Molecular Design and Synthesis of a Planar Telomestatin Analogue

Article abstract of DOI:10.1002/ejoc.201501103

Hypothetical macrocycles containing eight fused oxazole units would be logical planar analogues of telomestatin, but DFT calculations suggest the presence of excessive macrocyclic ring strain in such molecules that could complicate their synthesis and/or

Full text of DOI:10.1002/ejoc.201501103

DOI: 10.1002/ejoc.201501103
Full Paper
Macrocycle Synthesis
Molecular Design and Synthesis of a Planar Telomestatin
Analogue
[a]
[a]
[a]
Martin S. Seyfried, Jawad Alzeer, and Nathan W. Luedtke*
Abstract: Hypothetical macrocycles containing eight fused ox- symmetric macrocycle composed of four oxazole and four thi-
azole units would be logical planar analogues of telomestatin, azole units containing little or no ring strain. Cyclo(-ox-thia) (1)
4
but DFT calculations suggest the presence of excessive macro- was successfully prepared from serine and cysteine in 19 steps
cyclic ring strain in such molecules that could complicate their to furnish the first example of an octa-azole macrocycle con-
synthesis and/or stability. We therefore designed a planar, C4- taining eight fused azole units.
Introduction
Telomestatin is a natural product isolated from Streptomyces an-
ulatus 3533-SV4 containing a fascinating macrocyclic scaffold
composed of seven fused oxazoles and a thiazoline unit (Fig-
[
1]
ure 1). The evolutionary pressures associated with its biosyn-
[
2]
thetic production remain unclear, but telomestatin has molec-
ular dimensions similar to the G-tetrad units of G-quadruplex
[
3]
structures (Figure 1). Accordingly, telomestatin can bind vari-
[
4]
ous G-quadruplexes with good affinity (K = 10–100 n
M
)
and
). Telomes-
tatin is an inhibitor of telomerase, but it also inhibits the PCR
d
[
5]
it exhibits lower affinity for duplex DNA (K ≈ 1 μ
M
d
[
6]
[
7]
polymerases used for assaying telomerase inhibition. Telo-
mestatin induces the shortening of telomere in treated cells
more rapidly than what is expected for a single mechanism
[
8]
involving telomerase inhibition, and it induces senescence
and apoptosis in a variety of tumor cell types while exhibiting
less toxicity towards normal progenitor cells. The progression
of telomestatin as a drug candidate has been hindered by its
limited solubility and chemical stability properties that restrict
[
9]
[
10]
its synthetic scalability and handling.
Driven by potential biological applications, the total synthe-
[
10a]
[10c]
sis of telomestatin,
its enantiomer,
and a variety of re-
Based upon a recent
[
11]
Figure 1. Structures of telomestatin, the planar telomestatin analogue cyclo-
-ox-thia) (1), a G-tetrad, and the overlay of cyclo(-ox-thia) and a G-tetrad.
lated analogues have been reported.
(
4
4
high-resolution solution structure of a telomestatin analogue
[
12]
bound to a human telomeric G-quadruplex,
the relative
planarity of such macrocycles is important for mediating stack-
ing interactions with the planar array of guanine residues of cules, however, are highly challenging,[13,14] and a fully planar
the terminal G-tetrads of G-quadruplex structures. Telomestatin telomestatin analogue has not yet been reported. One concep-
itself is not fully planar due to the presence of a thiazoline unit tually simple approach would be the replacement of the thia-
(
Figure 2, a,b). To facilitate stacking interactions with G-tetrads, zoline unit in telomestatin with an oxazole unit. Indeed, the
a fully planar telomestatin analogue is therefore a high-value synthesis of macrocyclic octa-oxazoles containing eight oxazole
synthetic target. The synthetic pathways towards such mole- units has been proposed for over a decade,[ but no such
examples have been confirmed to exist. Herein we report that
14]
[
a] Department of Chemistry, University of Zürich,
Winterthurerstrasse 190, 8057 Zürich, Switzerland
E-mail: nathan.luedtke@chem.uzh.ch
macrocyclic ring strain disfavors the formation of macrocyclic
octa-oxazoles. By replacing four oxazoles with thiazole units,
ring strain can be minimized, thereby facilitating the synthesis
of planar macrocyclic octa-azoles such as cyclo(-ox-thia)4 (1;
Figure 1). This compound represents, to the best of our knowl-
http://www.bioorganic-chemistry.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501103.
