Synthesis of natural product derivatives containing 2,4-concatenated oxazoles

Article abstract of DOI:10.1002/ejoc.200800111

Herein is described the synthesis of several oxazole-containing derivatives of IB-01211. The macrocyclization reaction of peptide 14 containing a concatenated triazole was successful and afforded 3 by amide bond formation. However, for those compounds containing quaterazoles or quinqueazoles, the oxazole ring had to be formed during macrocyclization. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800111

FULL PAPER
DOI: 10.1002/ejoc.200800111
Synthesis of Natural Product Derivatives Containing 2,4-Concatenated
Oxazoles
Delia Hernández,[a,b] Estela Riego,[a,b] Fernando Albericio,*[a,b,c] and Mercedes Álvarez*[a,b,d]
Keywords: Concatenated oxazoles / Peptides / Nitrogen heterocycles / Macrocyclization
Herein is described the synthesis of several oxazole-contain-
ing derivatives of IB-01211. The macrocyclization reaction of
peptide 14 containing a concatenated triazole was successful
and afforded 3 by amide bond formation. However, for those
compounds containing quaterazoles or quinqueazoles, the
oxazole ring had to be formed during macrocyclization.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
has a hydroxymethyl group as a precursor of the exocyclic
methylidene unit. In order to obtain the same size macro-
cycle as that in IB-01211, the peptide chains of 2 and 3 were
conveniently modified by substitution of -Val with (S)-β-
Leu[14] or by addition of β-Ala, respectively.
The preparations of quinque-, quater-, and teroxazoles
followed by introduction of the peptidic chain and final
macrocyclization by formation of the amide bond indicated
in Figure 2 were examined. The number of oxazole rings is
crucial in the macrocyclization step and is only possible for
compound 3. Alternative methods of macrocyclization have
been essayed.
Introduction
Oxazole rings are present in a large amount of natural
products possessing a wide range of pharmacological activi-
ties. Several marine natural products with 2,4-concatenated
azoles have been isolated and synthesized during the past
few years.[1] Hennoxazoles[2] (potent antiherpes virus agents
and peripheral analgesics) contain a bioxazole unit; musco-
ride A[3] (an antibacterial agent) features a bioxazole with
methyl substituents at the 5-position of both oxazole rings;
the macrolactams ulapualides,[4] kabiramides,[5] mycalol-
ides,[6] and halichondramides[7] all contain a teroxazole
unit; and the structurally complex diazonamides,[8] te-
lomestatin,[9] YM-216391,[10] and IB-01211[11] all feature
2,4-concatenated polyoxazoles linked to other heterocycles
and/or peptidic fragments (Figure 1).
Results and Discussion
Following our studies on the synthesis of marine natural Synthesis of Peptides and Peptidic Bonds
products containing concatenated azoles,[12,13] we synthe-
sized IB-01211 analogs containing three, four, or five ox-
azole rings tethered by a peptidic chain to give the macro-
cycle.
Compound 1 contains a phenylquinqueoxazole system
that differs from IB-01211 in its azole system: it contains
an oxazole rather than a thiazole moiety. Compound 2 has
one oxazole less than 1 and a hydroxymethyl group as a
precursor of the exocyclic methylidene group. Finally, only
three oxazole rings are present in compound 3, which also
The peptides used in the syntheses of 1–3, and the amide
bond used to prepare the oxazoles, were formed in solution
by condensation of the appropriate acid and amine with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and
1-hydroxybenzotriazole (HOBT) as activating agents in
dichloromethane (DCM) as solvent. For all syntheses, the
protecting groups for the amine, hydroxy alcohol, and car-
boxylic acid were N-tert-butoxycarbonyl (N-Boc), O-tert-
butyl (O-tBu), and methyl ester, respectively. The N-Boc
and O-tBu groups were simultaneously cleaved with 95%
trifluoroacetic acid (TFA), whereas the methyl ester func-
tionalities were hydrolyzed by using LiOH, as detailed in
the Experimental Section.
[a] Institute for Research in Biomedicine, Barcelona Science Park-
University of Barcelona,
Baldiri Reixac 10, 08028 Barcelona, Spain
Fax: +34-934-037-126
E-mail: mercedes.alvarez@irbbarcelona.org
[b] CIBER-BBN, Networking Centre on Bioengineering, Biomate-
rials and Nanomedicine, Barcelona Science Park,
Baldiri Reixac 10, 08028 Barcelona, Spain
[c] Department of Organic Chemistry, University of Barcelona,
08028 Barcelona, Spain
Synthesis of 2,4-Concatenated Azoles
Quinqueazole 4, quaterazole 5, and terazole 6 were pre-
pared by cyclization of a Ser/oxazol-containing peptide
(OH from the Ser side chain and the carboxylamide of the
same Ser unit) to give an oxazoline, which was then oxid-
[d] Laboratory of Organic Chemistry, Faculty of Pharmacy, Uni-
versity of Barcelona,
08028 Barcelona, Spain
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D. Hernández, E. Riego, F. Albericio, M. Álvarez
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Figure 1. Oxazole-containing natural products: hennoxazoles, ulapualides, kabiramides, mycalolides, halichondramides, telomestatin, YM-
216391, and IB-01211.
ized to the oxazole. The cyclization agent was (dieth-
ylamino)sulfur trifluoride (DAST) and potassium carbon-
ate in DCM at low temperature, and the oxidation was per-
formed with 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU)/
CCl4 in MeCN/pyridine at room temperature.[15] Interest-
ingly, quinqueoxazole 4 was obtained in 42% yield by si-
multaneous formation of two oxazole rings from compound
7. Quaterazole 5 and terazole 6 were obtained in yields of
34 and 44%, respectively, by formation of one oxazole ring
from compounds 8 and 9, respectively (Scheme 1).
The synthetic precursors of 7–9 were the previously de-
scribed oxazoles 10 and 11 (Figure 3).[12,13] Compound 7
was obtained by coupling the deprotected amine of 10b
with N-Boc-O-tBu-Ser-OH, followed by N- and O-depro-
tection and, finally, by coupling the resulting free amine
with the acid of 11a (R1 = H). Oxazole derivative 8 was
obtained by coupling the free amine of 10b with the acid
of 11a (R2 = H). Likewise, compound 9 was obtained by
intermolecular peptide coupling between the free amino of
Figure 2. Structures of peptide–azoles 1–3.
