Solid-phase based synthesis of jasplakinolide analogs by intramolecular azide-alkyne cycloadditions

Article abstract of DOI:10.1039/b710650e

The synthesis of a focused library of jasplakinolide analogs with a 1,2,3-triazole in place of an E-configured double bond is described, featuring the Cu(i) catalyzed azide-alkyne cycloaddition reaction as an efficient macrocyclization tool. The Royal Society of Chemistry.

Full text of DOI:10.1039/b710650e

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Solid-phase based synthesis of jasplakinolide analogs by intramolecular
azide–alkyne cycloadditions{
Tai-Shan Hu,ab Rene´ Tannert,ab Hans-Dieter Arndtab and Herbert Waldmann*ab
Received (in Cambridge, UK) 11th July 2007, Accepted 27th July 2007
First published as an Advance Article on the web 14th August 2007
DOI: 10.1039/b710650e
in vivo is believed to involve a disruption of F-actin filaments and
the induction of actin polymerisation, rendering 1 a potential
chemotherapeutic agent.6 1 features a tripeptide (b-Tyr, D-Trp and
L-Ala) and a polyketide segment united in a macrocyclic ring. It
has been hypothesized that the polypropionate portion may adopt
a U-shaped conformation, leading to a b-II-hairpin-type con-
formation in the tripeptide segment.7 Recently, syntheses of
jasplakinolide analogs were reported8 where the polyketide part
was replaced by simplified building blocks.9 Interestingly,
cyclodepsipeptides closely related to 1 and active in actin
modulation have been uncovered also in nature.10
The synthesis of a focused library of jasplakinolide analogs with
a 1,2,3-triazole in place of an E-configured double bond is
described, featuring the Cu(I) catalyzed azide–alkyne cycloaddi-
tion reaction as an efficient macrocyclization tool.
Nature remains a constant source for new lead compounds in
chemical biology and medicinal chemistry investigations.1 One
approach to exploit this source further is to construct compound
libraries derived from natural product scaffolds. In benefiting from
evolutionary optimization, these collections can be expected to
yield hits at a very much reduced library size or help to uncover
new target proteins.2 Their synthesis furthermore stimulates
chemical development.3
We have recently introduced biology oriented synthesis (BIOS)2c
as a concept for the synthesis of focused compound collections.
Here, efficient methods for the synthesis of natural product
inspired compound collections are constantly required.4 In order
to advance such strategies to macrocycles we became interested in
chemically interrogating polyketide units, which are common to
many bioactive macrocyclic molecules, and opening up diversifica-
tion strategies for them.
We report here on the synthesis of jasplakinolide analogs 2 by
utilizing 1,4-disubstituted 1,2,3-triazoles for the diversification of
the macrocycle (Fig. 1). Importantly, the efficiency of Cu(I)-
catalyzed intramolecular alkyne–azide cycloadditions11 as
a
reliable macrocyclization method was demonstrated.
Simple 1,4-disubstituted 1,2,3-triazoles are readily available
from Cu(I)-catalyzed 1,3-dipolar cycloadditions of alkynes and
azides.12 A 1,2,3-triazole is found in many pharmaceuticals13 and
was discussed as trans-amide bond replacement with enhanced
hydrolytic and proteolytic stability.14 An E-configured trisubsti-
tuted double bond has similar structural parameters, and hence
should be likewise amenable to triazole replacement. In this case,
the triazole should confer sufficient lipophilicity to account for the
third substituent on the double bond.
The 19-membered cyclodepsipeptide jasplakinolide (1, also
named jaspamide) was selected as an exploratory test case
(Fig. 1). This natural product was isolated from marine Jaspis
sponges and is endowed with a remarkable cytotoxicity and
antitumor activity profile.5 The detailed mechanism of its action
A retrosynthetic analysis of triazole-containing jasplakinolide
analogs 2 is shown in Scheme 1. Two distinct approaches for
the macrocyclization were explored: a classical macrolactonization
or -lactamization with hydroxy or amino acids 3 as substrates, and
furthermore the Cu(I)-catalyzed intramolecular 1,3-dipolar
cycloaddition with azidoalkynes 4 as the precursor. For precursor
synthesis, a combination of solution phase and solid phase
Fig. 1 Jasplakinolide (1) and triazole analogs 2.
aUniversita¨t Dortmund, Fachbereich Chemie, Otto-Hahn-Str. 6,
D-44221 Dortmund, Germany
bMax-Plank-Institut fu¨r Molekulare Physiologie, Otto-Hahn-Str. 11,
D-44227 Dortmund, Germany.
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for 5b, 7j, 3a–3d, 3h, 10a–10c, 4a–4d,
4h–4l and 2a–2l. See DOI: 10.1039/b710650e
Scheme 1 Alternative retrosynthetic disconnections of 2.
3942 | Chem. Commun., 2007, 3942–3944
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methods was employed, relying on Fmoc protected amino acids
and 2-chlorotrityl chloride resin to anchor the growing chain.
The classical macrocyclization strategy with 3 as the linear
