Synthesis and Biological Evaluation of Modified Miuraenamides

Article abstract of DOI:10.1002/ejoc.201801391

Miuraenamides, secondary metabolites of the marine myxobacterium Paraliomyxa miuraensis do not only show a high structural similarity to other cyclodepsipeptides isolated from sponges or terrestrial myxobacteria but they also exhibit a similar mode of act

Full text of DOI:10.1002/ejoc.201801391

A Journal of
Accepted Article
Title: Synthesis and biological evaluation of (modified) miuraenamides
Authors: Sarah Kappler, Lisa Karmann, Cynthia Prudel, Jennifer
Herrmann, Giulia Caddeu, Rolf Müller, Angelika Vollmar,
Stefan Zahler, and Uli Kazmaier
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801391
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
FULL PAPER
D
Synthesis and biological evaluation of (modified) miuraenamides
Sarah Kappler,[a] Lisa Karmann,[a] Cynthia Prudel,[a] Jennifer Herrmann,[b] Giulia Caddeu,[c] Rolf
Müller,[b] Angelika M. Vollmar,[c] Stefan Zahler [c] and Uli Kazmaier*[a]
Abstract: Miuraenamides, secondary metabolites of the A late stage peptide modification allows the synthesis of a
marine myxobacterium Paraliomyxa miuraensis do not only library of (simplified) miuraenamide derivatives with different
show a high structural similarity to other cyclodepsipeptides halogenation and substitution pattern. Detailed SAR studies
isolated from sponges or terrestrial myxobacteria but they also indicate, that bromination of the central tyrosine is essential for
exhibit a similar mode of action. They accelerate nucleation good biological activity, while the side chain of the C-terminal
and polymerization of actin, and therefore interfere with cell amino acid can be varied or can even be removed.
division processes, at concentrations in the low nanomolar
range.
Introduction
Interestingly, the authors did not mention the formation of fruiting
bodies by this strain during cultivation. Investigating the second-
dary metabolites produced by this species resulted in the isolation
of miuraenamides A and B[6] and two years later also of the
derivatives C-F (Figure 1).[7]
Myxobacteria are highly interesting Gram-negative -proteo-
bacteria found widespread all over the globe, living on the bark of
trees, herbivore dung or decaying plants, using cellulose as food-
stuff.[1] In addition, as gliding bacteria they can also hunt for food,
especially other microorganisms such as fungi or bacteria.[2] One
of the most impressive characteristics is the formation of complex
fruiting bodies under starvation conditions.[3] In addition, their rich
secondary metabolism is worth mentioning, making them one of
the best natural product producers.[4] Myxobacteria were initially
considered as terrestrial microorganisms but also a lot of marine
representatives have been discovered during the last years.[5]
In 2006, Lizuka et al. isolated a novel, lightly halophilic myxo-
bacterium, called Paraliomyxa miuraensis, from a soil sample at
the coast of the Japanese island Miura.[6] Phylogenetic analysis
showed an identity of 93.0-93.3% to two other species, Nanno-
cystis exedens DSM 71 and Enhygromyxa salina JCM 11769.
[a] S. Kappler, Dr. L. Karmann, C. Prudel, Prof. Dr. U. Kazmaier*
Organic Chemistry, Saarland University, Campus C4.2, 66123
Saarbrücken, Germany
E-mail: u.kazmaier@mx.uni-saarland.de
http://www.uni-saarland.de/lehrstuhl/kazmaier.html
[b] Dr. J. Herrmann, Prof. Dr. Rolf Müller
Department Microbial Natural Products, Helmholtz-Institute for
Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for
Infection Research (HZI), German Center for Infection Research
(DZIF, Partner Site Hannover-Braunschweig) and Department of
Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken,
Germany
Figure 1. Natural occurring miuraenamides
Like many other cyclodepsipeptides the miuraenamides can be
divided into two major building blocks. A tripeptide containing a
[c] G. Caddeu, Prof. Dr. A. M. Vollmar, Prof. Dr. S. Zahler
Department of Pharmacy, Pharmaceutical Biology,
Ludwig-Maximilians-University Munich, Butenandtstr. 5-13,
81377 München, Germany
1

Supporting information and the ORCID identification numbers for the
authors of this article can be found under: https:
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
halogenated tyrosine in the central position and a polyketide
fragment. The derivatives mainly differ in the halogenation pattern
of the tyrosine and the C-terminal unusual amino acid containing a
methoxyacrylate motif. This part is not very common in marine
natural products, but is also found in antifungal compounds such
as the strobilurins and melithiazols.[8]
double bond). Therefore, the miuraenamides are ideal candidates
for the development of potential anti-tumor drugs.
By far most investigations concerning the biological activity and
the mode of action were carried out with jasplakinolide (jaspamide),
which shows high cytotoxicity towards a range of leukemia, breast
and prostate cancer cell lines.[14] Jasplakinolide was found to
initiate actin polymerization and stabilizes already formed actin
microfilaments, which causes significant morphological changes in
the cell.[15] The same effects were also observed for the
geodiamolides.[14] Interestingly, geodiamolide H showed cytotoxic
effects towards a range of tumor cell lines, while geodiamolide I
was inactive. [16] The interesting mode of action initiated several
synthetic approaches towards jasplakinolide[17] and geo-
diamolide,[18] while the other cyclodepsipeptides have not been
synthesized so far. Recently, we published the first synthesis of the
miuraenamides A, D and E,[19] while the group of Suenaga reported
also another synthetic protocol towards miuraenamides A and D
one year later.[20] In their synthesis, the unusual unsaturated C-
terminal amino acid was synthesized first and was incorporated
into the growing peptide chain. No question, this approach is
straightforward for the synthesis of the natural products them-
selves, but it is limited with respect to the synthesis of derivatives
for structure-activity relationship (SAR) studies. Having a closer
look at the cyclodepsipeptides shown in Fig. 2, thewerstern part of
the peptide (N-terminus) seems to be rather conserved, while the
C-terminus is relatively flexible, especially taking into account, that
both isomers (miuraenamide A and D) are found in nature. The
olefin geometry has a significant influence on the antifungal activity,
but not on the cytotoxicity. Both isomers are almost equipotent.[19]
Therefore, we designed our synthesis in such a way, that this
unusual amino acid is incorporated in almost the last step. For this
late stage modification, the corresponding glycine peptide is
converted into a cyclic glycine ester enolate, which should provide
a wide range of miuraenamide derivatives by trapping this enolate
with various types of electrophiles (Scheme 1). Using this approach,
we were interested to investigate the influence of the halogenation
pattern, the C-terminal side chain as well as the configuration of
the methyl group in the polyketide fragment on the cytotoxicity of
the miuraenamide derivatives.
Indeed, activity was observed for miuraenamide A against
Candida rugosa and this activity was proposed to result from an
inhibition of the mitochondrial cytochrome bc1 complex, as
reported for other compounds containing the methoxyacryl
pharmacophore. Therefore, it is not surprising that the antifungal
activity depends strongly on this subunit. Miuraenamide D, with the
opposite olefin geometry was found to be less active by factor 40,
while the antifungal activity of the ketone derivative miuraenamide
E was even worse (400-fold less active than miuraenamide A).
Interestingly, the halogenation pattern had no significant influence.
No antibacterial activity was observed, but miuraenamide A was
found to stabilize actin filaments in tumor cells.[9] Unfortunately, the
other derivatives were obtained only in tiny amounts, so that no
detailed investigations of their biological activity was possible.
The strong interaction with the actin skeleton is not really
surprising with respect to the close structural relationship of the
miuraenamides to other cyclodepsipeptides (Figure 2) such as the
geodiamolides,[10] seragamide,[11] pipestelide A,[12] or jasplaki-
nolide.[13] All these natural products have been isolated from
sponges, but probably they are not produced by them but are also
secondary metabolites from bacteria living in them. [7]
Scheme 1. Variations on the miuraenamide skeleton (in grey)
Figure 2. Structurally related cyclodepsipeptides from sponges
Results and Discussion
Since more than two decades our group is involved in the
synthesis of peptidic natural products[21] and we are developing
new synthetic protocols for unusual amino acids via modifications
of chelated glycine ester enolates.[22] These enolates are on one
hand thermally rather stable because of chelate complex formation,
but on the other hand they show the high reactivity of metal
enolates. The enolates undergo a wide range of reactions, such as
alkylations, aldol[23] or Michael additions,[24] epoxide opening[25] or
transition metal catalyzed allylic alkylations,[26] allowing the
introduction of almost “every” side chain, often in a highly selective
fashion. If the reactions are carried out with peptide esters or
All these cyclodepsipeptides contain the same C-8 polyketide
fragment and a tripeptide fragment containing an alanine, an N-
methylated halogenated aromatic amino acid and an - or -amino
acid at the C-terminus. All in marine surroundings ‘common’
halogens are incorporated into the central tyrosine, and the rings
are either 18- or 19-membered. The same is true for the
miuraenamides, but their structure is significantly simpler,
especially in the polyketide part. While the other natural products
contain six to seven stereogenic centres, the miuraenamides
contain only three asymmetric C-atoms (and one stereoisomeric
2
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
amides, the stereochemical outcome can be controlled by the
stereogenic centres in the peptide chain.[27] According to this
protocol, we wanted to modify the C-terminus of the miuraenamide
tripeptide (Scheme 1).
In this case, the stereochemical outcome of the modification
step is of minor importance, because in case the stereoisomeric
products can be separated, both isomers can be investigated
separately, and in case one is more active than the other one it can
also be synthesized in a conventional way.
tyrosine derivatives 14c and 14d. Subsequent saponification and
coupling with glycine ester using the TBTU protocol gave rise to
the dipeptides 10c and 10d. Prolongation towards the tripeptides
11c and 11d in analogy to the previous couplings proceeded in
comparable yields.
Compared to the other cyclodepsipeptides (Figure 2) the
polyketide fragment of the miuraenamides is by far the simplest
one and its synthesis is straightforward (Scheme 2). The key step
is a Johnson-Claisen rearrangement of allyl alcohol 1 towards ester
2.[19] Direct reduction of 2 gives access to primary alcohol 3’ which
can be used for the synthesis of miuraenamides without the methyl
group in the polyketide (series C). DibalH reduction of 2 and
addition of MeLi provides racemic secondary alcohol 3, which on
enzymatic kinetic resolution with Novozym gives access to (S)-3
which is used for the natural miuraenamide derivatives (series A),
while saponification of the (R)-acetate 4 provides (R)-3 which was
incorporated into the miuraenamides with inverted polyketide
centre (series B).[19] In principle (R)-3 can be interconverted into
(S)-3 via Mitsunobu reaction/saponification without loss of optical
purity.