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10a and the deprotected acid of 10a.
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Synthesis of Natural Product Derivatives Containing 2,4-Concatenated Oxazoles
Macrocyclization Studies
Introduction of the peptide chain into oxazoles 4–6
to give the corresponding peptide–heterocycles 12–14
(Scheme 2) was afforded by amide coupling of the acid at
the 4-position of the oxazole with the free amine of the
appropriate peptide, as described above. Macrocycle 3 was
obtained in 15% yield (global from 6) through cyclization
of 14 by using N,NЈ-diisopropylcarbodiimide (DIPCDI)
and 1-hydroxy-7-azabenzotriazole (HOAt) as activating
agents in DCM as solvent.
Attempts at macrocyclization of peptides 12 and 13 un-
der the same conditions, and also by using either 1-[bis-
(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyr-
idinium hexafluorophosphate 3-oxide (HATU) and N,N-di-
isopropylethylamine (DIEA) or EDC and HOAt as cycliza-
tion agents were unsuccessful.
Macrocyclization of the more flexible heterocyclic pep-
tides 16[16,17] and 17[18] was tested under the aforementioned
conditions, but gave only complex mixtures. However, cyclic
compound 18[19] (Scheme 3) was detected by HPLC–MS in
the crude mixture formed from treatment of 17 with
(7-azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium
hexafluorophosphate (PyAOP) and 1-hydroxy-7-azabenzo-
triazole (HOAt) in DMF/DCM.
The poor results obtained for the macrocyclization based
on amide coupling prompted us to change our strategy to
one similar to that used for the macrocyclization of IB-
01211.[12] Thus, heterocyclic peptide 20 obtained from
coupling of 11c to 19 was deprotected with formic acid.
The resulting α-bromo ketone was used for intramolecular
oxazole formation by reaction with the terminal amide un-
der Hantzsch synthesis conditions with simultaneous
macrocyclization and water elimination to give the exocyclic
double bond.
Scheme 1. Synthesis of concatenated azoles 4–6.
IB-01211 analog 1 (Scheme 4), whose central azole is a
thiazole instead of an oxazole as in the parent compound,
was obtained in 16% yield after deprotection, macrocycliza-
tion, and elimination.
Figure 3. Structures of oxazoles 10 and 11.
Conclusions
Quinqueazole 4, quaterazole 5, and terazole 6 were syn-
thesized from their corresponding serine-derived, N-substi-
For compound 4, simultaneous assembly of two oxazole tuted 2-hydroxyethylamides. Simultaneous formation of two
rings is advantageous over their sequential formation; this oxazole rings was the preferred route to 4, as it gave similar
involves fewer steps and provides greater yields. This pro- results to those previously obtained for 11a. However, si-
cedure was developed for the synthesis of 11a, but could multaneous formation of three oxazole rings could not be
not be used to prepare phenyl derivative 11b. The phenyl achieved.
ring favors elimination of water over cyclization and thus
Studies on the macrocyclization of 12, 13, and 14 corro-
formation of a conjugated vinylic system instead of an ox- borate our earlier results from the total synthesis of IB-
azoline ring.[12] As an alternative strategy, formation of 01211 and its epimer, in which the synthetic precursors were
three oxazole rings by cyclization and subsequent oxidation peptides containing
a
rigid quinqueazole system.[13]
of a tetraserine peptide was also evaluated. However, after Whereas macrocyclization of 14 was readily achieved,
several tests with the same reagents and various reaction attempts at macrocyclization of 12 and 13 failed by using
times and temperatures, only trace amounts of teroxazole 6 the same reaction conditions or by employing more active
1
were obtained (as detected by HPLC–MS and H NMR coupling agents. The use of more flexible precursors of 1
spectroscopy).
(compounds 16 and 17) only led to trace amounts of 18.
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D. Hernández, E. Riego, F. Albericio, M. Álvarez
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Scheme 2. Synthesis of peptides 12–14 and macrocycle 3.
Scheme 3. Synthesis of peptides 16 and macrocycle 18.
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Synthesis of Natural Product Derivatives Containing 2,4-Concatenated Oxazoles
Scheme 4. Synthesis of compound 1.
Peptide Bond Formation: The free carboxylic acid (1 mmol),
Finally, compound 1 was obtained from 20 by using a sim-
ilar strategy to that used for the synthesis of IB-01211,
which is based on assembly of the central oxazole ring dur-
ing macrocyclization reaction (Scheme 3).
EDC·HCl (1.1 mmol), HOBt (1.1 mmol), and DIEA (2 mmol) were
added to a solution of the free amine (1 mmol) in dry DCM
(10 mL) at 0 °C. The mixture was stirred at room temperature for
20 h. The organic solution was washed with 5% aqueous NaHCO3
and aqueous NH4Cl, dried, and concentrated.
Hydrolysis of Me Esters: LiOH (2 , 9 mmol) was added to a solu-
tion of methyl ester (3 mmol) in THF/H2O/MeOH (50:6:0.2 mL),
and the reaction mixture was stirred at room temperature for 1 h.
After this time, HCl (1 ) was added until pH 3, and the solution
was extracted with EtOAc. The organic solution was dried and
concentrated to afford the acid as a white solid.
Experimental Section
General: Melting points were determined with a Büchi Melting
Point B540 in open capillaries and are uncorrected. Microwave-
assisted reactions were carried out in a CEM Discover microwave.
Purifications were performed on a Teledyne Isco module Compan-
ion with a C18-RediSep column, a photodiode array absorbance
detector, and H2O (0.04% TFA) and MeCN (0.04% TFA) as el-
uents. Analytical HPLC was performed with a Waters Alliance sep-
aration module 2695 by using a Waters Xterra MS C18 column
(150ϫ4.6 mm, 5 mm) and a Waters 996 PDA detector at 254 nm
(using gradients of MeCN–0.036 TFA and H2O–0.045 TFA). Po-
larimetry studies were performed with a Perkin–Elmer 241 polari-
meter. 1H and 13C NMR spectra were recorded with a Varian Mer-
cury 400 MHz spectrometer. Multiplicity of the carbon atoms was
assigned with DEPT and gHSQC experiments. Spectra were refer-
enced to appropriate residual solvent peaks (CDCl3 or MeOD).