precursor was explored first (Scheme 2). Fmoc protected b-amino
acid 5 was attached to the solid support in the presence of
diisopropylethylamine. After release of the Fmoc group with 20%
piperidine in DMF, the chain was extended with Fmoc-D-Trp-OH
using N,N9-diisopropylcarbodiimide (DIC) and HOBt as the
coupling reagents. Two cycles of Fmoc deprotection and amide
bond forming reactions (with Fmoc-L-Ala and an azido acid 7,
respectively) afforded resin-bound azides 8, which reacted
smoothly with alkyne alcohols/amines 9 in the presence of CuI.
The progress of this on-resin Cu(I)-catalyzed intermolecular
1,3-dipolar cycloaddition15 was monitored with on-bead FTIR
by the disappearance of the strong absorption of the azido group
around 2100 cm21. Acid mediated cleavage from solid support
gave hydroxy/amino acids 3 in greater than 70% overall yield and
with greater than 95% purity. The acids 3 were then subjected to
modified Yamaguchi cyclization conditions16 or macrolactamiza-
tion conditions, respectively, to deliver the target compounds 2. All
results are summarized in Table 1 (entries 1–8, method A). The
macrolactones were obtained in moderate yields in the range of
28–59% (2a–d). For 2e–f, where (R)-N-Fmoc-O-TBS-b-tyrosine 5b
was used in the first step (R1 = 4-tert-butyldimethylsilyloxyphenyl),
TBS deprotection of the phenol followed after macrocyclization,
and the compounds were obtained in 15–32% yield in these cases
(2 steps). Unexpectedly, macrolactamization did not give clean
results under conventional conditions (HOBt, EDC), and 2h could
only be isolated in very low yield (entry 8, method A).
Table 1 Comparison of two different macrocyclization methods
Method Method
A (%)a B (%)b
Entry Compound R1 R2 R3
X
m
n
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
Zc
Zc
Zc
H
Zc
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
NH
O
0
0
1
1
0
1
1
0
0
1
1
0
1
2
1
2
1
1
2
1
2
1
1
2
37
28
45
59
15d
32d
26d
5
—
—
—
—
b
87
65
92
82
—
—
—
70
63d
75
70
57
10
11
12
a
2j
2k
2l
O
O
NH
Me Me
H
H
Macrolactonization or -lactamization (3 A 2). Intramolecular
c
d
cycloaddition (4 A 2). Z = 4-hydroxyphenyl. Combined yield for
cycloaddition and TBS ether deprotection (TBAF).
under acidic conditions, and the resulting peptide acids 10 then
appended with alkynes 9 in the presence of coupling reagents to
give terminal azidoalkynes 4 in 50–82% yields (Scheme 3). To our
delight, the Cu(I)-catalyzed intramolecular alkyne–azide reaction
of 4 proceeded cleanly and gave analogs 2 in good to excellent
yields when a mixture of CH3CN and THF were used as solvent
and 2,6-lutidine as an additive. 2a–d were obtained now in 65–92%
yields (Table 1, method B). The 63% yield for b-tyrosine
containing analog 2i (entry 9, method B) also improved when
compared with those of 2e–g (entries 5–7, method A). The
difference was even more striking for the lactam cases. 2h was
isolated in 70% yield, while the cyclization method described
before only gave a trace amount of the same compound.
Furthermore, it is worth noting that the intramolecular 1,3-dipolar
cycloaddition reaction was exceptionally clean and that in our
experiments the formation of dimers was not observed.17
Due to the scattered yields observed in the macrolactonization
and -lactamization attempts, the intramolecular 1,3-dipolar
cycloaddition was investigated as an alternative macrocyclization
variant. The resin-bound azides 8 were cleaved from solid support
In summary, 12 jasplakinolide analogs with varied substitution
patterns and ring sizes (18–20 membered) have been synthesized,
and an interesting triazole unit was successfully incorporated into
the analogs 2 by a Cu(I)-catalyzed alkyne–azide cycloaddition
Scheme 2 Synthesis of analogs 2 by macrolactonization or -lactamiza-
tion. Reagents and conditions: (a) 2-Cl-Trityl-Cl resin, (iPr)2NEt, CH2Cl2;
(b) 20% piperidine in DMF; (c) (i) Fmoc-D-Trp-OH, DIC, HOBt, DMF;
(d) (i) Fmoc-L-Ala-OH, DIC, HOBt, DMF; (e) 7, DIC, HOBt; (f) (i) 9,
CuI, (iPr)2NEt, THF; (ii) CH2Cl2–AcOH–TFE (8 : 1 : 1), .70% overall
yield; (g) 2,4,6-trichlorobenzoyl chloride for hydroxy acids, and EDC,
HOBt for amino acids; (h) TBAF, THF, for TBS-protected compounds
only, 5–59%.
Scheme 3 Synthesis of 2 by intramolecular cycloaddition. Reagents and
conditions: (a) CH2Cl2–AcOH–TFE (8 : 1 : 1); (b) 9, EDC, DMAP (or
HOBt), CH2Cl2–DMF, 50–82%; (c) CuI (0.1–0.5 eq.), (iPr)2NEt,
2,6-lutidine, CH3CN–THF, (then TBAF), 57–92%.
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Funding by the Fonds der Chemischen Industrie, the Max-
Planck-Society (to H. W.), and the Deutsche Forschungs-
gemeinschaft (to H.-D. A.) is appreciated. This work was
supported by the EU and the state of Nordrhein-Westfalen
(ZAGC). T.-S. H. thanks the Alexander von Humboldt
Foundation for a research fellowship.
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4 For selected reports on such syntheses from this laboratory, see:
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3944 | Chem. Commun., 2007, 3942–3944
This journal is ß The Royal Society of Chemistry 2007