Scheme 2. Synthesis of polyketide precursors 3 and 3’
For the synthesis of suitable protected tripeptides we used two
different approaches (Scheme 3). The non-halogenated and
chlorinated tripeptides were obtained from (R)-tyrosine (5) which
was mono-chlorinated with SO2Cl2 in good yield.[28] Subsequent
esterification and Boc-protection of 5 and 6, followed by allylation
of the phenol OH-group provided the fully protected tyrosine
derivatives 8a and 8b. For the introduction of the N-methyl group,
the methylester was saponified and after deprotonation of the
amide functionality, it was methylated in excellent yield over both
steps. Best results in the subsequent coupling with glycine esters
were obtained with TBTU and diisopropylethylamine (DIPEA) as a
base, while PyBOP was found to be the reagent of choice for the
coupling of the Boc-(S)-Ala to the N-methylated terminus of the
dipeptide. The syntheses of the brominated tripeptides 11c and
11d started from literature-known 12.[29] Monobromination was
carried out with pyridinium bromide perbromide,[30] while
chloramin-T and KI was used to introduce the iodine into the phenyl
ring.[31] Subsequent O-allylation provided the fully protected
Scheme 3. Synthesis of the desired glycine tripeptides 11
With these four tripeptides in hand, we next investigated the
synthesis of the linear peptide-polyketide conjugates and the
cyclization towards the glycine-miuraenamides (Table 1).
3
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
Table 1. Synthesis of the glycine cyclodepsipeptides 18
Yield
[%]
Yield
[%]
Yield
[%]
Yield
[%]
Entry
11
X
3
R
15
16
17
18
1
2
3
4
5
6
11a
11b
11c
11d
11b
11b
H
(S)-3
(S)-3
(S)-3
(S)-3
(R)-3
3’
15aA
15bA
15cA
15dA
15cB
15cC
67
87
78
71
82
82
16aA
16bA
16cA
16dA
16cB
16cC
92
90
86
84
88
83
17aA
17bA
17cA
17dA
17cB
17cC
64
53
76
59
68
37
18aA
18bA
18cA
18dA
18cB
18cC
63
59
55
59
45
42
Cl
Br
I
Br
Br
H
All four tripeptides 11 were coupled with the secondary alcohol
(S)-3 with the “correct” configuration in the polyketide (series A),
while only the brominated peptide 11c was coupled also with the
other two alcohols (entries 5 and 6, series B and C). The yields of
the different reaction steps are summarized in Table 1.
Saponification of the tripeptides 11 and subsequent esterification
according to the Steglich protocol[32] delivered the desired peptide
esters 15 in generally good yield. It is recommended to use a slight
excess of the alcohol (1.2-1.3 equiv.) for reproducible good yields.
The subsequent cleavage of the silyl protecting group to 16 was
also not a serious issue, but the subsequent oxidation towards the
desired carboxylic acid caused some problems at the beginning.
While oxidation, e.g. with Dess Martin periodinane[33] proceeded
cleanly, the further oxidation, e.g. via Lindgren-Pinnick oxidation[34]
was not successful, even when a scavenger was used. The major
problem was the addition of hypochloric acid formed toward on the
threefold substituted double bond in the polyketide fragment,
clearly indicating that this motif is sensitive towards acidic
conditions. Also other oxidation reagents such as CrO3/pyridine,
pyridinium chlorochromate or TEMPO gave unsatisfying results.
So far, the best yields of 17 could be obtained with CrO3/H2SO4
(Jones oxidation) even under these acidic conditions. This reaction
is very fast and one has to catch the best moment, when almost all
starting material is consumed and side reactions (Boc-deprotection
and addition toward the double bond) are not yet a serious issue.
The acid lability of the double bond is also not unproblematic in one
of the next steps, the deprotection of the Boc-protecting group
during ring closure. We decided to use Schmidt’s
pentafluorophenylester method for this approach since it allows a
separate activation of the carboxyl terminus and an N-deprotection
under high dilution conditions.[35] For the activation, we used EDC,
because it can easily be removed via aqueous workup.
Subsequently, the N-Boc protecting group was removed with TFA
in CH2Cl2 (1:4). After complete deprotection the solution was
diluted with CHCl3/NaHCO3 (c = 0.0025 M). Under these conditions
reproducible yields in the range of 60 ± 5% were obtained for the
derivatives of the A series, while the derivatives 18cB and 18cC
with the “unnatural” polyketide gave slightly lower yields but still in
a preparative useful range. It should be mentioned that replacing
the Boc-protecting group by an Fmoc group to avoid side reactions
during the acidic cleavage did not result in better overall yields.
With these cyclodepsipeptides 18 in hand, we next focused on
the introduction of different side chains at the C-terminal amino
acid of the tripeptide. To get access to the natural products them-
selves a benzoylation at this position seems to be appropriate. In
principle, such -amino--ketoesters can directly be obtained by
trapping a glycine enolate either with acyl halides or esters,[36] but
first attempts provided only yields around 20%. Therefore, we
decided to investigate
a
two-step approach of aldol
addition/oxidation. The stereochemical outcome of the aldol
reaction does not play any role here, since the stereogenic centres
are removed afterwards during oxidation and the -keto amino acid
can epimerize to the natural configured cyclic peptide. During
previous studies, we observed that the yields of aldol reactions can
be increased by using LDA as a base in excess. This is in agree-
ment with observations made by Seebach et al. who reported that
the solubility of polylithiated peptides at low temperature increased
with an excess of LDA.[37] Addition of 5 equiv. of LDA towards the
cyclodepsipeptides 18aA and 18cA resulted in the formation of a
dark red enolate solution. 2 equiv. of benzaldehyde were added
after 10 min at -78 °C and the reaction mixture was stirred vigo-
rously and slowly warmed up in the cooling bath. After 90 min the
reactions were quenched at low temperature and the desired aldol
products could be obtained in good yields as diastereomeric
mixtures (Table 2, entries 1 and 2).
4
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European Journal of Organic Chemistry
Table 2. Synthesis of miuraenamides and derivatives 21 and 22
Yield
[%]
Yield
[%]
diast.
ratio
Yield
[%]
ratio
E:Z
Yield
[%]
diast.
ratio
Entry
18
X
R
Reaction conditions
19
20
21
22
[b]
1
2
3
4
5
6
18aA
18bA
18cA
18dA
18cB
18cC
H
–78 °C to –60 °C, 90 min
–78 °C, 180 min
19aA
19bA
19cA
19dA
19cB
19cC
63[a]
64
66[c]
20aA
20bA
20cA
20dA
20cB
20cC
83[a]
49
73[c]
93:7
21aA
48
3:1
22aA
22bA
22cA
22dA
22cB
-
Cl
Br
I
82:18
91:9
78
10[d]
92:8
90:10
94:6
76:24
–78 °C to –70 °C, 90 min
–78 °C, 35 min
21cA
73
3:1
58
82
94:6
95
Br
Br
–78 °C, 150 min
68[e]
71
86
36[f]
76:24
71:29
91
H
–78 °C, 210 min
[a] Contaminated with 10% enol ether. [b] Side product of 21aA, but could not be isolated. [c] Contaminated with 2% enol ether. [d] Side product of 21cA. [e]
Contaminated with 4% enol ether. [f] Product is not stable and decomposes during storage.
Interestingly, the product was contaminated with some enol
ether, resulting from an isomerization of the allyl protecting group
under the basic reaction conditions.[38] This side reaction occurred
during the relatively long reaction time and was more significant in
case of the unhalogenated peptide 18aA (10%) which was warmed
to -60 °C, while only traces are found with the brominated 18cA
which was quenched at -70 °C. Therefore, the reaction of the
iodinated peptide 18dA (entry 3) was carried out at -78 °C and was
quenched after 35 min. The yield was comparable, but no isome-
rization occurred under these conditions. Although the enol ether
could not be separated at this stage, it was no problem to remove
it later on after cleavage of the allyl protecting group. Subsequent
Dess Martin oxidation of the aldol products 19 proceeded cleanly
providing the desired ketones 20 in generally good yield. According
to 1H NMR the diastereomers are found in a ratio of 93:7 (± 2%) in
CDCl3, except for the chlorinated product 20bA (entry 2). This ratio
obviously is solvent dependent. In d6-DMSO a ratio of 3:1 was
observed, clearly indicating that the -stereogenic centre can
easily epimerize towards the most stable configuration in solution.
To finalize the synthesis of the brominated miuraenamides A,
D and E, the ketone 20cA had to be converted into the corres-
ponding enol ether and the allyl protecting group had to be
removed from the tyrosine (entry 3). The enol ether formation was
not as easy as expected, and even with methyl triflate no complete
conversion of the ketone could be observed and a mixture of (E)-
and (Z)-enol ether with unreacted ketone was obtained. But since
all three derivatives are found in nature, the crude mixture was
subjected to allyl deprotection using CpRu(MeCN)3PF6 as a
catalyst.[39] The obtained mixture of miuraenamides could be
separated by preparative reverse phase HPLC providing miura-
enamide A (47%) and miuraenamide E (10%) in pure form, while
miuraenamide D was always contaminated with miuraenamide E,
although according to HPLC a clean separation should be possible.
Obviously, miuraenamide D hydrolyzes easily to miuraenamide E,
much faster than miuraenamide A, and therefore we assume that
the “natural” miuraenamide E might be an artefact of the isolation
and workup. The enol ether formed during the aldol addition did not
undergo cleavage, and therefore this side product could easily be
removed on this stage.
The same observation was also made with the non-halogen-
nated derivative 20aA (entry 1). In this case, (E)- 21aA could be
obtained, while the (Z)-isomer was contaminated with the ketone
22aA, which could not be isolated.
The configuration of the double bond in 21cA was determined
by H,H-NOESY-correlation. The major (E)-product showed clear
couplings between the aromatic protons of the brominated tyrosine
and the phenyl ring at the double bond, as well as interacttions of
the methoxy group and the methyl group of the polyketide.
First investigations of the biological activity of the miuraena-
mides towards several cancer cell lines indicated that the double
bond geometry obviously is not crucial and both isomers showed
comparable activity, while the ketone was a little less active by
factor 3-5, depending on the cell line. Because the enol ether
formation was not a trivial issue and because of the stability
5
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
problems of the enol ethers, we decided to investigate the influence
of the substitution pattern further on with the easier accessible and
more stable ketones. Both, the chlorinated (entry 2) and iodinated
ketones (entry 4), as well as the derivatives with the inverted and
simplified polyketide chains (B, C) (entries 5 and 6), were obtained
in an analogous way.. The relatively low yield observed for the
primary ester 20cC (entry 6) is caused by an instability of this
compound, and complete decomposition is observed upon storage,
even in the fridge.
