151.5 (q, C-Ar), 150.3 (t, C-Ar),
146.3 (q, C-ArTriazol), 143.9 (q, C-Ar), 142.8 (q, C-Ar), 142.3 (t, C-Ar), 141.1 (q,
C-Ar), 138.9 (q, C-Ar), 133.6 (q, C-Ar), 133.5 (q, C-Ar), 132.9 (t, CHallyl), 130.2
(2C, t, C-Ar), 129.3 (q, C-Ar), 128.2 (2C, t, C-Ar), 126.3 (q, C-Ar), 125.8 (2C, t,
C-Ar), 125.4 (q, C-Ar), 123.9 (t, C-Ar), 122.8 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.9
(t, C-Ar), 119.9 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.0 (s,
CH2allyl), 116.6 (q, CN), 111.8 (q, C-Ar), 80.4 (q, C(CH3)3), 80.0 (t, CHOMe),
76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.7 (p, OCH3), 55.7 (t, CHNH), 27.8
(3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C51H50N10O10Na [M + Na]+: 985.3609; found 985.3609.
HRMS (ESI): m/z calc. for C51H51N9O12Na [M
+
Na]+: 1004.3555; found
1004.3553.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(4-cyanobenzamido)-
benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-3-
isopropoxybenzamido)-benzoate (S11): Following the general procedure II
acid 20 (30.0 mg, 112 µmol, 2.5 eq) and amine 31 (32.0 mg, 44.9 µmol, 1.0 eq)
provided compound S11 as a colourless amorphous solid (19.2 mg, 20.0 µmol,
44%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 :
100 in 80 min; tr = 56 min). [α]D25 = +53.4° (c 1.9, DMSO); 1H-NMR (400 MHz,
DMSO-d6): δ = 10.8 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.90 (1H, s,
CHTriazol), 8.51 (1H, d, J = 8.1 Hz, NHCH), 8.13 (2H, m, ArH), 8.04 (2H, m, ArH),
7.94 – 7.90 (8H, m, ArH), 7.84 (2H, m, ArH), 7.79 (2H, m, ArH), 7.61 – 7.60 (2H,
m, ArH, CONH2), 7.53 (1H, d, J = 8.3 Hz, ArH), 7.47 (1H, s, CONH2), 6.05 –
5.97 (1H, m, CHallyl), 5.38 (1H, d, J = 17.3 Hz, CHallyl-trans), 5.20 (1H, d,
J = 10.5 Hz, CHallyl-cis), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.69 (2H, d, J = 5.0 Hz,
OCH2allyl), 4.28 (1H, hept, J = 6.0 Hz, CHMe2), 4.11 (1H, d, J = 8.1 Hz,
CHOMe), 3.31 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.0 Hz,
CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2
(q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.5 (q, CONH), 164.3 (q,
CONH), 150.3 (q, C-Ar), 146.3 (q, C-ArTriazol), 144.0 (q, C-Ar), 142.9 (q, C-Ar),
141.8 (q, C-Ar), 138.9 (q, C-Ar), 138.7 (q, C-Ar), 133.6 (q, C-Ar), 133.5 (q, C-Ar),
133.0 (t, CHallyl), 132.5 (2C, t, C-Ar), 130.2 (q, C-Ar), 129.0 (q, C-Ar), 128.7
(2C, t, C-Ar), 128.3 (2C, t, C-Ar), 126.3 (2C, t, C-Ar), 125.8 (2C, t, C-Ar), 125.4
(2C, t, C-Ar), 123.9 (t, C-Ar), 122.8 (t, C-ArTriazol), 120.9 (t, C-Ar), 119.8 (q, C-Ar),
119.6 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.3 (q, CN), 118.0 (s, CH2allyl), 114.1
(q, C-Ar), 80.4 (q, C(CH3)3), 80.1 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6 (s,
OCH2allyl), 57.7 (p, OCH3), 55.7 (t, CHNH), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p,
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C52H51N9O10Na [M + Na]+: 984.3657;
found 984.3649.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(4-cyano-3-fluoro-
benzamido)-benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-
triazol-1-yl)-3-isopropoxy-benzamido)benzoate (S14): Following the general
procedure II acid 41 (47.7 mg, 168 µmol, 2.5 eq) and amine 31 (48.0 mg,
67.2 µmol, 1.0 eq) provided compound S14 as a colourless amorphous solid
(56.2 mg, 57.4 µmol, 85%). Preparative HPLC (RP-18; run time 100 min;
H2O/MeCN = 70 : 30 → 0 : 100 in 80 min; tr = 59 min). [α]D23 = +36.7° (c 0.3,
MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.8 (1H, s, NH), 10.7 (1H, s, NH),
10.4 (1H, s, NH), 8.90 (1H, s, CHTriazol), 8.47 (1H, d, J = 8.4 Hz, NHCH), 8.17 –
8.13 (1H, m, ArH), 8.09 – 8.06 (1H, m, ArH), 7.99 – 7.96 (1H, m, ArH), 7.94 –
7.90 (8H, m, ArH), 7.84 (2H, m, ArH), 7.79 (2H, m, ArH), 7.61 (1H, d,
J = 8.3 Hz, ArH), 7.56 – 7.47 (3H, m, ArH, CONH2), 6.07 – 5.97 (1H, m, CHallyl),
5.38 (1H, dd, J = 1.5, 17.2 Hz, CHallyl-trans), 5.21 (1H, dd, J = 1.2, 10.4 Hz, CHallyl-
cis), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.69 (2H, d, J = 5.4 Hz, OCH2allyl), 4.28 (1H,
hept, J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 7.9 Hz, CHOMe), 3.31 (3H, s, OCH3),
1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100
MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.1 (q, CONH), 165.4 (q, CONH),
164.6 (q, CO2tBu), 164.3 (q, CONH), 163.5 (q, CONH), 162.1 (d, J = 223.0 Hz,
C-F), 150.3 (q, C-Ar), 146.3 (q, C-ArTriazol), 143.9 (q, C-Ar), 142.8 (q, C-Ar),
141.5 (d, J = 5.5 Hz, CCONH), 138.9 (q, C-Ar), 134.3 (t, C-Ar), 133.6 (q, C-Ar),
133.5 (t, CHallyl), 132.9 (q, C-Ar), 130.1 (2C, t, C-Ar), 129.2 (q, C-Ar), 128.3
(2C, t, C-Ar), 126.3 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 124.7 (d,
J = 3.3 Hz, CHCHCCONH), 123.9 (t, C-Ar), 122.7 (t, C-ArTriazol), 120.9 (t, C-Ar),
120.7 (q, CN), 119.8 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.0
(s, CH2allyl), 115.8 (d, J = 21.8 Hz, CHCF), 113.6 (q, C-Ar), 102.9 (d,
J = 15.3 Hz, CCN), 80.4 (q, C(CH3)3), 80.0 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(4-fluorobenzamido)-
benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-3-
isopropoxybenzamido)-benzoate (S12): Following the general procedure II
acid 39 (43.6 mg, 168 µmol, 2.5 eq) and amine 31 (48.0 mg, 67.2 µmol, 1.0 eq)
provided compound S12 as
Preparative HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 : 100 in
80 min; tr 59 min). TM
231 °C (decomposition); [α]D22 = +87.8° (c 0.5,
MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 10.7 (1H, s, NH), 10.5 (1H, s, NH),
a beige solid (33.9 mg, 35.5 µmol, 53%).