MS (MALDI-TOF or ES) were performed with a PerSeptive Bios-
ystems Voyager DE RP by using an ACH matrix or a Waters al-
liance 2795 HPLC equipped with a 2487 UV/Vis detector and cou-
pled to a ZQ electrospray mass detector. The samples were run
with MeCN (0.07% HCO2H) and H2O (0.1% HCO2H). HRMS
was performed with a Bruker Autoflex high-resolution mass spec-
trometer by the Mass Spectrometry Service of the University of
Santiago de Compostela. Compounds 10a, 10b, 11a, 11b, 11c, and
19 were synthesized as described in the literature.[12,13]
Elimination of the N-Boc and O-tBu Protecting Groups by TFA:
TFA (95%, 10 mL) was added to the oxazole (1.8 mmol), and the
solution was stirred at room temperature for 5 h. After this time,
the TFA was removed in vacuo. The crude material was used in
the following reaction without purification.
Oxazoline Formation: DAST (1.05 equiv.) was added dropwise to a
solution of peptidyl-Ser (1 equiv.) in DCM (13 mL) and cooled to
–78 °C under N2. The reaction mixture was stirred for 2 h. Anhy-
drous K2CO3 (2 equiv.) was then added in one portion, and the
reaction mixture was stirred for 15 min at –78 °C and then warmed
to room temperature and stirred for 20 min. The organic solution
was poured into saturated aqueous NaHCO3 and extracted with
DCM, dried, and concentrated to give the oxazoline as oil.
Oxidation of Oxazoline: DBU (4 mmol) was added to a cold –30 °C
solution of the oxazoline (1 mmol) in CCl4/MeCN/Pyr
(2.2:3.2:3.2 mL), and the solution was stirred for 48 h at room tem-
perature. The solvents were removed in vacuo, and the residue was
purified by column chromatography on silica gel.
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D. Hernández, E. Riego, F. Albericio, M. Álvarez
Boc-β-Ala-D-Ile-L-Val-OMe: H--Ile-Val-OMe (70 mg, 0.290 mmol) = 610 (28) [M + 39], 594 (100) [M + 23], 572 (13), 413 (15), 388
FULL PAPER
was coupled to Boc-β-Ala-OH (57.0 mg, 0.304 mmol) following the
general peptide synthesis procedure to give the title compound
(107.6 mg, 90%) as a white solid. Column chromatography (DCM/
EtOAc, 9:1) gave the peptide as a white solid. Rf = 0.57 (DCM/
MeOH, 95:5). M.p. 158–160 °C (CHCl3). [α]D = +27.0 (c = 0.78,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.89–0.95 (m, 12 H),
1.07–1.19 (m, 1 H), 1.41 (s, 9 H), 1.47–1.57 (m, 1 H), 1.84–1.92 (m,
1 H), 2.12–2.22 (m, 1 H), 2.37–2.49 (m, 2 H), 3.34–3.46 (m, 2 H),
3.73 (s, 3 H), 4.36 (dd, J = 6.8 and 8.6 Hz, 1 H), 4.51 (dd, J = 4.8
and 8.4 Hz, 1 H), 5.29 (br. s, 1 H), 6.25 (d, J = 8.8 Hz, 1 H), 6.57
(d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2
(q), 15.5 (q), 17.8 (q), 18.9 (q), 24.7 (t), 28.3 (q), 30.9 (d), 36.2 (t),
36.8 (t), 36.9 (d), 52.1 (q), 57.2 (d), 57.5 (d), 79.0 (s), 155.9 (s),
171.3 (s), 171.7 (s), 172.2 (s) ppm. MS (MALDI): m/z (%) = 454
(50) [M + 39], 438 (100) [M + 23]. HRMS: calcd. for C20H38N3O6
416.2755; found 416.2748.
(18), 304 (9), 295 (5). HRMS: calcd. for C26H34N7O8 [M + 1]
572.2452; found 572.2463.
Quinqueoxazole 4: Compound 7 (296 mg, 0.41 mmol) was cyclized
by using the general procedure with DAST/K2CO3 and DBU/CCl4
for the oxidation. The reaction crude was purified by column
chromatography (silica gel) to give 4 (42%) as a white solid. Rf =
0.65 (DCM/EtOAc, 1:1). M.p. 171–173 °C (CHCl3). [α]D = –12.05
1
(c = 0.7, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.11 (s, 9 H),
1.47 (s, 9 H), 3.73 (dd, J = 4.0 and 9.2 Hz, 1 H), 3.85–3.88 (m, 1
H), 3.97 (s, 3 H), 5.07 (br. s, 1 H), 5.58 (d, J = 9.2 Hz, 1 H), 7.48–
7.51 (m, 3 H), 8.15–8.17 (m, 2 H), 8.33 (s, 1 H), 8.44 (s, 1 H), 8.45
(s, 1 H), 8.48 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2
(q), 28.2 (q), 51.0 (d), 52.3 (q), 62.8 (t), 73.7 (s), 80.2 (s), 126.4 (s),
127.6 (s), 128.4 (2 d), 128.6 (2 d), 129.7 (s), 130.6 (d), 130.7 (d),
130.8 (s), 130.9 (s), 139.3 (s), 139.4 (d), 139.5 (d), 139.6 (d), 152.8
(s), 155.6 (s), 155.7 (s), 155.9 (s), 156.2 (s), 162.2 (s), 164.7 (s), 170.8
(s) ppm. MS (ES): m/z = 704 [M + 18], 575, 527, 121. HRMS:
calcd. for C34H38N7O10 [M + NH4] 704.2674; found 704.2665.
Cyclic Peptide–Quinqueoxazole 1: A solution of 20 (500 mg,
0.53 mmol) in HCO2H (98%, 10 mL) in a sealed tube was warmed
at 85 °C over 15 min in a microwave. The cooled reaction mixture
was poured into a solution of NaHCO3 and extracted with DCM.
The organic solution was dried and concentrated under reduced
pressure to give the deprotected hydroxy ketone as a yellow oil. A
solution of the oil in DCM (10 mL) and NaHCO3 (181 mg,
2.15 mmol) was stirred at room temperature for 5 h. The mixture
was filtered over alumina, and the solid was washed with DCM/
MeOH (4:1). The mixed organic solutions were concentrated to
give a crude material, which was dissolved in dry DCM (10 mL)
and cooled to –10 °C. Lutidine (0.76 mL, 5.39 mmol) and TFAA
(0.31 mL, 2.69 mmol) were added over the cold solution, and the
reaction mixture was stirred at 50 °C in a microwave for 30 min.