Scheme 4. Synthesis of a fluorogenic miuraenamide derivatibe 27
During our previous studies on the closely related chondra-
mides, we observed that incorporation of halogens into the C-
terminal aromatic amino acid had a positive effect on the biological
activity of these compounds,[40] so we decided to investigate the
influence of halogens on the aryl ketone also in this case (Table 3).
Although one might expect a higher reactivity of the halogenated
benzaldehydes, we observed a significantly slower reaction. Even
after prolonged reaction times and slightly increased temperature,
no complete decolourization of the dark red enolate solution was
observed. In some cases, the aldol products could not be separa-
ted from the starting material and therefore the crude reaction
mixture was subjected to Dess Martin periodinane oxidation. The
ketones were obtained in yields of 30-40% (for both steps) in all
cases. Subsequent allyl-deprotection proceeded cleanly giving
access to the desired dihalogenated miuraenamides 25 and 26.
Since our group is also involved in the development of new
techniques for the fluorescence labelling of amino acids and
peptides[41] we decided to synthesize also a fluorogenic miuraen-
amide with a coumarine side chain (Scheme 4). Such a fluorogenic
natural product should be helpful for live cell imaging, because the
local binding in the cell can directly be observed by fluorescence
microscopy. For this approach, a suitable substituted coumaryl
carbaldehyde is required, which can easily be obtained from the
corresponding triflate via vinylation/ozonolysis.[41c] Aldol reaction
under the usual reaction conditions provided the desired -
hydroxylated derivative 27cA in acceptable yield after preparative
RP-HPLC. Since we failed to oxidize the aldol product to the
corresponding ketone we decided to use 27cA directly for the live
cell imaging.
With respect to the fact that the side chain at the C-terminus
obviously has only a minor influence on the biological activity, at
least towards tumor cells, and that its introduction might cause
some problems, we were interested to see if the side chain is
required at all. Therefore, the allylated glycine peptides were
subjected to deprotection giving rise to the rather simple
cyclodepsipeptides containing only 2-3 stereogenic centres (Table
4).
Table 4. Synthesis of simplified miuraenamide derivitaves 29
Yield [%]
Entry
18c
X
R
29
1
2
3
4
5
6
18aA
18bA
18cA
18dA
18cB
18cC
H
29aA
29bA
29cA
29dA
29cB
29cC
90
99
98
99
91
99
Cl
Br
I
Br
Br
H
Table 3. Synthesis of dihalogenated miuraenamide derivatives 25 and 26
ArCHO
Yield [%] diast. ratio
Yield [%]
diast. ratio
Entry
18c
R
Reaction conditions
23,24
25,26
1
2
3
4
5
6
18cA
18cA
18cB
18cB
18cC
18cC
–78 °C, 150 min
–78 °C, 120 min
–65 °C, 180 min
–78 °C, 140 min
–65 °C, 120 min
–70 °C, 120 min
p-Br-Ph
p-F-Ph
p-Br-Ph
p-F-Ph
p-Br-Ph
p-F-Ph
23cA
24cA
23cB
24cB
23cC
24cC
19
87:13
68:32
75:25
75:25
79:21
78:22
25cA
26cA
25cB
26cB
25cC
26cC
66
73
80
91
95
99
80:20
90:10
70:30
73:27
79:21
72:28
26
31[a]
37
H
H
31[a]
40[a]
6
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
The cytotoxicity of all new cyclic miuraenamide derivatives
(18–29) was investigated using two human cancer cell lines, HCT-
116 (colon cancer) and U-2 OS (osteosarcoma). The results are
summarized in Table 5 ordered by protected and unprotected
derivatives.
Although, the two different cancer cell lines showed some
specific sensitivities towards single compounds, a general trend
can be observed. The O-protected derivatives are significantly less
active in comparison to the unprotected compounds, ranging from
100-fold in case of the miuraenamide E analogs (20, 23, 24 vs. 22,
25, 26) up to 1000-fold in case of the glycine-containing
“miuraenamides light” (18 vs. 29). Obviously, the OH-functionality
of the tyrosine is involved in the binding towards actin. This
interaction is probably modulated by the halogens on the aromatic
ring, because a strong influence of the halogenation pattern is also
observed. In general, the bromo derivatives display most
pronounced activity, followed by the iodo compounds, while
derivatives with non-halogenated tyrosines are significantly less
active (entries 1-4, 29-31). This effect is tremendous for the
“miuraenamide light” derivatives 29 (39-42), where the bromo
derivative 29cA is the most active compound of the whole series
(entry 41), while non-halogenated 29aA is almost inactive (entry
39). This example illustrates that the substituent at the C-terminus
does only play a minor role, because it can be removed completely,
as long as the halogenation pattern of the tyrosine is correct. This
unit seems to be essential for binding, while the C-terminal amino
acids seems to be not involved at all. Therefore, very similar
cytotoxicity values are obtained for a wide range of differently
substituted miuraenamides, in the protected (entries 13-24) and
unprotected series (entries 29-38). For example, the fluorogenic
aldol product 27cA (entry 24) was comparably active to fluorinated
aryl ketone 24cA (entry 21). However, removing the substituent
completely makes the derivatives more sensitive to additional
structural changes. Interconverting the stereogenic center in the
polyketide causes a drop in activity by around 1500 (HCT-116)
(entries 41/43), an effect which is only moderate in case of the
ketones 22, 25 and 26 (entries 14/17, 33-38). Removing the
stereogenic center in the polyketide part completely is well
Table 5. Cytotoxicity of miuraenamides 18-29
with O-protecting group
HCT-116[a]
IC50 [M]
U-2 OS[a]
IC50 [M]
Entry
Derivative
1
18aA
18bA
18cA
18dA
18cB
18cC
19aA
19bA
19cA
19cC
19dA
20aA
20bA
20cA
20dA
20cB
20cC
23cA
23cB
23cC
24cA
24cB
24cC
27cA
109
29.7
1.1
56.1
26.0
n.d.
7.3
2
3
4
8.1
5
33.3
2.9
33.8
2.4
6
7
4.7
1.9
8
0.39
0.23
1.72
0.54
19.2
1.38
0.42
3.9
0.18
10.3
0.69
0.35
16.5
0.86
9.5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2.1
8.0
11.7
2.01
0.62
8.8
4.31
1.27
6.9
6.7
2.3
2.33
4.5
1.92
5.6
accepted (entries 33/35, 36/38, 42/44).
For a subset of unprotected derivatives the effects on proliferation
was tested in non-tumor cells (HUVECs). The IC50 values (Table
5) are by tendency higher than for the tumor cells due to the
necessary experimental conditions. However, the overall potency
in the different cellular setups correlates well.
3.2
3.6
2.1
1.7
without O-protecting group
HCT-116[a]
IC50 [M]
U-2 OS[a]
IC50 [M]
HUVEC[b]
IC50 [M]
Entry
Derivative
An in vitro actin polymerization assay with pyrene labeled actin
showed a shift of the curve of fluorescence intensity to the left and
an increase of the slope with 10 µM 21cA (miuraenamide A),
indicating accelerated nucleation and polymerization of actin, as
was to be expected for an actin nucleating and filament stabilizing
compound (see Supporting Information, Fig. 1 A-E). At the same
concentration (10 µM), some compounds had an effect similar to
21cA (22cC, 26cC; SI Fig. 1 A and B), no effect (22cB, 25cB,
29bA, 29cC; SI Fig. 1 A, B, D and E) or even a paradoxical
inhibitory effect (27cA, 29aA, 29cA, 29dA, SI Fig. 1 C, D and E).
When the concentrations of the compounds were normalized to the
respective IC50 values of the cellular assay with HUVECs (IC50 from
Table 5 x 1000), they showed nearly equipotent effects as
compared to 21cA (SI Fig. 2 A-D). This means that the differences
in the potency of the derivatives is not due to uptake- or stability
issues in the cellular assays, but results from different affinities to
actin. For 27cA and 29aA this normalization was not possible due
to solubility issues. The paradoxical effects of 29cA and 29dA at
low concentrations, which are reversed at higher concentrations,
could hint towards an additional high affinity binding site
(responsible for an inhibition of polymerization) at the actin
molecule addressed by these compounds, which is then
overridden by lower affinity binding to a different binding site
(responsible for the nucleation and polymerization effect).
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
(E)-21aA
(Z)-21aA
(E)-21cA (Miu A)
(Z)-21cA (Miu D)
22bA
0.05
1.14
1.37
9.57
0.006
0.004
0.096
0.014
0.013
0.061
0.027
0.037
0.011
0.087
0.123
0.028
12.2
0.009
0.023
0.096
0.052
0.006
0.186
0.013
0.136
0.046
0.043
0.160
0.043
16.0
22cA (Miu E)
22dA
22cB
0.248
0.066
25cA
25cB
25cC
26cA
26cB
26cC
0.071
32.0
29aA
29bA
0.023
0.0012
0.0065
1.61
0.073
0.0048
0.011
2.00
0.214
0.04
29cA
29dA
0.128
29cB
29cC
0.018
0.056
0.163
[a] Half-inhibitory concentrations (IC50) were determined after 5 d incubation
in an tetrazolium salt (MTT) reduction assay. [b] IC50 values were determined
after 3 d incubation using crystal violet staining.
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801391
European Journal of Organic Chemistry
as colorless, viscous oil. [훼]퐷20 = +53.8 (c = 1.0, CHCl3). Major rotamer: 1H
NMR (CDCl3, 400 MHz): δ = 1.40 (s, 9 H), 2.74 (s, 3 H), 2.86 (dd, J = 14.6,
10.0 Hz, 1 H), 3.25 (dd, J = 14.4, 6.2 Hz, 1 H), 3.74 (s, 3 H), 3.87 (dd, J =
18.2, 4.2 Hz, 1 H), 4.16 (dd, J = 18.2, 6.6 Hz, 1 H), 4.55 (dt, J = 4.6 Hz, 1.3
Hz, 2 H), 4.89 (dd, J = 9.1, 6.3 Hz, 1 H), 5.29 (ddt, J = 10.6, 1.5, 1.5 Hz, 1
H), 5.49 (ddt, J = 17.3, 1.8, 1.8 Hz, 1 H), 6.03 (ddt, J = 17.1, 10.3, 4.8 Hz, 1
H), 6.69 (bs, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 7.15 (dd, J = 8.0, 2.0 Hz, 1 H),
7.61 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 28.3, 31.0, 32.5, 41.1, 52.3,
59.5, 69.8, 80.8, 86.5, 112.4, 117.6, 130.0, 131.9, 132.6, 139.8, 155.9,
156.6, 170.0, 170.8. Minor rotamer (selected signals): 1H NMR (CDCl3, 400
MHz): δ = 1.32 (s, 9 H), 2.79 (s, 3 H), 3.32 (dd, J = 5.0 Hz, 1 H), 3.76 (s, 3
H), 3.99 (dd, J = 18.0, 3.9 Hz, 1 H), 4.78 (m, 1 H), 6.40 (bs, 1 H), 7.06 (d, J
= 7.9 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 28.1, 30.6, 52.4, 61.3, 81.1,
86.9, 132.2, 139.7, 155.1, 155.9, 170.0, 170.5. HRMS (CI) calcd for
C21H30IN2O6+ [M+H]+: 533.1143, found: 533.1109.