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edge, the first confirmed example of a macrocycle containing mestatin will relieve some of this macrocyclic ring strain, per-
[
10a]
eight fused azole units.
haps explaining the feasibility of its synthesis.
Figure 3. Internal angles (φ) defined by the two exocyclic carbon–carbon
bonds of 2,4-dimethyloxazole and 2,4-dimethylthiazole according to DFT-op-
timized (SVWN/DN**) geometries. These same angles were observed in the
crystal structures of 2,4-diphenyloxazole and 2,4-diphenylthiazole deriva-
tives.[
16]
According to the results of DFT calculations (Figure 3) and
[
16]
crystallographic data,
2,4-disubstituted thiazoles prefer an
Figure 2. a) Top and b) side views of the DFT-optimized geometry (SVWN/
DN**) of telomestatin. c) Top and d) side views of the DFT-optimized geome-
try (SVWN/DN**) of a hypothetical, linearized telomestatin analogue.[
angle φ of 49°. This angle is larger than the internal angles
required by macrocycles containing eight 2,4-fused azole units
15]
(φ = 45°). DFT-based geometry optimization of a hypothetical
octa-thiazole containing eight identical units, cyclo(-thia) , re-
8
vealed a nonplanar, “saddle-shaped” molecule with twisting be-
tween the thiazole units that becomes more pronounced upon
linearization (Figure 4). These results suggested that the prepa-
Results and Discussion
DFT calculations revealed the presence of macrocyclic ring ration of cyclo(-thia) might be synthetically feasible, but that
8
strain in the natural product telomestatin and related macro- the product would probably not possess the desired planarity
cycles. Qualitative assessments of the ring strain were con- of an ideal telomestatin analogue.
ducted by taking a DFT-optimized structure of each macrocycle
and “cutting” it in silico across a single σ bond by the addition
of H . The conformation of the linear analogue was then calcu-
2
lated by using the geometry of the optimized macrocycle as a
[
15]
starting point.
By comparing the relative geometries of the
optimized linear and circular forms, the ring strain present in
the parent macrocycle can be assessed. Consistent with a high
degree of ring strain, the optimized geometry of linearized telo-
mestatin is splayed open, with the ends of the molecule ap-
proximately 10 Å apart (Figure 2, c, d). Similar results were also
obtained for the hypothetical octa-oxazole cyclo(-oxa) , with
8
the ends of the linearized molecule approximately 11 Å apart
(
see Figure S1 in the Supporting Information). We reasoned that
this type of ring strain originates from the relationship between
the number of units in the macrocycle and the preferred inter-
nal bond angles (φ) of each 2,4-substituted oxazole unit (Fig-
ure 3). According to DFT calculations and crystallographic
[
16]
data, 2,4-disubstituted oxazoles prefer an angle φ of 35°. The
same approximate angle was observed between the three ter-
minal oxazole units of the linearized telomestatin analogue
Figure 4. a) Top and b) side views of the DFT-optimized geometry (SVWN/
DN**) of the hypothetical macrocycle cyclo(-thia) . c) Top and d) side views
of the DFT-optimized geometry (SVWN/DN**) of a linearized, hypothetical
8
(
Figure 2, c). In contrast, in a hypothetical macrocycle contain-
ing eight 2,4-fused azole units, the angle φ is constrained to be
360°/8) = 45°. The difference between the preferred φ of 2,4-
[15]
8
cyclo(-thia) analogue.
(
Because 2,4-disubstituted oxazoles prefer an angle φ of 35°
disubstituted oxazoles (35°) and the φ required by the macrocy- and 2,4-disubstituted thiazoles prefer an angle φ of 49° (Fig-
cle (45°) multiplied over eight units explains the presence of ure 3), we speculated that a planar macrocycle with little or no
excessive macrocyclic ring strain in the hypothetical octa-ox- ring strain could be obtained by combining equal numbers of
azole cyclo(-oxa) (see Figure S1). These results may explain why thiazole and oxazole units. To mimic the pseudo C symmetry
8
4
this target has been pursued for over 10 years with no apparent of G-tetrads, we designed cyclo(-ox-thia) to contain four alter-
4
[
14]
synthetic success.