The reaction mixture was cooled, poured into a solution of
NaHCO3, extracted with DCM, dried, and concentrated under re-
duced pressure. The crude reaction mixture was purified by column
chromatography (silica gel; CH2Cl2/MeOH, 99:1) to give 1 as an
yellow solid (60 mg, 16%). [α]D = +10.8 (c = 0.25, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.20–1.26 (m, 12 H), 1.28–1.31 (m,
2 H), 2.02–2.13 (m, 2 H), 3.94–3.99 (m, 1 H), 4.78–4.91 (m, 1 H),
6.06 (s, 1 H), 6.69 (s, 1 H), 7.52–7.57 (m, 3 H), 7.86 (s, 1 H), 8.03–
8.10 (m, 2 H), 8.21 (s, 1 H), 8.26 (s, 1 H), 8.27 (s, 1 H), 8.31 (s, 1
H), 8.34 (s, 1 H), 8.45 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.1 (q), 15.0 (q), 26.8 (q), 27.2 (q), 28.2 (t), 31.8 (d), 42.2 (d),
57.8 (d), 61.6 (d), 109.3 (t), 120.2 (s), 125.1 (s), 125.8 (2 d), 128.3
(s), 128.8 (2 d), 129.3 (s), 129.7 (d), 131.8 (s), 134.4 (s), 137.4 (s),
142.3 (d), 142.8 (s), 143.4 (s), 149.9 (d), 146.2 (d), 146.3 (d), 150.5
(s), 152.1 (s), 154.5 (s), 156.9 (s), 162.6 (s), 168.9 (s), 169.7 (s) ppm.
MS (MALDI-TOF): m/z = 716 (100) [M + Na].
Quateroxazole 5: Compound 8 (164 mg, 0.25 mmol) was cyclized
by using the general procedure with DAST/K2CO3 and DBU/CCl4
for the oxidation. The reaction crude was purified by column
chromatography (silica gel; DCM/EtOAc, 6:1) to give 5 (34%) as
a white solid. Rf = 0.37 (DCM/EtOAc, 2:1). M.p. 199–201 °C
(CHCl3). [α]D = –20.1 (c = 0.79, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.10 (s, 9 H), 1.47 (s, 9 H), 3.72 (dd, J = 4.0 and
9.0 Hz, 1 H), 3.85–3.88 (m, 1 H), 3.97 (s, 3 H), 5.06–5.09 (m, 1 H),
5.58 (d, J = 8.2 Hz, 1 H), 7.47–7.52 (m, 3 H), 8.15–8.17 (m, 2 H),
8.34 (s, 1 H), 8.42 (s, 1 H), 8.47 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.2 (q), 28.3 (q), 50.0 (d), 52.4 (q), 62.8 (t), 73.7 (s),
80.2 (s), 126.4 (s), 127.6 (s), 128.4 (2 d), 128.6 (2 d), 129.7 (s), 130.6
(d), 130.8 (s), 130.9 (s), 139.2 (d), 139.3 (d), 139.5 (d), 152.8 (s),
155.3 (s), 155.6 (s), 155.8 (s), 156.2 (s), 162.3 (s), 164.6 (s) ppm.
MS (FAB): m/z (%) = 642 (25) [M + 23], 508 (100), 231 (63).
HRMS: calcd. for C31H33N5NaO9 [M + 1] 620.2356; found
620.2356.
Teroxazole 6: Compound 9 (215 mg, 0.43 mmol) was cyclized by
using the general procedure with DAST/K2CO3 and DBU/CCl4 for
the oxidation. The reaction crude was purified by column
chromatography (silica gel; hexane/EtOAc, 2:1) to give 6 (90.5 mg,
44%) as a white solid. Rf = 0.28 (hexane/EtOAc, 1:1). M.p. 205–
207 °C (CHCl3). [α]D = –62.35 (c = 0.51, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.08 (s, 9 H), 1.44 (s, 9 H), 3.70 (dd, J =
4.0 and 9.2 Hz, 1 H), 3.80–3.88 (m, 1 H), 3.93 (s, 3 H), 5.05 (br. s,
1 H), 5.56 (d, J = 8.0 Hz, 1 H), 8.29 (s, 1 H), 8.30 (s, 1 H), 8.40 (s)
ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2 (q), 28.2 (q), 50.0 (d),
52.3 (q), 62.8 (t), 73.7 (s), 80.2 (s), 129.7 (s), 130.7 (s), 134.3 (s),
139.2 (d), 139.5 (d), 143.8 (d), 155.3 (s), 155.4 (s), 156.2 (s), 161.2
(s), 164.7 (s) ppm. MS (ES): m/z (%) = 499 [M + 23], 494 [M + 18],
421, 365, 121. HRMS: calcd. for C22H32N5O8 [M + NH4] 494.2245;
found 494.2242.
Cyclic Peptide–Teroxazole 3: A solution of the carboxylic acid of
14 (19 mg, 18.2 µmol) in dry DCM/DMF (91 mL and 1 mL) was
cooled to 0 °C. HOAt (7.4 mg, 54.6 µmol), DIEA (3.0 µL,
18.2 µmol), and DIPCDI (8.5 mg, 54.6 µmol) were then added. The
mixture was stirred at room temperature for 120 h. The solvents
were removed, and the crude was purified by preparative silica gel
chromatography (DCM/MeOH, 6:1) to give 3 (2.5 mg, 15%) as a
white solid. Rf = 0.61 (DCM/MeOH, 9:1). [α]D = –34.8 (c = 0.13,
Peptide 7: The title compound was obtained as a yellow oil (86%).