=
=
11
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
(s, OCH2allyl), 57.7 (p, OCH3), 55.7 (t, CHNH), 27.8 (3C, p, C(CH3)3), 21.8 (2C,
p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C52H51N9O10F [M + H]+: 980.3743;
found 980.3753.
CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 170.4
(q, CONH), 168.2 (q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.3 (q,
CONH), 150.3 (q, C-Ar), 147.3 (q, C-Ar), 146.3 (q, C-ArTriazol), 143.9 (q, C-Ar),
142.8 (q, C-Ar), 142.1 (q, C-Ar), 138.9 (q, C-Ar), 133.6 (q, C-Ar), 133.5 (t,
CHallyl), 133.0 (q, C-Ar), 132.3 (2C, t, C-Ar), 130.2 (2C, t, C-Ar), 129.5 (2C, t,
C-Ar), 128.4 (2C, t, C-Ar), 128.0 (q, C-Ar), 126.3 (q, C-Ar), 125.8 (2C, t, C-Ar),
125.4 (q, C-Ar), 123.9 (t, C-Ar), 122.8 (t, C-ArTriazol), 120.9 (t, C-Ar), 119.8 (2C, t,
C-Ar), 119.0 (q, CN), 118.9 (2C, t, C-Ar), 118.2 (s, CH2allyl), 118.0 (2C, t, C-Ar),
108.9 (q, C-Ar), 80.4 (q, C(CH3)3), 80.0 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6 (s,
OCH2allyl), 57.7 (p, OCH3), 55.7 (t, CHNH), 37.1 (s, ArCH2CH2), 30.6 (s,
ArCH2CH2), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p, CH(CH3)2) ppm; HRMS (ESI):
m/z calc. for C54H56N9O10 [M + H]+: 990.4150; found 990.4148.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(isonicotinamido)-
benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-3-
isopropoxybenzamido)-benzoate (S15): Following to the general procedure II
acid 42 (32.2 mg, 133 µmol, 2.5 eq) and amine 31 (38.0 mg, 53.2 µmol, 1.0 eq)
provided compound S15 as a colourless amorphous solid (26.7 mg, 28.5 µmol,
54%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN = 70 : 30 → 0 :
100 in 80 min; tr = 50 min). [α]D24 = +32.4° (c 2.3, MeOH); 1H-NMR (400 MHz,
DMSO-d6): δ = 10.8 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.90 (1H, s,
CHTriazol), 8.81 (2H, d, J = 5.8 Hz, ArH), 8.51 (1H, d, J = 8.1 Hz, NHCH), 7.94 –
7.88 (10H, m, ArH), 7.85 (2H, m, ArH), 7.80 (2H, m, ArH), 7.62 – 7.47 (4H, m,
ArH, CONH2), 6.07 – 5.97 (1H, m, CHallyl), 5.38 (1H, dd, J = 1.6, 17.2 Hz, CHallyl-
trans), 5.21 (1H, dd, J = 1.5, 10.5 Hz, CHallyl-cis), 4.92 (1H, t, J = 8.1 Hz, CHNH),
4.69 (2H, d, J = 5.4 Hz, OCH2allyl), 4.28 (1H, hept, J = 6.1 Hz, CHMe2), 4.11
(1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01
(6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0
(q, CONH2), 168.2 (q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.3 (q,
CONH), 164.3 (q, CONH), 150.3 (2C, t, C-Ar), 150.3 (q, C-Ar), 146.3 (q, C-
ArTriazol), 143.9 (q, C-Ar), 142.8 (q, C-Ar), 141.7 (q, C-Ar), 141.6 (q, C-Ar), 138.9
(q, C-Ar), 133.6 (q, C-Ar), 133.5 (t, CHallyl), 132.9 (q, C-Ar), 130.1 (2C, t, C-Ar),
129.1 (q, C-Ar), 128.3 (2C, t, C-Ar), 126.3 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4
(2C, t, C-Ar), 123.9 (t, C-Ar), 122.8 (t, C-ArTriazol), 121.6 (2C, t, C-Ar), 120.9 (t, C-
Ar), 119.8 (q, C-Ar), 119.7 (2C, t, C-Ar), 118.9 (2C, t, C-Ar), 118.0 (s, CH2allyl),
80.4 (q, C(CH3)3), 80.1 (t, CHOMe), 76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.7
(p, OCH3), 55.7 (t, CHNH), 27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm;
HRMS (ESI): m/z calc. for C50H51N9O10Na [M + Na]+: 960.3657; found 960.3654.
tert-Butyl 4-(4-(4-(4-((2S,3R)-4-amino-3-methoxy-2-(4-(4-nitrobenzamido)-
benzamido)-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-
isopropoxybenzamido)-benzoate (S18): Following the general procedure VI
compound S10 (20.0 mg, 20.4 µmol, 1.0 eq) was used. Preparative HPLC (RP-
18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 53 min)
provided Phenol S18 as a yellow amorphous solid (8.5 mg, 9.03 µmol, 44%).
[α]D24 = +42.9° (c 0.9, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 11.1 (1H, br. s, NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 8.92 (1H, s,
CHTriazol), 8.44 (1H, d, J = 8.1 Hz, NHCH), 8.39 (2H, m, ArH), 8.21 (2H, m, ArH),
7.95 – 7.87 (11H, m, ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 46.5 Hz, CONH2),
7.30 (1H, d, J = 8.0 Hz, ArH), 4.93 (1H, t, J = 8.1 Hz, CHNH), 4.28 (1H, hept,
J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.56
(9H, s, C(CH3)3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz,
DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH), 167.4 (q, CONH), 165.4 (q,
CONH), 164.5 (q, CO2tBu), 164.2 (q, CONH), 151.5 (q, C-Ar), 149.3 (q, C-Ar),
146.2 (q, C-ArTriazol), 142.1 (q, C-Ar), 141.7 (q, C-Ar), 140.3 (q, C-Ar), 138.9 (q,
C-Ar), 138.9 (q, C-Ar), 134.3 (q, C-Ar), 130.0 (2C, t, C-Ar), 129.3 (2C, t, C-Ar),
129.1 (q, C-Ar), 128.3 (2C, t, C-Ar), 126.8 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (t,
C-Ar), 124.9 (q, C-Ar), 123.6 (2C, t, C-Ar), 122.6 (t, C-ArTriazol), 120.5 (2C, t, C-
Ar), 119.8 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.4 (q, C-Ar), 114.1 (t, C-Ar), 80.5
(q, C(CH3)3), 80.1 (t, CHOMe), 75.4 (t, CH(CH3)2), 57.7 (p, OCH3), 55.7 (t,
CHNH), 27.9 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C48H47N9O12Na [M + Na]+: 964.3242; found 964.3229.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(6-cyanonicotin-
amido)-benz-amido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-
1-yl)-3-isopropoxybenz-amido)benzoate (S16): Following the general
procedure II acid 43 (35.5 mg, 133 µmol, 2.5 eq) and amine 31 (38.0 mg,
53.2 µmol, 1.0 eq) provided compound S16 as a beige amorphous solid (34.4