The single thiazoline unit present in telo- nating 2,4-fused oxazole-thiazole units. DFT-based geometry
Eur. J. Org. Chem. 2016, 367–372
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368 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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optimization of cyclo(-ox-thia) revealed a fully planar macro- H-Cys-OMe·HCl to give thiazoline 4 in 65 % yield (Scheme 2).
4
cycle (Figure 5, a, b) with little or no ring strain (Figure 5, c, d). Thiazoline 4 was oxidized by using DBU (1,8-diazabicyclo-
[
21]
These results suggested that cyclo(-ox-thia)4 (1) should be a [5.4.0]undec-1-ene) and BrCCl3
synthetically feasible target, and that the resulting macrocycle 5 in 98 %.
should adopt a planar conformation.
to give the racemic thiazole
Scheme 2. Synthesis of racemic thiazole 5. Reagents and conditions:
a) 1.1 equiv. Et O·BF , 3 equiv. CaCO , CH Cl , room temp., Ar, 9 h;
b) 1.1 equiv. H-Cys-OMe·HCl, 1 equiv. Et N, CH Cl , room temp., N , 16 h,
, CH Cl , 0 °C to room temp., 1.5 h,
3
4
3
2
2
3
2
2
2
6
9
5 %; c) 2 equiv. DBU, 1.05 equiv. BrCCl
8 %.
3
2
2
Figure 5. a) Top and b) side views of the DFT-optimized geometry (SVWN/
DN**) of cyclo(-ox-thia) (1). c) Top and d) side views of the DFT-optimized
geometry (SVWN/DN**) of linearized, hypothetical cyclo(-ox-thia)
4
With a suitable amino acid of type C in hand, the construc-
tion of a macrocyclic lactam of type D was commenced
Scheme 1). Accordingly, amino acid 5 was deprotected by par-
The retrosynthetic analysis of cyclo(-ox-thia) (1) was simpli- allel treatment with LiOH in MeOH/H O or with TFA in CH Cl .
a
4
[
15]
analogue.
(
4
2
2
2
fied by its C symmetry. By cyclodehydrating a protected C - Upon work-up, these reactions furnished the free acid 6 and
4
4
symmetric tetra-alcohol derivative D, four oxazolines can be the ammonium chloride salt 7, respectively. Compounds 6 and
[
17]
generated in a single step and subsequent oxidation should 7 were coupled together by using 1 equiv. of TBTU (N,N,N′,N′-
[
18]
furnish to the target macrocycle 1.
The key precursor D can tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate)
be derived from four identical thiazole-containing amino acid and excess NMM (N-methylmorpholine) to give dipeptide 8 in
building blocks of type C (Scheme 1), which can be assembled 70 % yield over three steps (Scheme 3). Dimerization of 8 via
from Ser and Cys amino acids.
4
Scheme 1. Retrosynthetic analysis of cyclo(-ox-thia) (1). PG = protecting
group.
The synthesis of cyclo(-ox-thia)4 (1) commenced with the
preparation of a 2,4-disubstituted thiazole amino acid C
Scheme 3. Synthesis of dipeptides 8–10. Reagents and conditions: a) 6 equiv.
LiOH, MeOH/H O (1:2), room temp., N ; NaHSO ; b) TFA/CH Cl , (1:3), room
temp., N ; Amberlyst (Cl ); c) 1 equiv. TBTU, 5 equiv. NMM, room temp., N
16 h, 70 % (3 steps); d) 6 equiv. LiOH, MeOH/H O (1:2), room temp., N ; citric
(
Scheme 1). Commercially available Boc-Ser(OBn)-OH was
[
19]
2
2
4
2
2
treated with Boc anhydride and ammonium hydrocarbonate
–
2
2
,
to furnish Boc-Ser(OBn)-NH (2). Compound 2 was O-ethylated
2
2
2
[
20]
–
to give imidate 3, which, without isolation, was treated with
acid; e) TFA/CH
2
Cl
2
(1:3), room temp., N
2
; Amberlyst (Cl ).
