Synthesis and Biological Evaluation of Dichlorinated Chondramide Derivatives

Article abstract of DOI:10.1002/ejoc.201500369

Straightforward synthetic protocols for the synthesis of new ethyl-substituted dichlorinated chondramides with different methyl-substitution patterns in the polyketide fragment have been developed. The methyl groups at the ?-position can be removed comple

Full text of DOI:10.1002/ejoc.201500369

FULL PAPER
DOI: 10.1002/ejoc.201500369
Synthesis and Biological Evaluation of Dichlorinated Chondramide Derivatives
[a]
[a]
Dominic Becker and Uli Kazmaier*
Keywords: Total synthesis / Natural products / Peptides / Macrocycles / Structure–activity relationships / Cytotoxicity
Straightforward synthetic protocols for the synthesis of new
ethyl-substituted dichlorinated chondramides with different
methyl-substitution patterns in the polyketide fragment have
been developed. The methyl groups at the ε-position can be
removed completely without a significant influence on the
biological activity. In contrast, after removal of the α-methyl
group, a significant drop in activity is observed. This is also
observed if the configuration of the α-methyl group is in-
verted.
Introduction
Chondramides A–D, isolated by Höfle and Reichenbach
from terrestrial myxobacteria in 1995,[1] belong to a very
interesting class of cyclodepsipeptides. They are structurally
closely related to the highly cytotoxic jasplakinolide
[
2]
[3]
(
jaspamide) and geodeamolide (Figure 1), which were
isolated from sponges in the 1980s. Many of these
cyclic peptides show interesting biological properties, and
are therefore interesting candidates for the development of
drugs. They can stabilize the actin cytoskeleton,[5] thereby
[
4]
[
6]
altering, for example, anaphase chromosome movements,
and inducing apoptosis in a wide range of cancer cell
[
7]
lines. Recently, the miuraenamides, isolated from marine
[
8]
myxobacteria, joined this class of compounds, all of
which have a high affinity for actin.[ Biosynthetically, these
peptides are synthesized on multienzyme complexes con-
9]
sisting of polyketide synthase (PKS) modules and nonribo-
somal peptide synthetase (NRPS) modules.[
10]
While
jasplakinolide and geodeamolide are obviously produced by
the same (or at least very similar) PKS, variations are found
in the central part of the tripeptide fragment. On the other Figure 1. Actin-stabilizing cyclodepsipeptides.
hand, jasplakinolide and the chondramides have almost the
same peptide fragment, but differ slightly in the polyketide
unit.
Interestingly, in most derivatives, the central aromatic
4
chondramide A series (R = OCH ; A4), but so far not
3
4
in the chondramide C series (R = H). Interestingly, some
derivatives contain an ethyl substituent (R ) at the end of
3
amino acid is halogenated, even in the “terrestrial”
1
the hydroxycarboxylic acid (C1), which clearly indicates
that the biosynthesis of these compounds starts with the
incorporation of a propionyl-CoA and not as usual with
acetyl-CoA.
Interestingly, chondramide C has a slightly higher cyto-
toxicity than chondramides A and B, which shows that the
α-methoxy group on the tyrosine is not essential for a high
biological activity. Therefore, the structurally simpler
chondramide C should be a suitable candidate for the devel-
opment of actin-binding anticancer drugs. Very recently, we
showed that dichlorination significantly increases the cyto-
toxicity of chondramide derivatives. Even when the methyl
chondramides (Figure 1, R = Cl, at least in some deriva-
tives). Very recently, Müller et al. isolated a set of new
chondramide A and C derivatives (Figure 1), containing a
halogenated β-tyrosine at the C-terminus of the tripeptide
2
[11]
(
A3; R = Cl), and with excellent biological activities.
Doubly chlorinated derivatives could also be found in the
[
a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
E-mail: u.kazmaier@mx.uni-saarland.de
http://www.uni-saarland.de/lehrstuhl/kazmaier.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500369.
4198
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Dichlorinated Chondramide Derivatives
substituents in the polyketide fragment were removed com- depsipeptide the undesired stereoisomer could easily be re-
pletely, the biological activity could be retained by introduc- moved by flash chromatography. Therefore, (R)-2 was sub-
1
2
tion of a second chlorine atom into the β-tyrosine (R = R
jected to ozonolysis, which, after a reductive work-up, gave
rise to the corresponding aldehyde. This was directly (with-
[
12]
=
Cl).
These results were quite surprising, since structure– out further purification) transformed into allyl alcohol 3 by
[
13]
activity relationship (SAR) studies by Kalesse et al. and Grignard addition. The newly formed stereogenic centre
by Waldmann and Arndt et al.[ using nonhalogenated was obtained as a 1:1 mixture in good overall yield. For
chondramide C derivatives clearly indicate that the methyl the synthesis of the simplified hydroxy acid derivatives, this
groups in the polyketide fragment have an influence on the diastereomeric mixture was not separated, but directly sub-
conformation, and as a result of that, also on the biological jected to the next step, a Johnson ortho ester rearrange-
activity of the chondramides. Maier et al. investigated the ment.[18] α-Unsubstituted ester 4a was obtained from the
influence of several chondramide A derivatives bearing dif- orthoacetate, while α-methylated ester 4b was formed in the
14]
[
15]
ferent substituents in the para position of the β-tyrosine.
reaction with the corresponding orthopropionate. Both
No significant influence was observed if the OH function- esters were obtained in excellent yield.
ality was replaced by other small substituents (electron-do-
nating or -withdrawing). Obviously, this position is suitable
for modifications. To the best of our knowledge, (doubly)
halogenated derivatives have not been investigated so far,
except for our simplified chondramides described re-
[
12]
cently. Because of our ongoing interest in the synthesis of
peptidic natural products, especially those with anticancer
[
16]
activity,
we decided to also investigate the influence of
the substitution pattern on the cytotoxicity of dichlorinated
chondramides, focussing on the new ethyl-substituted deriv-
atives. We were interested in seeing whether we could re-
move some of the methyl groups individually, or whether
we could replace them by other functionalities to allow the
subsequent introduction of labels (fluorescence, photoaffin-
ity, etc.) for biological studies. The trans double bond of
the polyketide fragment should be introduced by a Claisen
rearrangement of a suitable acylated allyl alcohol according
to Scheme 1.
Scheme 2. Synthesis of simplified ω-hydroxy esters 5. (a) Allylmag-
nesium bromide (0.9 equiv.), Et O, –78 °C to room temp., 16 h;
b) EtCHO, –78 °C, 3 h; (c) TBSCl (TBS = tert-butyldimethylsilyl),
imidazole, DMF, 0 °C to r.t., 16 h; (d) 1. O , CH Cl , –78 °C;
. PPh , –78 °C, 1 h; (e) 2-propenylmagnesium bromide, THF, 0 °C
to r.t., 16 h; (f) RCH C(OEt) , EtCOOH, 136 °C, 16 h; (g) NaOH,
EtOH; (h) allyl bromide, K CO , DMF, r.t., 16 h; (i) AcOH, THF/
O, 50 °C, 2 h.
2
(
3
2
2
2
3
2
3
2
3
H
2
Ester 4b was used further as a diastereomeric mixture,
Scheme 1. Retrosynthesis of the polyketide fragment.
and the diastereomers were easily separated later in the cy-
clic peptide. This allows the influence of the α-methyl group
on the biological activity of the chondramide derivatives to
be determined. In principle, after desilylation, esters 4 can
be coupled to the corresponding peptide. But before the
Results and Discussion
We started our investigations with the simplest poly- cyclization can take place, the ethyl ester has to be removed,
ketide fragment containing only the ethyl substituent at C- and this caused problems in several cases, since we were
7
(Scheme 2). To introduce this (R)-configured stereogenic unable to cleave the ethyl ester selectively in presence of the
centre, we decided to use an enantioselective allylation β-tyrosine ester. Therefore, we decided to change the ester
using Brown’s B-allyldiisopinocampheylborane (Ipc B- functionality into an allyl ester, which can be removed by
2
all).[ This reagent can easily be prepared from commer- Pd catalysis. Subsequent desilylation gave hydroxy esters 5
17]
cially
available
B-methoxydiisopinocampheylborane in excellent overall yields.
(
Ipc B-OMe) and allylmagnesium bromide. Our best results
The synthesis of the more complex polyketide with all
2
were obtained when the Grignard reagent was used in a the substituents in place started with an aldol reaction using
slight shortfall (0.9 equiv.). In this case, an enantiomeric ra- Evans’s method (Scheme 3). The boron enolate of chirally
tio of 92:8 [(R)/(S)] could be obtained with an acceptable modified propionamide was treated with propionaldehyde
yield. Subsequent silylation of (R)-1 gave access to chiral to give syn-aldol product 6 in excellent yield and with excel-
[
19]
silyl ether (R)-2 (84% ee), which could be purified by micro- lent stereoselectivity. Only one stereoisomer could be de-
distillation. We did not try to increase the enantiomeric pu- tected by HPLC, which can be explained by a strong prefer-
rity of the alcohol (or the silyl ester), because in the cyclo- ence for one of the stereoisomeric cyclic transition states. In
Eur. J. Org. Chem. 2015, 4198–4213
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4199

D. Becker, U. Kazmaier
FULL PAPER
the presence of the Lewis acid Me Al, 6 could be directly
Weinreb amide 7 was directly converted into silyl-pro-
3
converted into the corresponding enantiopure Weinreb tected derivative 10, which then was then subjected to the
amide (i.e., 7) in excellent yield.[ It is worth mentioning Grignard addition to give protected ketone 11. Since the
that an alternative route under basic conditions using imid- Evans protocol is not applicable to protected hydroxy
azole and N,O-dimethylamine·HCl resulted in a partial epi- ketones, we investigated the reduction of the ketone with
merization of 6. Grignard addition of 2-propenylmagne- a wide range of other reducing reagents. No reaction was
sium bromide to 7 gave the α,β-unsaturated ketone 8, which observed using N-selectride or DIBAL-H (diisobutylalu-
had to be reduced to the anti,syn-configured diol. After se- minium hydride), but NaBH4 gave rise to a 6:1 dia-
lective protection of the secondary alcohol, this (S)-config- stereomeric mixture in around 55% yield, almost indepen-
ured allylic alcohol should allow the stereoselective intro- dent of the reaction temperature and the amount of reduc-
duction of the α-methyl group through an Ireland–Claisen ing agent used. By far the best results were obtained under
20]
[
22]
rearrangement. Because of the required anti orientation of Luche conditions using NaBH /CeCl at –78 °C. The re-
4
3
the two OH functionalities, we decided to apply Evans’s quired monoprotected diol (i.e., 12) was obtained in good
protocol for OH-directed ketone reduction using triacet- yield with a diastereomeric ratio of 10:1. Interestingly, the
[
21]
oxyborohydride. Coordination of the borohydride to the diastereomer formed had the opposite configuration to that
–
backward-oriented OH group of 8 should allow reduction formed in the (AcO) BH reduction (i.e., 9). Enantiomer-
3
of the ketone from the back side, resulting in an anti 1,3- ically pure 12 could be obtained by flash chromatography
diol. Surprisingly, the yield and diastereoselectivity of the (85% yield).
reduction were poor, and the best results were obtained
To establish the absolute configuration of the newly
using a carefully optimized temperature program. But nev- formed stereogenic centre, we converted 12 into the corre-
ertheless, we were not able to get a diastereoselectivity bet- sponding acetonide (i.e., 13; Scheme 3), which could be sub-
[
23]
ter than 4:1. Since we failed to introduce a silyl protecting jected to detailed NMR spectroscopic analysis. While the
group regioselectively onto the secondary alcohol of 9 with- syn,syn acetonide should exist in a well-defined chair con-
out affecting the allylic alcohol, we decided to change the formation, one might expect a twist-boat conformation for
order of the reaction steps.
the anti,syn isomer. The methyl groups of the acetal in par-
ticular, as well as the quaternary C-atom (C ), of these two
q
isomers differ significantly in their 13C NMR spectra. The
shifts observed (i.e., CH : δ = 23.70 and 24.90 ppm, C : δ
3
q
=
100.50 ppm) fit perfectly with the anti acetonide. This is
also true of the coupling constants (J4,5 = 8.8 and J3,4
.0 Hz), which indicate bond angles of around 20 or 170°.
To finish the synthesis of the required polyketide building
=
8
block, enantiopure 12 was coupled with propionic acid to
give allyl ester 14a, which could be subjected to a Claisen
rearrangement (Scheme 4). To get a clean chirality transfer
from the alcohol to the α substituent, the subsequent
Claisen rearrangement has to proceed via the correspond-
ing (Z)-enolate (derivative). For the rearrangement of prop-
[
24]
ionate 14a we chose the Ireland–Claisen variant,
an ap-
proach Maier et al. also used in their synthesis of geodeam-
Scheme 3. Stereoselective synthesis of chiral building block 12.
(
3 2 2 2
a) NEt , Bu BOTf, CH Cl , 0 °C; (b) 1. EtCHO, –78 °C, 30 min;
2
. –78 °C to room temp., 60 min; (c) MeONHMe·HCl, AlMe
CH Cl , –20 °C to r.t.; (d) 2-propenylmagnesium bromide, THF,
°C to r.t., 16 h; (e) Me
. –40 °C, 1 h; 2. –35 °C, 15 h; 3. –15 °C, 24 h; (f) TBSCl, imid-
3
,
2
2
+
–
0
1
4
N (AcO)
3
BH (8 equiv.), MeCN/AcOH, Scheme 4. Synthesis of ω-hydroxy esters 16a. (a) DCC (N,NЈ-di-
cyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine),
Et O, 0 °C to room temp., 16 h; (b) LDA (lithium diisoprop-
(1.05 equiv.), ylamide), DMPU, TMSCl, THF, 1. –78 °C, 1 h; 2. –78 °C to r.t.,
azole, DMF, r.t., 16 h; (g) 2-propenylmagnesium bromide, THF,
°C to r.t., 12 h; (h) NaBH (1.5 equiv.), CeCl
2
0
4
3
MeOH, –78 °C to r.t., 16 h; (i) TBAF (tetrabutylammonium fluor-
ide), THF, r.t., 16 h; (k) acetone, 2,2-dimethoxypropane, pyridin-
1 h; 3. 66 °C, 16 h; (c) K
2
CO
3
, allyl bromide, DMF, r.t., 16 h;
, THF,
(d) THF, H O/AcOH (1:3), 50 °C, 2 h; (e) LDA, ZnCl
2
2
ium p-toluenesulfonate, CH
2
Cl
2
, r.t., 16 h.
–78 °C to r.t., 16 h.
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Dichlorinated Chondramide Derivatives
olide.[25] In general, HMPA (hexamethylphosphoramide) is
used to generate the desired (Z)-enolate. To avoid the use
of this rather toxic compound, we used DMPU (dimethyl-
propenylurea) as a surrogate.[ But even when the silylket-
ene acetal formed was heated to reflux, the required γ,δ-
unsaturated acid (i.e., 15a) was obtained only in poor yield,
albeit with an acceptable diastereoselectivity [ratio (2S)/
26]
(2R) 9:1]. Unfortunately, attempts to improve the yield by
variation of the amount of TMSCl (trimethylsilyl chloride)
and base used (with or without DMPU) were unsuccessful.
Allylic alcohol 12 could be isolated as a side-product, obvi-
ously formed by decomposition of the enolate. Subsequent
reaction with allyl bromide gave the corresponding allyl es-
ter, which was directly desilylated to give hydroxy ester 16a.
With hydroxy esters 5 and 16a in hand, we next focussed
on the synthesis of the chondramide derivatives (Scheme 5).
Esterification of the OH functionality with chlorinated β-
tyrosine derivative 17[ using the Steglich protocol gave
the desired esters (i.e., 18) in excellent yield. Cleavage of
the N-Boc (tert-butoxycarbonyl) group and coupling with
chlorinated tryptophan dipeptide A gave access to tripept-
ide esters 19.
12]
[27]
During the coupling step, a partial epimerization of the
tryptophan was observed.[ This was not a serious issue
since the “wrong” diastereomer could be removed by
chromatography of the cyclic peptide. The allyl ester was
12]
[28]
cleaved using Pd(PPh ) /morpholine. Trifluoroacetic acid
3
4
was used to remove the N-Boc protecting group, and the
terminal deprotected linear precursors were subjected to cy-
®
clization under high-dilution conditions using T3P (prop-
ylphosphonic anhydride)[
29]
as coupling reagent. Finally,
the silyl protecting group was removed to give the free
Scheme 5. Synthesis of modified chondramides 20. (a) DCC,
DMAP, Et O, 0 °C to room temp., 16 h; (b) CF COOH, CH Cl
chondramide derivatives (i.e., 20a–20c). In all cases, accept-
2
3
2
2
,
able yields of the cyclized products in the range of 43–52% –20 °C, 12 h; (c) A, iPrNEt2, COMU® [(1-cyano-2-ethoxy-2-
(
over three steps) were obtained. In the case of 5b, which oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexa-
fluorophosphate], CH
morpholine, THF, r.t., 2 h; (e) T3P , iPrNEt
f) TBAF, THF, r.t., 1 h.
2
Cl
2
,
0 °C ®to r.t., 16 h; (d) Pd(PPh
3 4
) ,
was used as a 1:1 diastereomeric mixture, the two dia-
stereomeric cyclopeptides (i.e., 20b-1 and 20b-2) could be
separated by flash chromatography. The other peptides
could also be obtained enantiomerically pure.
2
, CH Cl , r.t., 16 h;
2
2
(
Since our group has been involved in Claisen rearrange- THF the Alloc group was also cleaved.[34] After the cleavage
ments for a long time, especially for the synthesis of unsatu- of the silyl protecting group, the Alloc protecting group was
[
30]
rated amino acids,
via chelated amino acid ester enolates.[
method for the introduction of an amine functionality (as (BODIPY = boron-dipyrromethene) pentafluorophenyl es-
we developed a protocol proceeding also removed from the α-amino group to give 20e. The
31]
To use this amine was subsequently coupled with BODIPY-substituted
[
35]
anchor for the introduction of labels), we also coupled 12 ter B to give fluorescence-labelled chondramide 20f.
to N-Alloc-protected (Alloc = allyloxycarbonyl) glycine (to After separation of the two diastereomeric peptides 20b-
give 14b; Scheme 6). And indeed, much better results were 1 and 20b-2, we wanted to assign the configuration of the
obtained in the chelate enolate Claisen rearrangement of α-methyl group by comparison of the NOESY spectra with
[
32]
glycine ester 14b.
The N-protected α-amino acid was those of derivatives of known configuration, e.g., 20c. In
formed in almost quantitative yield, and was then directly 20c, which has an (S) configuration at the α-C, a strong
converted into allyl ester 15b. The diastereoselectivity was NOE was observed between NHAla and the α-H of the
also high, as a result of a chair-like transition state of the carboxylic acid, while only a weak NOE was observed be-
chelated (Z)-enolate. Cleavage of the silyl protecting tween NHAla and the α-methyl group. The same situation
[
33]
group gave hydroxy ester 16b. The remainder of the syn- was found for 20b-1, while 20b-2 showed the opposite ef-
thesis proceeded as described for the other derivatives. It fects (strong NOE between NHAla and α-CH , weak NOE
3
should be mentioned that in dichloromethane, the Pd-cata- between NHAla and α-CH). Because the rest of the mol-
lysed cleavage of the allyl ester was selective, proceeding ecule was almost the same, we assigned the (S) configura-
without affecting the N-Alloc protecting group, whereas in tion to 20b-1, and the (R) configuration to 20b-2. One
Eur. J. Org. Chem. 2015, 4198–4213
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4201