mg, 35.7 µmol, 67%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN
= 70 : 30 → 0 : 100 in 80 min; tr = 55 min). [α]D23 = +30.5° (c 3.3, MeOH); 1H-
NMR (400 MHz, DMSO-d6): δ = 10.9 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s,
NH), 9.24 (1H, d, J = 1.9 Hz, ArH), 8.90 (1H, s, CHTriazol), 8.55 (1H, dd, J = 1.9,
8.0 Hz, ArH), 8.48 (1H, d, J = 8.2 Hz, NHCH), 8.25 (1H, d, J = 8.0 Hz, ArH),
7.94 – 7.88 (8H, m, ArH), 7.84 (2H, m, ArH), 7.79 (2H, m, ArH), 7.61 (1H, d,
J = 8.3 Hz, ArH), 7.54 (1H, d, J = 8.3 Hz, ArH), 7.52 (2H, d, J = 39.5 Hz,
CONH2), 6.07 – 5.97 (1H, m, CHallyl), 5.38 (1H, dd, J = 1.6, 17.2 Hz, CHallyl-trans),
5.21 (1H, dd, J = 1.5, 10.5 Hz, CHallyl-cis), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.69
(2H, d, J = 5.5 Hz, OCH2allyl), 4.28 (1H, hept, J = 6.1 Hz, CHMe2), 4.10 (1H, d,
J = 8.0 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d,
J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q,
CONH2), 168.2 (q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 164.3 (q,
CONH), 163.0 (q, CONH), 150.3 (q, C-Ar), 150.2 (t, C-Ar), 146.3 (q, C-ArTriazol),
143.9 (q, C-Ar), 142.8 (q, C-Ar), 141.5 (q, C-Ar), 138.9 (q, C-Ar), 137.3 (t, C-Ar),
134.5 (q, C-Ar), 133.6 (q, C-Ar), 133.5 (t, CHallyl), 133.4 (q, C-Ar), 132.9 (q, C-
Ar), 130.1 (2C, t, C-Ar), 129.2 (q, C-Ar), 128.8 (t, C-Ar), 128.3 (2C, t, C-Ar),
126.3 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 123.9 (t, C-Ar), 122.8 (t,
C-ArTriazol), 120.9 (t, C-Ar), 119.8 (2C, t, C-Ar), 119.6 (2C, t, C-Ar), 118.9 (2C, t,
C-Ar), 118.0 (s, CH2allyl), 117.1 (q, CN), 80.4 (q, C(CH3)3), 80.0 (t, CHOMe),
76.8 (t, CH(CH3)2), 74.6 (s, OCH2allyl), 57.7 (p, OCH3), 55.7 (t, CHNH), 27.8
(3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C51H51N10O10 [M + H]+: 963.3790; found 963.3795.
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(4-cyanobenzamido)benzamido)-
3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-
isopropoxybenzamido)-benzoate (S19): Following the general procedure VI
compound S11 (19.0 mg, 20.4 µmol, 1.0 eq) provided phenol S19 as a yellow
amorphous solid (10.1 mg, 11.0 µmol, 56%). Preparative HPLC (RP-18; run
time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 52 min).
[α]D23 = +49.6° (c 1.0, DMSO); 1H-NMR (500 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 11.0 (1H, br. s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.90 (1H, s,
CHTriazol), 8.44 (1H, d, J = 8.1 Hz, NHCH), 8.13 (2H, m, ArH), 8.05 (2H, m, ArH),
7.96 – 7.87 (11H, m, ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 37.9 Hz, CONH2),
7.32 (1H, d, J = 8.6 Hz, ArH), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.27 (1H, hept,
J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.56
(9H, s, C(CH3)3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz,
DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH), 167.4 (q, CONH), 165.4 (q,
CONH), 164.5 (q, CO2tBu), 164.5 (q, CONH), 155.0 (q, C-Ar), 146.2 (q,
C-ArTriazol), 142.0 (q, C-Ar), 141.8 (q, C-Ar), 138.9 (q, C-Ar), 138.8 (q, C-Ar),
138.7 (q, C-Ar), 134.3 (q, C-Ar), 132.5 (2C, t, C-Ar), 130.0 (2C, t, C-Ar), 129.0
(q, C-Ar), 128.6 (2C, t, C-Ar), 128.3 (2C, t, C-Ar), 126.9 (q, C-Ar), 125.8 (2C, t,
C-Ar), 125.4 (q, C-Ar), 123.6 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.5 (2C, t, C-Ar),
119.8 (2C, t, C-Ar), 119.6 (2C, t, C-Ar), 118.4 (q, C-Ar), 118.3 (q, CN), 114.4 (q,
C-Ar), 114.1 (t, C-Ar), 80.5 (q, C(CH3)3), 80.1 (t, CHOMe), 75.5 (t, CH(CH3)2),
57.7 (p, OCH3), 55.7 (t, CHNH), 27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2)
ppm; HRMS (ESI): m/z calc. for C49H48N9O10 [M + H]+: 922.3524; found
922.3529.
tert-Butyl-4-(2-(allyloxy)-4-(4-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)-
propan-amido)benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-
triazol-1-yl)-3-isopropoxybenzamido)benzoate (S17): Following the general
procedure II acid 44 (39.0 mg, 133 µmol, 2.5 eq) and amine 31 (38.0 mg,
53.2 µmol, 1.0 eq) provided phenol S19 as a yellow amorphous solid (10.1 mg,
11.0 µmol, 56%). Preparative HPLC (RP-18; run time 100 min; H2O/MeCN =
70 : 30 → 0 : 100 in 80 min; tr = 57 min). [α]D25 = +23.2° (c 2.7, MeOH); 1H-NMR
(400 MHz, DMSO-d6): δ = 10.7 (1H, s, NH), 10.4 (1H, s, NH), 10.2 (1H, s, NH),
8.90 (1H, s, CHTriazol), 8.41 (1H, d, J = 8.0 Hz, NHCH), 7.94 – 7.91 (4H, m, ArH),
7.86 – 7.75 (8H, m, ArH), 7.68 (2H, m, ArH), 7.61 (1H, d, J = 8.3 Hz, ArH),
7.57 – 7.53 (2H, m, ArH, CONH2), 7.49 – 7.47 (3H, m, ArH, CONH2), 6.07 –
5.97 (1H, m, CHallyl), 5.38 (1H, d, J = 17.2 Hz, CHallyl-trans), 5.21 (1H, d,
J = 10.4 Hz, CHallyl-cis), 4.89 (1H, t, J = 8.0 Hz, CHNH), 4.69 (2H, d, J = 5.1 Hz,
OCH2allyl), 4.28 (1H, hept, J = 6.0 Hz, CHMe2), 4.09 (1H, d, J = 8.0 Hz,
CHOMe), 3.30 (3H, s, OCH3), 3.01 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.71 (2H, t,
J = 7.4 Hz, ArCH2CH2), 1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.0 Hz,
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(4-fluorobenzamido)benzamido)-
3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-
isopropoxybenzamido)-benzoate (S20): Following the general procedure VI
compound S12 (33.9 mg, 35.5 µmol, 1.0 eq) provided Phenol S20 as a yellow
amorphous solid (20.1 mg, 22.0 µmol, 62%). Preparative HPLC (RP-18; run
time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 51 min).