Fluorogenic derivative 27cA was also used to visualize binding of
the miuraenamides towards actin (Figure 3). The fluorogenic
derivative 27cA does not bind to F-actin (Figure 3A) in the
equimolar (2 µM) presence of phalloidin, most likely due to
competition. But staining of F-actin (especially at the lamellipodia)
is clearly visible in the absence of phalloidin (Figure 3B).
A
B
(R)-(O-Allyl-N-tert-butoxycarbonyl-3-iodo-N-methyl-tyrosyl)-glycine
methyl ester (10d): Tyrosine methyl ester 14d (3.58 g, 7.53 mmol, 1.0 eq)
was dissolved in THF/MeOH (3:1, 60 mL) and a solution of LiOH (189 mg,
7.91 mmol, 1.05 eq) in dest. H2O (15 mL) was added at 0 °C. After complete
conversion (TLC-control), the solvent was evaporated in vacuo and the
residue was acidified with 1 M HCl solution to pH 2. The aqueous layer was
extracted with EtOAc, the combined organic layers were dried over Na2SO4
and the solvent was evaporated in vacuo.
Figure 3. Confocal image of a HUVEC cell. A: F-actin stained with 2 µM
rhodamine-phalloidin (red) and nuclei with Hoechst (blue). B: The fluorogenic
derivative 27cA shows excitation and emission characteristics similar to Hoechst.
Therefore 27cA (2 µM) shows up in the same fluorescence channel as Hoechst
staining.
To a solution of the crude acid (1.0 eq) and glycine methyl ester hydro-
chloride (1.04 g, 8.28 mmol, 1.1 eq) in dry CH2Cl2 (53 mL) DIPEA (2.69 mL,
15.8 mmol, 2.1 eq) and TBTU (2.66 g, 8.28 mmol, 1.1 eq) were added at
0 °C. After stirring overnight at room temperature, the solvent was
evaporated in vacuo and the residue was dissolved with EtOAc. The organic
layer was washed successively with 1 M KHSO4-, saturated NaHCO3-, and
saturated NaCl-solution. After drying over Na2SO4, the desired dipeptide
10c (3.56 g, 6.69 mmol, 89 %) was obtained by column chromatographie
Conclusion
In conclusion, we could show that a rather simple cyclodepsi-
peptide is an ideal precursors for late-stage modifications and
straightforward syntheses of miuraenamide derivatives. Detailed
SAR studies indicate that the C-terminus of the tripeptide fragment
allows a wide range of variations without affecting the high
cytotoxicity of these derivatives significantly. Removing the side
chain completely provides a highly active compound, which
becomes more sensitive towards further structural modifications.
Incorporation of a fluorogenic side chain allows the visualization of
the binding towards actin, while the miuraenamides initiate and
accelerate actin nucleation and filament stabilization.
(silica gel, petroleum ether/EtOAc 1:1) as colorless, viscous oil. [훼]퐷20
=
+53.8 (c = 1.0, CHCl3). Major rotamer: 1H NMR (CDCl3, 400 MHz): δ = 1.40
(s, 9 H), 2.74 (s, 3 H), 2.86 (dd, J = 14.6, 10.0 Hz, 1 H), 3.25 (dd, J = 14.4,
6.2 Hz, 1 H), 3.74 (s, 3 H), 3.87 (dd, J = 18.2, 4.2 Hz, 1 H), 4.16 (dd, J =
18.2, 6.6 Hz, 1 H), 4.55 (dt, J = 4.6 Hz, 1.3 Hz, 2 H), 4.89 (dd, J = 9.1, 6.3
Hz, 1 H), 5.29 (ddt, J = 10.6, 1.5, 1.5 Hz, 1 H), 5.49 (ddt, J = 17.3, 1.8, 1.8
Hz, 1 H), 6.03 (ddt, J = 17.1, 10.3, 4.8 Hz, 1 H), 6.69 (bs, 1 H), 6.71 (d, J =
8.4 Hz, 1 H), 7.15 (dd, J = 8.0, 2.0 Hz, 1 H), 7.61 (s, 1 H). 13C NMR (CDCl3,
100 MHz): δ = 28.3, 31.0, 32.5, 41.1, 52.3, 59.5, 69.8, 80.8, 86.5, 112.4,
117.6, 130.0, 131.9, 132.6, 139.8, 155.9, 156.6, 170.0, 170.8. Minor rotamer
(selected signals): 1H NMR (CDCl3, 400 MHz): δ = 1.32 (s, 9 H), 2.79 (s, 3
H), 3.32 (dd, J = 5.0 Hz, 1 H), 3.76 (s, 3 H), 3.99 (dd, J = 18.0, 3.9 Hz, 1 H),
4.78 (m, 1 H), 6.40 (bs, 1 H), 7.06 (d, J = 7.9 Hz, 1 H). 13C NMR (CDCl3,
100 MHz): δ = 28.1, 30.6, 52.4, 61.3, 81.1, 86.9, 132.2, 139.7, 155.1, 155.9,
Experimental Section
General remarks: All air- or moisture-sensitive reactions were carried out
in dried glassware (>100 °C) under an atmosphere of nitrogen. Dried
solvents were distilled before use: Dichloromethane was purchased from
Sigma-Aldrich. The products were purified by flash chromatography on
silica gel (0.063−0.2 mm). Mixtures of EtOAc and petroleum ether were
generally used as eluents. Analytical TLC was performed on pre-coated
silica gel plates (Macherey-Nagel, Polygram® SIL G/UV254). Visualization
was accomplished with UV-light, Ceric Ammonium Sulfate solution, KMnO4
solution or ninhydrin solution. Melting points were determined with a MEL-
TEMP II (Laboratory Devices) melting point apparatus and are uncorrected.
1H and 13C NMR spectra were recorded with a Bruker AC-400 [400 MHz
(1H) and 100 MHz (13C)]. Chemical shifts are reported in ppm relative to
TMS or internal solvent. Mass spectra were recorded with a Finnigan MAT
95 spectrometer (quadrupole) using the CI technique.
+
170.0, 170.5. HRMS (CI) calcd for C21H30IN2O6 [M+H]+: 533.1143, found:
533.1109.
(S)-(N-tert-Butoxycarbonyl-alanyl)-(R)-(O-allyl-3-iodo-N-methyl-tyro-
syl)-glycine-methyl ester (11d): To the Boc-protected dipeptide 10d (3.91
g, 7.34 mmol, 1.0 eq) a 4 M HCl/dioxane-solution (18.4 mL, 73.4 mmol, 10.0
eq) was added at 0 °C. After complete conversion (TLC-control), the solvent
was evaporated in vacuo. To a solution of the resulting hydrochloride in dry
CH2Cl2 (32 mL) Boc-(S)-alanine (1.53 g, 8.07 mmol, 1.1 eq), DIPEA (3.90
mL, 22.8 mmol, 3.1 eq) and PyBOP (4.20 g, 8.07 mmol, 1.1 eq) were added
successively at 0 °C. After stirring at room temperature overnight, the
solvent was evaporated in vacuo and the residue was dissolved in EtOAc.
The organic layer was washed successsively with 1 M KHSO4-, saturated
NaHCO3-, and saturated NaCl-solution. After drying over Na2SO4, column
chromatography (silica gel, petroleum ether/EtOAc 1:1, 4:6) gave rise to the
(R)-O-Allyl-N-tert-butoxycarbonyl-3-iodo-N-methyl-tyrosine
methyl-
ester (14d): Iodinated tyrosine 13d[42] (2.42 g, 5.56 mmol, 1.0 eq) was
dissolved in dry DMF (28 mL). Potassium carbonate (922 mg, 6.67 mmol,
2.0 eq) and allyl bromide (0.58 mL, 6.71 mmol, 2.0 eq) were added at room
temperature. After stirring overnight, the reaction mixture was diluted with
EtOAc and washed three times with H2O. The organic layer was dried over
Na2SO4. Column chromatography (silica gel, petroleum ether/EtOAc 8:2,
7:3) gave rise to the allyl protected tyrosine 14d (2.46 g, 5.18 mmol, 93 %)
desired tripeptide 11d (3.88 g, 6.43 mmol, 88 %) as colorless foam. [훼]퐷20
=
+33.9 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.98 (d, J = 6.9 Hz,
3 H), 1.40 (s, 9 H), 2.89 (dd, J = 15.2, 11.0 Hz, 1 H), 2.95 (s, 3 H), 3.33 (dd,
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801391
European Journal of Organic Chemistry
J = 15.2, 5.5 Hz, 1 H), 3.72 (s, 3 H), 3.83 (dd, J = 17.8, 5.2 Hz, 1 H), 4.13
(dd, J = 17.9, 6.5 Hz, 1 H), 4.42 (dq, J = 6.8, 6.8 Hz, 1 H), 4.53 (ddd, J =
4.8, 1.6, 1.6 Hz, 2 H), 5.22 (d, J = 7.0 Hz, 1 H), 5.28 (ddt, J = 10.6, 1.4, 1.4
Hz, 1 H), 5.47 (ddt, J = 17.3, 1.7, 1.7 Hz, 1 H), 5.54 (dd, J = 10.8, 5.6 Hz, 1
H), 6.01 (ddt, J = 17.2, 10.5, 4.9 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 6.93 (dd,
J = 6.6, 5.4 Hz, 1 H), 7.11 (dd, J = 8.4, 2.1 Hz, 1 H), 7.56 (d, J = 2.1 Hz, 1
H). 13C NMR (CDCl3, 100 MHz): δ = 17.5, 28.3, 30.8, 31.9, 41.0, 46.6, 52.2,
56.7, 69.7, 80.0, 86.4, 112.4, 117.6, 129.7, 131.3, 132.5, 139.4, 155.8,
86.4, 112.4, 117.6, 125.3, 129.8, 131.3, 132.5, 133.8, 139.4, 155.7, 155.9,
169.2, 169.9, 174.6. HRMS (CI) calcd for C34H53IN3O8+ [M+H]+: 758.2872,
found: 758.2886.