1
Rf = 0.35 (DCM/MeOH, 95:5). [α]D = –8.2 (c = 0.21, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.09 (s, 9 H), 1.45 (s, 9 H), 3.49–
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.89–0.98 (m, 12 H), 3.55 (m, 2 H), 3.63–3.77 (m, 2 H), 3.84 (s, 3 H), 3.97–4.10 (m, 1
1.49–1.68 (m, 1 H), 1.54–1.61 (m, 1 H), 2.27–2.35 (m, 1 H), 2.38–
2.47 (m, 1 H), 2.60–2.68 (m, 2 H), 3.33–3.43 (m, 1 H), 3.84–3.92
H), 4.16–4.32 (m, 1 H), 4.70–4.81 (m, 1 H), 5.01–5.11 (m, 1 H),
5.33–5.43 (m, 1 H), 5.58 (br. s, 1 H), 7.32 (br. s, 1 H), 7.39–7.50
(m, 1 H), 4.09 (d, J = 11.6 Hz, 1 H), 4.25–4.32 (m, 1 H), 4.80 (dd, (m, 3 H), 7.79 (br. s, 1 H), 7.92–8.01 (m, 2 H), 8.18 (s, 1 H), 8.22
J = 4.0 and 10.2 Hz, 1 H), 4.93 (dd, J = 3.2 and 9.0 Hz, 1 H), 5.44
(d, J = 7.2 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 7.6 Hz,
1 H), 7.97 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 8.06 (s, 1 H), 8.21 (s,
1 H), 8.25 (d, J = 7.6 Hz, 1 H) ppm. MS (MALDI-TOF): m/z (%)
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.3 (q), 27.1 (q),
50.0 (q), 52.2 (d), 52.3 (d), 62.7 (t), 62.8 (t), 62.9 (t), 64.1 (d), 73.7
(s), 80.3 (s), 126.1 (s), 126.5 (s), 128.4 (2 d), 128.5 (2 d), 129.4 (s),
129.8 (s), 130.8 (d), 133.3 (s), 139.8 (d), 141.6 (s), 144.5 (d), 155.4
3394
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3389–3396

Synthesis of Natural Product Derivatives Containing 2,4-Concatenated Oxazoles
(s), 160.0 (s), 160.4 (s), 162.2 (s), 164.9 (s), 169.0 (s) ppm. MS
(MALDI-TOF): m/z 745 [M 18]. HRMS: calcd. for
C34H43N6O12 727.2933; found 727.2940.
[M + 18], 832, 776, 282, 137. HRMS: calcd. for C42H57N8O11 [M
+ NH4] 849.4141; found 849.4122.
=
+
Peptide–Teroxazole 14: The title compound was obtained as a yel-
Peptide 8: The title compound was obtained as a yellow oil
low solid (81 mg, 83%). Rf = 0.4 (DCM/MeOH, 95:5). M.p. 163–
1
(296 mg, 95%). 1H NMR (400 MHz, CDCl3): δ = 1.09 (s, 9 H), 165 °C (CHCl3). H NMR (400 MHz, CDCl3): δ = 0.83–0.92 (m,
1.45 (s, 9 H), 3.68–3.74 (m, 1 H), 3.80–3.87 (m, 1 H), 3.91 (s, 3 H), 12 H), 1.08 (s, 9 H), 1.08–1.14 (m, 1 H), 1.45 (s, 9 H), 1.45–1.53
4.12 (dd, J = 4.4 and 11.4 Hz, 1 H), 4.30 (dd, J = 4.4 and 11.4 Hz,
1 H), 5.06 (br. s, 1 H), 5.56–5.61 (m, 2 H), 7.43–7.47 (m, 3 H), 7.87
(d, J = 8.8 Hz, 1 H), 7.98–8.02 (m, 2 H), 8.20 (s, 1 H), 8.27 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2 (q), 28.2 (q), 48.9
(q), 50.0 (d), 52.2 (d), 62.8 (t), 63.2 (t), 73.7 (s), 80.2 (s), 126.4 (s),
128.3 (2 d), 128.4 (2 d), 129.6 (s), 129.8 (s), 130.4 (d), 136.5 (s),
139.3 (d), 141.5 (d), 154.9 (s), 155.3 (s), 155.9 (s), 159.8 (s), 160.2
(s), 162.1 (s), 164.8 (s) ppm. MS (MALDI-TOF): m/z = 678 [M +
(m, 1 H), 1.81–1.89 (m, 1 H), 2.11–2.19 (m, 1 H), 2.57 (t, J =
6.1 Hz, 2 H), 3.69 (s, 3 H), 3.70–3.77 (m, 3 H), 3.84 (br. s, 1 H),
4.39 (dd, J = 7.3 and 8.5 Hz, 1 H), 4.51 (dd, J = 5.2 and 8.4 Hz, 1
H), 5.05 (br. s, 1 H), 5.58 (d, J = 8.0 Hz, 1 H), 6.39 (d, J = 8.4 Hz,
1 H), 6.50 (d, J = 8.4 Hz, 1 H), 7.59 (br. s, 1 H), 8.25 (s, 1 H), 8.30
(s, 1 H), 8.32 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2
(q), 15.4 (q), 17.8 (q), 19.0 (q), 24.8 (t), 27.2 (q), 28.2 (q), 30.9 (d),
35.5 (t), 35.8 (t), 36.7 (d), 50.0 (d), 52.2 (q), 57.2 (d), 57.7 (d), 62.8
39], 662 [M + 23]. HRMS: calcd. for C31H37N5NaO10 662.2433; (t), 73.7 (s), 80.1 (s), 129.7 (s), 130.9 (s), 137.1 (s), 138.9 (d), 139.5
found 662.2435.
(d), 141.1 (d), 154.3 (s), 155.2 (s), 156.2 (s), 160.4 (s), 164.6 (s),
171.1 (s), 171.3 (s), 172.2 (s) ppm. MS (ES): m/z = 777 [M + 18],
760 [M + 1]. HRMS: calcd. for C36H57N8O11 [M + 18] 777.4138;
found 777.4141.
Methyl 2-(1-{[2-(2-tert-Butoxy-1-tert-butoxycarbonylaminoethyl)ox-
azole-4-carbonyl]amino}-2-hydroxyethyl)oxazole-4-carboxylate (9):
The title compound was obtained as a white solid (407 mg, 85%).
1
M.p. 81–83 °C (CHCl3). H NMR (400 MHz, CDCl3): δ = 1.04 (s,
Compound 15a: The title compound was obtained as a yellow solid
9 H), 1.38 (s, 9 H), 3.57–3.63 (m, 1 H), 3.65–3.71 (m, 1 H), 3.81 (s, (188 mg, 97%). M.p. 133–135 °C. [α]D = –16.2 (c = 0.52, CHCl3).