[α]D24 = +29.2° (c 1.8, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 11.4 (1H, s, NH), 10.5 (1H, s, NH), 10.4 (1H, s, NH), 8.91 (1H, s,
CHTriazol), 8.42 (1H, d, J = 8.1 Hz, NHCH), 8.08 – 8.05 (2H, m, ArH), 7.95 – 7.86
(11H, m, ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 30.8 Hz, CONH2), 7.39 (2H,
m, ArH), 7.25 (1H, d, J = 8.6 Hz, ArH), 4.93 (1H, t, J = 8.1 Hz, CHNH), 4.32 (1H,
hept, J = 6.1 Hz, CHMe2), 4.10 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3),
1.55 (9H, s, C(CH3)3), 1.01 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100
12
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH), 167.4 (q, CONH),
165.0 (q, CONH), 164.7 (q, CO2tBu), 164.6 (q, CONH), 164.2 (d, J = 249.2 Hz,
C-F), 156.0 (q, C-Ar), 146.1 (q, C-ArTriazol), 142.2 (q, C-Ar), 142.1 (q, C-Ar),
139.0 (q, C-Ar), 138.8 (q, C-Ar), 134.2 (q, C-Ar), 131.1 (d, J = 2.9 Hz, C-Ar),
130.5 (2C, d, J = 9.2 Hz, C-Ar), 130.0 (2C, t, C-Ar), 128.6 (q, C-Ar), 128.2 (2C, t,
C-Ar), 126.7 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.5 (q, C-Ar), 123.6 (t, C-Ar), 122.6
(t, C-ArTriazol), 120.3 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.5 (2C, t, C-Ar), 118.4
(q, C-Ar), 115.4 (2C, d, J = 21.8 Hz, C-Ar), 113.5 (t, C-Ar), 80.5 (q, C(CH3)3),
80.1 (t, CHOMe), 75.1 (t, CH(CH3)2), 57.7 (p, OCH3), 55.6 (t, CHNH), 27.8 (3C,
p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C48H47N8O10FNa [M + Na]+: 937.3297; found 937.3273.
CHMe2), 4.10 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.56 (9H, s,
C(CH3)3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz,
DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH), 167.4 (q, CONH), 165.4 (q,
CONH), 164.5 (q, CO2tBu), 163.0 (q, CONH), 154.6 (q, C-Ar), 150.4 (2C, t,
C-Ar), 146.3 (q, C-ArTriazol), 141.9 (q, C-Ar), 141.6 (q, C-Ar), 138.9 (q, C-Ar),
138.7 (q, C-Ar), 134.4 (q, C-Ar), 131.5 (q, C-Ar), 130.0 (2C, t, C-Ar), 129.1 (q,
C-Ar), 128.8 (2C, t, C-Ar), 127.0 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar),
123.6 (t, C-Ar), 122.6 (t, C-ArTriazol), 121.8 (2C, t, C-Ar), 120.6 (2C, t, C-Ar),
119.8 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.4 (q, C-Ar), 114.7 (t, C-Ar), 80.5 (q,
C(CH3)3), 80.1 (t, CHOMe), 76.7 (t, CH(CH3)2), 57.7 (p, OCH3), 55.7 (t, CHNH),
27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C47H48N9O10 [M + H]+: 898.3524; found 898.3525.
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(5-cyanopicolinamido)-benz-
amido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-
hydroxy-3-isopropoxy-benzamido)benzoate (S21): Following the general
procedure VI compound S13 (23.0 mg, 23.9 µmol, 1.0 eq) provided phenol S21
as a yellow amorphous solid (21.8 mg, 23.6 µmol, 99%). Preparative HPLC
(RP-18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 51 min).
[α]D24 = +15.4° (c 1.1, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 11.0 (1H, s, NH), 10.4 (1H, s, NH), 9.22 (1H, br. s, ArH), 8.87 (1H, s,
CHTriazol), 8.60 (1H, dd, J = 2.0, 8.1 Hz, ArH), 8.44 (1H, d, J = 8.1 Hz, NHCH),
8.31 (1H, d, J = 8.1 Hz, ArH), 8.06 (2H, m, ArH), 7.92 – 7.85 (9H, m, ArH), 7.78
(2H, m, ArH), 7.50 (2H, d, J = 31.1 Hz, CONH2), 7.08 (1H, br. s, ArH), 4.92 (1H,
t, J = 8.1 Hz, CHNH), 4.40 (1H, br. s, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe),
3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.00 (6H, d, J = 6.1 Hz, CH(CH3)2)
ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.1 (q, CONH),
167.3 (q, CONH), 165.4 (q, CONH), 164.6 (q, CO2tBu), 163.0 (q, C-Ar), 161.7 (q,
CONH), 152.3 (q, C-Ar), 151.5 (t, C-Ar), 146.0 (q, C-ArTriazol), 142.7 (q, C-Ar),
142.3 (t, C-Ar), 141.0 (q, C-Ar), 139.5 (q, C-Ar), 138.8 (q, C-Ar), 134.0 (q, C-Ar),
130.0 (2C, t, C-Ar), 129.3 (q, C-Ar), 128.2 (2C, t, C-Ar), 126.2 (q, C-Ar), 125.8
(2C, t, C-Ar), 125.6 (q, C-Ar), 123.7 (t, C-Ar), 122.6 (t, C-Ar), 122.6 (t, C-ArTriazol),
120.0 (2C, t, C-Ar), 119.9 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 118.5 (q, C-Ar),
116.6 (q, CN), 111.8 (q, C-Ar), 80.4 (q, C(CH3)3), 80.1 (t, CHOMe), 74.4 (t,
CH(CH3)2), 57.7 (p, OCH3), 55.7 (t, CHNH), 27.9 (3C, p, C(CH3)3), 21.9 (2C, p,
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(6-cyanonicotinamido)-benz-
amido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-
hydroxy-3-isopropoxy-benzamido)benzoate (S24): Following to the general
procedure VI compound S16 (26.7 mg, 27.7 µmol, 1.0 eq) provided phenol S24
as a yellow amorphous solid (24.4 mg, 26.5 µmol, 95%). Preparative HPLC
(RP-18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 47 min).
[α]D23 = +19.5° (c 1.2, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 11.4 (1H, br. s, NH), 10.9 (1H, s, NH), 10.4 (1H, s, NH), 9.24 (1H, d,
J = 2.0 Hz, ArH), 8.90 (1H, s, CHTriazol), 8.55 (1H, dd, J = 2.0, 8.1 Hz, ArH), 8.46
(1H, d, J = 8.2 Hz, NHCH), 8.25 (1H, d, J = 8.1 Hz, ArH), 7.94 – 7.86 (11H, m,
ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 31.3 Hz, CONH2), 7.25 (1H, d,
J = 8.5 Hz, ArH), 4.93 (1H, t, J = 8.1 Hz, CHNH), 4.31 (1H, hept, J = 6.0 Hz,
CHMe2), 4.10 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.55 (9H, s,
C(CH3)3), 1.02 (6H, d, J = 6.0 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz, DMSO-
d6): δ = 171.0 (q, CONH2), 168.1 (q, CONH), 167.4 (q, CONH), 165.4 (q,
CONH), 164.6 (q, CO2tBu), 163.0 (q, CONH), 155.9 (q, C-Ar), 150.2 (t, C-Ar),
146.1 (q, C-ArTriazol), 142.2 (q, C-Ar), 141.5 (q, C-Ar), 139.0 (q, C-Ar), 138.8 (q,
C-Ar), 137.3 (t, C-Ar), 134.5 (q, C-Ar), 134.2 (q, C-Ar), 133.4 (q, C-Ar), 130.0
(2C, t, C-Ar), 129.2 (q, C-Ar), 128.8 (t, C-Ar), 128.3 (2C, t, C-Ar), 126.7 (q, C-Ar),
125.8 (2C, t, C-Ar), 125.5 (q, C-Ar), 123.6 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.4
(2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.6 (2C, t, C-Ar), 118.4 (q, C-Ar), 117.1 (q,
CN), 113.5 (t, C-Ar), 80.5 (q, C(CH3)3), 80.1 (t, CHOMe), 75.2 (t, CH(CH3)2),
57.7 (p, OCH3), 55.7 (t, CHNH), 27.9 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2)
ppm; HRMS (ESI): m/z calc. for C48H47N10O10 [M + H]+: 923.3477; found
923.3469.