(9S,5E)-9-((S)-(N-tert-Butoxycarbonyl-alanyl)-(R)-(O-allyl-3-iodo-N-
methyl-tyrosyl)-glycinyl-oxy)-6-methyldec-5-enoic acid (17dA):
Jones-solution (3 M): 1.0 g CrO3, 2.91 mL H2O, 0.84 mL H2SO4
A 3 M Jones-solution (3.30 mL, 9.90 mmol, 3.0 eq) was added to a solution
of alcohol 16dA (2.51 g, 3.31 mmol, 1.0 eq) in acetone (23 mL). After
complete oxidation (TLC-control, 15 min), the reaction was quenched with
isopropanol and the solvent was evaporated in vacuo. The residue was
diluted with H2O and was extracted with EtOAc. The combined organic
layers were washed with saturated NaCl-solution and dried over Na2SO4.
Purification by column chromatography (silica gel, CH2Cl2/Et2O 9:1, 8:2, 7:3)
gave rise to the desired depsipeptide acid 17dA (1.51 g, 1.96 mmol, 59 %)
as colorless foam. [훼]퐷20 = +24.1 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400
MHz): δ = 0.87 (d, J = 6.9 Hz, 3 H), 1.24 (d, J = 6.2 Hz, 3 H), 1.39 (s, 9 H),
1.56 (s, 3 H), 1.60–1.76 (m, 4 H), 1.95–2.09 (m, 4 H), 2.23 (t, J = 7.8 Hz, 2
H), 2.85 (dd, J = 15.2, 11.6 Hz, 1 H), 2.95 (s, 3 H), 3.42 (dd, J = 15.3, 5.3
Hz, 1 H), 3.64 (dd, J = 17.8, 4.5 Hz, 1 H), 4.27 (dd, J = 17.8, 7.3 Hz, 1 H),
4.53–4.60 (m, 3 H), 4.79 (m, 1 H), 5.04 (t, J = 6.8 Hz, 1 H), 5.28 (ddt, J =
10.6, 1.5, 1.5 Hz, 1 H), 5.44–5.51 (m, 2 H), 5.63 (dd, J = 11.3, 5.3 Hz, 1 H),
6.01 (ddt, J = 17.2, 10.6, 4.8 Hz, 1 H), 6.69 (d, J = 8.5 Hz, 1 H), 7.11 (dd, J
= 8.4, 2.2 Hz, 1 H), 7.17 (dd, J = 7.1, 4.1 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 15.4, 18.0, 20.3, 24.9, 27.0, 28.3, 30.8,
32.3, 33.1, 33.4, 35.6, 41.3, 46.7, 56.8, 69.7, 71.6, 80.3, 86.4, 112.4, 117.6,
124.6, 129.8, 131.4, 132.5, 134.7, 139.5, 155.9, 156.1, 169.4, 170.2, 174.7,
+
155.9, 169.9, 170.1, 174.7. HRMS (CI) calcd for C24H35IN3O7 [M+H]+:
604.1514, found: 604.1485.
(S)-(N-tert-Butoxycarbonyl-alanyl)-(R)-(O-allyl-3-iodo-N-methyl-tyro-
syl)-glycine-(2S,5E)-10-(tert-butyldimethylsiloxy)-5-methyl-dec-5-en-2-
ylester (15dA): Tripeptide 11d (3.53 g, 5.85 mmol, 1.0 eq) was dissolved
in THF/MeOH (3:1, 47 mL) and a solution of LiOH (147 mg, 6.14 mmol, 1.05
eq) in H2O (12 mL) was added at 0 °C. After complete conversion (TLC-
control), the solvent was evaporated in vacuo and the residue was acidified
with 1 M HCl solution to pH 2. The aqueous layer was extracted with EtOAc,
the combined organic layers were dried over Na2SO4 and the solvent was
evaporated in vacuo.
To a solution of the crude acid (1.0 eq) in dry CH2Cl2 (47 mL) alcohol (S)-3
(2.11 g, 7.02 mmol, 1.2 eq), DMAP (72 mg, 0.589 mmol, 0.1 eq) and a
solution of DCC (1.45 g, 7.02 mmol, 1.2 eq) in dry CH2Cl2 (21 mL) were
added. After stirring the mixture overnight at room temperature, the solvent
was evaporated in vacuo and the residue was dissolved in Et2O. The
precipitated urea derivative was filtered off and the solvent was evaporated.
Purification by column chromatography (silica gel, petroleum ether/EtOAc
7:3, 6:4, 1:1) gave rise to depsipeptide 15dA (3.64 g, 4.17 mmol, 71 %) as
pale yellow oil. [훼]2퐷0 = +18.5 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6.3 Hz,
3 H), 1.32–1.42 (m, 11 H), 1.50 (m, 2 H), 1.54–1.61 (m, 4 H), 1.66 (m, 1 H),
1.92–2.01 (m, 4 H), 2.88 (dd, J = 15.2, 11.1 Hz, 1 H), 2.96 (s, 3 H), 3.33 (dd,
J = 15.3, 5.5 Hz, 1 H), 3.59 (t, J = 6.5 Hz, 2 H), 3.78 (dd, J = 18.0, 4.9 Hz, 1
H), 4.13 (dd, J = 17.7, 6.6 Hz, 1 H), 4.43 (dq, J = 6.8, 6.8 Hz, 1 H), 4.54
(ddd, J = 4.6, 1.5, 1.5 Hz, 2 H), 4.91 (m, 1 H), 5.11 (t, J = 7.0 Hz, 1 H), 5.23
(d, J = 7.0 Hz, 1 H), 5.28 (ddt, J = 10.6, 1.4, 1.4 Hz, 1 H), 5.47 (ddt, J = 17.3
Hz, 1.6, 1.6 Hz, 1 H), 5.54 (dd, J = 10.9, 5.6 Hz, 1 H), 6.01 (ddt, J = 17.2,
10.4 Hz, 4.8 Hz, 1 H), 6.69 (d, J = 8.5 Hz, 1 H), 6.89 (dd, J = 7.0, 4.6 Hz, 1
H), 7.11 (dd, J = 8.4, 2.1 Hz, 1 H), 7.56 (d, J = 2.1 Hz, 1 H). 13C NMR (CDCl3,
100 MHz): δ = −5.3, 16.0, 17.5, 18.4, 19.9, 26.0, 26.0, 27.6, 28.3, 30.8, 32.0,
32.5, 34.2, 35.3, 41.3, 46.6, 56.7, 63.2, 69.7, 72.3, 79.9, 86.4, 112.3, 117.6,
125.1, 129.7, 131.3, 132.5, 133.9, 139.4, 155.7, 155.9, 169.0, 169.9, 174.7.
HRMS (CI) calcd for C35H59IN3O6Si+ [M−Boc+2H]+: 772.3212, found:
772.3188.
+
177.0. HRMS (CI) calcd for: C34H51IN3O9 [M+H]+: 772.2664, found:
772.2648.
(6R,9S,19S,15E)-6-(4-Allyloxy-3-iodobenzyl)-7,9,16,19-tetramethyl-1-
oxa-4,7,10-triazacyclononadec-15-en-2,5,8,11-tetraone (18dA):
EDC·HCl (276 mg, 1.44 mmol, 1.1 eq) was added to a solution of cyclization
precursor 17dA (1.01 g, 1.31 mmol, 1.0 eq) and pentafluorophenol (265 mg,
1.44 mmol, 1.1 eq) in dry CH2Cl2 (4.3 mL) at 0 °C. After stirring overnight at
room temperature, the mixture was diluted with EtOAc and washed with
saturated NaHCO3-solution. After extraction of the aqueous layer, the
combined organic layers were dried over Na2SO4 and the solvent was
evaporated. The obtained crude active ester was diluted with CH2Cl2/TFA
(4:1, 13 mL). After complete deprotection (TLC-control, 90 min), the reaction
mixture was diluted with CH2Cl2 (26 mL/mmol) and was slowly added over
75 min to a two-phase-mixture of CHCl3 and saturated NaHCO3-solution
(7:1, 525 mL) at 40 °C. After complete addition, the mixture was heated to
60 °C and stirred vigorously overnight. The aqueous layers was extracted
with CH2Cl2 and the combined organic layers were dried over Na2SO4.