D. Becker, U. Kazmaier
FULL PAPER
The activity of 20 towards a panel of tumor cell lines
[
36]
was investigated using the MTT-assay.
The results are
summarized in Table 1. Also included for reference are data
for chondramide C, chondramide C1, and dichlorodes-
methyl chondramide C, a synthetic analogue in which all
the substituents on the polyketide unit are removed. In pre-
vious studies, we found this derivative to have comparable
activity to chondramide C (at least towards HCT-116
[
12]
cells).
Table 1. Cytotoxicity of chondramide derivatives 20 towards tumor
cells.[
11]
[
a]
GI50 [nm]
[b]
KB-3.1[c] RAW246.7[d] U-2OS[e]
HCT-116
Chondramide C
Dichlorodesmethyl 30
Chondramide C
34
37
376
26
197
26
67
Chondramide C1 42
56
15
2
2
2
2
2
2
0a
200
16
800
83
1100
98
1900
800
75
1800
600
54
1300
30
2500
50000
0b-1
0b-2
0c
0e
0f
280
[
a] 50% of maximal inhibition of cell proliferation. [b] Human
colon cancer. [c] Human cervical carcinoma. [d] Leukemic mouse
macrophage. [e] Human bone osteosarcoma.
We observed previously that removal of the methyl
groups causes a significant drop in biological activity, an
effect that could be compensated by the introduction of two
chlorine substituents. Therefore, dichlorodesmethyl chond-
ramide C shows similar activity towards some cell lines,
against others it was worse (KB-3.1). Interestingly, the in-
troduction of an ethyl group at the ester functionality (20a)
resulted in a significant drop of activity (by a factor of 10–
30). Incorporation of the α-methyl group brought back the
high cytotoxicity, but only for one stereoisomer. The excel-
lent activity of 20b-1 indicates that our assignment as the
natural (S) isomer was obviously correct. In contrast, the
[
14b]
(R) isomer was less active by a factor of 20–40.
The
introduction of the “third” substituent (20c) brought no
further improvement. We also investigated the activity of
+
amine 20e, since the NH3 group that would probably form
under physiological conditions, should be isosteric to the
methyl group, but with an additional positive charge. Inter-
Scheme 6. Synthesis of fluorescence-labelled chondramide 20f. estingly, the activity of 20e towards HCT-116 cells was only
(
a) DCC, DMAP, Et
THF, –78 °C to r.t., 16 h; (c) K
d) THF, H
2
O, 0 °C to room temp., 16 h; (b) LDA, ZnCl
CO , allyl bromide, DMF, r.t., 16 h;
O/AcOH (1:3), 50 °C, 2 h; (e) 17, DCC, DMAP, Et O,
°C to r.t., 16 h; (f) CF COOH, CH Cl , –20 °C, 12 h; (g) A,
, COMU® [(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)di-
2
,
slightly worse than that of desmethyl derivative 20a, while
a significant drop in activity was observed for U-2OS cells.
The fluorescence-labelled derivative 20f was found to be al-
most inactive.
2
3
(
0
2
2
3
2
2
iPrNEt
2
methylaminomorpholinocarbenium
CH Cl , 0 °C to r.t., 16 h; (h) Pd(PPh
h; (i) T3P , iPrNEt
l) Pd(OAc) HNEt
sulfonic acid trisodium salt], MeCN/H
iPrNEt , CH Cl , DMSO, r.t., 16 h.
hexafluorophosphate],
, morpholine, THF, r.t.,
2
2
3
)
4
®
2
(
2
2
,
, CH
TPPTS [triphenylphosphine-3,3Ј,3ЈЈ-tri-
O/EtOH (8:3:3), 1 h; (m) B,
2 2
Cl , r.t., 16 h; (k) TBAF, THF, r.t., 1 h;
Conclusions
2
,
2
In conclusion, we have shown that the structure of “ethyl
chondramides” can be simplified by removing the methyl
group at the ε-position (C-6). As long as both aromatic
amino acids are chlorinated, antitumor activities compar-
2
2
2
might expect that the configuration at this position should able to those of chondramide C and C1 are observed. Re-
also be reflected in the biological activity of the peptides. moval of the α-methyl group results in a significant drop in
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Dichlorinated Chondramide Derivatives
3
activity, a situation that is even worse if the configuration (400 MHz, CDCl ): δ = 0.96 (t, J = 7.5 Hz, 3 H), 1.50 (m, 2 H),
1
.62 (br. s, 1 H), 2.14 (m, 1 H), 2.32 (m, 1 H), 3.58 (m, 1 H), 5.12
at this stereogenic centre is inverted. This is in contrast to
results obtained with the dichlorinated desmethyl derivative.
1
3
(
m, 1 H), 5.15 (m, 1 H), 5.83 (m, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 9.9, 29.5, 41.4, 72.0, 118.0, 134.9 ppm.
3
(
(
R)-Hex-5-en-3-ol tert-Butyldimethylsilyl Ether (2):[17] TBSCl
4.17 g, 27.7 mmol) and imidazole (1.88 g, 27.7 mmol) were added
Experimental Section
to a solution of homoallylic alcohol (R)-1 (2.31 g, 23.1 mmol, 84%
ee) in anhydrous DMF (60 mL) at 0 °C. The mixture was allowed
General Remarks: All air- or moisture-sensitive reactions were car-
ried out in dried glassware (Ͼ100 °C) under an atmosphere of to warm to room temperature overnight. The solution was diluted
nitrogen or argon. Dried solvents were distilled before use; THF
with diethyl ether, washed with HCl (1 m aq.), satd. aq. NaHCO3,
was distilled from LiAlH or Na. Abs. dichloromethane and DMF
4
and brine, and dried with Na SO , and the solvent was removed
2
4
were 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. Analyti-
cal TLC was carried out on precoated silica gel plates (Macherey–
Nagel, Polygram® SIL G/UV254). Visualization was accomplished
by distillation. Purification by fractional distillation (15 mbar, b.p.
74–84 °C) gave 2 (4.27 g, 19.9 mmol, 86%, 84% ee) as a colourless
2
0
oil. R : 0.77 (petroleum ether/ethyl acetate, 9:1). [α] = +13.2 (c =
f
D
1
2.1, CHCl , 84% ee). H NMR (400 MHz, CDCl ): δ = 0.05 (s, 6
3
3
H), 0.86 (t, J = 5.0 Hz, 3 H), 0.89 (s, 9 H), 1.46 (m, 2 H), 2.21 (m,
2 H), 3.62 (tt, J = 5.8 Hz, 1 H), 5.01 (m, 1 H), 5.04 (m, 1 H), 5.82
with UV light, KMnO
4
solution, or ninhydrin solution. Melting
1
3
points were determined with a Dr. Tottoli (Büchi) melting point
(ddt, J = 17.3, 10.3, 7.0 Hz, 1 H) ppm. C NMR (100 MHz,
1
13
apparatus. H and C NMR spectra were recorded with a Bruker
CDCl ): δ = –4.6, 9.6, 18.2, 25.9, 29.5, 41.5, 73.2, 116.5, 135.6 ppm.
3
1
13
AC-400 instrument [400 MHz ( H) and 100 MHz ( C)]. Chemical
shifts are reported in ppm, and spectra were calibrated using resid-
ual solvent signals. Diastereomeric ratios were determined by
NMR spectroscopy or HPLC. Selected signals of minor isomers
are extracted from the NMR spectra of the isomeric mixtures. En-
antiomeric and diastereomeric ratios were determined by HPLC
(
5R)-5-(tert-Butyldimethylsilyloxy)-2-methylhept-1-en-3-ol
Ozone was bubbled through a solution of silyl ether 2 (0.98 g,
.57 mmol, 84% ee) in anhydrous CH Cl (45 mL) at –78 °C until
the characteristic blue colour appeared. PPh (1.21 g, 4.61 mmol)
(3):
4
2
2
3
was added in one portion. The mixture was stirred for 1 h, then it
was allowed to warm up to room temperature, and concentrated
under reduced pressure (Ͼ500 mbar).
(
Merck–Hitachi LaChrom D-7000, Merck’s Multi-HSM-Manager)
using a chiral column (Reprosil 100 Chiral-NR 8 μm or OD-H
50ϫ4.6 mm). Gas chromatography (GC) was carried out using a
2
The crude aldehyde was slowly treated with a 2-propenylmagne-
GC-2010 Shimadzu gas chromatograph, and data were analysed sium bromide solution (0.5 m in THF; 10.9 mL, 5.46 mmol) at 0 °C.
using the Shimadzu GC Solution software. A Chirasil-Dex CB
capillary column was used (25 m length, 0.25 mm internal dia-
meter) as the stationary phase, and the carrier gas used was nitro-
gen. Preparative high-performance liquid chromatography (prep.
HPLC) was carried out using an instrument from Merck–Hitachi
After the addition was complete, the mixture was allowed to warm
to room temperature overnight. The reaction was quenched with
satd. NH Cl, and the mixture was extracted with diethyl ether. The
4
combined organic layers were washed with brine, dried with
Na SO , and concentrated in vacuo. Purification by flash
2
4
(LaChrom D-7150, Interface D-700, UV Detector L-7400, Pump
chromatography (petroleum ether/ethyl acetate, 95:5) gave allylic
L-7150, Super Fraction Collector SF-3120, Merck’s Multi-HSM-
Manager) and a Reprosil 100 C-18 column (100ϫ20 mm, 5 μm
particle size; Altmann Analytics). HPLC–MS analysis was carried
out with a Shimadzu system (LC: 10A-series + Autosampler, MS:
LCMS-2020) and an achiral column (Luna 3μ C18, 50ϫ4.6 mm).
Mass spectra were recorded with a Finnigan MAT 95 spectrometer
alcohol 3 (0.91 g, 3.52 mmol, 77%) as a colourless oil, a 1:1 dia-
stereomeric mixture. R : 0.21 (petroleum ether/ethyl acetate, 95:5).
f
1
H NMR (400 MHz, CDCl ): δ = 0.08 (s, 1.5 H), 0.10 (s, 1.5 H),
3
0.10 (s, 1.5 H), 0.12 (s, 1.5 H), 0.81 (t, J = 7.5 Hz, 1.5 H), 0.86 (t,
J = 7.5 Hz, 1.5 H), 0.90 (s, 4.5 H), 0.91 (s, 4.5 H), 1.51–1.68 (m, 4
H), 1.72 (s, 1.5 H), 1.73 (s, 1.5 H), 3.19 (d, J = 2.3 Hz, 0.5 H), 3.24
(d, J = 1.5 Hz, 0.5 H), 3.91 (m, 1 H), 4.18 (d, J = 9.0 Hz, 0.5 H),
(quadrupole) using the CI technique. Elemental analyses were per-
1
3
formed at the Saarland University.
4.33 (t, J = 5.5 Hz, 0.5 H), 4.91 (m, 1 H), 5.00 (m, 1 H) ppm.
NMR (100 MHz, CDCl ): δ = –4.8, –4.7, –4.5, –4.0, 8.8, 9.9, 18.0,
8.0, 18.1, 18.2, 25.8, 25.9, 29.1, 30.5, 39.9, 41.0, 72.1, 72.5, 74.2,
5.0, 109.9, 110.4, 147.4, 147.8 ppm. HRMS (CI): calcd. for
Si [M + H]+ 259.2088; found 259.2085. C14
Si
258.47): calcd. C 65.06, H 11.70; found C 65.01, H 11.25.
C
R)-Hex-5-en-3-ol (1):[17] Allylmagnesium bromide (1 m in diethyl
3
(
1
7
ether; 32.9 mL, 23.9 mmol) was added to a solution of (–)-B-meth-
oxydiisopinocamphenylborane (11.5 g, 36.4 mmol) in anhydrous
diethyl ether (42 mL) at –78 °C, and the reaction mixture was al-
lowed to warm up to room temperature overnight. The mixture
was then cooled to –78 °C, and propionic aldehyde (2.61 mL,
C
14
H
31
O
2
30 2
H O
(
Ethyl
(R,E)-7-(tert-Butyldimethylsilyloxy)-4-methylnon-4-enoate
3
6.4 mmol) was added. The reaction mixture was stirred for 3 h at
(4a): Allylic alcohol 3 (1.10 g, 4.27 mmol) and propionic acid
(10.0 μL, 0.13 mmol) were dissolved in triethyl orthoacetate
(4.70 mL, 25.6 mmol), and the mixture was heated at reflux over-
night. After the alcohol had been completely consumed, the solvent
was removed under reduced pressure (40 mbar, 140 °C) with a Vig-
this temperature. NaOH (3 m in H O; 14.5 mL) and H (30%
2
2 2
O
aq.; 28.9 mL) were then added, and the mixture was heated at re-
flux for 3 h. The phases were separated, and the aqueous layer was
extracted with diethyl ether. The combined organic extracts were
washed with HCl (1 m), H
2 3
O, satd. aq. NaHCO , and brine, and reux column. Purification by flash chromatography (petroleum
dried with Na SO , and the solvent was removed by distillation. ether/ethyl acetate, 95:5) gave 4a (1.24 g, 3.77 mmol, 88%, 84% ee)
2
4
Purification by fractional distillation (125 mbar, b.p. 75–77 °C,
micro distillery) gave 1 (2.59 g, 25.9 mmol, 79%, 84% ee) as a [α]
f
as a colourless oil. R : 0.42 (petroleum ether/ethyl acetate, 95:5).
2
0
1
D
= +7.4 (c = 0.9, CHCl
3
, 84% ee). H NMR (400 MHz,
colourless oil. The ee value was determined by GC (Chirasil-Dex-
CDCl ): δ = 0.03 (s, 6 H), 0.86 (t, J = 7.2 Hz, 3 H), 0.88 (s, 9 H),
3
CB) after conversion of the alcohol into the corresponding acetate
1.25 (t, J = 7.2 Hz, 3 H), 1.42 (m, 2 H), 1.61 (s, 3 H), 2.13 (m, 2
H), 2.31 (m, 2 H), 2.39 (m, 2 H), 3.56 (tt, J = 5.8, 5.8 Hz, 1 H),
[T
0
= 80 C (3 min), 2 °C/min, Tend = 200 °C (10 min): (S)-1Acetate
= 5.63 min (R)-1Acetate: t = 6.05 min]. R : 0.41 (petroleum ether/
= +9.8 (c = 1.8, CHCl
:
1
3
t
R
R
f
4.11 (q, J = 7.1 Hz, 2 H), 5.18 (tq, J = 7.3, 1.3 Hz, 1 H) ppm.
C
2
0
1
ethyl acetate, 7:3). [α]
D
3
, 84% ee). H NMR
NMR (100 MHz, CDCl ): δ = –4.6, –4.5, 9.7, 14.2, 16.1, 18.1, 25.9,
3
Eur. J. Org. Chem. 2015, 4198–4213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4203