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C48H46N10O10Na [M
945.3296; found 945.3298.
+
Na]+:
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(4-cyano-3-fluorobenzamido)-
benzamido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-
hydroxy-3-isopropoxy-benzamido)benzoate (S22): Following to the general
procedure VI compound S14 (56.2 mg, 57.4 µmol, 1.0 eq) provided phenol
S22 as a colourless amorphous solid (22.4 mg, 23.8 µmol, 42%). Preparative
HPLC (RP-18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr =
50 min). [α]D23 = +21.8° (c 1.1, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ = 12.2
(1H, br. s, OH), 11.0 (1H, s, NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 8.92 (1H, s,
CHTriazol), 8.45 (1H, d, J = 8.1 Hz, NHCH), 8.16 – 8.13 (1H, m, ArH), 8.09 – 8.06
(1H, m, ArH), 7.99 – 7.86 (12H, m, ArH), 7.79 (2H, m, ArH), 7.51 (2H, d,
J = 30.5 Hz, CONH2), 7.32 (1H, d, J = 8.6 Hz, ArH), 4.93 (1H, t, J = 8.1 Hz,
CHNH), 4.28 (1H, hept, J = 6.1 Hz, CHMe2), 4.10 (1H, d, J = 8.1 Hz, CHOMe),
3.32 (3H, s, OCH3), 1.55 (9H, s, C(CH3)3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2)
ppm; 13C-NMR (100 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH),
167.4 (q, CONH), 165.4 (q, CONH), 164.5 (q, CO2tBu), 163.5 (q, CONH), 162.1
(d, J = 223.6 Hz, C-F), 155.2 (q, C-Ar), 146.2 (q, C-ArTriazol), 142.0 (q, C-Ar),
141.5 (q, C-Ar), 141.5 (d, J = 7.2 Hz, CCONH), 141.5 (q, C-Ar), 138.9 (q, C-Ar),
138.8 (q, C-Ar), 134.3 (d, J = 7.0 Hz, CHCCN), 130.0 (2C, t, C-Ar), 129.2 (q, C-
Ar), 128.3 (2C, t, C-Ar), 126.9 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar),
124.7 (d, J = 3.5 Hz, CHCHCCONH), 123.6 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.5
(2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.3 (q, CN), 115.8 (d,
J = 21.3 Hz, CHCF), 114.2 (t, C-Ar), 113.6 (q, C-Ar), 102.9 (d, J = 15.3 Hz,
CCN), 80.5 (q, C(CH3)3), 80.1 (t, CHOMe), 75.5 (t, CH(CH3)2), 57.7 (p, OCH3),
55.7 (t, CHNH), 27.8 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2) ppm; HRMS
(ESI): m/z calc. for C49H46N9O10FNa [M + Na]+: 962.3249; found 962.3253.
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(3-(4-cyanophenyl)-propan-
amido)-benz-amido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-
1-yl)-2-hydroxy-3-isopropoxybenzamido)benzoate (S25): Following to the
general procedure VI compound S17 (29.5 mg, 29.8 µmol, 1.0 eq) provided
Phenol S25 as
a yellow amorphous solid (19.8 mg, 20.9 µmol, 70%).
Preparative HPLC (RP-18; run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in
70 min; tr = 49 min). [α]D22 = +14.9° (c 1.0, MeOH); 1H-NMR (400 MHz, DMSO-
d6): δ = 12.2 (1H, br. s, OH), 11.2 (1H, s, NH), 10.4 (1H, s, NH), 10.2 (1H, s,
NH), 8.92 (1H, s, CHTriazol), 8.37 (1H, d, J = 8.0 Hz, NHCH), 7.95 – 7.87 (7H, m,
ArH), 7.83 – 7.75 (6H, m, ArH), 7.68 (2H, m, ArH), 7.54 – 7.46 (4H, m, ArH,
CONH2), 7.29 (1H, d, J = 8.5 Hz, ArH), 4.90 (1H, t, J = 8.0 Hz, CHNH), 4.29 (1H,
hept, J = 6.1 Hz, CHMe2), 4.08 (1H, d, J = 8.0 Hz, CHOMe), 3.31 (3H, s, OCH3),
3.01 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.71 (2H, t, J = 7.5 Hz, ArCH2CH2), 1.55
(9H, s, C(CH3)3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ = 171.1 (q, CONH2), 170.5 (q, CONH), 168.2 (q, CONH), 167.4 (q,
CONH), 165.5 (q, CONH), 164.6 (q, CO2tBu), 147.3 (q, C-Ar), 146.2 (q,
C-ArTriazol), 142.1 (q, C-Ar), 139.0 (q, C-Ar), 138.9 (q, C-Ar), 134.3 (q, C-Ar),
132.3 (2C, t, C-Ar), 130.0 (2C, t, C-Ar), 129.5 (2C, t, C-Ar), 128.4 (2C, t, C-Ar),
128.1 (q, C-Ar), 126.9 (q, C-Ar), 125.9 (2C, t, C-Ar), 125.5 (q, C-Ar), 123.6 (t,
C-Ar), 122.6 (t, C-ArTriazol), 120.5 (2C, t, C-Ar), 119.9 (2C, t, C-Ar), 119.0 (q,
C-Ar), 118.5 (q, CN), 118.3 (2C, t, C-Ar), 108.9 (q, C-Ar), 80.6 (q, C(CH3)3),
80.1 (t, CHOMe), 75.4 (t, CH(CH3)2), 57.8 (p, OCH3), 55.7 (t, CHNH), 37.2 (s,
ArCH2CH2), 30.6 (s, ArCH2CH2), 27.9 (3C, p, C(CH3)3), 21.8 (2C, p, CH(CH3)2)
ppm; HRMS (ESI): m/z calc. for C51H51N9O10Na [M + Na]+: 972.3657; found
972.3661.
tert-Butyl-4-(4-(4-(4-((2S,3R)-4-amino-2-(4-(isonicotinamido)benzamido)-3-
methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-
isopropoxybenzamido)-benzoate (S23): Following to the general procedure
VI compound S15 (26.7 mg, 28.4 µmol, 1.0 eq) provided phenol S23 as a
yellow amorphous solid (16.5 mg, 18.4 µmol, 65%).. Preparative HPLC (RP-18;
run time 80 min; H2O/MeCN = 70 : 30 → 0 : 100 in 70 min; tr = 45 min).