Purification by column chromatography (silica gel, CH2Cl2/Et2O 7:3, 6:4)
gave rise to cyclic depsipeptide 18dA (501 mg, 0.767 mmol, 59 %) as
colorless, shiny foam. [훼]2퐷0 = −7.6° (c = 1.0, CHCl3). Melting range: 59–
64 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.24 (d, J = 6.3 Hz, 3 H), 1.29 (d, J
= 6.5 Hz, 3 H), 1.50–1.57 (m, 4 H), 1.63–1.86 (m, 3 H), 1.91 (m,1 H), 2.02–
2.09 (m, 3 H), 2.19 (m, 2 H), 2.80 (dd, J = 14.4, 7.2 Hz, 1 H), 2.91 (s, 3 H),
3.27 (dd, J = 14.3, 8.5 Hz, 1 H), 3.40 (dd, J = 17.9, 3.3 Hz, 1 H), 4.41 (dd, J
= 17.9, 9.6 Hz, 1 H), 4.55 (ddd, J = 4.7, 1.5, 1.5 Hz, 2 H), 4.82 (dq, J = 6.5,
6.5 Hz, 1 H), 4.94 (m, 1 H), 5.05 (t, J = 7.0 Hz, 1 H), 5.29 (ddt, J = 10.6, 1.5,
1.5 Hz, 1 H), 5.34 (dd, J = 8.3, 7.5 Hz, 1 H), 5.49 (ddt, J = 17.3, 1.6, 1.6 Hz,
1 H), 6.03 (ddt, J = 17.2, 10.4, 4.9 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 6.75
(dd, J = 9.5, 3.1 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 7.13 (dd, J = 8.4, 2.1 Hz,
1 H), 7.62 (d, J = 2.1 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 16.2, 17.5,
19.5, 25.7, 26.3, 30.2, 31.3, 33.0, 34.7, 35.0, 40.8, 45.9, 56.5, 69.7, 71.2,
86.7, 112.3, 117.6, 125.4, 129.9, 131.0, 132.5, 134.4, 139.7, 156.0, 169.8,
(S)-(N-tert-Butoxycarbonyl-alanyl)-(R)-(O-allyl-3-iodo-N-methyl-tyro-
syl)-glycine-(2S,5E)-10-hydroxy-5-methyl-dec-5-ene-2-yl ester (16dA):
To a solution of silyl-protected depsipeptide 15dA (3.53 g, 4.05 mmol, 1.0
eq) in dry THF (4.9 mL) a 1 M TBAF-solution in dry THF (4.90 mL, 4.90
mmol, 1.2 eq) was added. After complete deprotection (TLC-control), the
reaction mixture was diluted with EtOAc, washed with 1 M HCl- and
saturated NaCl-solution and was dried over Na2SO4. Purification by column
chromatography (silica gel, CH2Cl2/Et2O 7:3) gave rise to alcohol 16dA
(2.58 g, 3.41 mmol, 84 %) as pale yellow oil. [훼]2퐷0 = +23.7 (c = 1.0, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 0.94 (d, J = 6.9 Hz, 3 H), 1.23 (d, J = 6.2
Hz, 3 H), 1.33–1.42 (m, 11 H), 1.49–1.63 (m, 6 H), 1.70 (m, 1 H), 1.97–2.05
(m, 4 H), 2.87 (dd, J = 15.2, 11.1 Hz, 1 H), 2.96 (s, 3 H), 3.34 (dd, J = 15.2,
5.5 Hz, 1 H), 3.61 (t, J = 6.6 Hz, 2 H), 3.73 (dd, J= 17.9, 4.9 Hz, 1 H), 4.17
(dd, J = 17.9, 6.7 Hz, 1 H), 4.43 (m, 1 H), 4.54 (ddd, J = 4.8, 1.6, 1.6 Hz, 2
H), 4.86 (m, 1 H), 5.10 (t, J = 6.6 Hz, 1 H), 5.25–5.30 (m, 2 H), 5.47 (ddt, J
= 17.3, 1.7, 1.7 Hz, 1 H), 5.55 (dd, J = 10.9, 5.5 Hz, 1 H), 6.01 (ddt, J= 17.2,
10.5, 4.8 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 7.08–7.12 (m, 2 H), 7.56 (d, J
= 2.1 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 15.7, 17.6, 20.1, 25.7, 27.4,
28.2, 30.8, 32.1, 32.1, 33.6, 35.5, 41.3, 46.6, 56.7, 62.8, 69.7, 71.9, 80.0,
+
170.2, 173.1, 173.6, HRMS (CI) calcd for: C29H40IN3O6 [M]+: 653.1956,
found: 653.1952.
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801391
European Journal of Organic Chemistry
(6R,9S,19S,E)-6-(4-Allyloxy-3-iodo-benzyl)-3-(hydroxy(phenyl)methyl)-
7,9,16,19-tetramethyl-1-oxa-4,7,10-triazacyclononadec-15-en-2,5,8,11-
tetraon (19dA): Under a nitrogen atmosphere DIPA (0.32 mL, 2.30 mmol,
5.1 eq) was dissolved in dry THF (5.5 mL), cooled to –40 °C before 1.6 M
nBuLi-solution in hexane (1.4 mL, 2.25 mmol, 5.0 eq) was slowly added.
The freshly prepared base solution was stirred for 10 min at room
temperature and then cooled to –78 °C. In a second flask macrocycle 18dA
(294 mg, 0.450 mmol, 1.0 eq) was dissolved in dry THF (3.4 mL) and was
also cooled to –78 °C. Afterwards the resulting LDA-solution was slowly
added to the 18dA solution to generate a bright red enolate solution. After
stirring for 5–10 min at –78 °C, a solution of benzaldehyde (91 µL, 0.900
mmol, 2.0 eq) in dry THF (1.8 mL) was added to the enolate. After complete
conversion (TLC-control), the reaction mixture was quenched with 1 M HC
solution at –78 °C and was allowed to warm to room temperature. The
aqueous layer was extracted with EtOAc and the combined organic layer
were dried over Na2SO4. Purification by column chromatography (silica gel,
petroleum ether/EtOAc 8:2, 7:3, 6:4, 1:1, 4:6, 3:7) gave rise to a
diastereomeric mixture of 19dA (200 mg, 0.263 mmol, 58 %), which could
be partially seperated. Three fractions were obtained as colorless foam:
diastereomer 1 (45.6 mg, 0.060 mmol, 13 %), diastereomer 2 (95.8 mg
(0.126 mmol, 28 %) and diastereomer 3 and 4 (7:3, 58.5 mg (0.077 mmol,
17 %). Additionally a mixed fraction (48.4 mg, 15:85) of educt 18dA (0.010
mmol, 2 %) and product 19dA (0.055 mmol, 12 %) was isolated. The
diastereomers 1 and 2 were formed in a 7:3 ratio to the diastereomers 3 and
4. Melting range: 65–69 °C. Diastereomer 1: 1H NMR (CDCl3, 400 MHz): δ
= 1.02 (d, J = 6.9 Hz, 3 H), 1.30 (d, J = 6.1 Hz, 3 H), 1.53 (s, 3 H), 1.63–
1.75 (m, 3 H), 1.89–2.22 (m, 5 H), 2.31 (m, 1 H), 2.39–2.45 (m, 4 H), 2.63
(dd, J = 15.3, 11.1 Hz, 1 H), 3.33 (dd, J = 15.3, 5.7 Hz, 1 H), 4.37 (m, 1 H),
4.52 (ddd, J = 4.7, 1.2, 1.2 Hz, 2 H), 4.76 (m, 1 H), 4.98 (t, J = 5.0 Hz, 1 H),
5.05 (dd, J = 9.4, 2.8 Hz, 1 H), 5.27 (ddt, J = 10.6, 1.4, 1.4 Hz, 1 H), 5.46
(ddt, J = 17.3, 1.6, 1.6 Hz, 1 H), 5.50–5.58 (m, 3 H), 6.01 (ddt, J = 17.2, 10.4,
4.8 Hz, 1 H), 6.10 (d, J = 5.0 Hz, 1 H), 6.64 (d, J = 8.5 Hz, 1 H), 6.77 (d, J =
9.3 Hz, 1 H), 7.03 (dd, J = 8.4, 2.0 Hz, 1 H), 7.21 (m, 1 H), 7.30 (m, 2 H),
7.40 (d, J = 7.6 Hz, 2 H), 7.46 (d, J = 2.0 Hz, 1 H). 13C NMR (CDCl3, 100
MHz): δ = 15.2, 16.0, 20.3, 23.1, 27.5, 30.2, 31.6, 33.0, 34.7, 35.3, 46.0,
56.3, 58.7, 69.7, 71.7, 72.8, 86.2, 112.3, 117.6, 124.7, 125.6, 127.1, 128.1,
129.6, 131.4, 132.5, 134.4, 139.2, 140.8, 155.8, 169.4, 170.0, 173.6, 175.4.
Diastereomer 2: 1H NMR (CDCl3, 400 MHz): δ = 1.00 (d, J = 6.8 Hz, 3 H),
1.24 (d, J = 6.2 Hz, 3 H), 1.51 (s, 3 H), 1.53–1.72 (m, 3 H), 1.83–2.17 (m, 6
H), 2.33–2.41 (m, 4 H), 2.65 (dd, J = 15.5, 11.6 Hz, 1 H), 3.36 (dd, J = 15.5,
5.3 Hz, 1 H), 4.41 (m, 1 H), 4.52 (ddd, J = 4.8, 1.2, 1.2 Hz, 2 H), 4.72 (d, J
= 3.1 Hz, 1 H), 4.81 (m, 1 H), 4.94 (t, J = 6.4 Hz, 1 H), 4.97 (dd, J = 8.2, 6.6
Hz, 1 H), 5.25–5.29 (m, 2 H), 5.45 (ddt, J = 17.2, 1.6, 1.6 Hz, 1 H), 5.55 (dd,
J = 11.5, 5.3 Hz, 1 H), 5.95–6.05 (m, 2 H), 6.65 (d, J = 8.4 Hz, 1 H), 7.05
(dd, J = 8.4, 2.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.25 (m, 1 H), 7.32 (m,
2 H), 7.39 (d, J = 7.1 Hz, 2 H), 7.47 (d, J = 2.0 Hz, 1 H). 13C NMR (CDCl3,
100 MHz): δ = 15.3, 16.4, 20.1, 23.6, 27.5, 30.1, 31.6, 32.9, 34.8, 35.7, 45.6,
56.3, 57.8, 69.7, 71.6, 74.2, 86.3, 112.3, 117.6, 125.3, 127.2, 128.0, 128.2,
129.5, 131.3, 132.5, 133.9, 139.1, 139.7, 155.8, 169.7, 170.3, 174.0, 174.2.
125.6, 125.7, 126.1, 128.0, 128.0, 128.2, 128.3, 129.6, 129.8, 130.8, 130.9,
132.5, 132.5, 134.0, 134.4, 139.1, 139.4, 139.5, 140.1, 155.8, 156.0, 169.3,
169.6, 169.8, 170.0, 172.9, 173.2, 173.5, 173.5. HRMS (CI) calcd for:
C36H46IN3O7+ [M]+: 759.2375, found: 759.2364. Elemental analysis calcd for
C36H46IN3O7 (757.65): C 56.92, H 6.10, N 5.53, found: C 56.92, H 5.91, N
5.34.
(6R,9S,19S,E)-6-(4-Allyloxy-3-iodo-benzyl)-3-benzoyl-7,9,16,19-tetra-
methyl-1-oxa-4,7,10-tri-azacyclononadec-15-en-2,5,8,11-tetraon
(20dA): The aldol product 19dA (183 mg, 241 µmol, 1.0 eq) was dissolved
in dry CH2Cl2 (4.8 mL) and Dess Martin periodinane (123 mg, 289 µmol, 1.2
eq) was slowly added at room temperature. After complete oxidation (TLC-
control, 75 min), the reaction mixture was diluted with Et2O, washed with a
mixture of 1 M NaOH- and saturated Na2S2O3- as well as saturated NaCl-
solution. The aqueous layer was extracted with EtOAc and the combined
organic layers were dried over Na2SO4. The solvent was evaporated in
vacuo and the residue was purified by column chromatography (silica gel,
CH2Cl2/Et2O 9:1, 8:2). The desired ketone 20dA (149 mg, 197 µmol, 82 %)
was obtained as colorless foam. The diastereomers were formed in a 94:6
ratio (in CDCl3). [훼]2퐷0 = +8.7 (c = 1.0, CHCl3). Melting range: 60–65 °C.
Major Diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.19 (d, J = 6.3 Hz, 3
H), 1.32 (d, J = 6.5 Hz, 3 H), 1.35–1.53 (m, 6 H), 1.61–1.72 (m, 3 H), 1.98
(m, 2 H), 2.18 (m, 2 H), 2.83 (dd, J = 14.4, 7.4 Hz, 1 H), 2.96 (s, 3 H), 3.26
(dd, J = 14.4, 8.4 Hz, 1 H), 4.54 (ddd, J = 4.8, 1.1, 1.1 Hz, 2 H), 4.80 (t, J =
7.3 Hz, 1 H), 4.85 (m, 1 H), 4.97 (dq, J = 8.5, 6.5 Hz, 1 H), 5.28 (ddt, J =
10.8, 1.5, 1.5 Hz, 1 H), 5.40–5.50 (m, 2 H, 5-H), 6.02 (ddt, J = 17.1, 10.5,
4.8 Hz, 1 H), 6.11 (d, J = 8.6 Hz, 1 H), 6.53 (d, J = 8.3 Hz, 1 H), 6.68 (d, J =
8.5 Hz, 1 H), 7.12 (dd, J = 8.4, 2.1 Hz, 1 H), 7.46–7.52 (m, 3 H), 7.62–7.66
(m, 2 H), 8.06 (d, J = 7.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 15.5,
18.0, 20.0, 25.8, 26.5, 30.3, 31.2, 32.4, 34.5, 35.3, 45.3, 56.2, 57.6, 69.7,
72.0, 86.6, 112.4, 117.6, 125.7, 128.8, 129.7, 129.8, 131.0, 132.5, 133.7,
134.0, 134.6, 139.8, 156.0, 166.2, 169.5, 172.9, 174.1, 191.0. Minor
diastereomer (selected signals): 1H NMR (CDCl3, 400 MHz): δ = 1.09 (d, J
= 6.8 Hz, 3 H), 1.17 (d, J = 6.4 Hz, 3 H), 2.95 (s, 3 H), 3.32 (dd, J = 15.4,
6.2 Hz, 1 H), 4.48 (ddd, J = 5.4, 1.6, 1.6 Hz, 2 H), 5.09 (t, J = 6.8 Hz, 1 H),
5.38 (ddt, J = 17.3, 1.5, 1.5 Hz, 1 H), 5.60 (dd, J = 10.4, 6.2 Hz, 1 H), 5.94
(d, J = 6.8 Hz, 1 H), 6.36 (d, J = 7.1 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 7.09
(dd, J = 8.5, 2.2 Hz, 1 H). The 13C signals of the minor diastereomer are not
visible in the background noise of the spectrum. LC-MS: Luna, 0.6 mL/min,
254 nm, ACN/H2O 7:3 tR = 2.98, 3.61 min. HRMS (CI) calcd for:
C36H45IN3O7+ [M+H]+: 758.2297, found: 758.2269. Elemental analysis calcd
for C36H44IN3O7 (757.65): C 57.07, H 5.85, N 5.55, found: C 57.27, H 5.73,
N 5.40.
(6R,9S,19S,E)-3-Benzoyl-6-(3-iodo-4-hydroxybenzyl)-7,9,16,19-tetra-
methyl-1-oxa-4,7,10-triaza-cyclononadec-15-en-2,5,8,11-tetraon
(22dA): The protected ketone 20dA (50 mg, 66.0 µmol, 1.0 eq) was
dissolved in dry MeOH (1.0 mL). Quinaldic acid (1.1 mg, 6.6 µmol, 0.1 eq)
as well as Ru-catalyst (2.9 mg, 6.6 µmol, 0.1 eq) were added at room
temperature. After complete deprotection (LC-MS-control, 1 h 45 min),
DMSO (23 µL, 330 µmol) was added and stirred overnight. The solvent was
evaporated in vacuo and purified by column chromatography (silica gel,
CH2Cl2/Et2O 95:5, 9:1, 8:2, 7:3). Deprotected ketone 22dA (44.8 mg, 62.4
µmol, 95 %) was obtained as colorless solid. The diastereomers were
formed in a 94:6 ratio (in CDCl3). Major diastereomer: 1H NMR (CDCl3, 400
MHz): δ = 1.18 (d, J = 6.3 Hz, 3 H), 1.30 (d, J = 6.5 Hz, 3 H), 1.34–1.49 (m,
5 H), 1.60–1.67 (m, 3 H), 1.98 (m, 2 H), 2.19 (m, 2 H), 2.82 (dd, J = 14.4,
7.5 Hz, 1 H), 2.96 (s, 3 H), 3.24 (dd, J = 14.4, 8.3 Hz, 1 H), 4.78 (t, J = 7.1
Hz, 1 H), 4.83 (m, 1 H), 4.97 (m, 1 H), 5.45 (dd, J = 8.0, 7.3 Hz, 1 H), 6.10
(d, J = 8.5 Hz, 1 H), 6.53 (bs, 1 H), 6.59 (d, J = 8.3 Hz, 1 H), 6.84 (d, J = 8.3
Hz, 1 H), 7.06 (dd, J = 8.3, 1.9 Hz, 1 H), 7.48–7.51 (m, 4 H), 7.63 (m, 1 H),
8.06 (d, J = 7.5 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 15.5, 17.9, 20.0,
25.8, 26.5, 30.4, 31.2, 32.3, 34.5, 35.3, 45.3, 56.3, 57.6, 72.0, 85.2, 115.0,
125.7, 128.8, 129.7, 130.3, 130.5, 133.7, 134.0, 134.7, 138.6, 154.2, 166.1,
1
Diastereomeres 3 und 4: H NMR (CDCl3, 400 MHz): δ = 1.09 (d, J = 6.3
Hz, 1.0 H), 1.17 (d, J = 6.5 Hz, 1.0 H), 1.25 (d, J = 6.4 Hz, 2.0 H), 1.26 (d, J
= 6.2 Hz, 2.0 H), 1.53 (s, 1.0 H), 1.55 (s, 2.0 H), 1.57–2.26 (m, 10 H), 2.70
(dd, J = 14.7, 8.1 Hz, 0.7 H), 2.76–2.81 (m, 3.3 H), 3.03 (dd, J = 14.7, 7.8
Hz, 0.7 H), 3.14 (dd, J = 14.7, 7.7 Hz, 0.3 H), 3.63 (d, J = 2.7, 0.7 H), 3.75
(d, J = 4.8 Hz, 0.3 H), 4.54 (m, 2.0 H), 4.62 (dd, J = 9.4, 1.8 Hz, 0.7 H),
4.72–4.84 (m, 1.6 H,), 4.94–5.04 (m, 1.0 H), 5.09 (t, J = 6.8 Hz, 0.7 H), 5.14
(dd, J = 4.9, 3.5 Hz, 0.3 H), 5.25–5.36 (m, 2.7 H), 5.49 (m, 1.0 H), 6.03 (m,
1 H), 6.45 (d, J = 7.9 Hz, 0.3 H), 6.58 (d, J = 8.5 Hz, 0.7 H), 6.68 (d, J = 8.5
Hz, 0.3 H), 6.83 (d, J = 7.9 Hz, 0.7 H), 6.91 (dd, J = 8.4, 2.0 Hz, 0.4 H), 7.02
(d, J = 8.7 Hz, 0.3 H), 7.05–7.07 (m, 1.0 H), 7.25–7.36 (m, 5 H), 7.46 (d, J
= 2.0 Hz, 0.7 H), 7.55 (d, J = 2.0 Hz, 0.3 H). 13C NMR (CDCl3, 100 MHz): δ
= 15.9, 16.1, 17.5, 17.7, 19.2, 19.9, 25.2, 25.7, 26.2, 26.4, 30.0, 30.1, 30.8,
31.1, 32.7, 32.7, 34.8, 34.8, 34.9, 45.4, 45.7, 56.0, 56.1, 57.9, 58.4, 69.7,
69.7, 71.0, 71.8, 72.9, 73.6, 86.5, 86.6, 112.2, 112.3, 117.5, 117.6, 125.2,
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801391
European Journal of Organic Chemistry
169.5, 173.2, 174.1, 191.0. Minor diastereomer (selected signals): 1H NMR
(CDCl3, 400 MHz): δ = 1.03 (d, J = 6.8 Hz, 3 H), 1.17 (d, J = 6.4 Hz, 3 H),
2.38 (m, 2 H), 3.33 (dd, J = 15.2, 6.5 Hz, 1 H), 5.06 (t, J = 7.1 Hz, 1 H), 5.61
(dd, J = 10.5, 6.0 Hz, 1 H), 5.98 (d, J = 7.0 Hz, 1 H), 6.47 (d, J = 7.0 Hz, 1
H), 7.02 (dd, J = 8.5, 1.9 Hz, 1 H), 7.59 (m, 1 H), 8.00 (d, J = 7.4 Hz, 2 H).
The 13C signals of the minor diastereomer are not visible in the background
noise of the spectrum. LC-MS: Luna, 0.6 mL/min, 254 nm, ACN/H2O 7:3, tR
deprotection (LC-MS-control, 2 h), DMSO (23 µl, 330 µmol) was added and
stirred over night. The solvent was evaporated in vacuo and purified by
column chromatography (silica gel, CH2Cl2/Et2O 7:3). Deprotected
cyclopeptide 29cA (36.6 mg, 64.6 µmol, 98 %) was obtained as colorless
solid. [훼]2퐷0 = +2.7 (c = 1.00, CHCl3). Melting range: 75–79 °C. 1H NMR
(CDCl3, 400 MHz): δ = 1.23 (d, J = 6.3 Hz, 3 H), 1.28 (d, J = 6.5 Hz, 3 H),
1.50–1.56 (m, 4 H), 1.62–1.84 (m, 3 H), 1.90 (m, 1 H), 2.01–2.10 (m, 3 H),
2.19 (m, 2 H), 2.80 (dd, J = 14.4, 7.2 Hz, 1 H), 2.91 (s, 3 H), 3.28 (dd, J =
14.3, 8.5 Hz, 1 H), 3.40 (dd, J = 17.9, 3.2 Hz, 1 H), 4.40 (dd, J = 17.9, 9.6
Hz, 1 H), 4.82 (m, 1 H), 4.93 (m, 1 H), 5.04 (t, J = 6.9 Hz, 1 H), 5.33 (dd, J
= 8.7, 7.1 Hz, 1 H), 6.29 (bs, 1 H), 6.77 (dd, J = 9.5, 3.0 Hz, 1 H), 6.90 (d, J
= 8.4 Hz, 1 H), 6.92 (d, J = 7.9 Hz, 1 H), 7.04 (dd, J = 8.3, 1.9 Hz, 1 H), 7.30
(d, J = 1.8 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 16.2, 17.4, 19.6, 25.7,
26.2, 30.2, 31.5, 32.9, 34.7, 35.0, 40.8, 45.9, 56.6, 71.3, 110.1, 116.2, 125.3,
129.5, 130.0, 132.4, 134.4, 151.4, 169.8, 170.2, 173.3, 173.6. LC-MS: Luna,
0.6 mL/min, 254 nm, ACN/H2O 7:3, tR = 1.44 min. HRMS (CI) calcd for:
C26H38BrN3O6+ [M+2H]+: 567.1938, found: 567.1955.