3 H), 3.96–4.07 (m, 1 H), 4.09–4.21 (m, 1 H), 4.88 (br. s, 1 H), 1H NMR (400 MHz, CDCl3): δ = 1.09 (s, 9 H), 1.45 (s, 9 H), 3.71
5.36–5.46 (m, 1 H), 5.62 (br. s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 8.09
(dd, J = 4.4 and 9.2 Hz, 1 H), 3.82–3.87 (m, 1 H), 3.97 (s, 3 H),
(s, 1 H), 8.17 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.1 4.11 (dd, J = 4.0 and 11.6 Hz, 1 H), 4.31 (dd, J = 4.0 and 11.6 Hz,
(q), 28.1 (q), 48.9 (d), 49.7 (d), 52.0 (q), 62.4 (t), 62.7 (t), 73.6 (s),
80.1 (s), 132.9 (s), 135.2 (s), 141.6 (d), 144.3 (d), 155.2 (s), 160.5
(s), 161.2 (s), 162.8 (s), 162.9 (s) ppm. MS (ES): m/z = 514 [M +
18], 497, 441, 385, 341, 323. HRMS: calcd. for C22H36N5O9 [M +
NH4] 514.2507; found 514.2502.
1 H), 5.06 (br. s, 1 H), 5.53–5.62 (m, 2 H), 7.87 (d, J = 8.8 Hz, 1
H), 8.21 (s, 1 H), 8.27 (s, 1 H), 8.29 (s, 1 H), 8.33 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 27.0 (q), 28.1 (q), 49.0 (d), 49.8
(d), 52.1 (d), 62.6 (t), 73.6 (s), 80.0 (s), 129.4 (s), 133.9 (s), 136.3
(s), 139.3 (d), 139.9 (d), 141.5 (d), 143.7 (d), 154.7 (s), 155.2 (s),
155.3 (s), 160.2 (s), 161.0 (s), 163.0 (s), 164.6 (s), 170.8 (s) ppm.
MS (ES): m/z = 648.2 [M + 18], 519, 475, 121. HRMS: calcd. for
C28H38N7O11 [M + NH4] 648.2623; found 648.2615.
Peptide–Quinqueoxazole 12: The title compound was obtained as a
yellow solid (35 mg, 66%). M.p. 220–222 °C (CHCl3). [α]D = –6.8
1
(c = 0.67, CHCl3). H NMR (400 MHz, CD3OD): δ = 0.90 (d, J
= 6.8 Hz, 3 H), 0.97 (dd, J = 6.8 and 11.4 Hz, 6 H), 1.05 (d, J =
6.8 Hz, 3 H), 1.16 (s, 9 H), 1.17–1.34 (m, 1 H), 1.46 (s, 9 H), 1.57–
Peptide–Heterocycle 16a: The title compound was obtained as a
yellow solid (76 mg, 55%). M.p. 162–164 °C (CHCl3). [α]D = +25.1
1.72 (m, 1 H), 2.02–2.10 (m, 1 H), 2.13–2.24 (m, 1 H), 3.81 (d, J (c = 0.52, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.86–0.96 (m,
= 5.6 Hz, 2 H), 4.30 (d, J = 4.8 Hz, 1 H), 4.59 (d, J = 5.6 Hz, 1 12 H), 1.09 (s, 9 H), 1.15–1.22 (m, 1 H), 1.44 (s, 9 H), 1.53–1.65
H), 7.46–7.52 (m, 3 H), 8.29–8.32 (m, 2 H), 8.65 (s, 1 H), 8.77 (s, (m, 1 H), 1.92–2.02 (m, 1 H), 2.18–2.26 (m, 1 H), 3.67–3.77 (m, 1
1 H), 8.81 (s, 1 H), 8.85 (s, 1 H) ppm. 13C NMR (100 MHz,
CD3OD): δ = 11.9 (q), 16.3 (q), 18.4 (q), 20.2 (q), 27.6 (q), 28.7
(q), 32.6 (d), 39.1 (t), 59.6 (d), 61.0 (d), 63.8 (t), 71.6 (s), 82.2 (s),
121.3 (s), 121.6 (s), 128.7 (d), 129.4 (2 d), 129.5 (2 d), 129.7 (s),
130.8 (s), 131.4 (d), 131.8 (d), 131.9 (s), 141.8 (d), 141.9 (d), 142.3
(s), 149.5 (s), 149.7 (s), 151.3 (s), 153.6 (s), 154.0 (s), 157.7 (s), 157.8
(s), 162.8 (s), 171.4 (s), 177.5 (s) ppm. MS (ES): m/z = 922.4 [M +
39], 902.4 [M + 18], 680, 563, 338, 282, 121. HRMS: calcd. for
C44H56N9O12 [M + NH4] 902.4042; found 902.4033.
H), 3.79–3.91 (m, 1 H), 4.11–4.24 (m, 1 H), 4.26–4.40 (m, 1 H),
4.53–4.69 (m, 2 H), 5.08 (br. s, 1 H), 5.56–5.64 (m, 1 H), 5.66–5.78
(m, 1 H), 7.35 (br. s, 1 H), 7.77 (br. s, 1 H), 8.09 (br. s, 1 H), 8.23
(s, 1 H), 8.27 (s, 1 H), 8.29 (s, 1 H), 8.31 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.0 (q), 15.3 (q), 17.8 (q), 19.0 (q), 25.0
(t), 27.2 (q), 28.3 (q), 31.0 (d), 37.2 (d), 49.3 (d), 50.0 (d), 57.3 (d),
57.7 (d), 62.9 (t), 63.0 (t), 73.8 (s), 80.3 (s), 129.6 (s), 129.7 (s),
136.4 (s), 136.6 (s), 139.5 (d), 140.0 (d), 141.7 (d), 141.8 (d), 154.5
(s), 154.9 (s), 155.4 (s), 160.4 (s), 163.3 (s), 164.8 (s), 171.4 (s), 173.9
(s) ppm. MS (ES): m/z = 846 [M + 18], 829, 773, 729, 282, 254,
149, 109. HRMS: calcd. for C38H56N9O13 [M + NH4] 846.3992;
found 846.3979.
Peptide–Quateroxazole 13: The title compound was obtained as a
yellow solid (57 mg, 95%). M.p. 130–132 °C (CHCl3). [α]D = –27.59
(c = 0.54, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.87–0.98 (m,
12 H), 1.10 (s, 9 H), 1.17–1.26 (m, 2 H), 1.46 (s, 9 H), 1.57–1.67
(m, 1 H), 1.89–2.03 (m, 2 H), 2.63 (dd, J = 4.4 and 16.8 Hz, 1 H),
2.73 (dd, J = 4.4 and 16.8 Hz, 1 H), 3.72 (dd, J = 4.0 and 9.2 Hz,
1 H), 3.82–3.90 (m, 1 H), 3.94–4.03 (m, 1 H), 4.78 (t, J = 8.0 Hz,
Peptide–Heterocycle 16b: The title compound was obtained as a
yellow solid (35 mg, 48%). M.p. 148–150 °C (CHCl3). [α]D = +24.9
(c = 0.53, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.87–1.03 (m,
12 H), 1.09 (s, 9 H), 1.19–1.30 (m, 1 H), 1.45 (s, 9 H), 1.56–1.68
1 H), 5.08 (br. s, 1 H), 5.61 (d, J = 8.4 Hz, 1 H), 7.42–7.49 (m, 3 (m, 1 H), 1.95–2.06 (m, 1 H), 2.13–2.25 (m, 1 H), 3.67–3.76 (m, 1
H), 7.61 (d, J = 9.6 Hz, 1 H), 8.05 (d, J = 10.0 Hz, 1 H), 8.21–8.26 H), 3.78–3.88 (m, 1 H), 4.07–4.22 (m, 1 H), 4.24–4.37 (m, 1 H),
(m, 2 H), 8.35 (s, 1 H), 8.40 (s, 1 H), 8.46 (s, 1 H) ppm. 13C NMR 4.46–4.64 (m, 1 H), 4.78 (br. s, 1 H), 5.08 (br. s, 1 H), 5.53–5.61
(100 MHz, CDCl3): δ = 10.7 (q), 15.3 (q), 19.5 (q), 19.6 (q), 25.1
(t), 27.2 (q), 28.2 (q), 30.6 (d), 35.4 (t), 37.4 (d), 50.0 (d), 51.4 (d),
57.6 (d), 62.8 (t), 73.7 (s), 80.2 (s), 126.6 (s), 128.8 (2 d), 128.5 (s),
(m, 1 H), 5.65–5.76 (m, 1 H), 7.22 (br. s, 1 H), 7.34–7.47 (m, 3 H),
8.0 (br. s, 1 H), 8.09–8.18 (m, 2 H), 8.22–8.36 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 11.4 (q), 15.8 (q), 18.1 (q), 19.2 (q),
128.6 (2 d), 129.4 (s), 129.7 (s), 130.2 (s), 130.7 (d), 130.9 (d), 139.3 25.2 (t), 27.5 (q), 28.5 (q), 29.9 (d), 37.7 (d), 49.4 (d), 50.3 (d), 57.7
(d), 139.6 (d), 151.8 (s), 153.2 (s), 155.3 (s), 155.9 (s), 156.2 (s), (d), 57.8 (d), 63.0 (t), 63.2 (t), 74.0 (s), 80.5 (s), 126.7 (s), 128.5 (2
161.0 (s), 164.7 (s), 170.5 (s), 174.6 (s) ppm. MS (ES): m/z = 849 d), 128.6 (2 d), 129.7 (s), 129.8 (d), 130.4 (s), 130.6 (s), 136.7 (s),
Eur. J. Org. Chem. 2008, 3389–3396
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3395

D. Hernández, E. Riego, F. Albericio, M. Álvarez
FULL PAPER
139.8 (d), 140.0 (d), 142.0 (d), 152.0 (s), 153.0 (s), 155.2 (s), 155.6
(s), 160.6 (s), 161.5 (s), 163.6 (s), 165.0 (s), 171.7 (s), 174.0 (s) ppm.
MS (ES): m/z = 904 [M], 805, 388, 282. HRMS: calcd. for
C44H60N9O13 [M + NH4] 922.4305; found 922.4280.
[1] For recent reviews, see: a) V. S. C. Yeh, Tetrahedron 2004, 60,
11995–12042; b) E. Riego, D. Hernández, F. Albericio, M.
Álvarez, Synthesis 2005, 1907–1922; c) R. A. Hughes, C. J.
Moody, Angew. Chem. Int. Ed. 2007, 46, 2–27.
[2] T. Ichiba, W. Y. Yoshida, P. J. Scheuer, J. Am. Chem. Soc. 1991,
113, 3173–3175.
Peptide 17: The title compound was obtained as a yellow oil
(748 mg, 50%). Rf = 0.4 (DCM/MeOH, 95:5). [α]D = +8.9 (c =
0.62, CHCl3).1H NMR (400 MHz, CDCl3): δ = 0.90–1.0 (m, 12 H),
1.10 (s, 9 H), 1.15–1.25 (m, 2 H), 1.46 (s, 1 H), 1.98–2.10 (m, 1 H),
2.13–2.23 (m, 1 H), 3.40–3.61 (m, 2 H), 3.67 (s, 3 H), 3.69–3.77 (m,
2 H), 3.81–3.97 (m, 2 H), 4.42–4.60 (m, 1 H), 4.73–4.81 (m, 1 H),
5.03–5.16 (m, 1 H), 5.31–5.44 (m, 1 H), 5.59 (br. s, 1 H), 6.64 (br.
s, 1 H), 7.37–7.47 (m, 3 H), 7.82 (br. s, 1 H), 8.16–8.23 (m, 2 H),
8.24 (s, 1 H), 8.29 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 11.5 (q), 15.9 (q), 18.1 (q), 19.2 (q), 25.2 (t), 27.5 (q), 28.5 (q),
31.4 (d), 37.1 (d), 49.8 (d), 50.3 (d), 52.4 (q), 53.3 (d), 57.4 (d), 58.1
(d), 61.6 (t), 63.1 (2t), 73.9 (s), 80.4 (s), 126.9 (s), 127.6 (s), 128.5
(2 d), 128.8 (2 d), 130.1 (s), 130.3 (d), 136.9 (s), 139.8 (s), 141.6 (d),
141.7 (d), 155.1 (s), 155.5 (s), 160.5 (s), 160.7 (s), 161.3 (s), 165.0
(s), 170.4 (s), 171.1 (s), 172.2 (s) ppm. MS (MALDI-TOF): m/z (%)
= 977 (80) [M + 39], 961 (100) [M + 23].
[3] A. Nagatsu, H. Kajitani, J. Sakakibara, Tetrahedron Lett. 1995,
36, 4097–4100.