[α]D23 = +22.1° (c 0.9, MeOH); 1H-NMR (600 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 10.8 (1H, s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.93 (1H, s,
CHTriazol), 8.82 (2H, m, ArH), 8.45 (1H, d, J = 8.1 Hz, NHCH), 7.97 – 7.87 (13H,
m, ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 49.8 Hz, CONH2), 7.36 (1H, d,
J = 8.6 Hz, ArH), 4.93 (1H, t, J = 8.0 Hz, CHNH), 4.25 (1H, hept, J = 6.1 Hz,
4-(4-(4-(4-((2S,3R)-4-Amino-3-methoxy-2-(4-(4-nitrobenzamido)benzamido)-
4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-isopropoxy-
benzamido)-benzoic acid (45): Following to the general procedure V Phenol
S18 (8.5 mg, 9.03 µmol, 1.0 eq) was stirred for 6 h. Acid 45 was obtained as a
colourless amorphous solid (6.2 mg, 7.00 µmol, 78%). [α]D24 = +37.1° (c 0.1,
DMSO); 1H-NMR (500 MHz, DMSO-d6): δ = 12.9 (1H, br. s, CO2H), 12.2 (1H, br.
s, OH), 10.8 (1H, br. s, NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 8.93 (1H, s,
CHTriazol), 8.44 (1H, d, J = 8.1 Hz, NHCH), 8.39 (2H, m, ArH), 8.21 (2H, m, ArH),
8.00 – 7.87 (11H, m, ArH), 7.79 (2H, m, ArH), 7.50 (2H, d, J = 39.2 Hz, CONH2),
7.37 (1H, d, J = 8.6 Hz, ArH), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.24 (1H, hept,
13
This article is protected by copyright. All rights reserved.

10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.02
(6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.0
(q, CONH2), 168.2 (q, CONH), 167.5 (q, CONH), 166.9 (q, CO2H), 165.4 (q,
CONH), 164.2 (q, CONH), 154.5 (q, C-Ar), 149.3 (q, C-Ar), 146.3 (q, C-ArTriazol),
141.9 (q, C-Ar), 141.7 (q, C-Ar), 140.3 (q, C-Ar), 138.9 (q, C-Ar), 138.7 (q, C-Ar),
134.4 (q, C-Ar), 130.7 (2C, t, C-Ar), 130.3 (q, C-Ar), 129.4 (2C, t, C-Ar), 128.7
(2C, t, C-Ar), 128.3 (q, C-Ar), 126.5 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (t, C-Ar),
123.6 (2C, t, C-Ar), 122.6 (t, C-ArTriazol), 120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar),
119.7 (2C, t, C-Ar), 118.4 (q, C-Ar), 114.8 (t, C-Ar), 80.1 (t, CHOMe), 75.7 (t,
CH(CH3)2), 57.7 (p, OCH3), 55.7 (t, CHNH), 21.8 (2C, p, CH(CH3)2) ppm; HRMS
(ESI): m/z calc. for C44H40N9O12 [M + H]+: 886.2796; found 886.2798.
141.0 (q, C-Ar), 138.9 (q, C-Ar), 138.7 (q, C-Ar), 134.4 (q, C-Ar), 130.3 (2C, t,
C-Ar), 129.3 (q, C-Ar), 128.2 (2C, t, C-Ar), 126.5 (q, C-Ar), 125.8 (2C, t, C-Ar),
125.4 (q, C-Ar), 123.5 (t, C-Ar), 122.6 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.6 (2C, t,
C-Ar), 119.9 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 118.4 (q, C-Ar), 116.7 (q, CN),
114.8 (t, C-Ar), 111.8 (q, C-Ar), 80.1 (t, CHOMe), 75.7 (t, CH(CH3)2), 57.7 (p,
OCH3), 55.6 (t, CHNH), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C44H39N10O10 [M + H]+: 867.2851; found 867.2857.
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(4-cyano-3-fluorobenzamido)benzamido)-
3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-
isopropoxybenzamido)-benzoic acid (49): Following the general procedure V
phenol S22 (22.4 mg, 23.8 µmol, 1.0 eq) was stirred for 2 h. Acid 49 was
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(4-cyanobenzamido)benzamido)-3-
methoxy-4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-iso-
propoxybenzamido)-benzoic acid (46): Following the general procedure V
Phenol S19 (10.1 mg, 11.0 µmol, 1.0 eq) was stirred for 3 h. Acid 46 was
obtained as a beige amorphous solid (7.4 mg, 8.55 µmol, 78%). [α]D25 = +55.9°
(c 0.2, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.8 (1H, br. s, CO2H), 12.2
(1H, br. s, OH), 10.8 (1H, br. s, NH), 10.7 (1H, s, NH), 10.4 (1H, s, NH), 8.93
(1H, s, CHTriazol), 8.43 (1H, d, J = 8.1 Hz, NHCH), 8.13 (2H, m, ArH), 8.05 (2H,
m, ArH), 7.99 – 7.87 (11H, m, ArH), 7.79 (2H, m, ArH), 7.50 (2H, d, J = 45.0 Hz,
CONH2), 7.34 (1H, d, J = 7.0 Hz, ArH), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.26 (1H,
hept, J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3),
1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ =
171.0 (q, CONH2), 168.2 (q, CONH), 167.4 (q, CONH), 166.8 (q, CO2H), 165.4
(q, CONH), 164.5 (q, CONH), 154.7 (q, C-Ar), 146.2 (q, C-ArTriazol), 141.9 (q,
C-Ar), 141.7 (q, C-Ar), 138.9 (q, C-Ar), 138.8 (q, C-Ar), 138.7 (q, C-Ar), 134.3 (q,
C-Ar), 132.5 (2C, t, C-Ar), 130.3 (2C, t, C-Ar), 129.0 (q, C-Ar), 128.6 (2C, t,
C-Ar), 128.3 (2C, t, C-Ar), 126.4 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar),
123.5 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar),
119.6 (2C, t, C-Ar), 118.4 (q, C-Ar), 118.3 (q, CN), 114.6 (q, C-Ar), 114.0 (t,
C-Ar), 80.1 (t, CHOMe), 75.6 (t, CH(CH3)2), 57.7 (p, OCH3), 55.6 (t, CHNH),
21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C45H40N9O10 [M + H]+:
866.2898; found 866.2897.
obtained as a beige amorphous solid (21.0 mg, 23.8 µmol, quant.).
[α]D24 = +39.5° (c 1.3, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.8 (1H, br.
s, CO2H), 12.2 (1H, br. s, OH), 10.8 (1H, s, NH), 10.8 (1H, s, NH), 10.4 (1H, s,
NH), 8.93 (1H, s, CHTriazol), 8.45 (1H, d, J = 8.1 Hz, NHCH), 8.16 – 8.13 (1H, m,
ArH), 8.09 – 8.07 (1H, m, ArH), 8.00 – 7.96 (4H, m, ArH), 7.93 – 7.87 (8H, m,
ArH), 7.79 (2H, m, ArH), 7.51 (2H, d, J = 47.9 Hz, CONH2), 7.37 (1H, d,
J = 8.6 Hz, ArH), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.25 (1H, hept, J = 6.1 Hz,
CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.03 (6H, d,
J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.0 (q,
CONH2), 168.2 (q, CONH), 167.5 (q, CONH), 166.9 (q, CO2H), 165.4 (q,
CONH), 163.2 (q, CONH), 162.2 (d, J = 256.3 Hz, C-F), 154.5 (q, C-Ar), 146.3
(q, C-ArTriazol), 141.9 (q, C-Ar), 141.5 (d, J = 6.1 Hz, CCONH), 138.9 (q, C-Ar),
138.7 (q, C-Ar), 134.4 (d, J = 7.0 Hz, CHCCN), 130.7 (q, C-Ar), 130.3 (2C, t,
C-Ar), 129.2 (q, C-Ar), 128.8 (q, C-Ar), 128.3 (2C, t, C-Ar), 126.5 (q, C-Ar),
125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 124.7 (d, J = 3.4 Hz, CHCHCCONH), 123.5
(t, C-Ar), 122.6 (t, C-ArTriazol), 120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.7 (2C,
t, C-Ar), 118.4 (q, CN), 115.8 (d, J = 21.3 Hz, CHCF), 114.8 (t, C-Ar), 113.6 (q,
C-Ar), 102.9 (d, J = 15.3 Hz, CCN), 80.1 (t, CHOMe), 75.7 (t, CH(CH3)2), 57.7 (p,
OCH3), 55.7 (t, CHNH), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for
C45H39N9O10F [M + H]+: 884.2804; found 884.2808.