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intermediates 9 and 10 to the tetrapeptide 11 was conducted room temperature[18] to give a 46 % yield of the macrocycle 17
in an analogous fashion by using 1.5 equiv. of PyBOP (benzotri- as a mixture of diastereoisomers (Scheme 4). The oxidation of
azol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) 17 to the target molecule 1 was performed with a mixture of
[
21]
as coupling reagent; tetrapeptide 11 was obtained in an overall BrCCl and DBU overnight at room temperature. The desired
3
yield of 70 % (Schemes 3 and 4). Compound 11 is sparingly product cyclo(-ox-thia) (1) was isolated as a white solid by cen-
4
soluble in CDCl , showing line broadening and splitting in its trifugation and was thoroughly washed with CHCl , EtOAc, and
3
3
1
H NMR spectrum consistent with the formation of aggregates. MeOH. Cyclo(-ox-thia) (1) is sparingly soluble in DMSO and in-
4
1
soluble in H O. The H NMR spectroscopic data collected in
2
[
D ]DMSO are consistent with a single, planar molecule with C4
6
symmetry (part a of Figure 6 and Figure S4 in the Supporting
Information) and the HR-ESI-MS data are consistent with the
expected elemental composition of cyclo(-ox-thia) (1; part b of
4
[
24]
Figure 6 and Figure S5).
Scheme 4. Reagents and conditions: a) 1.5 equiv. PyBOP, 6 equiv. NMM, dry
DMF, room temp., N
temp., N ; NaHSO ; c) TFA/CH
d) 5 equiv. PyBOP, 10 equiv. NMM, dry DMF, 30 h, 54 %; e) 40 equiv. BF
CH Cl /Ac O (1:1), room temp., N , 16 h, 72 %; f) 10 equiv. LiOH, MeCN/
MeOH/H O (1:1:1), 45 °C, 8 min, 89 %; g) 12 equiv. DAST, dry CH Cl , room
, 46 equiv. DBU, DMF, 0 °C to room
2
, 16 h, 70 %; b) 5 equiv. LiOH, MeOH/H
Cl (1:1), room temp., N ; Amberlyst (Cl );
·Et O,
2
O (1:3), room
–
2
4
2
2
2
3
2
2
2
2
2
2
2
2
temp., N
temp., N
2
, 24 h, 46 %; h) 12 equiv. BrCCl
, 16 h, 43 %.
3
Figure 6. a) Expanded 1H NMR spectrum (300 MHz, [D ]DMSO) of 1. b) Re-
corded and simulated HR-ESI-MS of 1 in the m/z region of [M + H] . For the
2
6
+
full spectra, see Figures S4 and S5.
The limited solubility of 11 necessitated the use of HPLC
to monitor the progress of the deprotection reactions for its
conversion into 12 and 13 (Scheme 4). For the macrolactamiza-
tion of 13, a dilute solution in DMF (1.5 m
M) was treated with
Conclusions
5
equiv. of PyBOP and excess NMM for 30 h to give 14 in an
isolated yield of 54 %. Removal of the benzyl protecting groups Given their high potential for biological and medicinal applica-
[
11a,11b]
[11c,11l]
from 14 proved to be challenging. Catalytic hydrogenation us- tions, telomestatin analogues containing four,
ing 10 % Pd on activated charcoal in MeOH or AcOEt was not six,[11d–11g,11m,13d] and seven[11f,11h–11k] oxazole units have been
successful. Transhydrogenation with cyclohexene and Pd(OH)
previously synthesized. Like telomestatin itself, these analogues
also did not work. The deprotection of macrocycle are all nonplanar molecules. Planar telomestatin analogues con-
4 using anisole and AlCl in CH Cl resulted in partial conver- taining eight oxazole units have been proposed for over a dec-
five,
2
[
22]
in EtOH
1
3
2
2
[
14]
sion, with one or two of the benzyl groups being converted ade, but no example of a macrocyclic octa-oxazole has been
into alcohol groups. A two-step approach to deprotection was confirmed to exist, despite extensive synthetic efforts towards
[
14]
therefore conducted. Macrocycle 14 in a mixture of Ac O and this goal.
Our computational results suggest that excessive
to give the tetra-acetate ring strain in octa-oxazole macrocycles poses a barrier to their
5 (Scheme 4) in an isolated yield of 72 %. Tetra-acetate 15 was preparation. We therefore incorporated four thiazole units into
then treated with LiOH in a mixture of MeCN/MeOH/H O to our design of cyclo(-ox-thia) (1) to eliminate macrocyclic ring
2
[
23]
CH Cl was treated with BF ·Et O
2
2
3
2
1
2
4
give the corresponding tetra-alcohol 16 in an isolated yield of strain. Accordingly, 1 could be prepared by using standard syn-
89 %.
thetic transformations. To the best of our knowledge, cyclo(-ox-
Tetra-cyclodehydration of 16 was conducted by using thia)4 represents the first fully planar telomestatin analogue,
1
2 equiv. of DAST (diethylaminosulfur trifluoride) in CH Cl at and it is the first example of an octa-azole macrocycle contain-
2
2
Eur. J. Org. Chem. 2016, 367–372
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370
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ing eight fused azole units. Our approach to the molecular de-
sign of unstrained macrocycles will facilitate the synthesis of
water-soluble octa-azole macrocycles with interesting biological
properties.