+
= 2.24, 2.67 min. HRMS (CI) calcd for: C33H40IN3O7 [M+H]+: 717.1905,
found: 717.1871.
(6R,9S,19S,15E)-6-(4-Allyloxy-3-bromo-benzyl)-3-((7-(diethylamino)-2-
oxo-2H-chrom-en-4-yl)(hydroxy)methyl)-7,9,16,19-tetramethyl-1-oxa-
4,7,10-triazacyclonona-dec-15-en-2,5,8, 11-tetraon (27cA): Under
a
nitrogen atmosphere DIPA (0.13 mL, 928 µmol) was dissolved in dry THF
(1.4 mL), cooled to –40 °C before 1.6 M nBuLi-solution in hexane (0.55 mL,
875 µmol) was slowly added. The freshly prepared base solution was stirred
for 10 min at room temperature and then cooled to –78 °C. In a second flask
dried zinc chloride (31.1 mg, 228 µmol) and macrocycle 18cA[19] (106 mg,
175 µmol) were dissolved in dry THF (1.7 mL), also cooled to –78 °C and
slowly added to the freshly prepared LDA-solution. After stirring the bright
red enolate solution for 30 min at –78 °C for transmetallation, a solution of
7-(diethylamino)-2-oxo-2H-chromen-4-carbaldehyde[41c] (64.5 mg, 263
µmol) in dry THF (0.5 mL) was added. After complete conversion (TLC-
control), the reaction mixture was diluted with Et2O, hydrolyzed with 1 M
NH4Cl-solution and allowed to warm up to room temperature. The aqueous
layer was extracted with EtOAc and the combined organic layers were dried
over Na2SO4. After evaporation of the solvent, the residue was separated
by preparative HPLC (RP, Reprosil, ACN/H2O 7:3) in two fractions. Aldol
product 27cA (56.8 mg, 66.7 µmol, 38 %) was obtained as a yellow solid
and the corresponding vinyl ether (6.0 mg, 7.0 µmol, 4 %) was isolated.
Since the signals of two diastereomers are overlapping in the NMR-
spectrum, there are three sets of signals in a 6:2:2 ratio. Mixture of
diastereomers: 1H NMR (CDCl3, 400 MHz): δ = 1.02 (d, J = 6.3 Hz, 1.8 H),
1.08 (d, J = 6.9 Hz, 0.6 H), 1.16–1.25 (m, 9 H), 1.33 (d, J = 6.3 Hz, 0.6 H),
1.43 (m, 0.6 H), 1.48 (s, 0.6 H), 1.56 (s, 2.4 H), 1.59–1.86 (m, 3.4 H), 1.88–
2.36 (m, 6 H), 2.75–2.95 (m, 4 H), 3.07 (dd, J = 15.2, 7.0 Hz, 0.3 H), 3.27
(dd, J = 15.0, 6.9 Hz, 0.7 H), 3.33–3.43 (m, 4 H), 4.25 (d, J = 4.1 Hz, 0.5 H),
4.41 (d, J = 3.0 Hz, 0.2 H), 4.55–4.59 (m, 2.2 H), 4.75–4.94 (m, 2.5 H), 5.00–
5.14 (m, 1.3 H), 5.26–5.31 (m, 2.1 H), 5.37–5.52 (m, 1.8 H), 5.61 (dd, J =
11.1, 5.6 Hz, 0.2 H), 5.70 (m, 0.2 H), 6.03 (m, 1.0 H), 6.28 (d, J = 0.9 Hz,
0.6 H), 6.35–6.37 (m, 0.6 H), 6.44 (d, J = 2.5 Hz, 0.2 H), 6.50 (d, J = 2.5 Hz,
0.8 H), 6.58 (dd, J = 9.1, 2.5 Hz, 0.2 H), 6.66 (dd, J = 9.1, 2.6 Hz, 0.8 H),
6.75–6.83 (m, 1.8 H), 6.95 (dd, J = 8.5, 2.1 Hz, 0.2 H), 7.05 (dd, J = 8.4, 2.2
Hz, 0.8 H), 7.09 (d, J = 9.6 Hz, 0.3 H), 7.26 (m, 0.2 H), 7.32 (d, J = 2.1 Hz,
0.2 H), 7.34 (d, J = 2.1 Hz, 0.6 H), 7.38–7.40 (m, 0.4 H), 7.46 (d, J = 8.7 Hz,
0.5 H), 7.58 (d, J = 9.1 Hz, 0.6 H), 7.82 (d, J = 9.1 Hz, 0.2 H). 13C NMR
(CDCl3, 100 MHz): δ = 12.5, 15.3, 15.8, 16.2, 16.3, 17.7, 17.7, 19.0, 20.0,
20.2, 23.6, 25.3, 25.6, 26.3, 26.4, 27.0, 30.2, 30.2, 30.6, 30.9, 31.2, 32.7,
32.8, 31.1, 34.8, 34.8, 35.0, 35.2, 44.7, 45.4, 45.6, 46.1, 53.4, 55.7, 55.8,
56.2, 56.3, 56.7, 68.4, 69.6, 69.7, 70.5, 70.9, 71.5, 72.2, 72.5, 97.8, 97.9,
98.0, 105.4, 105.9, 106.2, 106.8, 108.0, 108.8, 109.0, 111.9, 112.0, 112.2,
113.6, 113.7, 117.6, 117.7, 117.8, 123.8, 124.7, 125.1, 125.2, 125.3, 125.9,
128.0, 128.5, 130.1, 130.3, 130.5, 132.5, 132.7, 133.1 133.4, 133.5, 133.8,
134.2, 134.6, 150.3, 150.4, 150.6, 153.5, 153.6, 153.7, 153.8, 154.0, 154.3,
156.2, 156.4, 162.3, 162.4, 162.5, 167.7, 168.2, 169.2, 169.6, 169.9, 170.0,
173.1, 173.3, 174.0, 174.2, 174.6, 175.0. LC-MS: Luna, 0.6 mL/min, 254
nm, ACN/H2O 7:3, tR = 5.11 min. HRMS (CI) calcd for: C43H55BrN4O9+ [M]+:
850.3147, found: 850.3158.
(6R,9S,19S,15E)-6-(3-Iodo-4-hydroxybenzyl)-7,9,16,19-tetramethyl-1-
oxa-4,7,10-triaza-cyclononadec-15-en-2,5,8,11-tetraon (29dA): To the
allyl ether 18dA (35.0 mg, 53.6 µmol, 1.0 eq) dissolved in dry MeOH (0.8
mL) quinaldic acid (1.0 mg, 5.90 µmol, 0.11 eq) as well as Ru-catalyst (2.3
mg, 5.36 µmol, 0.1 eq) were added at room temperature. After complete
deprotection (LC-MS-control, 1 h), DMSO (19 µl, 268 µmol) was added and
stirred over night. The solvent was evaporated in vacuo and purified by
column chromatography (silica gel, CH2Cl2/Et2O 6:4, 1:1). Deprotected
cyclopeptide 29dA (32.9 mg, 53.6 µmol, 99 %) was obtained as colorless
solid. [훼]2퐷0 = –10.2 (c = 1.00, CHCl3). Melting range: 79–83 °C. 1H NMR
(CDCl3, 400 MHz): δ = 1.23 (d, J = 6.3 Hz, 3 H), 1.27 (d, J = 6.5 Hz, 3 H),
1.50–1.56 (m, 4 H), 1.63–1.84 (m, 3 H), 1.91 (m,1 H), 2.01–2.10 (m, 3 H),
2.20 (m, 2 H), 2.80 (dd, J = 14.4, 7.4 Hz, 1 H), 2.91 (s, 3 H), 3.26 (dd, J =
14.4, 8.4 Hz, 1 H), 3.42 (dd, J = 17.9, 3.3 Hz, 1 H), 4.40 (dd, J = 17.9, 9.5
Hz, 1 H), 4.81 (dq, J = 6.5, 6.5 Hz, 1 H), 4.93 (m, 1 H), 5.05 (t, J = 6.9 Hz, 1
H), 5.34 (dd, J = 8.5, 7.3 Hz, 1 H), 6.52 (s, 1 H), 6.78 (dd, J = 9.5, 3.2 Hz, 1
H), 6.86 (d, J = 8.3 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 7.06 (dd, J = 8.3, 2.0
Hz, 1 H), 7.50 (d, J = 2.0 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 16.2,
17.4, 19.6, 25.6, 26.2, 30.3, 31.3, 33.0, 34.7, 35.0, 40.8, 45.9, 56.6, 71.3,
85.2, 115.1, 125.3, 130.4, 130.5, 134.4, 138.6, 154.2, 169.8, 170.1, 173.4,
173.6. LC-MS: Luna, 0.6 mL/min, 254 nm, ACN/H2O 7:3, tR = 1.50 min.
HRMS (CI) calcd for: C26H36IN3O6+ [M]+: 613.1643, found: 613.1645.
Experimental procedures, spectroscopic data, and copies of 1H
and 13C NMR spectra are available in the Supporting Information.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(FOR 1406, Ka 880/11-2) is gratefully acknowledged. The
authors would also like to thank Viktoria Schmitt for technical
assistance with cytotoxicity assays.
Keywords: actin, cyclodepsipeptides, late stage
modifications, natural products, peptide modifications
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12
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10.1002/ejoc.201801391
European Journal of Organic Chemistry
Entry for the Table of Contents
Natural product modification
Sarah Kappler, Lisa Karmann,
Cynthia Prudel, Jennifer Herrmann,
Giulia Caddeu, Rolf Müller, Angelika
M. Vollmar, Stefan Zahler, Uli
Kazmaier
Page No. – Page No.
Synthesis and biological evaluation of
(modified) miuraenamides
Late stage peptide modification allows
the synthesis of a library of (simplified)
miuraenamide derivatives with different
halogenation and substitution pattern.
SAR studies indicate, that bromination of
the central tyrosine is essential for good
biological activity, while the C-terminal
side chain can be removed.
Keywords: actin, cyclodepsipeptides,
late stage modifications, natural products,
peptide modifications
13
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