D. Becker, U. Kazmaier
9.5, 33.2, 34.8, 35.5, 60.2, 73.6, 121.8, 134.6, 173.5 ppm. HRMS chromatography (petroleum ether/ethyl acetate, 9:1) gave hydroxy
FULL PAPER
2
+
(
CI): calcd. for C18
H
37
O
3
Si [M + H] 329.2506; found 329.2478;
ester 5b (1.40 g, 5.82 mmol, 93%) as a colourless oil, a 1:1 dia-
stereomeric mixture. R : 0.09 (petroleum ether/ethyl acetate, 9:1).
H NMR (400 MHz, CDCl ): δ = 0.94 (t, J = 7.5 Hz, 1.5 H), 0.95
t, J = 7.5 Hz, 1.5 H), 1.13 (d, J = 7.0 Hz, 1.5 H), 1.14 (d, J =
.0 Hz, 1.5 H), 1.46 (m, 2 H), 1.59 (br. s, 0.5 H), 1.63 (s, 3 H), 1.70
br. s, 0.5 H), 2.08–2.18 (m, 3 H), 2.40 (dd, J = 13.6, 8.0 Hz, 1 H),
+
calcd. for C18
H
36
O
3
Si [M] 328.2428; found 328.2440.
f
1
3
Ethyl (7R,E)-7-(tert-Butyldimethylsilyloxy)-2,4-dimethylnon-4-eno-
ate (4b): Ester 4b was prepared analogously to ester 4a, starting
from allylic alcohol 3 (1.72 g, 6.65 mmol), propionic acid (15.0 μL,
.20 mmol), and 1,1,1-triethoxypropane (7.98 mL, 39.8 mmol). Pu-
rification by flash chromatography (petroleum ether/ethyl acetate,
(
7
(
0
2
5
1
.67 (m, 1 H), 3.51 (tt, J = 6.5, 6.5 Hz, 1 H), 4.55 (m, 2 H), 5.17–
.24 (m, 2 H), 5.31 (ddt, J = 17.3, 1.5, 1.5 Hz, 1 H), 5.91 (ddt, J =
7.3, 10.3, 5.8 Hz, 0.5 H), 5.92 (ddt, J = 17.3, 10.3, 5.8 Hz, 0.5 H)
9
1
9
5:5) gave ester 4b (2.15 g, 6.28 mmol, 94%) as a colourless oil, a
:1 diastereomeric mixture. R : 0.66 (petroleum ether/ethyl acetate,
5:5). H NMR (400 MHz, CDCl ): δ = 0.03 (s, 3 H), 0.04 (s, 3
f
1
3
1
ppm. C NMR (100 MHz, CDCl
3
): δ = 10.0, 16.0, 16.1, 16.8, 29.5,
5.5, 35.7, 38.18, 38.22, 44.1, 44.3, 64.94, 64.91, 72.8, 72.9, 118.0,
18.1, 122.7, 122.9, 132.3, 135.6, 135.7, 176.0 ppm. HRMS (CI):
[M + H]+ 241.1798; found 241.1807.
3
3
1
H), 0.86 (t, J = 7.5 Hz, 1.5 H), 0.86 (t, J = 7.5 Hz, 1.5 H), 0.88 (s,
H), 1.09 (d, J = 6.9 Hz, 1.5 H), 1.10 (d, J = 7.0 Hz, 1.5 H), 1.24
t, J = 7.0 Hz, 1.5 H), 1.25 (t, J = 7.0 Hz, 1.5 H), 1.42 (m, 2 H),
.59 (s, 3 H), 2.14 (m, 2 H), 2.30 (dd, J = 13.6, 7.8 Hz, 1 H), 2.38
dd, J = 13.6, 7.3 Hz, 1 H), 2.59 (m, 1 H), 3.58 (tt, J = 5.0, 5.0 Hz,
H), 4.10 (q, J = 7.0 Hz, 1 H), 4.11 (q, J = 7.0 Hz, 1 H), 5.18 (t,
9
(
1
(
25 3
calcd. for C14H O
(S)-4-Benzyl-3-[(2S,3R)-3-hydroxy-2-methylpentanoyl]-oxazolidin-2-
one (6):[ Bu BOTf (1 m in CH Cl ; 35.4 mL, 35.4 mmol) and
19]
2
2
2
1
NEt (5.52 mL, 39.7 mmol) were successively added to a solution
3
1
3
J = 7.2 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = –4.6,
of (S)-4-benzyl-3-propionyloxazolidin-2-one (7.00 g, 30.0 mmol) in
–
3
4.5, 9.7, 14.2, 15.9, 15.9, 16.6, 16.7, 18.1, 25.9, 29.4, 35.6, 35.6, anhydrous CH Cl (67 mL) at 0 °C. (The internal temperature
2 2
7.9, 37.9, 44.1, 44.1, 60.1, 73.5, 123.5, 123.5, 133.5, 176.6 ppm.
should not exceed 2 °C.) After the addition was complete, freshly
distilled propionic aldehyde (2.39 mL, 33.3 mmol) was added at
–78 °C. The reaction mixture was stirred for a further 30 min, and
then it was allowed to warm up to 0 °C over a period of 1 h. After
a further 1 h, the solution was quenched with aq. phospate buffer
+
HRMS (CI): calcd. for C19
43.2647.
39 3
H O Si [M + H] 343.2663; found
3
Allyl (R,E)-7-Hydroxy-4-methylnon-4-enoate (5a): NaOH (1 m aq.;
.75 mL, 4.75 mmol) was added dropwise to a solution of unsatu-
4
(
pH 7; 33.0 mL) and MeOH (98.0 mL) (Tintern Ͻ 6 °C) and further
treated with a mixture of MeOH and H (30% aq.) (2:1;
8.0 mL) (Tintern Ͻ 10 °C). After 45 min, the organic solvent was
rated ethyl ester 4a (1.20 g, 3.65 mmol, 84% ee) in EtOH (12 mL)
at 0 °C. The mixture was allowed to warm to room temperature
overnight, then the solvent was removed under reduced pressure,
and H O was added to the residue. The aqueous solution was acidi-
2
fied to pH 2–3 with HCl (1 m aq.), and extracted with ethyl acetate.
The combined organic layers were washed with brine, dried with
2 4
Na SO , and concentrated in vacuo to give the crude acid as a
colourless oil.
2
O
2
9
evaporated under reduced pressure, and the aqueous layer was ex-
tracted with diethyl ether. The combined organic layers were
washed twice with satd. aq. NaHCO
Na SO , and concentrated under reduced pressure. Purification by
recrystallization (diethyl ether/pentane) gave 6 (8.52 g, 29.2 mmol,
7%) as a colourless solid, m.p. 75–77 °C. R : 0.35 (petroleum
3
and brine, dried with
2
4
9
f
The crude acid was dissolved in anhydrous DMF (12 mL). The
solution was cooled to 0 °C, and K CO (1.01 g, 7.30 mmol) and
2 3
20
1
ether/ethyl acetate, 1:1). [α]
400 MHz, CDCl ): δ = 0.98 (t, J = 7.4 Hz, 3 H), 1.25 (d, J =
.0 Hz, 3 H), 1.47 (m, 1 H), 1.58 (m, 1 H), 2.79 (dd, J = 13.4,
D 3
= +46.1 (c = 1.0, CHCl ). H NMR
(
3
allyl bromide (0.47 mL, 5.48 mmol) were added. The mixture was
allowed to warm to room temperature overnight, then it was di-
luted with H
organic layers were further washed with H
Na SO , and concentrated under reduced pressure to give the allyl
ester.
7
9
3
3
7
.4 Hz, 1 H), 2.86 (br. s, 1 H), 3.26 (dd, J = 13.3, 3.3 Hz, 1 H),
.79 (qd, J = 7.0, 2.8 Hz, 1 H), 3.87 (m, 1 H), 4.19 (dd, J = 9.3,
.3 Hz, 1 H), 4.23 (dd, J = 9.0, 7.5 Hz, 1 H), 4.71 (dddd, J = 9.3,
2
O, and extracted with ethyl acetate. The combined
2
O and brine, dried with
2
4
.3, 3.3, 3.3 Hz, 1 H), 7.21 (d, J = 6.8 Hz, 2 H), 7.29 (m, 1 H), 7.34
13
(
3
m, 2 H) ppm. C NMR (100 MHz, CDCl ): δ = 10.2, 10.4, 26.7,
The crude allyl ester was dissolved[33] in THF (7 mL), AcOH
21 mL), and H O (7 mL). The reaction mixture was heated at
0 °C for 2 h, then it was diluted with diethyl ether, washed twice
37.8, 41.7, 55.1, 66.2, 72.9, 127.4, 128.9, 129.4, 135.0, 153.0,
(
5
2
R
177.6 ppm. HPLC (Reprosil; hexane/i-PrOH, 7:3; 1 mL/min): t =
6.68 min.
with H
2
O and brine, dried with Na
2
SO
4
, and concentrated in
(7):[20]
(
2S,3R)-3-Hydroxy-N-methoxy-N,2-dimethylpentanamide
Al(CH
pension of N,O-dimethylhydroxylamine·HCl (6.50 g, 66.6 mmol) in
anhydrous CH Cl (238 mL) at 0 °C over a period of 20 min. The
vacuo. Purification by flash chromatography (petroleum ether/ethyl
acetate, 9:1) gave hydroxy ester 5a (0.76 g, 3.36 mmol, 92%, 84%
3 3
) (2 m in hexane; 33.3 mL, 66.6 mmol) was added to a sus-
ee) as a colourless oil. R
f
: 0.08 (petroleum ether/ethyl acetate, 9:1).
= –5.5 (c = 1.0, CHCl
, 84% ee). 1H NMR (400 MHz,
CDCl ): δ = 0.94 (t, J = 7.5 Hz, 3 H), 1.46 (m, 2 H), 1.64 (s, 3 H),
.71 (br. s, 1 H), 2.14 (m, 2 H), 2.35 (m, 2 H), 2.46 (m, 2 H), 3.51
tt, J = 7.0, 5.3 Hz, 1 H), 4.55 (ddd, J = 5.8, 1.5, 1.5 Hz, 2 H),
.18–5.24 (m, 2 H), 5.30 (ddt, J = 17.1, 1.5, 1.5 Hz, 1 H), 5.90 (ddt,
2
2
2
0
[α]
D
3
reaction mixture was allowed to warm to room temperature, and
was stirred for a further 2 h to give a clear solution. A solution of
3
1
(
5
oxazolidinone 6 (9.70 g, 33.3 mmol) in anhydrous CH
was then added at –15 °C. The mixture was stirred for a further
0 min at 0–10 °C, then it was cooled to –20 °C, and allowed to
warm up to room temperature overnight. The reaction was
quenched with Rochelle salt (1 m in H O; 200 mL), and the mixture
was extracted with CH Cl . The combined organic layers were
washed with brine, dried with Na SO , and concentrated under
reduced pressure. Purification by flash chromatography (petroleum
ter 5b was prepared analogously to hydroxy ester 5a, starting from ether/ethyl acetate, 7:3) gave Weinreb amide 7 (5.82 g, 33.2 mmol,
ester 4b (2.14 g, 6.25 mmol), NaOH (1 m aq.; 8.11 mL, 8.11 mmol) 99%) as a colourless oil. R : 0.12 (petroleum ether/ethyl acetate,
2 2
Cl (60 mL)
9
13
J = 17.1, 10.5, 5.8 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
10.0, 16.1, 29.5, 32.9, 34.8, 35.6, 60.1, 72.9, 118.2, 121.3, 132.2,
36.7, 173.0 ppm. HRMS (CI): calcd. for C13
[M + H]+
27.1642; found 227.1637.
3
): δ
=
1
2
2
23 3
H O
2
2
2
4
Allyl (7R,E)-7-Hydroxy-2,4-dimethylnon-4-enoate (5b): Hydroxy es-
f
2
0
1
in EtOH (20 mL); K
2
CO
0.81 mL, 9.36 mmol) in anhydrous DMF (30 mL); and THF
12 mL), H O (12 mL), and AcOH (36 mL). Purification by flash
3
(1.73 g, 12.5 mmol) and allyl bromide
D 3 3
7:3). [α] = +17.4 (c = 0.6, CHCl ). H NMR (400 MHz, CDCl ):
δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.16 (d, J = 7.0 Hz, 3 H), 1.40 (m, 1
H), 1.57 (m, 1 H), 2.91 (br. s, 1 H), 3.20 (s, 3 H), 3.70 (s, 3 H),
(
(
2
4204
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4198–4213

Dichlorinated Chondramide Derivatives
3
1
.73–3.77 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl
0.3, 26.7, 31.9, 38.2, 61.5, 73.0, 178.4 ppm.
3
): δ = 10.0, H), 1.48 (m, 1 H), 1.87 (s, 3 H), 3.56 (qd, J = 7.0, 7.0 Hz, 1 H),
1
3
3.90 (dt, J = 6.5, 5.3 Hz, 1 H), 5.78 (s, 1 H), 5.95 (s, 1 H) ppm.
NMR (100 MHz, CDCl ): δ = –4.5, –4.2, 8.9, 14.2, 17.9, 18.1, 25.9,
8.2, 44.2, 74.7, 124.3, 144.3, 205.1 ppm. HRMS (CI): calcd. for
C
3
(4S,5R)-5-Hydroxy-2,4-dimethylhept-1-en-3-one (8): Following the
2
C
Grignard addition procedure used for the synthesis of 3, ketone 8
was prepared from 7 (1.62 g, 9.25 mmol) and 2-propenylmagne-
sium bromide solution (0.5 m in THF; 55.5 mL, 27.7 mmol) in an-
hydrous THF (19 mL). Purification by flash chromatography (pe-
troleum ether/ethyl acetate, 8:2) gave 8 (0.90 g, 5.76 mmol, 62%) as
+
11 21 2 4 9
H O Si [M – C H ] 213.1305; found 213.1295.
(3S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylhept-1-en-3-
ol (12):[ CeCl
38]
3 2 4
·7H O (0.81 g, 2.17 mmol) and NaBH (117 mg,
3.09 mmol) were added to a solution of ketone 11 (0.56 g,
2.07 mmol) in anhydrous MeOH (21 mL) at –78 °C. After 16 h at
2
0
a colourless oil. R
+3.3 (c = 0.5, CHCl
t, J = 7.4 Hz, 3 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.38 (m, 1 H), 1.54 NH
m, 1 H), 1.88 (s, 3 H), 2.99 (d, J = 3.0 Hz, 1 H), 3.24 (qd, J = 7.3, layers were washed with brine, dried with Na
.0 Hz, 1 H), 3.78 (m, 1 H), 5.84 (q, J = 1.5 Hz, 1 H), 5.97 (s, 1 trated in vacuo. Purification by flash chromatography (petroleum
f
: 0.26 (petroleum ether/ethyl acetate, 8:2). [α]
D
1
=
(
(
3
). H NMR (400 MHz, CDCl
3
): δ = 0.96 this temperature, the resulting mixture was quenched with satd.
Cl, and extracted with diethyl ether. The combined organic
SO , and concen-
4
2
4
3
1
3
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 10.4, 11.2, 17.7, 27.1, ether/ethyl acetate, 9:1) gave isomerically pure 12 (0.48 g,
1.76 mmol, 85%) as a colourless oil. R : 0.43 (petroleum ether/ethyl
42.9, 73.0, 125.5, 143.6, 207.7 ppm. HRMS (CI): calcd. for C
9
H
14
O
f
+
20
1
[M – H
2
O] 139.1117; found 139.1086.
acetate, 9:1). [α]
CDCl ): δ = 0.09 (s, 3 H), 0.13 (s, 3 H), 0.70 (d, J = 7.3 Hz, 3 H),
.92 (s, 9 H), 0.93 (t, J = 7.5 Hz, 3 H), 1.58 (m, 2 H), 1.71 (s, 3 H),
.86 (m, 1 H), 3.76 (ddd, J = 7.8, 4.8, 2.5 Hz, 1 H), 4.01–4.04 (m,
D 3
= +10.2 (c = 0.9, CHCl ). H NMR (400 MHz,
3R,4S,5R)-2,4-Dimethylhept-1-ene-3,5-diol (9):[21] A solution of
3
(
0
1
2
ketone 8 (236 mg, 1.51 mmol) in anhydrous acetonitrile (1.50 mL)
was added to a solution of (CH NBH(OAc) (3.17 g, 12.1 mmol)
in anhydrous acetonitrile (4.60 mL) and AcOH (4.60 mL) at
40 °C. The mixture was stirred for 1 h at this temperature, then it
3
)
4
3
1
3
H), 4.85 (m, 1 H), 4.89 (s, 1 H) ppm. C NMR (100 MHz,
): δ = –4.4, 11.3, 12.9, 16.2, 18.0, 24.6, 25.9, 39.4, 78.3, 79.3,
13.2, 145.9 ppm. HRMS (CI): calcd. for C15
CDCl
1
3
–
+
33 2
H O Si [M + H]
was stirred for 15 h at –35 °C, and for a further 24 h at –15 °C. The
reaction was quenched with satd. aq. Rochelle salt, and the mixture
was extracted with diethyl ether. The combined organic layers were
273.2244; found 273.2259.
(4R,5S,6S)-4-Ethyl-2,2,5-trimethyl-6-(prop-1-en-2-yl)-1,3-dioxane
(13):[ TBAF (1 m in THF; 140 μL, 140 μmol) was added to a
solution of ketone 12 (38.0 mg, 140 μmol) in anhydrous THF
(1 mL), and the mixture was stirred for 16 h at room temperature.
39]
washed with satd. aq. NaHCO
Na SO , and concentrated under reduced pressure. Purification by
flash chromatography (petroleum ether/ethyl acetate, 8:2) gave iso-
merically pure 9 (154 mg, 0.97 mmol, 64%) as a colourless oil. R
3 2
, H O, and brine, dried with
2
4
f
:
The resulting mixture was quenched with satd. NH
tracted with diethyl ether. The combined organic layers were
): δ = 0.82 (d, J = washed with brine, dried with Na SO , and concentrated in vacuo.
.0 Hz, 3 H), 0.96 (t, J = 7.5 Hz, 3 H), 1.47 (m, 1 H), 1.58 (m, 1
4
Cl, and ex-
2
0
0
D
.15 (petroleum ether/ethyl acetate, 8:2 + 1% EtOH). [α] = +7.7
1
(c = 1.1, CHCl
3
). H NMR (400 MHz, CDCl
3
2
4
7
The crude diol was dissolved in acetone (1 mL), and treated with
,2-dimethoxypropane (1.29 mL, 10.5 mmol) and pyridinium p-
toluenesulfonate (1 m in anhydrous CH Cl ; 14.0 μL, 14.0 μmol) at
H), 1.69 (s, 3 H), 1.72 (m, 1 H), 2.65 (br. s, 2 H), 3.79 (ddd, J =
.8, 5.8, 2.0 Hz, 1 H), 4.27 (s, 1 H), 4.93 (q, J = 1.5 Hz, 1 H), 5.03
m, 1 H) ppm. 13C NMR (100 MHz, CDCl
): δ = 4.2, 10.5, 19.6,
8.3, 38.0, 77.9, 79.7, 110.2, 145.7 ppm. HRMS (CI): calcd. for
[M + H]+ 159.1380; found 159.1371.
2
7
(
2
2
2
3
room temperature. After stirring for 16 h, the resulting mixture was
diluted with diethyl ether. The organic layer was washed twice with
9 19 2
C H O
satd. aq. NaHCO
3 2 4
and brine, dried with Na SO , and concentrated
(
2S,3R)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N,2-dimethyl- in vacuo to give crude acetonide 13 (22.0 mg, 111 μmol, 80%) as a
[
37]
1
pentanamide (10):
(
(
TBSCl (5.49 g, 36.4 mmol) and imidazole
2.48 g, 36.4 mmol) were added to a solution of Weinreb amide 7
5.80 g, 33.1 mmol) in anhydrous DMF (110 mL) at 0 °C, and the
colourless oil. R
NMR (400 MHz, CDCl
f
: 0.56 (petroleum ether/ethyl acetate, 9:1). H
): δ = 0.84 (d, J = 7.0 Hz, 3 H), 0.93 (t, J
3
= 7.4 Hz, 3 H), 1.36 (s, 3 H), 1.38 (s, 3 H), 1.44 (m, 2 H), 1.77 (s,
mixture was allowed to warm to room temperature overnight. The
solution was diluted with ethyl acetate, washed with HCl (1 m aq.),
3 H), 1.84 (m, 1 H), 3.71 (d, J = 8.0 Hz, 1 H), 3.74 (dt, J = 8.8,
1
3
5.0 Hz, 1 H), 4.85 (m, 1 H), 4.93 (s, 1 H) ppm. C NMR
(100 MHz, CDCl ): δ = 10.6, 11.7, 18.0, 23.7, 23.9, 24.9, 37.1, 70.9,
79.0, 100.5, 112.1, 144.2 ppm.
satd. aq. NaHCO
3
and brine, and dried with Na
2
SO
4
, and the sol-
3
vents were evaporated in vacuo. Purification by flash chromatog-
raphy (petroleum ether/ethyl acetate, 9:1) gave 10 (8.71 g,
[
(3S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylhept-1-en-3-
3
f
0.1 mmol, 91%) as a colourless oil. R : 0.43 (petroleum ether/ethyl
yl] Propionate (14a): DMAP (0.14 g, 1.15 mmol) and DCC (1.72 g,
8
6
diethyl ether (28.0 mL) at 0 °C, and the mixture was allowed to
warm up to room temperature overnight. The precipitate was re-
20
1
acetate, 9:1). [α]
D 3
= +2.6 (c = 1.3, CHCl ). H NMR (400 MHz,
.34 mmol) were added to a solution of propionic acid (0.50 mL,
.68 mmol) and allylic alcohol 12 (1.52 g, 5.58 mmol) in anhydrous
CDCl
.89 (s, 9 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.46 (m, 1 H), 1.54 (m, 1
H), 2.99 (br. s, 1 H), 3.17 (s, 3 H), 3.69 (s, 3 H), 3.89 (dt, J = 8.0,
3
): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.88 (t, J = 7.3 Hz, 3 H),
0
4
8
.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl
.5, 14.7, 18.2, 25.9, 28.1, 32.1, 40.0, 61.4, 74.2, 176.8 ppm.
3
): δ = –4.4, –4.2,
moved by filtration, and the filtrate was washed twice with KHSO
1 m aq.), H O, satd. aq. NaHCO , and brine, dried with Na SO
4
(
2
3
2
4
(
(
4S,5R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylhept-1-en-3-one and concentrated in vacuo. Purification by flash chromatography
11): Following the Grignard addition procedure used for the syn- (petroleum ether/ethyl acetate, 9:1) gave allylic ester 14a (1.83 g,
5.58 mmol, 99%) as a colourless oil. R : 0.67 (petroleum ether/ethyl
thesis of 3, ketone 11 was prepared from 10 (8.70 g, 30.1 mmol) and
2
6
f
2
0
1
-propenylmagnesium bromide solution (0.5 m in THF; 120 mL,
D 3
acetate, 9:1). [α] = –4.2 (c = 0.5, CHCl ). H NMR (400 MHz,
0.0 mmol) in anhydrous THF (60 mL). Purification by flash
CDCl ): δ = –0.01 (s, 3 H), 0.02 (s, 3 H), 0.72 (d, J = 7.0 Hz, 3 H),
3
chromatography (petroleum ether/ethyl acetate, 95:5) gave 11
0.84 (t, J = 7.5 Hz, 3 H), 0.88 (s, 9 H), 1.13 (t, J = 7.5 Hz, 3 H),
1.53 (m, 2 H), 1.66 (s, 3 H), 1.81 (m, 1 H), 2.31 (q, J = 7.5 Hz, 2
H), 3.73 (ddd, J = 8.5, 5.8, 1.5 Hz, 1 H), 4.95–4.97 (m, 2 H, 6-H),
(
f
7.69 g, 28.4 mmol, 95%) as a colourless oil. R : 0.36 (petroleum
20
1
ether/ethyl acetate, 8:2). [α]
D 3
= +24.4 (c = 0.9, CHCl ). H NMR
1
3
(400 MHz, CDCl
3 3
): δ = 0.02 (s, 3 H), 0.04 (s, 3 H), 0.85 (t, J = 4.99 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = –5.1, –3.8,
7.5 Hz, 3 H), 0.88 (s, 9 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.41 (m, 1 8.3, 9.2, 10.2, 17.5, 18.2, 25.9, 27.9, 28.2, 37.5, 71.8, 79.4, 115.4,
Eur. J. Org. Chem. 2015, 4198–4213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4205