Keywords: Synthesis design · Density functional calculations ·
Natural products · Macrocycles · Nitrogen heterocycles
[
[
[
1] K. Shin-ya, K. Wierzba, K. Matsuo, T. Ohtani, Y. Yamada, K. Furihata, Y.
Hayakawa, H. Seto, J. Am. Chem. Soc. 2001, 6, 1262.
2] X. H. Jian, H. X. Pan, T. T. Ning, Y. Y. Shi, Y. S. Chen, Y. Li, X. W. Zeng, J.
Xu, G. L. Tang, ACS Chem. Biol. 2012, 7, 646.
3] a) K. Mu-Yong, H. Vankayalapati, K. Shin-Ya, K. Wierzba, L. H. Hurley, J.
Am. Chem. Soc. 2002, 124, 2098; b) T. T. Charvat, D. J. Lee, W. E. Robinson,
A. R. Chamberlin, Bioorg. Med. Chem. 2006, 14, 4552; c) S. Agrawal, R. P.
Ojha, S. Maiti, J. Phys. Chem. B 2008, 112, 6828; d) A. K. Chaubey, K. D.
Dubey, R. P. Ojha, J. Comput.-Aided Mol. Des. 2012, 26, 289; e) M. Toro, P.
Bucek, A. Avino, J. Jaumot, C. Gonzalez, R. Eritja, R. Gargallo, Biochimie
Experimental Section
Materials and Methods
General Synthetic Methods and Reagents: Unless otherwise
noted, all reactions were performed under nitrogen. Distilled sol-
vents were used for all reactions, work-up procedures, TLC, and pre-
parative column chromatography. All additional chemicals were
purchased from Bachem, Fluka, Sigma–Aldrich, Merck, and Novabio-
2009, 91, 894–902.
chem in purum or puriss. grades. For all aq. solutions, H O was
2
[4] a) M. Kim, M. Gleason-Guzman, E. Izbicka, D. Nishioka, L. H. Hurley, Can-
cer Res. 2003, 63, 3247; b) M. Kim, H. Vankayalapati, K. Shin-ya, K.
Wierzba, L. H. Hurley, J. Am. Chem. Soc. 2002, 124, 2098; c) E. M. Rezler,
J. Seenisamy, S. Bashyam, M. Y. Kim, E. White, W. D. Wilson, L. H. Hurley,
J. Am. Chem. Soc. 2005, 127, 9439.
purified on a Purelab Ultra MK2 apparatus from ELGA Labwater.
Melting points were determined by using an Olympus microscope
with a TECON-Controller Series 150. TLC was performed on alumina
plates layered with 0.2 mm silica 60 F254 from Merck and were de-
veloped in a solvent-saturated chamber. Preparative column chro-
matography was performed by using silica 60 (particle size 43–
[
5] a) J. Seenisamy, S. Bashyam, V. Gokhale, H. Vankayalapati, D. Sun, A. Sid-
diqui-Jain, N. Streiner, K. Shin-Ya, E. White, W. D. Wilson, L. H. Hurley, J.
Am. Chem. Soc. 2005, 127, 2944; b) D. Monchaud, M.-P. Teulade-Fichou,
Org. Biomol. Chem. 2008, 6, 627.
6
3 μm) from Merck. Analytical HPLC was performed with a Varian
ProStar instrument with two solvent delivery Modules Model 210
and a Varian ProStar UV/Vis Detector Model 335 on a reversed-
phase MODULO-CART QS UPTISPHERE 300 10ODB column from IN-
TERCHROM (250 × 4.6 mm, N° Serie 329548b). Solvent mixtures of
MeCN and water containing 0.03 % TFA were used as eluent for all
substances. Gradients were varied according to the polarity of the
substances. For semi-preparative HPLC a YMCbasic BA99S11-
[
[
6] K. Shin-ya, Nihon Rinsho 2004, 62, 1277.