[4] J. A. Roesener, P. J. Scheuer, J. Am. Chem. Soc. 1986, 108, 846–
847.
[5] S. Matsunaga, N. Fusetani, K. Hashimoto, K. Koseki, M.
Noma, J. Am. Chem. Soc. 1986, 108, 847–849.
[6] P. Phuwapraisirisan, S. Matsunaga, R. W. M. van Soest, N. Fu-
setani, J. Nat. Prod. 2002, 65, 942–943.
[7] S. Matsunaga, N. Fusetani, K. Hashimoto, K. Koseki, M.
Noma, H. Noguchi, U. Sankawa, J. Org. Chem. 1989, 54, 1360–
1363.
[8] N. Lindquist, W. Fenical, G. D. Van Duyne, J. Clardy, J. Am.
Chem. Soc. 1991, 113, 2303–2304.
[9] a) K. Shin-ya, K. Wierzba, K. Matsuo, T. Ohtani, Y. Yamada,
K. Furihata, Y. Hayakawa, H. Seto, J. Am. Chem. Soc. 2001,
123, 1262–1263; b) M.-Y. Kim, H. Vankayalapati, K. Shin-ya,
K. Wierzba, L. H. Hurley, J. Am. Chem. Soc. 2002, 124, 2098–
2099.
[10] A. Hayata, Y. Takebashi, K. Nagai, M. Hiramoto (Japan Ko-
kai Tokkyo Koho), JP11180997-A, 1999 [Chem. Abstr. 1999,
131, 101307].
[11] a) F. Romero, L. Malet, M. L. Cañedo, C. Cuevas, F. Reyes,
WO 2005/000880 A2, 2005; b) the same structure was proposed
for Merchercharmycin A, which was isolated from a marine-
derived Thermoactinomices sp. by K. Kanoh, Y. Matsuo, K.
Adachi, H. Imagawa, M. Nishizawa, Y. Shizuri, J. Antibiot.
2005, 58, 289–292.
[12] D. Hernández, G. Vilar, E. Riego, L. M. Cañedo, C. Cuevas,
F. Albericio, M. Álvarez, Org. Lett. 2007, 9, 809–811.
[13] D. Hernández, E. Riego, A. Francesch, C. Cuevas, F. Albericio,
M. Álvarez, Tetrahedron 2007, 63, 9862–9870.
[14] -Ile or -Ile was used for the previous studies of preparation
of analogs instead of the -Allo-Ile present in the natural prod-
uct for economical reasons.
[15] J. C. Muir, G. Pattenden, R. M. Thomas, Synthesis 1998, 613.
[16] Peptides 16a and 16b were obtained by amide bond formation
between the peptide H--Ile--Val-OMe and the free acid of
15a or 15b, respectively. Peptides 15a and 15b were obtained
by amide bond formation between the free amine of 11a and
11b and the free carboxylic acid of 11a, respectively.
[17] Compound 16a, which has the same structure as that of 16b
but without the phenyl ring, did not undergo macrocyclization
under the conditions tested for 16b.
Peptide–Heterocycle 20: The title compound was formed by coup-
ling of the acid of 19 (406 mg, 0.639 mmol) to the free amine of 11c
(197 mg, 0.671 mmol) by using the general procedure for peptide
synthesis. After 20 h, crude 20 was obtained as an oil. Purification
by column chromatography (silica gel; hexane/EtOAc, 8:2 to 4:6)
afforded pure 20 (547 mg, 94%) as a yellow oil. Rf = 0.37 (DCM/
MeOH, 95:5). [α]D = +6.5 (c = 0.97, CHCl3).1H NMR (400 MHz,
CDCl3): δ = 0.89–1.03 (m, 12 H), 1.06 (s, 9 H), 1.20–1.30 (m, 1 H),
1.47–1.58 (m, 1 H), 2.07–2.16 (m, 1 H), 2.20–2.28 (m, 1 H), 3.37
(s, 6 H), 3.68–3.75 (m, 1 H), 3.81 (dd, J = 4.6 and 9.4 Hz, 1 H),
3.89 (s, 2 H), 4.41–4.55 (m, 1 H), 4.59–4.70 (m, 1 H), 5.29–5.43 (m,
1 H), 5.98 (br. s, 1 H), 6.96–7.20 (m, 2 H), 7.38–7.46 (m, 3 H),
7.78–7.88 (m, 1 H), 8.07 (s, 1 H), 8.11 (s, 1 H), 8.22–8.33 (m, 3 H),
8.35 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.5 (q), 14.8
(q), 17.8 (q), 19.2 (q), 26.3 (t), 27.2 (q), 30.6 (d), 31.7 (t), 37.2 (d),
48.6 (d), 50.3 (2q), 57.2 (d), 58.4 (d), 62.3 (t), 73.9 (s), 99.3 (s),
126.6 (s), 127.2 (s), 128.3 (2 d), 128.5 (2 d), 129.6 (s), 130.2 (d),
136.7 (s), 139.3 (d), 140.0 (d), 141.6 (d), 151.7 (s), 153.0 (s), 154.7
(s), 161.3 (s), 161.4 (s), 162.3 (s), 163.9 (s), 170.8 (s), 171.1 (s), 171.3
(s), 171.4 (s) ppm. MS (MALDI-TOF): m/z (%) = 935 (42) [MBr81
+ Na], 933 (100) [MBr79 + Na]. HRMS: calcd. for C41H52BrN8O11
911.2933 and 913.2943; found 911.2951 and 913.2923.
[18] Peptide 17 was obtained from the free acid of 7 and H--Ile-
-Val-OMe by using the general procedure described for pep-
tide bond formation.
[19] The high polarity of macrocycle 18 with two hydroxy groups
precluded its purification from a complex crude reaction mix-
ture in which HPLC shows 18 with an area of around 8% (tR
= 7.56 min; MS: m/z = 845 [M + K], 829 [M + Na]).
Received: February 8, 2008
Acknowledgments
This study was partially supported by CICYT (BQU 2006-03794),
Generalitat de Catalunya, and the Barcelona Science Park. Thanks
to CIBER-BBN, Networking Centre on Bioengineering, Biomateri-
als and Nanomedicine D. H. thanks the Ministerio de Educación
y Ciencia for a predoctoral fellowship, and E. R. thanks the Princi-
pado de Asturias for a postdoctoral fellowship.
Published Online: May 15, 2008
3396
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3389–3396