D. Becker, U. Kazmaier
FULL PAPER
1
2
42.4, 173.4 ppm. HRMS (CI): calcd. for C14
71.1724; found 271.1706.
H
27
O
3
Si [M – C
4
H
9
]+
freshly distilled diisopropylamine (3.11 mL, 21.8 mmol) in anhy-
drous THF (21 mL) in a dry Schlenk flask at –30 °C under nitro-
gen. After 5 min at this temperature, the mixture was stirred at
room temperature for 30 min, and was cooled to –78 °C. In a sec-
N-Allyloxycarbonylglycine-[(3S,4R,5R)-5-(tert-butyldimethylsilyl-
oxy)-2,4-dimethylhept-1-en-3-yl] Ester (14b): Following the method
used for the synthesis of allylic ester 14a, 14b was prepared from
N-Alloc-glycine (0.33 g, 2.07 mmol), allylic alcohol 12 (0.47 g,
1
2
ond Schlenk flask ZnCl
(
(
2
(1.19 g, 8.73 mmol) and allylic ester 14b
3.01 g, 7.28 mmol) were dissolved successively in anhydrous THF
17 mL) under nitrogen, and the solution was cooled to –78 °C.
.72 mmol), DMAP (42.0 mg, 0.34 mmol), and DCC (0.53 g,
.57 mmol) in anhydrous diethyl ether (12 mL). Purification by
The base solution was slowly transferred to the substrate solution
at –78 °C by cannula. The reaction mixture was allowed to warm
to room temperature overnight, then it was diluted with diethyl
ether, quenched with HCl (1 m aq.), and extracted with diethyl
ether. The organic layer was further washed with HCl (1 m aq.) and
flash chromatography (petroleum ether/ethyl acetate, 9:1) gave all-
ylic ester 14b (0.70 g, 1.70 mmol, 99%) as a colourless oil. R : 0.19
= –9.1 (c = 1.1, CHCl ).
): δ = –0.03 (s, 3 H), 0.03 (s, 3 H), 0.73
f
2
0
(
petroleum ether/ethyl acetate, 9:1). [α]
H NMR (400 MHz, CDCl
D
3
1
3
brine, dried with Na
crude acid.
2 4
SO , and concentrated in vacuo to give the
(
(
d, J = 7.0 Hz, 3 H), 0.84 (t, J = 7.5 Hz, 3 H), 0.88 (s, 9 H), 1.51
m, 2 H), 1.66 (s, 3 H), 1.84 (m, 1 H), 3.69 (m, 1 H), 3.96 (d, J =
5
.0 Hz, 2 H), 4.58 (d, J = 5.5 Hz, 2 H), 4.98 (m, 1 H), 5.01 (s, 1
The crude acid was dissolved in anhydrous DMF (17 mL), and the
CO (1.21 g, 8.73 mmol) and allyl
H), 5.06 (d, J = 10.3 Hz, 1 H), 5.17–5.23 (m, 2 H), 5.31 (ddt, J = solution was cooled to 0 °C. K
2
3
1
7.3, 1.5, 1.5 Hz, 1 H), 5.91 (ddt, J = 17.1, 10.3, 5.8 Hz, 1 H) ppm.
bromide (1.89 mL, 21.8 mmol) were added. The mixture was al-
lowed to warm to room temperature overnight, then it was diluted
1
3
C NMR (100 MHz, CDCl
3
): δ = –5.1, –3.7, 8.2, 10.2, 17.3, 18.2,
2
1
3
5.9, 27.9, 37.4, 42.9, 65.8, 71.7, 81.1, 116.3, 117.8, 132.6, 141.6,
with H
layers were further washed with H
5
Si (413.62): calcd. C 60.98, and concentrated under reduced pressure. Purification by flash
2
O, and extracted with ethyl acetate. The combined organic
+
55.9, 169.1 ppm. HRMS (CI): calcd. for C17
56.1888; found 356.1911. C21 39NO
H
30NO
5
Si [M – C
4
H
9
]
2
O and brine, dried with Na SO ,
2
4
H
H 9.50, N 3.39; found C 61.09, H 9.49, N 3.36.
chromatography (petroleum ether/ethyl acetate, 9:1) gave unsatu-
rated allylic ester 15b (3.15 g, 6.94 mmol, 95%) as a colourless oil.
(
2S,6R,7R,E)-7-(tert-Butyldimethylsilyloxy)-2,4,6-trimethylnon-4-
n-Butyllithium (2.5 m in hexane; 4.55 mL,
1.4 mmol) was added to a solution of freshly distilled diisopropyl-
20
R
f
: 0.30 (petroleum ether/ethyl acetate, 9:1). [α]
CHCl
NMR (400 MHz, CDCl
J = 7.4 Hz, 3 H), 0.87–8.89 (m, 12 H), 1.43 (m, 2 H), 1.64 (d, J =
.0 Hz, 3 H), 2.28 (dd, J = 13.6, 9.0 Hz, 1 H), 2.46 (m, 1 H), 2.54
D
= +7.3 (c = 1.8,
[
24–26]
enoic Acid (15a):
1
1
3
). 94:6 Mixture of diastereomers. Major diastereomer:
H
3
): δ = 0.02 (s, 3 H), 0.03 (s, 3 H), 0.83 (t,
amine (1.70 mL, 11.9 mmol) in anhydrous THF (19 mL) in a dry
Schlenk flask at –30 °C under nitrogen. After 5 min at this tem-
perature, the mixture was stirred at room temperature for 30 min.
DMPU (4.80 mL, 39.7 mmol, 19 vol.-%) was added, and the solu-
tion was cooled to –78 °C. In a second Schlenk flask, allylic ester
1
(
(
(
(
3
1
dd, J = 13.4, 4.9 Hz, 1 H), 3.40 (dt, J = 5.3, 5.3 Hz, 1 H), 4.45
ddd, J = 8.5, 8.5, 5.3 Hz, 1 H), 4.53–4.63 (m, 4 H), 5.06–5.10
13
m, 2 H), 5.18–5.36 (m, 4 H), 5.84–5.96 (m, 2 H) ppm. C NMR
1
4a (1.87 g, 5.69 mmol) was dissolved in anhydrous THF (19 mL)
100 MHz, CDCl
3
): δ = –4.5, –4.2, 8.9, 15.9, 16.4, 18.2, 25.9, 27.2,
6.9, 42.8, 52.2, 65.7, 65.9, 76.9, 117.7, 118.8, 128.5, 131.6, 132.6,
33.7, 155.6, 172.2 ppm. HRMS (CI): calcd. for C24 Si [M
under nitrogen, and the solution was cooled to –78 °C. The base
solution was slowly transferred to the substrate solution at –78 °C
by cannula. After 30 min, TMSCl (2.55 mL, 19.9 mmol) was
added, and stirring was continued for 60 min at this temperature.
The cooling bath was removed, and the reaction mixture was al-
lowed to warm to room temperature. The mixture was then heated
to 60 °C for 16 h, after which time it was allowed to cool to room
temperature. The mixture was diluted with diethyl ether, and
quenched with HCl (1 m aq.). The organic layer was further washed
H
44NO
5
+
+
H] 454.2983; found 454.2972.
Allyl (2S,6R,7R,E)-7-Hydroxy-2,4,6-trimethylnon-4-enoate (16a):
Following the method used for the esterification and deprotection
of 5, 16a was prepared from 15a (0.38 g, 1.16 mmol), K
(0.18 g, 1.29 mmol), and allyl bromide (0.20 mL, 2.29 mmol) in an-
hydrous DMF (12 mL) and THF (2.7 mL), H O (2.7 mL), and
2 3
CO
2
with HCl (1 m aq.) and brine, dried with Na
2
SO
4
, and concentrated
AcOH (8.1 mL). Purification by flash chromatography (petroleum
in vacuo. Purification by flash chromatography (petroleum ether/
ether/ethyl acetate, 9:1) gave 16a (0.27 g, 1.06 mmol, 91%) as a
ethyl acetate, 9:1) gave unsaturated acid 15a (0.41 g, 1.25 mmol,
colourless oil, a 9:1 mixture of diastereomers. R
f
: 0.15 (petroleum
= +24.1 (c = 1.1, CHCl ). Major dia-
stereomer: H NMR (400 MHz, CDCl ): δ = 0.93 (t, J = 7.5 Hz, 3
3
): δ = H), 0.95 (d, J = 6.8 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3 H), 1.26 (m, 1
2
0
2
2%) as a colourless oil, and a 9:1 mixture of diastereomers. R
f
:
ether/ethyl acetate, 9:1). [α]
D
3
20
1
0
.25 (petroleum ether/ethyl acetate, 9:1). [α]
). Major diastereomer: 1H NMR (400 MHz, CDCl
.03 (s, 6 H), 0.82 (t, J = 7.5 Hz, 3 H), 0.89–0.90 (m, 12 H), 1.12
d, J = 7.0 Hz, 3 H), 1.43 (m, 2 H), 1.62 (s, 3 H), 2.03 (dd, J =
D
= +2.4 (c = 0.9,
3
CHCl
0
3
H), 1.48 (br. s, 1 H), 1.54 (m, 1 H), 1.63 (d, J = 1.5 Hz, 3 H), 2.06
(dd, J = 13.4, 7.2 Hz, 1 H), 2.39 (dd, J = 13.6, 8.3 Hz, 1 H), 2.44
(m, 1 H), 2.65 (m, 1 H), 3.27 (ddd, J = 9.3, 6.3, 3.3 Hz, 1 H), 4.54
(m, 2 H), 5.01 (d, J = 9.8 Hz, 1 H), 5.22 (ddt, J = 10.5, 1.3, 1.3 Hz,
(
1
2
1
1
1
3.6, 8.0 Hz, 1 H), 2.39 (dd, J = 13.1, 6.5 Hz, 1 H), 2.45 (m, 1 H),
.62 (m, 1 H), 3.39 (dt, J = 6.5, 5.0 Hz, 1 H), 5.04 (d, J = 9.3 Hz,
H) ppm. 13C NMR (100 MHz, CDCl
3
): δ = –4.5, –4.2, 8.5, 15.8, 1 H), 5.31 (ddt, J = 17.1, 1.5, 1.5 Hz, 1 H), 5.90 (ddt, J = 17.3,
1
3
6.2, 16.9, 18.2, 25.9, 27.4, 36.8, 37.7, 43.8, 76.9, 130.4, 131.6, 10.5, 5.5 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 10.4,
1
82.8 ppm. Minor diastereomer (selected signals): H NMR 16.1, 16.3, 16.8, 26.9, 38.1, 38.3, 44.2, 64.9, 77.3, 117.9, 129.9,
1
3
(400 MHz, CDCl ): δ = 0.04 (s, 6 H), 0.83 (t, J = 7.5 Hz, 3 H), 132.3, 132.8, 176.1 ppm. Minor diastereomer (selected signals): H
.67 (s, 3 H), 5.14 (d, J = 9.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
): δ = 8.7, 27.3, 36.9, 37.8, 130.6, 131.3 ppm. HRMS (CI): NMR (100 MHz, CDCl
calcd. for C18 77.4, 129.8, 132.3, 132.7 ppm. HPLC (OD-H; hexane/iPrOH, 95:5;
Si [M – H]– 327.2361; found 327.2348.
Si (328.56): calcd. C 65.80, H 11.04; found C 65.36, H 0.5 mL/min): (R)-16a: t = 10.19 min; (S)-16a: t = 10.83 min.
HRMS (CI): calcd. for C15
[M + H]+ 255.1955; found
55.1925; calcd. for C15
[M]+ 254.1876; found 254.1870.
NMR (400 MHz, CDCl
): δ = 1.12 (d, J = 7 Hz, 3 H) ppm.
3
): δ = 10.3, 16.4, 16.7, 27.2, 38.4, 44.0,
13
C
1
3
CDCl
3
35 3
H O
C
1
18
H
36
O
3
R
R
0.73.
27 3
H O
2
26 3
H O
Allyl (2S,6R,7R,E)-2-(Allyloxycarbonylamino)-7-(tert-butyldi-
methylsilyloxy)-4,6-dimethylnon-4-enoate (15b):[ n-Butyllithium
32]
Allyl (2S,6R,7R,E)-2-(Allyloxycarbonylamino)-7-hydroxy-4,6-di-
methylnon-4-enoate (16b): Following the method used for the de-
(2.5 m in hexane; 8.44 mL, 21.1 mmol) was added to a solution of
4206
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4198–4213

Dichlorinated Chondramide Derivatives
protection of 5, 16b was prepared from 15b (3.03 g, 6.68 mmol),
(t, J = 7.4 Hz, 3 H), 1.01 (s, 9 H), 1.09 (d, J = 7.0 Hz, 3 H), 1.42
(s, 9 H), 1.47 (m, 2 H), 1.57 (s, 3 H), 2.04 (dd, J = 13.6, 7.5 Hz, 1
H), 2.17 (m, 2 H), 2.38 (dd, J = 13.6, 7.3 Hz, 1 H), 2.63 (tq, J =
7.3, 7.3 Hz, 1 H), 2.74 (m, 1 H), 2.81 (dd, J = 15.3, 6.3 Hz, 1 H),
4.54 (ddd, J = 5.5, 1.5, 1.5 Hz, 2 H), 4.71 (tt, J = 6.5, 6.5 Hz, 1 H),
4.99 (m, 1 H), 5.07 (t, J = 7.3 Hz, 1 H), 5.22 (d, J = 11.0 Hz, 1 H),
5.30 (ddt, J = 17.3, 1.3, 1.3 Hz, 1 H), 5.58 (br. s, 1 H), 5.90 (ddt, J
= 17.1, 10.3, 5.8 Hz, 1 H), 6.81 (d, J = 8.3 Hz, 1 H), 7.05 (dd, J =
THF (16 mL), H
2
O (16 mL), and AcOH (48 mL). Purification by
flash chromatography (petroleum ether/ethyl acetate, 7:3) gave 16b
(
2.24 g, 6.60 mmol, 99%) as a colourless oil, a 94:6 mixture of dia-
2
0
f D
stereomers. R : 0.23 (petroleum ether/ethyl acetate, 7:3). [α] =
+
1
17.7 (c = 1.2, CHCl
3
). Major diastereomer: H NMR (400 MHz,
CDCl
3
): δ = 0.93–0.97 (m, 6 H), 1.31 (m, 1 H), 1.49–1.58 (m, 2 H),
1
1
3
.67 (d, J = 1.0 Hz, 3 H), 2.31 (dd, J = 13.6, 8.3 Hz, 1 H), 2.46 (m,
H), 2.54 (dd, J = 13.6, 5.5 Hz, 1 H), 3.31 (ddd, J = 9.0, 6.0, 8.4, 2.4 Hz, 1 H), 7.27 (d, J = 2.3 Hz, 1 H) ppm. C NMR
.3 Hz, 1 H), 4.48 (ddd, J = 8.3, 8.3, 5.5 Hz, 1 H), 4.54–4.67 (m, 4 (100 MHz, CDCl ): δ = –4.4, 9.5, 15.9, 15.9, 16.6, 16.7, 18.3, 25.6,
1
3
3
H), 5.09 (d, J = 9.0 Hz, 1 H), 5.16 (br. s, 1 H), 5.18–5.36 (m, 4 H), 26.2, 28.3, 31.9, 32.0, 37.9, 40.8, 43.8, 43.8, 50.4, 64.9, 75.9, 79.7,
5
1
1
.85–5.96 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl
5.9, 16.4, 27.0, 38.3, 42.9, 52.6, 65.8, 65.9, 77.2, 117.8, 118.9, 150.8, 154.9, 170.6, 175.9 ppm. Minor diastereomer (selected sig-
3
): δ = 10.4, 118.0, 120.6, 121.4, 121.5, 125.4, 125.6, 128.0, 132.3, 135.2, 135.2,
1
30.3, 131.5, 132.3, 132.6, 155.6, 171.9 ppm. HPLC (OD-H; hex-
R
= 9.49 min; (S)-16b: t =
nals): H NMR (400 MHz, CDCl
1.56 (s, 3 H), 6.76 (d, J = 8.5 Hz, 1 H) ppm. HPLC (OD-H; hexane/
3
): δ = 0.78 (t, J = 6.5 Hz, 3 H),
ane/iPrOH, 8:2; 0.5 mL/min): (R)-16b: t
0.33 min. HRMS (CI): calcd. for C18
found 340.2112. C18 29NO (339.43): calcd. C 63.69, H 8.61, N 10.29/10.75 min. HPLC–MS (H
.13; found C 63.52, H 8.49, N 4.04. 10.72 min; m/z = 674 [C34 54ClNO
for C34 55ClNO
Si [M + H]+ 652.3431; found 652.3439.
54ClNO Si (652.33): calcd. C 62.60, H 8.34, N 2.15; found C
2.35, H 8.38, N 2.37.
R
+
1
H
30NO
5
[M + H] 340.2118; iPrOH, 95:5; 0.5 mL/min): (S)-18b: t
R
= 9.52 min; (R)-18b: t
R
=
=
H
5
2
O/MeCN, 1:9; 0.6 mL/min): t
R
+
4
H
7
Si + Na] . HRMS (CI): calcd.
H
7
N-tert-Butoxycarbonyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-
phenylalanine-{[(R,E)-4-methylnon-4-enoic Acid Allyl Ester]-7-yl}
Ester (18a): DMAP (13.0 mg, 0.10 mmol) and DCC (116 mg,
34
C H
7
6
0
.56 mmol) were added to a solution of chlorinated β-tyrosine de-
rivative 17 (0.21 g, 0.51 mmol) and ω-hydroxy ester 5a (127 mg,
.56 mmol, 84% ee) in anhydrous diethyl ether (3.4 mL) at 0 °C,
N-tert-Butoxycarbonyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-
phenylalanine-{[(2S,6S,7R,E)-2,4,6-trimethylnon-4-enoic Acid Allyl
Ester]-7-yl} ester (18c): Following the method used for the synthesis
0
and the mixture was allowed to warm up to room temperature of β-tyrosine ester 18a, ester 18c was prepared from chlorinated
overnight. The precipitate was removed by filtration. The filtrate
was washed twice with KHSO (1 m aq.), H O, satd. aq. NaHCO
and brine, dried with Na SO , and concentrated in vacuo. Purifica-
β-tyrosine derivative 17 (0.32 g, 0.74 mmol), ω-hydroxy ester 16a
(0.21 g, 0.82 mmol), DMAP (18.0 mg, 0.15 mmol), and DCC
(0.23 g, 1.11 mmol) in anhydrous diethyl ether (5 mL). Purification
by flash chromatography (petroleum ether/ethyl acetate, 8:2) gave
4
2
3
,
2
4
tion by flash chromatography (petroleum ether/ethyl acetate, 8:2)
gave β-tyrosine ester 18a (309 mg, 0.48 mmol, 95%) as a colourless
f
ester 18c (0.44 g, 0.66 mmol, 89%) as a colourless oil. R : 0.37 (pe-
2
0
1
oil, a 92:8 mixture of diastereomers. R
f
: 0.30 (petroleum ether/ethyl
= +26.2 (c = 1.9, CHCl ). Major diastereomer:
H NMR (400 MHz, CDCl ): δ = 0.19 (s, 6 H), 0.71 (t, J = 7.3 Hz, H), 0.80 (d, J = 6.5 Hz, 3 H), 1.01 (s, 9 H), 1.11 (d, J = 7.0 Hz, 3
H), 1.01 (s, 9 H), 1.42 (s, 9 H), 1.47 (m, 2 H), 1.60 (s, 3 H), 2.16 H), 1.30 (m, 1 H), 1.41 (s, 9 H), 1.49 (m, 1 H), 1.57 (d, J = 1.3 Hz,
m, 2 H), 2.31 (m, 2 H), 2.42 (m, 2 H), 2.74 (dd, J = 15.3, 6.0 Hz, 3 H), 2.02 (dd, J = 13.7, 6.9 Hz, 1 H), 2.39 (dd, J = 13.6, 7.5 Hz,
troleum ether/ethyl acetate, 8:2). [α]
D 3
= +22.7 (c = 1.4, CHCl ). H
20
acetate, 8:2). [α]
D
3
NMR (400 MHz, CDCl ): δ = 0.19 (s, 6 H), 0.63 (t, J = 7.3 Hz, 3
3
1
3
3
(
1
1
H), 2.81 (dd, J = 14.6, 6.0 Hz, 1 H), 4.56 (ddd, J = 5.8, 1.5, 1 H), 2.51 (m, 1 H), 2.63 (m, 1 H), 2.77 (dd, J = 15.6, 6.0 Hz, 1
.5 Hz, 2 H), 4.71 (tt, J = 6.0, 6.0 Hz, 1 H), 4.99 (m, 1 H), 5.07 (t, H), 2.85 (dd, J = 15.3, 6.0 Hz, 1 H), 4.54 (m, 2 H), 4.60 (ddd, J =
J = 7.3 Hz, 1 H), 5.23 (ddt, J = 10.4, 1.3, 1.3 Hz, 1 H), 5.31 (ddt,
J = 17.3, 1.5, 1.5 Hz, 1 H), 5.57 (br. s, 1 H), 5.90 (ddt, J = 17.3,
8.3, 8.3, 3.3 Hz, 1 H), 4.92 (d, J = 8.8 Hz, 1 H), 4.99 (br. s, 1 H),
5.22 (ddt, J = 10.3, 1.3, 1.3 Hz, 1 H), 5.30 (ddt, J = 17.3, 1.8,
1.8 Hz, 1 H), 5.59 (br. s, 1 H), 5.90 (ddt, J = 17.1, 10.3, 5.8 Hz, 1
1
2
0.5, 5.8 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 7.05 (dd, J = 8.5,
.3 Hz, 1 H), 7.27 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR (100 MHz, H), 6.81 (d, J = 8.5 Hz, 1 H), 7.06 (dd, J = 8.4, 2.1 Hz, 1 H), 7.28
1
3
3 3
CDCl ): δ = –4.4, 9.6, 16.1, 18.3, 25.6, 26.2, 28.3, 32.0, 33.0, 34.6, (d, J = 2.3 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = –4.4,
4
1
0.8, 50.4, 65.0, 75.9, 79.7, 118.2, 119.8, 120.6, 125.4, 125.6, 128.0,
32.2, 136.3, 136.3, 150.8, 154.9, 170.6, 172.9 ppm. Minor dia-
9.5, 16.1, 16.8, 16.9, 18.3, 24.6, 25.6, 28.3, 35.9, 37.9, 40.7, 43.8,
50.4, 64.9, 79.7, 79.7, 118.0, 120.6, 125.4, 125.6, 128.1, 128.8, 132.3,
132.9, 135.3, 150.8, 154.9, 170.8, 175.9 ppm. HPLC (OD-H; hex-
1
stereomer (selected signals): H NMR (400 MHz, CDCl
t, J = 7.4 Hz, 3 H), 1.58 (s, 3 H), 6.76 (d, J = 8.5 Hz, 1 H) ppm.
HPLC (OD-H; hexane/iPrOH, 95:5; 0.5 mL/min): (S)-16b: t
3
): δ = 0.78
(
ane/iPrOH, 95:5; 0.5 mL/min): (S)-18c: t
= 11.43 min. HPLC–MS (H O/MeCN, 1:9; 0.6 mL/min): t
7.88 min; m/z = 688 [C35 56ClNO
for C35 56ClNO
Si [M + H]+ 666.3587; found 666.3589.
56ClNO Si (666.36): calcd. C 63.09, H 8.47, N 2.10; found C
R
= 9.84 min; (R)-18c: t
R
R
=
2
R
=
+
1
0
0.16 min; (R)-16b: t
.6 mL/min): t = 8.51 min; m/z = 660 [C33
53ClNO
R
= 10.89 min. HPLC–MS (H
2
O/MeCN, 1:9;
H
7
Si + Na] . HRMS (CI): calcd.
+
R
H
52ClNO
7
Si + Na] .
H
7
+
HRMS (CI): calcd. for C33
38.3237. C33 52ClNO
found C 62.18, H 8.26, N 2.61.
H
7
Si [M + H] 638.3274; found
35
C H
7
6
H
7
Si (638.31): calcd. C 62.09, H 8.21, N 2.19; 62.69, H 8.37, N 2.11.
N-tert-Butoxycarbonyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-
N-tert-Butoxycarbonyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β- phenylalanine-{[(2S,6R,7R,E)-2-(allyloxycarbonylamino)-4,6-di-
phenylalanine-{[(7R,E)-2,4-dimethylnon-4-enoic Acid Allyl Ester]-7- methylnon-4-enoic Acid Allyl Ester]-7-yl} Ester (18d): Following the
yl} Ester (18b): Following the method used for the synthesis of β-
tyrosine ester 18a, ester 18b was prepared from chlorinated β-tyro-
sine derivative 17 (0.60 g, 1.39 mmol), ω-hydroxy ester 5b (0.34 g,
method used for the synthesis of β-tyrosine ester 18a, ester 18d was
prepared from chlorinated β-tyrosine derivative 17 (0.69 g,
1.60 mmol), ω-hydroxy ester 16b (0.60 g, 1.77 mmol), DMAP
1
1
.41 mmol), DMAP (17.0 mg, 0.14 mmol), and DCC (0.32 g, (39.0 mg, 0.32 mmol), and DCC (0.49 g, 2.37 mmol) in anhydrous
.55 mmol) in anhydrous diethyl ether (9.4 mL). Purification by
diethyl ether (11 mL). Purification by flash chromatography (petro-
flash chromatography (petroleum ether/ethyl acetate, 9:1) gave ester
8b (0.83 g, 1.27 mmol, 91%) as a colourless oil, a 92:8 mixture of
diastereomers. R : 0.16 (petroleum ether/ethyl acetate, 9:1). Major
leum ether/ethyl acetate, 8:2) gave ester 18d (1.06 g, 1.41 mmol,
1
88%) as a colourless oil, a 94:6 mixture of diastereomers. R
f
: 0.19
= +21.7 (c = 1.2, CHCl ).
Major diastereomer: H NMR (400 MHz, CDCl ): δ = 0.19 (s, 6
2
0
f
(petroleum ether/ethyl acetate, 8:2). [α]
D
3
1
1
diastereomer: H NMR (400 MHz, CDCl
3
): δ = 0.19 (s, 6 H), 0.71
3
Eur. J. Org. Chem. 2015, 4198–4213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4207

D. Becker, U. Kazmaier
FULL PAPER
H), 0.66 (t, J = 7.0 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H), 1.01 (s, 9 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl
H), 1.33 (m, 1 H), 1.41 (s, 9 H), 1.49 (m, 1 H), 1.60 (s, 3 H), 2.32 16.1, 80.6, 122.7, 128.5, 168.3 ppm. HPLC–MS (H O/MeCN, 1:9;
dd, J = 13.7, 7.9 Hz, 1 H), 2.49–2.58 (m, 2 H), 2.79 (dd, J = 15.1, 0.6 mL/min): t = 7.76 min; m/z = 965 [C48
.8 Hz, 1 H), 2.85 (dd, J = 15.1, 5.8 Hz, 1 H), 4.48 (m, 1 H), 4.54– HRMS (CI): calcd. for C48 70Cl Si [M + 2H] 944.4284;
): δ = 9.5,
3
2
+
(
R
2 4 9
H68Cl N O Si + Na] .
+
5
4
5
8
1
1
7
1
H
2 4 9
N O
.66 (m, 5 H), 4.96 (d, J = 9.8 Hz, 1 H), 5.01 (br. s, 1 H), 5.18–
.36 (m, 5 H), 5.54 (br. s, 1 H), 5.95–5.95 (m, 2 H), 6.81 (d, J =
.5 Hz, 1 H), 7.06 (dd, J = 8.4, 2.1 Hz, 1 H), 7.28 (d, J = 2.0 Hz,
found 944.4284.
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-2-chlorotrypto-
phanyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-phenylalanine-
[(7R,E)-2,4-dimethylnon-4-enoic Acid Allyl Ester]-7-yl} Ester (19b):
Tripeptide 19b was prepared following the method used for the
synthesis of 19a, starting from β-tyrosine ester 18b (0.43 g,
.66 mmol) and TFA (2.02 mL, 26.3 mmol) in anhydrous CH
4.7 mL), and chlorinated dipeptide A (0.33 g, 0.78 mmol), iPr NEt
0.21 mL, 1.18 mmol), and COMU® (0.34 g, 0.79 mmol) in anhy-
Cl (1.9 mL). Purification by flash chromatography (pe-
troleum ether/ethyl acetate, 7:3) gave 19b (0.50 g, 0.52 mmol, 79%)
as a slightly yellow foam, an 82:18 mixture of diastereomers. R
H) ppm. 13C NMR (100 MHz, CDCl
3
): δ = –4.4, 9.7, 16.2, 16.3,
{
8.3, 24.5, 25.6, 28.3, 35.9, 40.7, 42.7, 50.4*, 52.2, 65.8, 65.9, 79.3,
9.8, 117.8, 118.9, 120.6, 125.5, 125.6, 128.1, 130.7, 131.1, 131.5,
32.6, 135.3, 150.8, 154.9, 155.6, 170.8, 171.9 ppm (*determined
0
(
(
2 2
Cl
from C,H-COSY). HPLC (Reprosil; hexane/iPrOH, 6:4; 1 mL/
min): (R)-18d: t = 6.23 min; (S)-18d: t = 7.07 min. HPLC–MS
O/MeCN, 2:8; 0.6 mL/min): t = 13.59 min; m/z = 773
Si + Na] . HRMS (CI): calcd. for C34 50ClN Si
]+ 693.2969; found 693.2935. C38
59ClN Si (751.42):
2
R
R
(
H
2
R
drous CH
2
2
+
[
[
C
M – C
38
H
59ClN
2
O
9
H
2 9
O
4
H
9
H
2 9
O
f
:
calcd. C 60.74, H 7.91, N 3.73; found C 60.37, H 7.96, N 3.54.
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-2-chlorotrypto- NMR (400 MHz, CDCl
phanyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-phenylalanine- H), 0.74 (t, J = 7.4 Hz, 3 H), 1.02 (s, 9 H), 1.10 (d, J = 6.8 Hz, 3
1
0
.20 (petroleum ether/ethyl acetate, 7:3). Major diastereomer: H
3
): δ = 0.20 (s, 6 H), 0.68 (d, J = 6.8 Hz, 3
{
[(R,E)-4-methylnon-4-enoic Acid Allyl Ester]-7-yl} Ester (19a): A
solution of β-tyrosine ester 18a (0.50 g, 0.78 mmol) in anhydrous
CH Cl
.40 mL, 31.5 mmol) at –20 °C, and the mixture was stirred for 7.5 Hz, 1 H), 2.95 (s, 3 H), 3.21 (dd, J = 15.1, 10.8 Hz, 1 H), 3.41
H), 1.37 (s, 9 H), 1.43 (m, 2 H), 1.58 (s, 3 H), 2.05 (dd, J = 13.6,
7.8 Hz, 1 H), 2.15 (m, 2 H), 2.39 (dd, J = 13.2, 6.9 Hz, 1 H), 2.63
2
(5.6 mL) was treated with TFA (trifluoroacetic acid; (m, 1 H), 2.74 (dd, J = 16.1, 4.8 Hz, 1 H), 2.90 (dd, J = 15.8,
2
2
1
6 h at this temperature. The mixture was poured into satd. aq.
, and extracted with CH Cl . The combined organic lay-
(dd, J = 15.3, 5.8 Hz, 1 H), 4.26 (dq, J = 6.8, 6.8 Hz, 1 H), 4.54
(ddd, J = 5.8, 1.3, 1.3 Hz, 2 H), 4.71 (tt, J = 6.5, 6.5 Hz, 1 H),
NaHCO
3
2
2
ers were further washed with brine, dried with Na
centrated in vacuo.
2
SO
4
, and con- 5.05–5.09 (m, 2 H), 5.21 (ddt, J = 9.3, 1.0, 1.0 Hz, 1 H), 5.30 (ddt,
J = 17.3, 1.0, 1.0 Hz, 1 H), 5.35 (ddd, J = 7.0, 7.0, 7.0 Hz, 1 H),
5
1
8
.63 (dd, J = 10.5, 5.5 Hz, 1 H), 5.89 (ddt, J = 17.3, 10.5, 5.5 Hz,
H), 6.77 (d, J = 8.3 Hz, 1 H), 7.02–7.04 (m, 2 H), 7.07 (dd, J =
.0, 8.0 Hz, 1 H), 7.12 (dd, J = 6.8, 6.8 Hz, 1 H), 7.19–7.23 (m, 2
The resulting crude amine was dissolved in anhydrous CH
2
Cl
2
(2.3 mL), and the solution was cooled to at 0 °C. Chlorinated di-
2
peptide A (0.40 g, 0.94 mmol), iPr NEt (0.25 mL, 1.42 mmol), and
1
3
COMU® [(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethyl-
aminomorpholinocarbenium hexafluorophosphate][40] (0.40 g,
H), 7.49 (d, J = 7.8 Hz, 1 H), 8.33 (br. s, 1 H) ppm. C NMR
(100 MHz, CDCl ): δ = –4.4, 9.4, 15.9, 16.6, 16.6, 18.3, 22.3, 25.6,
6.0, 28.3, 31.6, 31.9, 37.9, 40.3*, 43.8, 46.4, 49.1, 56.3, 64.9, 75.8,
3
2
7
1
1
0.94 mmol) were added. The mixture was allowed to warm up to
9.8, 107.3, 110.4, 118.0, 118.3, 120.2, 120.6, 120.7, 121.4, 122.3,
25.5, 125.8, 127.3, 128.3, 132.3, 134.4, 134.6, 136.1, 150.9, 155.6,
room temperature overnight, then it was concentrated to dryness,
and the residue was dissolved in ethyl acetate. The organic layer
69.2, 170.2, 174.2, 176.1 ppm (*determined from C,H-COSY).
was washed with KHSO
brine, dried with Na SO
4
(1 m aq.), H
, and concentrated under reduced pres-
2 3
O, satd. aq. NaHCO , and
1
Minor diastereomer (selected signals): H NMR (400 MHz,
2
4
CDCl
.71 (s, 3 H), 3.31 (dd, J = 15.6, 3.8 Hz, 1 H), 4.01 (m, 1 H), 4.77
m, 1 H), 4.86 (d, J = 6.3 Hz, 1 H), 4.93 (dd, J = 10.9, 3.4 Hz, 1
H), 5.47 (m, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1
3
): δ = 0.19 (s, 6 H), 1.01 (s, 9 H), 1.39 (s, 9 H), 1.59 (s, 3 H),
sure. Purification by flash chromatography (petroleum ether/ethyl
acetate, 7:3) gave 19a (0.52 g, 0.55 mmol, 70%) as a slightly yellow
2
(
f
foam, an 86:14 mixture of diastereomers. R : 0.17 (petroleum ether/
1
ethyl acetate, 7:3). Major diastereomer: H NMR (400 MHz,
CDCl ): δ = 0.20 (s, 6 H), 0.67 (d, J = 6.8 Hz, 3 H), 0.74 (t, J =
.4 Hz, 3 H), 1.01 (s, 9 H), 1.37 (s, 9 H), 1.43 (m, 2 H), 1.60 (s, 3
H), 2.15 (m, 2 H), 2.32 (dd, J = 8.0, 8.0 Hz, 2 H), 2.43 (dd, J =
1
3
H) ppm. C NMR (100 MHz, CDCl
28.5. 150.8, 154.9, 155.6, 170.8, 171.9 ppm. HPLC (OD-H; hex-
ane/iPrOH, 9:1; 1 mL/min): (R/S)-19b: t = 14.08 min. HPLC–MS
O/MeCN, 1:9; 0.6 mL/min): (R/S)-19b: t = 10.15 min; m/z =
Si + Na] . HRMS (CI): calcd. for
3
): δ = –4.4, 9.5, 16.5, 122.7,
3
1
7
R
(
H
2
R
9.5, 8.0 Hz, 2 H), 2.78 (dd, J = 16.1, 7.0 Hz, 1 H), 2.89 (dd, J =
15.9, 7.7 Hz, 1 H), 2.95 (s, 3 H), 3.20 (dd, J = 15.2, 10.9 Hz, 1 H),
3.41 (dd, J = 15.3, 5.5 Hz, 1 H), 4.25 (dq, J = 6.8, 6.8 Hz, 1 H),
4
5
+
9
2 4 9
79 [C4 9 H7 0 Cl N O
+
49 2 4 9
C H71Cl N O Si [M + H] 957.4362; found 957.4401.
.56 (ddd, J = 5.5, 1.3, 1.3 Hz, 2 H), 4.71 (tt, J = 5.8, 5.8 Hz, 1 H), N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-2-chlorotrypto-
.05–5.09 (m, 2 H), 5.22 (ddt, J = 10.3, 1.3, 1.3 Hz, 1 H), 5.30 (ddt, phanyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-phenylalanine-
J = 17.2, 1.4, 1.4 Hz, 1 H), 5.36 (ddd, J = 7.3, 7.3 Hz, 1 H), 5.63
{[(2S,6S,7R,E)-2,4,6-trimethylnon-4-enoic Acid Allyl Ester]-7-yl}
(dd, J = 10.5, 5.3 Hz, 1 H), 5.90 (ddt, J = 17.3, 10.5, 5.8 Hz, 1 H), Ester (19c): Tripeptide 19c was prepared following the method used
6
6
7
.77 (d, J = 8.3 Hz, 1 H), 7.02–7.04 (m, 2 H), 7.07 (dd, J = 6.8,
for the synthesis of 19a, starting from β-tyrosine ester 18c (0.36 g,
Cl
NEt
(114 μL, 0.65 mmol), and COMU® (0.28 g, 0.65 mmol) in anhy-
drous CH Cl (1.6 mL). Purification by flash chromatography (pe-
troleum ether/ethyl acetate, 7:3) gave 19c (0.51 g, 0.52 mmol, 96%)
as a slightly yellow foam, an 89:11 mixture of diastereomers. R
.8 Hz, 1 H), 7.11 (dd, J = 6.9, 6.9 Hz, 1 H), 7.19–7.23 (m, 2 H), 0.54 mmol) and TFA (1.68 mL, 21.8 mmol) in anhydrous CH
2
2
.49 (d, J = 7.8 Hz, 1 H), 8.39 (br. s, 1 H) ppm. 1 C NMR
3
(3.9 mL), and chlorinated dipeptide A (0.28 g, 0.66 mmol), iPr
2
(100 MHz, CDCl
3
): δ = –4.4, 9.5, 16.1, 16.4, 18.3, 22.3, 25.6, 26.1,
2
1
1
1
8.3, 31.6, 31.9, 32.9, 34.6, 40.3, 46.4, 49.1, 56.3, 65.0, 75.8, 79.8,
07.3, 110.4, 118.2, 118.3, 119.7, 120.1, 120.6, 121.6, 122.3, 125.5,
25.8, 127.3, 128.3, 132.2, 134.4, 134.6, 136.3, 150.8, 155.7, 169.2,
2
2
f
:
1
1
70.2, 172.9, 174.3 ppm. Minor diastereomer (selected signals): H 0.20 (petroleum ether/ethyl acetate, 7:3). Major diastereomer: H
NMR (400 MHz, CDCl
9
4
3
): δ = 0.19 (s, 6 H), 1.01 (s, 9 H), 1.39 (s, NMR (400 MHz, CDCl
H), 1.61 (s, 3 H), 2.71 (s, 3 H), 3.31 (dd, J = 15.6, 3.3 Hz, 1 H), 0.79 (d, J = 7.4 Hz, 3 H), 1.02 (s, 9 H), 1.10 (d, J = 6.8 Hz, 3 H),
.01 (m, 1 H), 4.77 (m, 1 H), 4.89 (d, J = 6.3 Hz, 1 H), 4.93 (dd, J 1.28 (m, 1 H), 1.37 (s, 9 H), 1.50 (m, 1 H), 1.57 (s, 3 H), 2.02 (dd,
3
): δ = 0.20 (s, 6 H), 0.64–0.69 (m, 6 H),
=
10.9, 3.4 Hz, 1 H), 5.47 (m, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 7.49 J = 13.7, 7.4 Hz, 1 H), 2.38 (dd, J = 13.7, 7.4 Hz, 1 H), 2.50 (m, 1
4
208 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 4198–4213
www.eurjoc.org

Dichlorinated Chondramide Derivatives
H), 2.62 (m, 1 H), 2.77 (dd, J = 15.8, 6.5 Hz, 1 H), 2.91–2.95 (m, luted with ethyl acetate, washed twice with HCl (1 m aq.) and brine,
4
1
4
1
H), 3.21 (dd, J = 15.3, 10.8 Hz, 1 H), 3.41 (dd, J = 15.3, 5.5 Hz,
H), 4.26 (dq, J = 6.8, 6.8 Hz, 1 H), 4.54 (m, 2 H), 4.58 (m, 1 H), fication by flash chromatography (petroleum ether/ethyl acetate, 7:3
.91 (d, J = 9.8 Hz, 1 H), 5.07 (d, J = 6.3 Hz, 1 H), 5.21 (ddt, J = to 1:1 + 1% AcOH) gave acid 20aЈ (0.34 g, 0.38 mmol, 99%) as a
2 4
dried with Na SO , and concentrated under reduced pressure. Puri-
0.5, 1.5, 1.5 Hz, 1 H), 5.30 (ddt, J = 16.8, 1.5, 1.5 Hz, 1 H), 5.34 colourless solid, an 86:14 mixture of diastereomers. R
leum ether/ethyl acetate, 7:3 + 1% AcOH). Major diastereomer: H
.89 (ddt, J = 17.3, 10.5, 5.5 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), NMR (400 MHz, CDCl ): δ = 0.20 (s, 6 H), 0.67 (t, J = 7.4 Hz, 3
.01–7.05 (m, 2 H), 7.07 (dd, J = 6.8, 6.8 Hz, 1 H), 7.12 (dd, J = H), 0.73 (d, J = 6.8 Hz, 3 H), 1.02 (s, 9 H), 1.38 (s, 9 H), 1.40 (m,
.9, 6.9 Hz, 1 H), 7.19–7.24 (m, 2 H), 7.49 (d, J = 7.5 Hz, 1 H), 2 H), 1.62 (s, 3 H), 2.18 (m, 2 H), 2.32 (m, 2 H), 2.48 (dd, J = 8.5,
f
: 0.16 (petro-
1
(ddd, J = 7.3, 7.3, 7.3 Hz, 1 H), 5.62 (dd, J = 10.5, 5.5 Hz, 1 H),
5
7
6
8
1
4
1
1
1
3
.27 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl
6.0 Hz, 2 H), 2.74 (dd, J = 13.3, 5.5 Hz, 1 H), 2.85 (dd, J = 15.6,
7.0 Hz, 1 H), 3.02 (s, 3 H), 3.22 (dd, J = 15.1, 10.3 Hz, 1 H), 3.36
(dd, J = 15.1, 5.8 Hz, 1 H), 4.40 (dq, J = 7.0, 7.0 Hz, 1 H), 4.75
(tt, J = 6.5, 6.5 Hz, 1 H), 5.11 (t, J = 6.7 Hz, 1 H), 5.31–5.37 (m,
3
): δ = –4.4, 9.5,
6.1, 16.6, 16.6, 17.1, 18.3, 22.3, 24.7, 25.6, 28.3, 31.6, 36.0, 37.9,
0.1, 43.8, 46.4, 49.1, 56.3, 64.9, 75.6, 79.8, 107.4, 110.4, 118.0,
18.4, 120.2, 120.7, 121.6, 122.4, 125.6, 125.9, 127.3, 128.3, 128.9,
32.3, 132.8, 134.4, 134.6, 150.9, 155.6, 169.2, 170.4, 174.2, 2 H), 5.59 (dd, J = 9.8, 5.8 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H),
1
76.0 ppm. Minor diastereomer (selected signals): H NMR 7.01 (d, J = 9.0 Hz, 1 H), 7.07 (dd, J = 7.5, 7.5 Hz, 1 H), 7.13 (dd,
(
1
400 MHz, CDCl
3
): δ = 0.19 (s, 6 H), 1.01 (s, 9 H), 1.40 (s, 9 H),
J = 8.0, 8.0 Hz, 1 H), 7.19–7.23 (m, 2 H), 7.38 (d, J = 8.3 Hz, 1
1
3
.59 (s, 3 H), 3.27 (dd, J = 10.0, 3.5 Hz, 1 H), 3.46 (m, 1 H), 4.01
H), 7.49 (d, J = 7.8 Hz, 1 H), 8.17 (br. s, 1 H) ppm. C NMR
): δ = –4.4, 9.6, 16.2, 16.9, 18.3, 22.6, 25.6, 26.5,
28.3, 31.7, 32.0, 32.5, 34.4, 40.1, 46.5, 49.1, 56.4, 75.8, 79.8, 107.0,
): δ = 110.4, 118.3, 119.9, 120.2, 120.6, 121.7, 122.3, 125.5, 125.7, 127.3,
.5, 36.0, 49.6, 118.0, 125.6 ppm. HPLC (OD-H; hexane/i-PrOH, 128.3, 134.4, 134.5, 136.0, 150.8, 155.6, 169.4, 170.3, 174.4,
:2; 0.5 mL/min): t = 8.16 min. HPLC–MS (H O/MeCN, 1:9; 175.7 ppm. Minor diastereomer (selected signals): H NMR
.6 mL/min): t = 6.51 min; m/z = 993 [C50
(m, 1 H), 4.66 (m, 1 H), 4.85 (d, J = 6.0 Hz, 1 H), 4.93 (m, 1 H), (100 MHz, CDCl
3
5
7
9
8
0
.48 (m, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 7.31 (d, J = 2.3 Hz, 1 H),
.43 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl
3
1
R
2
+
R
H
72Cl
2
N
4
O
9
+
Si + Na] .
(400 MHz, CDCl
3
): δ = 0.19 (s, 6 H), 1.01 (s, 9 H), 1.39 (s, 9 H),
HRMS (CI): calcd. for C50
found 971.4569.
H73Cl N O Si [M + H] 971.4518; 1.64 (s, 3 H), 2.73 (s, 3 H), 4.03 (m, 1 H), 4.83 (m, 1 H), 4.99 (m,
2 4 9
1
3
1 H), 6.78 (d, J = 8.5 Hz, 1 H), 7.47 (m, 1 H) ppm. C NMR
(
(
[
100 MHz, CDCl
3
): δ = 32.0, 49.1, 122.6, 175.7 ppm. HPLC–MS
O/MeCN, 2:8; 0.6 mL/min): t = 3.26 min; m/z = 925
S i + N a ] . H R M S ( C I ) : c a l c d . f o r
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-2-chlorotrypto-
phanyl-(R)-3-chloro-4-tert-butyldimethylsilyloxy-β-phenylalanine-
H
C
2
R
+
4 5
H
6 4 C l
2 4 9
N O
{
[(2S,6R,7R,E)-2-(Allyloxycarbonylamino)-4,6-dimethylnon-4-enoic
–
C
45
H
63Cl N O Si [M – H] 901.3747; found 301.3768.
2 4 9
Acid Allyl Ester]-7-yl} Ester (19d): Tripeptide 19d was prepared fol-
lowing the method used for the synthesis of 19a, starting from β-
tyrosine ester 18d (1.02 g, 1.36 mmol) and TFA (4.20 mL,
TFA (1.69 mL, 21.9 mmol) was added to a solution of acid 20aЈ
(
0.33 g, 0.36 mmol) in anhydrous CH Cl (3.6 mL) at –20 °C, and
2
2
5
4.6 mmol) in anhydrous CH
2
Cl
2
(9.8 mL), and chlorinated dipept-
NEt (0.29 mL, 1.64 mmol), and
the mixture was stirred for 16 h at this temperature. The solvent
was removed under reduced pressure.
ide A (0.69 g, 1.63 mmol), iPr
2
COMU® (0.70 g, 1.63 mmol) in anhydrous CH
Cl
fication by flash chromatography (petroleum ether/ethyl acetate,
2
2
(3.9 mL). Puri-
The crude amine was dissolved in anhydrous CH
iPr
1
allowed to warm up to room temperature overnight, then it was
concentrated to dryness, and the residue was dissolved in ethyl acet-
ate. The organic layer was washed with HCl (1 m), satd. aq.
NaHCO
in vacuo.
2
Cl
2
(80 mL).
®
NEt (0.51 mL, 2.92 mmol) and T3P (50 wt.-% in ethyl acetate;
7:3) gave 19d (1.05 g, 0.99 mmol, 73%) as a slightly yellow foam, a
2
.61 g, 2.56 mmol)[ were added at 0 °C. The reaction mixture was
29]
9
4:6 mixture of diastereomers. R : 0.28 (petroleum ether/ethyl acet-
f
20
1
ate, 6:4). [α]
NMR (400 MHz, CDCl
0
D
= +20.2 (c = 1.5, CHCl
): δ = 0.20 (s, 6 H), 0.68–0.71 (m, 6 H),
.81 (t, J = 6.5 Hz, 3 H), 1.02 (s, 9 H), 1.31–1.37 (m, 10 H), 1.50
3
). Major diastereomer: H
3
3 2 2 4
, H O, and brine, dried with Na SO , and concentrated
(m, 1 H), 1.62 (s, 3 H), 2.31 (dd, J = 13.7, 8.7 Hz, 1 H), 2.50–2.56
(m, 2 H), 2.78 (dd, J = 15.3, 6.0 Hz, 1 H), 2.91–2.95 (m, 4 H), 3.19
(dd, J = 15.3, 10.8 Hz, 1 H), 3.40 (dd, J = 15.2, 5.7 Hz, 1 H), 4.27
(dq, J = 6.8, 6.8 Hz, 1 H), 4.45 (m, 1 H), 4.54–4.65 (m, 5 H), 4.96
(d, J = 9.5 Hz, 1 H), 5.08 (d, J = 6.3 Hz, 1 H), 5.17–5.33 (m, 5 H),
The crude macrocycle was dissolved in anhydrous THF (3.6 mL),
and TBAF (1 m in THF; 0.40 mL, 0.40 mmol) was added. The re-
action mixture was stirred for 16 h, then it was diluted with ethyl
acetate, washed twice with HCl (1 m aq.) and brine, dried with
5
6
7
7
.36 (m, 1 H), 5.63 (dd, J = 10.5, 5.5 Hz, 1 H), 5.83–5.94 (m, 2 H),
.77 (d, J = 8.3 Hz, 1 H), 6.98–7.05 (m, 2 H), 7.08 (dd, J = 7.0,
.0 Hz, 1 H), 7.13 (dd, J = 6.0, 6.0 Hz, 1 H), 7.19–7.24 (m, 2 H),
.49 (d, J = 7.5 Hz, 1 H), 8.18 (br. s, 1 H) ppm. 1 C NMR
2 4
Na SO , and concentrated under reduced pressure. Purification by
flash chromatography (petroleum ether/ethyl acetate, 3:7) gave
macrocycle 20a (134 mg, 199 μmol, 55%; 78% purity of the major
diastereomer) [equates to 105 mg of enantiomerically pure 20a
3
3
(100 MHz, CDCl ): δ = –4.4, 9.6, 16.1, 16.4, 16.6, 18.3, 22.3, 24.6,
2
7
1
1
5.6, 28.3, 31.5, 35.9, 40.2, 42.8, 46.4, 49.1, 52.3, 56.2, 65.7, 65.9,
9.2, 79.7, 107.4, 110.3, 117.8, 118.4, 119.9, 120.2, 120.7, 121.5,
22.4, 125.5, 125.9, 127.3, 128.3, 130.6, 131.2, 131.5, 132.6, 134.3,
34.6, 150.9, 155.6, 155.6, 169.2, 170.3, 171.9, 174.1 ppm. HPLC–
(
156 μmol, 43%)] as a colourless solid. Removal of undesired dia-
stereomers was achieved by further preparative RP-HPLC (aceto-
20
nitrile/H
.0, CHCl
400 MHz, CDCl
2
O, 6:4) purification, m.p. 125–127 °C. [α]
). R : 0.16 (petroleum ether/ethyl acetate, 3:7). H NMR
): δ = 0.72 (t, J = 7.4 Hz, 3 H), 0.86 (d, J =
.8 Hz, 3 H), 1.43 (m, 2 H), 1.61 (s, 3 H), 1.81 (br. s, 1 H), 2.17–
.26 (m, 3 H), 2.37–2.44 (m, 3 H), 2.77 (d, J = 5.3 Hz, 2 H), 2.96
D
= +44.2 (c =
1
1
(
6
2
3
f
MS (H
2
O/MeCN, 1:9; 0.6 mL/min): t
R
= 3.93 min; m/z = 1079
3
+
[
C
5 3
H
7 5 C l
2 5
N O 1 1 S i + N a ] . H R M S ( C I ) : c a l c d . fo r
+
C
53
H
76Cl N O11Si [M + H] 1056.4682; found 1056.4769.
2 5
(
4
4R,7R,10S,18R,E)-7-(2-Chloro-1H-indol-3-ylmethyl)-4-(3-chloro- (s, 3 H), 3.25 (dd, J = 15.1, 9.8 Hz, 1 H), 3.34 (dd, J = 15.1, 6.8 Hz,
-hydroxyphenyl)-18-ethyl-8,10,15-trimethyl-1-oxa-5,8,11-triaza- 1 H), 4.65 (dq, J = 7.0, 7.0 Hz, 1 H), 4.72 (tt, J = 5.8, 5.8 Hz, 1
cyclooctadec-15-en-2,6,9,12-tetraone (20a): Pd(PPh
0.0 μmol) and morpholine (66.0 μL, 0.76 mmol) were added to a
solution of tripeptide 19a (0.36 g, 0.38 mmol) in anhydrous THF
3.8 mL). The reaction mixture was stirred for 2 h, then it was di-
3
)
4
(44.0 mg,
H), 5.14 (t, J = 6.8 Hz, 1 H), 5.29 (dt, J = 9.5, 5.0 Hz, 1 H), 5.38
(dd, J = 9.2, 7.2 Hz, 1 H), 6.55 (d, J = 6.8 Hz, 1 H), 6.84 (d, J =
8.5 Hz, 1 H), 6.91 (dd, J = 8.5, 2.0 Hz, 1 H), 7.08 (dd, J = 7.5,
7.5 Hz, 1 H), 7.12–7.17 (m, 2 H), 7.18–7.25 (m, 2 H), 7.49 (d, J =
4
(
Eur. J. Org. Chem. 2015, 4198–4213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4209

D. Becker, U. Kazmaier
FULL PAPER
8
.0 Hz, 1 H), 8.50 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl
3
): J = 15.6, 4.3 Hz, 1 H), 3.02 (s, 3 H), 3.25 (dd, J = 14.8, 9.0 Hz, 1
H), 3.32 (dd, J = 14.8, 7.3 Hz, 1 H), 4.61–4.68 (m, 2 H), 5.10 (t, J
= 6.9 Hz, 1 H), 5.27–5.35 (m, 2 H), 6.48 (d, J = 6.8 Hz, 1 H), 6.85
(d, J = 8.5 Hz, 1 H), 6.89 (dd, J = 8.5, 1.8 Hz, 1 H), 6.96 (d, J =
δ = 9.7, 16.2, 17.8, 22.8, 26.5, 31.9, 31.9, 33.7, 34.5, 39.7, 45.8, 48.6,
5
1
1
6.7, 76.7*, 106.7, 110.6, 116.3, 118.1, 120.0, 120.2, 120.4, 121.7,
22.5, 126.0, 126.8, 127.0, 133.7, 134.4, 135.9, 150.7, 169.4, 170.9,
71.6, 173.9 ppm (*determined from C,H-COSY). HPLC–MS 8.8 Hz, 1 H), 7.08–7.11 (m, 2 H), 7.16 (dd, J = 7.3, 7.3 Hz, 1 H),
(
H
2
O/MeCN, 1:1; 0.6 mL/min): t
R
= 4.31 min; m/z = 693 7.24 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 8.35 (br. s, 1
+
13
[
[
C
34
H
40Cl
2
+
N
4
O
6
+ Na] . HRMS (CI): calcd. for C34
H
41Cl
2
N
4
O
6
H) ppm. C NMR (100 MHz, CDCl
(671.61): 23.5, 26.2, 31.9, 32.0, 39.8, 40.2, 44.3, 45.5, 48.9, 56.2, 76.8, 106.5,
110.6, 116.4, 118.0, 120.0, 120.1, 120.5, 121.8, 122.6, 126.1, 126.9,
27.0, 133.9, 134.4, 136.5, 150.7, 169.4, 170.8, 173.8, 174.8 ppm.
HPLC–MS (H O/MeCN, 4:6, 0.6 mL/min): t = 3.13 min; m/z =
0 7 [ C 3 5 + N a] . HRMS (C I) : cal cd. for
43Cl
3
): δ = 9.7, 16.4, 18.2, 18.6,
M + H] 671.2398; found 671.2394. C34
H
40Cl N O
2 4 6
calcd. C 60.80, H 6.00, N 8.34; found C 60.49, H 6.32, N 8.01.
1
(
4R,7R,10S,13S,18R,E)-7-(2-Chloro-1H-indol-3-ylmethyl)-4-(3-
2
R
chloro-4-hydroxyphenyl)-18-ethyl-8,10,13,15-tetramethyl-1-oxa-
,8,11-triazacyclooctadec-15-en-2,6,9,12-tetraone [(S)-20b-1] and
4R,7R,10S,13R,18R,E)-7-(2-Chloro-1H-indol-3-ylmethyl)-4-(3-
chloro-4-hydroxyphenyl)-18-ethyl-8,10,13,15-tetramethyl-1-oxa-
,8,11-triazacyclooctadec-15-en-2,6,9,12-tetraone [(R)-20b-2]: Fol-
lowing the method used for the synthesis of acid 20aЈ, 20bЈ was
prepared from tripeptide 19b (0.43 g, 0.45 mmol), Pd(PPh
52.0 mg, 45.0 μmol), and morpholine (79.0 μL, 0.90 mmol) in an-
+
7
C
H
4 2 C l
2
N
4
O
6
+
5
(
35
H
2
N
4
O
6
[M + H] 685.2554; found 685.2536.
Data for [(R)-20b-2]: m.p. 115–118 °C. [α]2
CHCl ). R
400 MHz, CDCl
0
= +47.1 (c = 0.9,
D
1
3
f
: 0.15 (petroleum ether/ethyl acetate, 4:6). H NMR
): δ = 0.74 (t, J = 7.5 Hz, 3 H), 0.78 (d, J =
.8 Hz, 3 H), 1.17 (d, J = 7.0 Hz, 3 H), 1.27 (m, 1 H), 1.43 (m, 1
5
(
3
6
3 4
)
H), 1.60 (s, 3 H), 2.06–2.14 (m, 2 H), 2.19–2.29 (m, 2 H), 2.58 (m,
(
1
1
1
5
H), 2.69 (dd, J = 15.3, 3.8 Hz, 1 H), 2.76 (dd, J = 15.3, 8.3 Hz,
H), 2.95 (s, 3 H), 3.23 (dd, J = 15.1, 9.8 Hz, 1 H), 3.32 (dd, J =
5.3, 7.0 Hz, 1 H), 4.64 (dq, J = 6.8, 6.8 Hz, 1 H), 4.77 (m, 1 H),
.08 (t, J = 6.0 Hz, 1 H), 5.31 (ddd, J = 8.3, 8.3, 3.5 Hz, 1 H), 5.54
hydrous THF (4.5 mL). Purification by flash chromatography (pe-
troleum ether/ethyl acetate, 7:3 to 1:1 + 1% AcOH) gave acid 20bЈ
(
0.36 g, 0.39 mmol, 87%) as a colourless foam, an 82:18 mixture of
diastereomers. R : 0.20 (petroleum ether/ethyl acetate, 7:3 + 1%
AcOH). Major diastereomer: 1H NMR (400 MHz, CDCl
): δ =
.19 (s, 3 H), 0.21 (s, 3 H), 0.63–0.78 (m, 6 H), 1.01 (s, 4.5 H), 1.02
s, 4.5 H), 1.22 (d, J = 6.8 Hz, 1.5 H), 1.27 (d, J = 7.0 Hz, 1.5 H),
f
(dd, J = 9.5, 7.0 Hz, 1 H), 6.11 (br. s, 1 H), 6.57 (d, J = 7.0 Hz, 1
H), 6.82–6.86 (m, 2 H), 6.92 (dd, J = 8.5, 2.3 Hz, 1 H), 7.09 (d, J
=
3
0
(
7.0, 7.0 Hz, 1 H), 7.13–7.17 (m, 2 H), 7.23 (d, J = 8.0 Hz, 1 H),
1
3
7
.48 (d, J = 7.5 Hz, 1 H), 8.48 (br. s, 1 H) ppm. C NMR
1
2
3
.37 (s, 9 H), 1.43 (m, 2 H), 1.61 (s, 1.5 H), 1.63 (s, 1.5 H), 2.01–
.40 (m, 4 H), 2.63–2.95 (m, 3 H), 3.04 (s, 1.5 H), 3.06 (s, 1.5 H),
.31 (m, 2 H), 4.40 (dq, J = 7.3, 7.3 Hz, 1 H), 4.74 (m, 1 H), 4.91
(
100 MHz, CDCl ): δ = 9.8, 16.1, 17.9, 18.6, 22.7, 25.9, 31.1, 31.4,
3
4
1
1
0.9, 40.9, 45.6, 45.6, 49.1, 56.1, 76.8, 106.6, 110.6 116.5, 118.1,
20.1, 120.4, 120.9, 121.7, 122.5, 125.9, 126.6, 127.0, 133.9, 134.4,
35.4, 150.8, 169.1, 170.7, 173.9, 174.5 ppm. HPLC–MS (H O/
2
(m, 1 H), 5.24–5.39 (m, 2 H), 5.62 (m, 1 H), 6.77 (d, J = 8.3 Hz, 1
H), 7.00–7.23 (m, 5 H), 7.32–7.63 (m, 2 H), 8.04 (br. s, 0.5 H), 8.07
br. s, 0.5 H) ppm. 1 C NMR (100 MHz, CDCl
3
M e C N, 4 : 6 ; 0 . 6 m L / m i n ) : t = 2 . 7 0 m i n ; m / z = 7 0 7
(
3
): δ = –4.4, –4.4,
R
+
[C
35
H
42Cl
2 4 6 2 4 6
N O + Na] . HRMS (CI): calcd. for C35H43Cl N O
9
2
5
1
1
1
.5, 9.7, 16.1, 16.3, 17.1, 17.8, 18.3, 22.6, 22.9, 25.6, 26.1, 26.5,
8.3, 31.4, 31.7, 31.9, 32.0, 38.3, 39.7, 40.5, 44.2, 46.5, 48.7, 49.4,
5.8, 56.7, 75.7, 75.9, 79.8, 110.0, 110.4, 118.3, 120.2, 120.5, 120.6,
20.6, 121.7, 121.7, 122.3, 125.5, 125.7, 125.7, 127.2, 127.3, 128.1,
28.4, 134.4, 135.2, 135.6, 150.9, 155.6, 169.5, 170.4, 174.2, 174.4,
+
[M + H] 685.2554; found 685.2558.
(
(
4R,7R,10S,13S,17R,18R,E)-7-(2-Chloro-1H-indol-3-ylmethyl)-4-
3-chloro-4-hydroxyphenyl)-18-ethyl-8,10,13,15,17-pentamethyl-1-
oxa-5,8,11-triazacyclooctadec-15-en-2,6,9,12-tetraone (20c): Fol-
lowing the method used for the synthesis of acid 20aЈ, 20cЈ was
prepared from tripeptide 19c (0.46 g, 0.47 mmol), Pd(PPh
1
78.6, 178.7 ppm. Minor diastereomer (selected signals): H NMR
(
2
400 MHz, CDCl
3
): δ = 0.18 (s, 6 H), 1.00 (s, 9 H), 1.65 (s, 3 H),
.72 (s, 3 H), 7.62 (d, J = 8.3 Hz, 1 H) ppm. HPLC–MS (H O/
= 2 . 8 9 m i n ; m / z = 9 3 9
S i + N a ] . H R M S ( C I ) : c a l c d . f o r
3 4
)
2
(
55.0 mg, 48.0 μmol), and morpholine (83.0 μL, 0.95 mmol) in an-
M e C N, 2 : 8 ; 0 . 6 m L / m i n ) : t
[
C
R
hydrous THF (4.8 mL). Purification by flash chromatography (pe-
troleum ether/ethyl acetate, 7:3 to 1:1 + 1 % AcOH) gave 20cЈ
+
C
4 6
H
6 6 C l
2 4 9
N O
+
46
H
68Cl N O Si [M + 2H] 918.4127; found 918.4153.
2 4 9
(
0.40 g, 0.43 mmol, 91%) as a colourless foam, an 89:11 mixture of
diastereomers. R : 0.22 (petroleum ether/ethyl acetate, 7:3 + 1%
AcOH). Major diastereomer: H NMR (400 MHz, CDCl
.21 (s, 6 H), 0.60 (t, J = 7.4 Hz, 3 H), 0.65 (d, J = 6.8 Hz, 3 H),
0.87 (d, J = 6.8 Hz, 3 H), 1.02 (s, 9 H), 1.27 (d, J = 7.0 Hz, 3 H),
.32 (m, 1 H), 1.38 (s, 9 H), 1.45 (m, 1 H), 1.61 (s, 3 H), 2.09 (dd,
J = 12.9, 4.6 Hz, 1 H), 2.36 (dd, J = 11.0, 7.8 Hz, 1 H), 2.60–2.82
m, 4 H), 3.07 (s, 3 H), 3.18 (d, J = 8.3 Hz, 2 H), 4.40 (dq, J = 7.0,
.0 Hz, 1 H), 4.67 (m, 1 H), 5.06 (d, J = 10.0 Hz, 1 H), 5.24–5.29
m, 2 H), 5.73 (t, J = 8.2 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 7.03–
f
Following the method used for the synthesis of macrocycle 20a, 20b
was prepared from 20bЈ (0.27 g, 0.29 mmol) and TFA (1.37 mL,
1
3
): δ =
0
1
2
7.8 mmol) in anhydrous CH
2
Cl
2
(2.9 mL), iPr
2
NEt (0.42 mL,
Cl
.38 mmol) and T3P® (1.31 g, 2.08 mmol) in anhydrous CH
2
2
1
(65 mL), and TBAF (1 m in THF; 0.33 mL, 0.33 mmol) in anhy-
drous THF (2.9 mL). Purification by flash chromatography (petro-
leum ether/ethyl acetate, 4:6) gave macrocycle (S)-20b-1 (52 mg,
(
7
(
7
4
6 μmol, 26%; 84% purity of the major diastereomer) [equates to
4 mg enantiomerically pure 20b-1 (64 μmol, 22%)] and (R)-20b-2
7
7
.08 (m, 2 H), 7.13 (dd, J = 7.2, 7.2 Hz, 1 H), 7.19–7.23 (m, 2 H),
.48 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 7.8 Hz, 1 H), 8.27 (br. s, 1
(
69 mg, 100 μmol, 34%; 64% purity of the major diastereomer)
equates to 44 mg of enantiomerically pure 20b-2 (64 μmol, 22%)]
as colourless solids. Removal of the undesired diastereomers was
[
1
3
H) ppm. C NMR (100 MHz, CDCl
3
): δ = –4.4, 10.4, 15.8, 16.3,
1
4
1
7.4, 17.7, 18.3, 22.6, 23.4, 25.6, 28.3, 31.2, 35.2, 39.5, 41.0, 45.2,
6.4, 49.9, 55.1, 79.7, 79.9, 106.7, 110.4, 118.3, 120.1, 120.6, 121.7,
22.4, 125.5, 125.6, 127.2, 128.2, 129.0, 133.5, 134.3, 135.6, 150.8,
achieved by further preparative RP-HPLC (acetonitrile/H
2
O, 6:4)
purification.
Data for [(S)-20b-1]: m.p. 130–132 °C. [α]20
CHCl ). R : 0.23 (petroleum ether/ethyl acetate, 4:6). H NMR
400 MHz, CDCl ): δ = 0.79 (t, J = 7.4 Hz, 3 H), 0.91 (d, J = 3 H), 0.81 (m, 3 H), 1.02 (s, 9 H), 1.59 (s, 3 H), 2.99 (s, 3 H), 4.32
= +42.3 (c = 0.7,
155.2, 169.2, 170.5, 174.1, 178.4 ppm. Minor diastereomer (selected
D
1
1
3
f
3
signals): H NMR (400 MHz, CDCl ): δ = 0.20 (s, 6 H), 0.69 (m,
(
3
6
2
.8 Hz, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.48 (qd, J = 7.3, 7.3 Hz,
H), 1.65 (s, 3 H), 1.77 (br. s, 1 H), 1.94–2.06 (m, 2 H), 2.14–2.29
(m, 1 H), 4.61 (m, 1 H), 4.96 (d, J = 8.3 Hz, 1 H), 5.58 (m, 1 H),
1
3
6.78 (d, J = 8.5 Hz, 1 H), 8.54 (br. s, 1 H) ppm. C NMR
): δ = 35.4, 51.8, 80.6 ppm. HPLC–MS (H O/
(m, 2 H), 2.42 (m, 1 H), 2.68 (dd, J = 15.6, 8.3 Hz, 1 H), 2.76 (dd, (100 MHz, CDCl
3
2
4210
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4198–4213