7] A. De Cian, G. Cristofari, P. Reichenbach, E. De Lemos, D. Monchaud, M. P.
Teulade-Fichou, K. Shin-Ya, L. Lacroix, J. Lingner, J. L. Mergny, Proc. Natl.
Acad. Sci. USA 2007, 104, 17347.
[8] a) T. Tauchi, K. Shin-Ya, G. Sashida, M. Sumi, A. Nakajima, T. Shimamoto,
J. H. Ohyashiki, K. Ohyashiki, Oncogene 2003, 22, 5338; b) D. Gomez, N.
Aouali, A. Renaud, C. Douarre, K. Shin-Ya, J. Tazi, S. Martinez, C. Trente-
saux, H. Morjani, J. F. Riou, Cancer Res. 2003, 63, 6149.
1
1
510WT B-22-10P instrument from YMC Europe GmbH [S-10Pμm,
50 × 10 mm, No. 101504729 (W)] was used. For preparative HPLC
[
9] M. A. Shammas, R. J. Shmookler Reis, C. Li, H. Koley, L. H. Hurley, K. C.
Anderson, N. C. Munshi, Clin. Cancer Res. 2004, 10, 770.
a Varian ProStar instrument with two solvent delivery Modules
Model 218, a Varian ProStar UV/Vis Detector Model 325, and a re-
versed-phase C18 5 μm OBD column from Waters XBridge
[
[
10] a) T. Doi, M. Yoshida, K. Shin-ya, T. Takahashi, Org. Lett. 2006, 8, 4165; b)
D. Monchaud, A. Granzhan, N. Saettel, A. Guedin, J. L. Mergny, M. P.
Teulade-Fichou, J. Nucleic Acids 2010, 1; c) T. Doi, K. Shibata, M. Yoshida,
M. Takagi, M. Tera, K. Nagasawa, K. Shin-ya, T. Takahashi, Org. Biomol.
Chem. 2011, 9, 387.
11] a) Z. Zhang, G. Yuan, ARKIVOC 2011, 360; b) X. Liu, H. T. Ngo, Z. Ge, S. J.
Butler, K. A. Jolliffe, Chem. Sci. 2013, 4, 1680; c) S. K. Chattopadhyay, S.
Biswas, S. K. Ghosh, Synthesis 2008, 7, 1029; d) J. Linder, T. P. Garner, H. E.
Williams, M. S. Searle, C. J. Moody, J. Am. Chem. Soc. 2011, 133, 1044; e)
K. Iida, M. Tera, T. Hirokawa, K. Shin-Ya, K. Nagasawa, J. Nucleic Acids
(
19 × 50 mm, Part. No. 186002977 154138338112 04) were used.
2
0
Optical rotations ([α] ) were measured with a Perkin–Elmer 241MC
D
Polarimeter. IR spectra were recorded with a Perkin–Elmer-Spectrum
ONE FT-IR spectrometer. NMR spectra were recorded with a Bruker
AV-300 or AV2-400 spectrometer. ESI mass spectra were recorded
with a triple stage quadrupole instrument (Finnigan TSQ 700, San
Jose, CA) equipped with a combined Finnigan atmospheric pressure
2010, 1; f) G. S. Minhas, D. S. Pilch, J. E. Kerrigan, E. J. LaVoie, J. E. Rice,
–
1
ion (API) source. The solutions (ca. 0.1–1 μmol mL ) were continu-
ously introduced through the electrospray interface with a syringe
infusion pump (Harvard Instruments, Southnatick, MA) at a flow rate
Bioorg. Med. Chem. Lett. 2006, 16, 3891; g) S. G. Rzuczek, D. S. Pilch, E. J.
LaVoie, J. E. Rice, Bioorg. Med. Chem. Lett. 2008, 18, 913; h) M. Tera, K.
Iida, H. Ishizuka, M. Takagi, M. Suganuma, T. Doi, K. Shin-ya, K. Nagasawa,
ChemBioChem 2009, 10, 431; i) M. Tera, K. Iida, K. Shin-ya, K. Nagasawa,
Nucleic Acids Symp. Ser. 2009, 231; j) K. Shibata, M. Yoshida, T. Takahashi,
M. Takagi, K. Shin-ya, T. Doi, Bull. Chem. Soc. Jpn. 2013, 86, 1453; k) M.
Satyanarayana, S. G. Rzuczek, E. J. Lavoie, D. S. Pilch, A. Liu, L. F. Liu, J. E.