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(isonicotinamido)benzamido)-3-methoxy-
4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-isopropoxy-
benzamido)-benzoic acid (50): Following the general procedure V phenol S23
(16.5 mg, 18.4 µmol, 1.0 eq) was stirred for 4 h. Acid 50 was obtained as a
yellow amorphous solid (13.7 mg, 16.3 µmol, 89%). [α]D24 = +22.6° (c 1.4,
DMSO); 1H-NMR (500 MHz, DMSO-d6): δ = 12.2 (1H, br. s, OH), 10.8 (1H, s,
NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 8.93 (1H, s, CHTriazol), 8.85 (2H, m,
ArH), 8.44 (1H, d, J = 8.0 Hz, NHCH), 8.13 – 7.87 (13H, m, ArH), 7.79 (2H, m,
ArH), 7.50 (2H, d, J = 31.9 Hz, CONH2), 7.37 (1H, d, J = 8.6 Hz, ArH), 4.92 (1H,
t, J = 8.0 Hz, CHNH), 4.25 (1H, hept, J = 6.1 Hz, CHMe2), 4.09 (1H, d,
J = 8.0 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.03 (6H, d, J = 6.1 Hz, CH(CH3)2)
ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH),
167.5 (q, CONH), 166.9 (q, CO2H), 165.4 (q, CONH), 164.1 (q, CONH), 154.5
(q, C-Ar), 149.8 (2C, t, C-Ar), 146.3 (q, C-ArTriazol), 141.9 (q, C-Ar), 141.5 (q,
C-Ar), 138.9 (q, C-Ar), 138.7 (q, C-Ar), 134.4 (q, C-Ar), 130.3 (2C, t, C-Ar),
129.2 (q, C-Ar), 128.3 (2C, t, C-Ar), 126.5 (q, C-Ar), 125.9 (q, C-Ar),125.8 (2C, t,
C-Ar), 125.4 (q, C-Ar), 123.5 (t, C-Ar), 122.6 (t, C-ArTriazol), 122.0 (2C, t, C-Ar),
120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.7 (2C, t, C-Ar), 118.4 (q, C-Ar),
114.8 (t, C-Ar), 80.1 (t, CHOMe), 75.7 (t, CH(CH3)2), 57.7 (p, OCH3), 55.7 (t,
CHNH), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C43H40N9O10 [M
+ H]+: 842.2898; found 842.2903.
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(4-fluorobenzamido)benzamido)-3-
methoxy-4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-iso-
propoxybenzamido)-benzoic acid (47): Following the general procedure V
phenol S20 (20.1 mg, 22.0 µmol, 1.0 eq) was stirred for 3.5 h. Acid 47 was
obtained as an orange amorphous solid (19.1 mg, 19.6 µmol, 89%).
[α]D24 = +27.6° (c 0.9, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.2 (1H, br.
s, OH), 10.8 (1H, s, NH), 10.5 (1H, s, NH), 10.4 (1H, s, NH), 8.93 (1H, s,
CHTriazol), 8.41 (1H, d, J = 8.1 Hz, NHCH), 8.07 – 8.05 (2H, m, ArH), 8.00 – 7.87
(11H, m, ArH), 7.79 (2H, m, ArH), 7.50 (2H, d, J = 47.2 Hz, CONH2), 7.40 –
7.36 (3H, m, ArH), 4.92 (1H, t, J = 8.1 Hz, CHNH), 4.25 (1H, hept, J = 6.1 Hz,
CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.03 (6H, d,
J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.0 (q,
CONH2), 168.2 (q, CONH), 167.5 (q, CONH), 166.9 (q, CO2H), 165.0 (q,
CONH), 164.7 (q, CONH), 164.4 (d, J = 311.0 Hz, C-F), 158.2 (TFA), 154.5 (q,
C-Ar), 146.3 (q, C-ArTriazol), 142.1 (q, C-Ar), 141.9 (q, C-Ar), 138.9 (q, C-Ar),
138.7 (q, C-Ar), 134.4 (q, C-Ar), 131.1 (d, J = 2.8 Hz, C-Ar), 130.5 (2C, d,
J = 9.1 Hz, C-Ar), 130.3 (2C, t, C-Ar), 129.8 (TFA), 128.6 (q, C-Ar), 128.2 (2C, t,
C-Ar), 126.5 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 123.5 (t, C-Ar), 122.6
(t, C-ArTriazol), 120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.5 (2C, t, C-Ar), 118.4
(q, C-Ar), 115.4 (2C, d, J = 21.8 Hz, C-Ar), 114.8 (t, C-Ar), 80.1 (t, CHOMe),
75.7 (t, CH(CH3)2), 57.7 (p, OCH3), 55.6 (t, CHNH), 21.8 (2C, p, CH(CH3)2)
ppm; HRMS (ESI): m/z calc. for C44H40N8O10F [M + H]+: 859.2851; found
859.2851.
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(6-cyanonicotinamido)benzamido)-3-
methoxy-4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-iso-
propoxybenzamido)benzoic acid (51): Following the general procedure V
phenol S24 (24.4 mg, 26.5 µmol, 1.0 eq) was stirred for 5 h. Acid 51 was
obtained as a beige amorphous solid (15.6 mg, 18.0 µmol, 68%). [α]D22 = +25.1°
(c 1.5, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.8 (1H, br. s, CO2H), 12.2
(1H, br. s, OH), 10.9 (1H, br. s, NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 9.24 –
9.23 (1H, m, ArH), 8.93 (1H, s, CHTriazol), 8.55 – 8.53 (1H, m, ArH), 8.45 (1H, d,
J = 8.1 Hz, NHCH), 8.26 – 8.25 (1H, m, ArH), 8.00 – 7.87 (11H, m, ArH), 7.79
(2H, m, ArH), 7.50 (2H, d, J = 46.3 Hz, CONH2), 7.37 (1H, d, J = 8.6 Hz, ArH),
4.92 (1H, t, J = 8.1 Hz, CHNH), 4.25 (1H, hept, J = 6.0 Hz, CHMe2), 4.09 (1H, d,
J = 8.1 Hz, CHOMe), 3.32 (3H, s, OCH3), 1.03 (6H, d, J = 6.0 Hz, CH(CH3)2)
ppm; 13C-NMR (125 MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH),
167.5 (q, CONH), 166.8 (q, CO2H), 165.3 (q, CONH), 163.0 (q, CONH), 154.5
(q, C-Ar), 150.2 (t, C-Ar), 146.3 (q, C-ArTriazol), 141.9 (q, C-Ar), 141.5 (q, C-Ar),
138.9 (q, C-Ar), 138.7 (q, C-Ar), 137.3 (t, C-Ar), 134.5 (q, C-Ar), 134.4 (q, C-Ar),
133.4 (q, C-Ar), 130.3 (2C, t, C-Ar), 129.2 (q, C-Ar), 128.8 (t, C-Ar), 128.3 (2C, t,
C-Ar), 126.5 (q, C-Ar), 125.8 (2C, t, C-Ar), 125.4 (q, C-Ar), 123.5 (t, C-Ar), 122.6
(t, C-ArTriazol), 120.6 (2C, t, C-Ar), 119.8 (2C, t, C-Ar), 119.6 (2C, t, C-Ar), 118.4
(q, C-Ar), 117.1 (q, CN), 114.8 (t, C-Ar), 80.0 (t, CHOMe), 75.7 (t, CH(CH3)2),
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(5-cyanopicolinamido)benzamido)-3-
methoxy-4-oxo-butanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-3-iso-
propoxybenzamido)benzoic acid (48): Following the general procedure V
phenol S21 (21.8 mg, 23.6 µmol, 1.0 eq) was stirred for 6 h. Acid 48 was
obtained as a yellow amorphous solid (8.2 mg, 9.47 µmol, 40%). [α]D24 = +27.2°
(c 0.8, DMSO); 1H-NMR (600 MHz, DMSO-d6): δ = 12.9 (1H, br. s, CO2H), 12.2
(1H, br. s, OH), 11.0 (1H, s, NH), 10.8 (1H, s, NH), 10.4 (1H, s, NH), 9.22 (1H,
dd, J = 0.7, 2.0 Hz, ArH), 8.93 (1H, s, CHTriazol), 8.61 (1H, dd, J = 2.0, 8.2 Hz,
ArH), 8.43 (1H, d, J = 8.1 Hz, NHCH), 8.31 (1H, dd, J = 0.7, 8.2 Hz, ArH), 8.06
(2H, m, ArH), 7.99 – 7.87 (9H, m, ArH), 7.79 (2H, m, ArH), 7.50 (2H, d,
J = 43.0 Hz, CONH2), 7.37 (1H, d, J = 8.6 Hz, ArH), 4.91 (1H, t, J = 8.1 Hz,
CHNH), 4.24 (1H, hept, J = 6.1 Hz, CHMe2), 4.09 (1H, d, J = 8.1 Hz, CHOMe),
3.32 (3H, s, OCH3), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (125
MHz, DMSO-d6): δ = 171.0 (q, CONH2), 168.2 (q, CONH), 167.5 (q, CONH),
166.8 (q, CO2H), 165.4 (q, CONH), 161.7 (q, CONH), 154.5 (q, C-Ar), 152.3 (q,
C-Ar), 151.5 (t, C-Ar), 146.3 (q, C-ArTriazol), 142.3 (t, C-Ar), 141.9 (q, C-Ar),
14
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10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
57.7 (p, OCH3), 55.6 (t, CHNH), 21.8 (2C, p, CH(CH3)2) ppm; HRMS (ESI): m/z
calc. for C44H39N10O10 [M + H]+: 867.2851; found 867.2858.
Received: ((will be filled in by the editorial staff))
Revised: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
4-(4-(4-(4-((2S,3R)-4-Amino-2-(4-(3-(4-cyanophenyl)-propanamido)-benz-
amido)-3-methoxy-4-oxobutanamido)phenyl)-1H-1,2,3-triazol-1-yl)-2-
hydroxy-3-isopropoxy-benzamido)benzoic acid (52): Following the general
procedure V phenol S25 (19.8 mg, 20.9 µmol, 1.0 eq) was stirred for 4.5 h. Acid
52 was obtained as a grey amorphous solid (18.6 mg, 20.9 µmol, quant.).
[α]D24 = +20.8° (c 1.9, DMSO); 1H-NMR (400 MHz, DMSO-d6): δ = 12.8 (1H, br.
s, CO2H), 12.2 (1H, br. s, OH), 10.8 (1H, s, NH), 10.3 (1H, s, NH), 10.2 (1H, s,
NH), 8.92 (1H, s, CHTriazol), 8.35 (1H, d, J = 8.1 Hz, NHCH), 8.00 – 7.95 (3H, m,
ArH), 7.93 – 7.87 (4H, m, ArH), 7.82 – 7.75 (6H, m, ArH), 7.67 (2H, m, ArH),
7.53 – 7.45 (4H, m, ArH, CONH2), 7.37 (1H, d, J = 8.6 Hz, ArH), 4.90 (1H, t,
J = 8.1 Hz, CHNH), 4.25 (1H, hept, J = 6.1 Hz, CHMe2), 4.07 (1H, d, J = 8.1 Hz,
CHOMe), 3.31 (3H, s, OCH3), 3.01 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.71 (2H, t,
J = 7.5 Hz, ArCH2CH2), 1.02 (6H, d, J = 6.1 Hz, CH(CH3)2) ppm; 13C-NMR (100
MHz, DMSO-d6): δ = 171.0 (q, CONH2), 170.4 (q, CONH), 168.2 (q, CONH),
167.5 (q, CONH), 166.8 (q, CO2H), 165.4 (q, CONH), 154.5 (q, C-Ar), 147.3 (q,
C-Ar), 146.3 (q, C-ArTriazol), 142.1 (q, C-Ar), 141.9 (q, C-Ar), 138.9 (q, C-Ar),
138.7 (q, C-Ar), 134.4 (q, C-Ar), 132.2 (2C, t, C-Ar), 130.3 (2C, t, C-Ar), 129.5
(2C, t, C-Ar), 128.3 (2C, t, C-Ar), 128.0 (q, C-Ar), 126.5 (q, C-Ar), 125.8 (2C, t,
C-Ar), 125.4 (q, C-Ar), 123.5 (t, C-Ar), 122.6 (t, C-ArTriazol), 120.6 (2C, t, C-Ar),
119.8 (2C, t, C-Ar), 119.0 (q, C-Ar), 118.4 (q, CN), 118.2 (2C, t, C-Ar), 114.8 (t,
C-Ar), 108.9 (q, C-Ar), 80.1 (t, CHOMe), 75.7 (t, CH(CH3)2), 57.7 (p, OCH3),
55.6 (t, CHNH), 37.1 (s, ArCH2CH2), 30.6 (s, ArCH2CH2), 21.8 (2C, p,
CH(CH3)2) ppm; HRMS (ESI): m/z calc. for C47H43N9O10 [M + H]+: 916.3031;
found 916.3029.
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Biological Activity
Minimal inhibitory concentrations (MIC). MIC values were determined in
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standard microbroth dilution assays as described elsewhere[1,2]
.
Acknowledgement
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[9]
This work was supported by the German Center for Infection Research (DZIF)
and the Bundesministerium für Bildung und Forschung (BMBF; project
OpCyBac).
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Weston, R. D. Süssmuth, Chem. Eur. J. 10.1002/chem.201904752.
Keywords: amides, antibiotics, medicinal chemistry, triazoles,
chemical synthesis, urea
15
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10.1002/chem.201904073
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
Entry for the Table of Contents
FULL PAPER
Fighting Gram-negative and Gram-positive bacteria: Thirteen new cystobactamids, that
derive from cystobactamid 861-2 are prepared by chemical synthesis. Main modifications
are exchange of the amide group by the chemically more stable urea group and the triazole
ring as well as located in ring A. Antibiotic activities against Gram-negative and -positive
bacteria including a multidrug-resistant strain can be preserved, when the urea function is
located between rings A and B and the triazole is positioned beween rings C and D.
█ Antibiotics
T. Planke, K. Cirnski, J.
Herrmann, R. Müller, A.
Kirschning*
■■ – ■■
Synthetic and Biologic
Studies on New Urea and
Triazole Containing
Cystobactamid
Derivatives
16
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