Dichlorinated Chondramide Derivatives
M e C N, 2 : 8 ; 0 . 6 m L / m i n ) : t
R
= 2 . 7 0 m i n ; m / z = 9 5 3 130.4, 131.2, 132.7, 134.3, 135.5, 150.9, 155.6, 155.6, 169.2, 170.3,
+
[
C
C
4 7
H
69Cl
6 8 C l
2
N
4
O
9
S i + N a ] . H R M S ( C I ) : c a l c d . f o r 173.7, 174.4 ppm. HPLC–MS (H O/MeCN, 1:9; 0.6 mL/min): t =
2
R
+
+
47
H
2
N
4
O
9
Si [M + H] 931.4205; found 931.4256.
2.56 min; m/z = 1038 [C50
calcd. for C50 72Cl
016.4399.
H
O
71Cl
2 5
N O11Si + Na] . HRMS (CI):
+
H
2 5
N
11Si [M + H] 1016.4369; found
Following the method used for the synthesis of macrocycle 20a,
1
2
1
1
0c was prepared from 20cЈ (355 mg, 381 μmol) and TFA (1.17 mL,
5.2 mmol) in anhydrous CH Cl (2.7 mL), iPr NEt (0.33 mL,
.90 mmol) and T3P® (0.96 g, 1.52 mmol) in anhydrous CH
Cl
2
2
2
Following the method used for the synthesis of macrocycle 20a, 20d
was prepared from 20dЈ (405 mg, 398 μmol) and TFA (1.23 mL,
2
2
(95 mL), and TBAF (1 m in THF; 0.42 mL, 0.42 mmol) in anhy-
1
1
5.9 mmol) in anhydrous CH
2
Cl
2
(2.9 mL), and iPr
2
NEt (0.35 mL,
Cl
2
drous THF (3.5 mL). Purification by flash chromatography (petro-
leum ether/ethyl acetate, 3:7) gave macrocycle 20c (162 mg,
.99 mmol) and T3P® (1.00 g, 1.59 mmol) in anhydrous CH
2
(
100 mL). Purification by flash chromatography (petroleum ether/
2
1
32 μmol, 61%; 81% purity of the major diastereomer) [equates to
31 mg of enantiomerically pure 20c (188 μmol, 49%)] as a colour-
ethyl acetate, 1:1) gave macrocycle 20d (185 mg, 206 μmol, 52%) as
20
a colourless solid, m.p. 142–144 °C. [α]
: 0.28 (petroleum ether/ethyl acetate, 1:1). H NMR (400 MHz,
CDCl ): δ = 0.23 (s, 3 H), 0.24 (s, 3 H), 0.80–0.84 (m, 6 H), 0.88
d, J = 6.8 Hz, 3 H), 1.04 (s, 9 H), 1.48 (m, 1 H), 1.56–1.62 (m, 4
D 3
= –10.4 (c = 1.7, CHCl ).
less solid. Removal of the undesired diastereomers was achieved by
further preparative RP-HPLC (acetonitrile/H O, 6:4) purification,
= +68.8 (c = 1.0, CHCl ). R : 0.26 (petro-
leum ether/ethyl acetate, 3:7). H NMR (400 MHz, CDCl ): δ =
.72 (t, J = 7.5 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 1.00 (d, J =
.8 Hz, 3 H), 1.20 (d, J = 7.0 Hz, 3 H), 1.48 (m, 2 H), 1.59 (s, 3
1
R
f
2
3
m.p. 135–137 °C. [α]2
0
D
3
f
(
1
3
H), 2.24 (dd, J = 13.7, 2.4 Hz, 1 H), 2.43–2.51 (m, 3 H), 2.85 (dd,
J = 16.8, 12.3 Hz, 1 H), 2.91 (dd, J = 14.0, 7.0 Hz, 1 H), 3.18 (dd,
J = 14.2, 8.2 Hz, 1 H), 3.33 (s, 3 H), 4.38 (dd, J = 13.3, 4.0 Hz, 1
H), 4.47 (dd, J = 13.6, 5.0 Hz, 1 H), 4.69 (d, J = 9.3 Hz, 1 H), 4.79
0
6
H), 2.07 (d, J = 14.1 Hz, 1 H), 2.38 (dd, J = 14.6, 10.8 Hz, 1 H),
2
2
.48–2.54 (m, 2 H), 2.74 (s, 3 H), 2.77 (dd, J = 16.8, 5.5 Hz, 1 H),
.89 (dd, J = 16.8, 4.5 Hz, 1 H), 3.40 (d, J = 7.3 Hz, 2 H), 4.54
(
t, J = 7.5 Hz, 1 H), 4.83 (br. s, 1 H), 5.03 (dq, J = 6.3, 6.3 Hz, 1
H), 5.18 (ddt, J = 10.5, 1.3, 1.3 Hz, 1 H), 5.24–5.32 (m, 2 H), 5.60
dd, J = 7.8, 7.8 Hz, 1 H), 5.82–5.91 (m, 2 H), 6.74 (d, J = 8.3 Hz,
H), 6.94 (dd, J = 7.5, 7.5 Hz, 1 H), 7.07–7.13 (m, 2 H), 7.21 (d,
J = 8.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1
(dq, J = 6.8, 6.8 Hz, 1 H), 4.65 (td, J = 8.0, 2.5 Hz, 1 H), 4.99 (t,
(
1
J = 5.8 Hz, 1 H), 5.12 (d, J = 9.5 Hz, 1 H), 5.37 (ddd, J = 9.3, 4.8,
4
6
.8 Hz, 1 H), 6.76 (d, J = 6.8 Hz, 1 H), 6.87 (d, J = 8.5 Hz, 1 H),
.98 (dd, J = 8.5, 2.0 Hz, 1 H), 7.07 (dd, J = 7.2, 7.2 Hz, 1 H), 7.14
13
H), 8.04 (br. s, 1 H), 8.18 (br. s, 1 H), 8.31 (br. s, 1 H) ppm.
NMR (100 MHz, CDCl ): δ = –4.3, 10.3, 13.2, 18.3, 18.6, 18.7,
C
(
dd, J = 7.7, 7.7 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.25 (d, J =
.8 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H),
.84 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl
): δ = 10.3, 14.5,
6.1, 17.9, 20.3, 22.2, 25.4, 33.8, 35.0, 38.8, 39.8, 43.8, 46.1, 48.1,
9.2, 79.8, 107.0, 110.7, 116.3, 117.9, 120.1, 120.3, 121.7, 122.5,
26.0, 126.9, 127.1, 128.9, 133.0, 133.6, 134.5, 150.8, 169.4, 171.4,
3
7
8
1
5
1
1
3
2
7
1
1
0
4.9, 25.6, 27.4, 30.9, 35.1, 41.9, 43.9, 46:7, 49.4, 54.1, 55.2, 65.9,
9.0, 106.2, 110.4, 117.1, 117.4, 120.1, 120.4, 121.9, 122.5, 125.3,
26.6, 126.9, 127.5, 130.4, 131.9, 132.5, 134.3, 136.7, 150.5, 155.1,
3
68.8, 168.8, 169.1, 173.9 ppm. HPLC–MS (H
.6 mL/min): t = 8.54 min; m/z = 920 [C45
61ClN Si [M – Cl] 862.3972; found
2
O/MeCN, 3:7;
+
R
2 5 8
H61Cl N O Si + Na] .
73.6, 174.7 ppm. HPLC–MS (H
2
O/MeCN, 6:4; 0.6 mL/min): t
R
=
+
HRMS (CI): calcd. for C45
62.3934.
H
5 8
O
+
.32 min; m/z = 721 [C36
H
44Cl
2 4 6
N O + Na] . HRMS (CI): calcd.
8
+
for C36
H
45Cl N O [M + H] 699.2711; found 699.2755.
2 4 6
(
4R,7R,10S,13S,17R,18R,E)-13-Amino-7-(2-chloro-1H-indol-3-yl-
Allyl-[(4R,7R,10S,13S,17R,18R,E)-4-(4-tert-butyldimethylsilyloxy-
methyl)-4-(3-chloro-4-hydroxyphenyl)-18-ethyl-8,10,15,17-tetra-
methyl-1-oxa-5,8,11-triazacyclooctadec-15-en-2,6,9,12-tetraone
3
8
-chlorophenyl)-7-(2-chloro-1H-indol-3-ylmethyl)-18-ethyl-
,10,15,17-tetramethyl-2,6,9,12-tetraoxo-1-oxa-5,8,11-triazacyclo-
(
20e): TBAF (1 m in THF; 0.12 mL, 0.12 mmol) was added to a
octadec-15-en-13-yl]carbamate (20d): Morpholine (55.0 μL,
solution of 20d (98.0 mg, 109 μmol) in anhydrous THF (1.1 mL).
The mixture was stirred for 1 h at room temperature, then it was
diluted with ethyl acetate, washed twice with HCl (1 m aq.) and
0
0
1
.58 mmol) was added to a solution of tripeptide 19d (0.55 g,
.52 mmol), Pd(PPh (30.0 mg, 26.0 μmol), and PPh (28.0 mg,
07 μmol) in anhydrous CH
(1.5 mL) at 0 °C.[ The reaction
Cl . The
organic phase was washed twice with HCl (1 m aq.) and brine, dried
with Na SO , and concentrated under reduced pressure. Purifica-
tion by flash chromatography (petroleum ether/ethyl acetate, 6:4 to
:1 + 1% AcOH) gave 20dЈ (0.36 g, 0.44 mmol, 84%) as a colour-
less solid, a 94:6 mixture of diastereomers, m.p. 64–64 °C. R : 0.26
= +24.8 (c
). Major diastereomer: H NMR (400 MHz, CDCl
δ = 0.21 (s, 6 H), 0.65–0.68 (m, 6 H), 0.87 (d, J = 6.8 Hz, 3 H),
3
)
4
3
34]
2 2
Cl
brine, dried with Na
sure.
2 4
SO , and concentrated under reduced pres-
mixture was stirred for 1 h, then it was diluted with CH
2
2
2
4
The crude product was dissolved in acetonitrile (0.8 mL), H
(0.3 mL), and EtOH (0.3 mL), and was treated with Pd(OAc)
(1.0 mg, 4.45 μmol), NHEt (57.0 μL, 0.55 mmol) and TPPTS [Tri-
phenylphosphine-3,3Ј,3ЈЈ-trisulfonic acid trisodium salt] (3.0 mg,
2
O
2
1
2
f
2
0
[41]
(petroleum ether/ethyl acetate, 6:4 + 1% AcOH). [α]
D
5.28 μmol) at room temperature.
The reaction mixture was
1
=
2.6, CHCl
3
3
): stirred for 1 h (complete consumption, TLC control), and then it
was concentrated to dryness under reduced pressure. Purification
1
8
2
=
4
.02 (s, 9 H), 1.38–1.47 (m, 11 H), 1.60 (s, 3 H), 2.41 (dd, J = 12.8,
.0 Hz, 1 H), 2.52–2.63 (m, 2 H), 2.75 (dd, J = 15.3, 6.5 Hz, 1 H), (46.0 mg, 66 μmol, 60%) as a colourless solid, m.p. 134–136 °C.
.93–2.99 (m, 4 H), 3.18 (dd, J = 14.8, 10.3 Hz, 1 H), 3.26 (dd, J [α]
15.1, 6.0 Hz, 1 H), 4.42–4.49 (m, 2 H), 4.61 (d, J = 5.3 Hz, 2 H), 0.80–0.85 (m, 6 H), 0.90 (d, J = 7.0 Hz, 3 H), 1.40 (m, 1 H), 1.54
.66 (td, J = 8.7, 8.7 Hz, 1 H), 5.04 (d, J = 9.8 Hz, 1 H), 5.22–5.36 (m, 1 H), 1.63 (s, 3 H), 2.26 (m, 2 H), 2.59–2.65 (m, 2 H), 2.90 (dd,
2
by preparative RP-HPLC (acetonitrile/H O) gave macrocycle 20eЈ
2
0
1
D 3 3
= 24.9 (c = 1.0, CHCl ). H NMR (400 MHz, CDCl ): δ =
(
m, 4 H), 5.52 (d, J = 8.3 Hz, 1 H), 5.65 (dd, J = 9.2, 6.2 Hz, 1 H),
J = 15.4, 9.2 Hz, 1 H), 2.95 (s, 3 H), 3.18 (dd, J = 15.1, 10.8 Hz, 1
.95 (ddd, J = 17.1, 10.5, 5.5 Hz, 1 H), 6.76 (d, J = 8.3 Hz, 1 H, H), 3.41–3.49 (m, 2 H), 4.33 (dq, J = 5.5, 5.5 Hz, 1 H), 4.63 (ddd,
3-H), 7.02 (d, J = 8.5 Hz, 1 H), 7.05 (dd, J = 7.0, 7.0 Hz, 1 H), J = 7.8, 4.0, 4.0 Hz, 1 H), 4.96 (d, J = 9.3 Hz, 1 H), 5.21 (ddd, J
5
2
7
7
.12 (dd, J = 7.2, 7.2 Hz, 1 H), 7.19–7.22 (m, 2 H), 7.46 (d, J =
= 8.5, 8.5, 2.8 Hz, 1 H), 5.61 (dd, J = 10.2, 5.4 Hz, 1 H), 6.71 (d,
): J = 8.3 Hz, 1 H), 6.87 (dd, J = 8.4, 1.6 Hz, 1 H), 7.06 (dd, J = 7.4,
7.4 Hz, 1 H), 7.12 (dd, J = 7.4, 7.4 Hz, 1 H), 7.16 (d, J = 4.8 Hz,
.8 Hz, 1 H), 8.29 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl
3
δ = –4.4, 10.3, 15.7, 16.2, 17.2, 18.3, 22.7, 22.7, 25.6, 28.3, 31.1,
3
1
5.2, 40.1, 43.1, 46.5, 49.6, 52.5, 55.5, 65.7, 79.3, 80.1, 106.9, 110.4, 1 H), 7.19–7.21 (m, 2 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.74 (d, J =
1
3
17.9, 118.2, 120.2, 120.7, 121.7, 122.4, 125.6, 125.9, 127.2, 128.4,
7.5 Hz, 1 H), 8.81 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl
3
):
Eur. J. Org. Chem. 2015, 4198–4213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4211

D. Becker, U. Kazmaier
FULL PAPER
δ = 11.2, 15.5, 16.3, 16.9, 22.1, 23.8, 31.9, 35.5, 40.9, 45.6, 46.9,
[5] a) S. C. Posey, B. E. Bierer, J. Biol. Chem. 1999, 274, 4259–
4265; b) X. Zhang, X. Cui, L. Cheng, X. Guan, H. Li, X. Li,
5
1
1
0.1, 54.1, 56.7, 80.4, 106.9, 110.6, 116.6, 118.1, 120.1, 120.1, 121.6,
22.2, 125.3, 127.2, 127.3, 128.9, 132.8, 134.4, 134.5, 151.4, 169.7,
M. Cheng, PLoS One 2012, 7, e50899.
6] L. Xie, A. Forer, Cell Motil. Cytoskel. 2008, 65, 876–889.
[
71.0, 173.9, 174.0 ppm. HPLC–MS (H
= 2.18 min; m/z = 722 [C35
CI): calcd. for C35 44Cl [M + H] 700.2663; found
2
O/MeCN, 1:1; 0.6 mL/
+
[7] a) C. Odaka, M. L. Sanders, P. Crews, Clin. Diagn. Lab. Immu-
nol. 2000, 7, 947–952; b) D. P. Cioca, K. Kitano, Cell. Mol.
Life Sci. 2002, 59, 1377–1387; c) M. Matsuki-Fukushima, S.
Hashimoto, M. Murakami, Y. Ogata, J. Fujita-Yoshigaki, T.
Narita, H. Sugiya, Arch. Oral Biol. 2012, 57, 567–576.
[8] a) T. Iizuka, R. Fudou, Y. Jojima, S. Ogawa, S. Yamanaka, Y.
Inukai, M. Ojika, J. Antibiot. 2006, 59, 385–391; b) M. Ojika,
Y. Inukai, Y. Kito, M. Hirata, T. Iizuka, R. Fudou, Chem.
Asian J. 2008, 3, 126–133.
min): t
(
R
2 5 6
H43Cl N O + Na] . HRMS
+
H
2 5 6
N O
700.2673.
1
0-(4-{[(4R,7R,10S,13S,17R,18R,E)-7-(2-Chloro-1H-indol-3-yl-
methyl)-4-(3-chloro-4-hydroxyphenyl)-18-ethyl-8,10,15,17-tetra-
methyl-2,6,9,12-tetraoxo-1-oxa-5,8,11-triazacyclooctadec-15-en-13-
yl]amino}-4-oxobutyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrr-
olo[1,2-c:2Ј,1Ј-f][1,3,2]diazaborinin-4-ium-5-ide (20f): BODIPY B[
34]
[9] a) E. Sumiya, H. Shimogawa, H. Sasaki, M. Tsutsumi, K.
(
15.0 mg, 30.0 μmol) and iPr
a solution of macrocycle 20e·HCl (20.0 mg, 27.0 μmol) in anhy-
drous CH Cl (1.0 mL) and anhydrous DMSO (0.3 mL). The reac-
2
NEt (7.0 μL, 40 μmol) were added to
Yoshita, M. Ojika, K. Suenaga, M. Uesugi, ACS Chem. Biol.
2
011, 6, 425–431; b) L. Karmann, K. Schulz, J. Herrmann, R.
2
2
Müller, U. Kazmaier, DOI: Angew. Chem. 2015, 127,
DOI:10.1002/ange.201411212.
tion mixture was stirred overnight at room temperature, and then
the solvent was removed under reduced pressure. Purification by
[
10] S. Rachid, D. Krug, B. Kunze, I. Kochems, M. Scharfe, T. M.
Zabriskie, H. Blöcker, R. Müller, Chem. Biol. 2006, 13, 667–
681.
2
preparative RP-HPLC (acetonitrile/H O) gave macrocycle 20e
(
(
(
9.0 mg, 8.90 μmol, 33%) as a reddish solid, m.p. 180–182 °C
1
dec.). H NMR (400 MHz, CDCl
d, J = 7.0 Hz, 3 H), 1.49 (m, 2 H), 1.59 (s, 3 H), 1.80 (m, 1 H),
.94 (m, 1 H), 2.22–2.54 (m, 12 H), 2.56 (s, 6 H), 2.81–3.03 (m, 4 [12] D. Becker, U. Kazmaier, Eur. J. Org. Chem. 2015, 12, 2591–
602.
3
): δ = 0.81–0.84 (m, 6 H), 0.91 [11] J. Herrmann, S. Hüttel, R. Müller, ChemBioChem 2013, 14,
1573–1580.
1
2
H), 3.17 (dd, J = 13.7, 8.7 Hz, 1 H), 3.36 (s, 3 H), 4.69 (br. s, 1 H),
[
13] U. Eggert, R. Diestel, F. Sasse, R. Jansen, B. Kunze, M. Ka-
lesse, Angew. Chem. Int. Ed. 2008, 47, 6478–6482; Angew.
Chem. 2008, 120, 6578–6582.
4
1
1
1
.77 (m, 1 H), 5.03 (br. s, 1 H), 5.14 (br. s, 1 H), 5.20 (t, J = 9.0 Hz,
H), 5.53 (t, J = 7.3 Hz, 1 H), 5.97 (s, 2 H), 6.12 (s, 1 H), 6.21 (s,
H), 6.64 (s, 1 H), 6.83–6.89 (m, 2 H), 6.93 (dd, J = 8.5, 1.8 Hz,
H), 6.99 (m, 1 H), 7.15 (d, J = 1.8 Hz, 1 H), 7.27 (s, 1 H), 7.78
[
14] a) H. Waldmann, T. S. Hu, S. Renner, S. Menninger, R. Tan-
nert, T. Oda, H. D. Arndt, Angew. Chem. Int. Ed. 2008, 47,
(
s, 1 H), 8.41 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl
3
): δ =
6473–6477; Angew. Chem. 2008, 120, 6573–6577; b) R. Tannert,
1
3
1
1
1
0.3, 13.2, 14.6, 16.4, 16.6, 18.7, 18.9, 22.7, 24.8, 27.1, 27.5, 29.7,
0.9, 35.2, 35.8, 41.2, 42.0, 43.9, 49.3, 53.9, 53.9, 78.8, 106.1, 110.3,
15.9, 117.6, 119.4, 120.1, 121.7, 122.2, 125.4, 126.9, 127.5, 129.9,
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[
69.2, 169.7, 173.8 ppm. HPLC–MS (H
= 1.99 min; m/z = 1038 [C52
2
O/MeCN, 2:8; 0.6 mL/
+
min): t
HRMS (CI): calcd. for C52
found 1016.4273.
R
H
62BCl
2 2 7 7
F N O + Na] .
+
[16]
H
63BCl
2
F
2
N
7
O
7
[M + H] 1016.4222;
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Received: March 20, 2015
Published Online: May 27, 2015
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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