Rice, Bioorg. Med. Chem. Lett. 2008, 18, 3802; l) D. Hernándeza, E. Riegoa,
A. Franceschb, C. Cuevasb, F. Albericioa, M. Álvareza, Tetrahedron 2007,
–1
of 3 μL min . The spray voltage was held at 4.5 kV, the source
analyzer transfer capillary was kept at 200 °C, and the sheath gas
used was N with an inlet pressure of 30 psi. The resolution was
2
adjusted at a peak width of 0.7 to 0.8 u at half peak height for both
scanning quadrupoles. Representative mass spectra were obtained
with an average of 20 scans. EI mass spectra were recorded with a
sector field mass analyzer (Finnigan MAT95, San Jose, CA). The ioni-
6
3, 9862; m) S. K. Chattopadhyay, S. Biswas, Tetrahedron Lett. 2006, 47,
7
897.
zation energy was 70 eV for EI and 150 eV for CI with NH as reac-
tant gas.
[12] W. J. Chung, B. Heddi, M. Tera, K. Iida, K. Nagasawa, A. T. Phan, J. Am.
Chem. Soc. 2013, 135, 13495.
3
[
13] a) J. Deeley, A. Bertram, G. Pattenden, Org. Biomol. Chem. 2008, 6, 1994;
b) D. S. Pilch, C. M. Barbieri, S. G. Rzuczek, E. J. Lavoie, J. E. Rice, Biochimie
Supporting Information (see footnote on the first page of this
article): Further details of the synthesis and characterization of
2008, 90, 1233; c) A. Bertram, N. Maulucci, O. M. New, S. M. Mohd Nor,
cyclo(-ox-thia) (1).
4
G. Pattenden, Org. Biomol. Chem. 2007, 5, 1541; d) M. Satyanarayana,
S. G. Rzuczek, E. J. Lavoie, D. S. Pilch, A. Liu, L. F. Liu, J. E. Rice, Bio-
org. Med. Chem. Lett. 2008, 18, 3802.
Acknowledgments
[
[
14] a) C. M. Marson, M. Saadi, Org. Biomol. Chem. 2006, 4, 3892; b) E. J.
Lavoie, J. E. Rice, L. F. Liu, US Pat. 8093235 B2, 2012, accession number:
BCI: BCI201200113908, ISSN: 0098-1133.
15] The reported conformations of the linearized molecules represent local,
not global, energetic minima.
The authors thank the Swiss National Science Foundation (grant
number 146754) and the University of Zurich for financial sup-
port.
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371
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
16] a) M. J. Thompson, H. Adams, B. Chen, J. Org. Chem. 2009, 74, 3856; b)
K. S. Nayak, K. N. Venugopala, D. Chopra, T. Govender, G. Kruger, G. E. M.
Maguireb, T. N. Guru Rowa, Acta Crystallogr., Sect. E 2009, 65, 2611.
17] M. Brandstätter, F. Roth, N. W. Luedtke, J. Org. Chem. 2015, 80, 40.
18] A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Org. Lett. 2000, 2,
[22] S. Hanessian, T. J. Liak, B. Vanasse, Synthesis 1981, 396.
[23] C. F. Garbers, J. A. Steenkamp, H. E. Visagie, Tetrahedron Lett. 1975, 16,
3753.
[24] While attempting to collect 13C NMR spectroscopic data, stock solutions
[
[
4 6
of cyclo(-ox-thia) prepared in [D ]DMSO degraded over time (see Fig-
1
165.
ure S6 in the Supporting Information). Although the reason for this insta-
bility is unknown, similar behavior has been observed for telomestatin
and related oligo-oxazoles.[
[
[
19] V. F. Pozdnev, Tetrahedron Lett. 1995, 36, 7115.
20] B. Wagner, D. Schumann, U. Linne, U. Koert, M. A. Marahiel, J. Am. Chem.
Soc. 2006, 128, 10513.
11f]
[
21] a) S. L. You, J. W. Kelly, Org. Lett. 2004, 6, 1681; b) D. R. Williams, S.
Patnaik, M. P. Clark, J. Org. Chem. 2001, 66, 8463.
Received: August 26, 2015
Published Online: December 2, 2015
Eur. J. Org. Chem. 2016, 367–372
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim