Synthesis and structural revision of eurypamides isolated from the Palauan sponge Microciona eurypa

Article abstract of DOI:10.1016/j.tetlet.2003.08.105

Eurypamides A and B, 1 and 2, were successfully synthesized by employing Tl(NO₃)₃ (TTN) oxidation of the corresponding halogenated phenols, 9, 16, and 26. This investigation revealed that the dihydroxyarginine residue of 1 should be

Full text of DOI:10.1016/j.tetlet.2003.08.105

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7949–7952
Synthesis and structural revision of eurypamides isolated from
the Palauan sponge Microciona eurypa
Miyuki Ito, Maki Yamanaka, Noriki Kutsumura and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 25 July 2003; revised 25 August 2003; accepted 29 August 2003
Abstract—Eurypamides A and B, 1 and 2, were successfully synthesized by employing Tl(NO3)3 (TTN) oxidation of the
corresponding halogenated phenols, 9, 16, and 26. This investigation revealed that the dihydroxyarginine residue of 1 should be
revised to possess (2S,3R,4S)-configuration. In addition, the synthesis of 2 provided a pure sample, which was previously
characterized in a mixture.
© 2003 Elsevier Ltd. All rights reserved.
Eurypamides A–D, 1–4, isolated from the Palauan
sponge Microciona eurypa,1 are typical members of
such cyclic isodityrosines, as vancomycin, K-13, and
OF-4949s. Eurypamide A 1 consists of isodityrosine
and a novel dihydroxyarginine: the stereochemistry of
the (3S,4R)-dihydroxyl unit was deduced from theoreti-
cal calculation. The other three congeners were unfor-
tunately not separated, and their structures were
determined by direct spectroscopic measurement of a
enzyme-inhibitory activities, eurypamides have been
reported not to have such activities. Against this back-
ground, we initiated study of the chemistry of the
eurypamides, as part of our extensive investigation of
the isodityrosine-class natural products from the stand-
points of synthetic methodology employing phenolic
oxidation, as well as molecular recognition related to
MRSA.3 We describe herein the findings obtained in
the synthesis of eurypamides A and B, 1 and 2.
mixture, although the pure data of 3 carrying L-serine,
were obtained from a synthetic sample2 (Fig. 1).
Synthesis of eurypamide B 2. At the outset, a synthesis
of eurypamide B 2, was performed to confirm the
feasibility of our phenolic oxidation approach employ-
ing TTN as an oxidant.3 In addition, the synthetic
sample obtained would contribute to assessment of its
biological activities. Thus, the dibromotyrosine deriva-
In contrast to diverse biological activities of the cyclic
isodityrosines involving antimicrobial, cytotoxic, and
tive 54 was coupled with Boc-
-threonine 6 under BOP
L
conditions to give dipeptide 7, which on connection
with the diiodotyrosine 85 gave the desired tripeptide 9
(Scheme 1).
The TTN oxidation of 9 in THF–MeOH effected the
cyclization to give the 17-membered ring product 10 in
50% yield:6 the required cyclization mode was con-
firmed by an EI mass spectrum indicating the existence
of two bromines and one iodine, along with the high-
field shift (l 5.77) of the aromatic proton signal (*) by
1
Figure 1. Proposed structures of eurypamides.
the anisotropy effect of another aromatic ring in its H
NMR spectrum. Compound 10 was submitted to
hydrogenolysis, followed by successive alkaline and
TFA treatments to provide eurypamide B 27 in good
overall yield. Amino acid analysis of a crude product of
the acid hydrolysis of 2 clearly indicated the existence
Keywords: Microciona eurypa; isodityrosine; phenolic oxidation; thal-
lium(III) nitrate; dihydroxyarginine.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail:
nisiyama@chem.keio.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.105

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M. Ito et al. / Tetrahedron Letters 44 (2003) 7949–7952
Scheme 1. Reagents and conditions: a. BOP, Et3N/DMF, 90%. b. i) TFA/CH2Cl2; ii) 8, BOP, Et3N/DMF, 39% in two steps. c.
TTN/MeOH–THF (1:4), 50%. d. i) H2, NaOAc, 10% Pd–C/MeOH, 82%; ii) 1 M aq. NaOH/MeOH, 98%; iii) TFA/CH2Cl2,
quant.
tripeptide sequence of 1 was constructed by essentially
the same procedure as 2 (Scheme 2).
of
L
-threonine: the phenolic oxidation of 9 carrying a
-threonine residue, gave rise to cycliza-
relatively labile
L
tion without serious racemization and/or elimination
reactions. These results prompted us to undertake the
synthesis of eurypamide A 1.
Thus, the optically active 11, obtained by condensation
of 2,3-O-isopropylidene-D-glyceraldehyde with methyl
isocyanoacetate,8 was converted into 12. A TBS group
at the terminal position was selectively removed, fol-
lowed by esterification and azidation to give 13, which
on successive DIBAL reduction and TEMPO oxidation
Synthesis of eurypamide A 1. The synthesis commenced
with preparation of the appropriately protected
(3S,4R)-dihydroxyarginine derivative, from which the
Scheme 2. Reagents and conditions: a. i) DIBAL-H/CH2Cl2; ii) NaBH4/MeOH, 84% in two steps; iii) PivCl, pyr., 80%; iv)
TBSOTf, 2,6-lutidine/CH2Cl2, 85%; v) H2, 10% Pd–C/MeOH; vi) Boc2O, NaHCO3/aq. dioxane, 100% in two steps. b. i)
PPTS/MeOH, 62%; ii) MsCl, pyr.; iii) NaN3/DMF, 79% in two steps. c. i) DIBAL-H/CH2Cl2, 90%; ii) TEMPO, KBr, NaClO,
NaHCO3/aq. acetone, 88%. d. 5, BOP, Et3N/DMF, 86%. e. i) TFA/CH2Cl2; ii) 8, BOP, Et3N/DMF, 65% in two steps. f.
TTN/MeOH–THF (1:4), 63%. g. i) Ph3P/aq. THF; ii) 18, HgCl2, Et3N/DMF, 59% in two steps; iii) H2, NaOAc, 10%
Pd–C/MeOH, 88%; iv) TBAF, 77%; v) 1 M aq. NaOH/MeOH; iii) TFA/CH2Cl2, quant in two steps.

M. Ito et al. / Tetrahedron Letters 44 (2003) 7949–7952
7951
afforded the amino acid 14 in good yield. The acid 14
was condensed with 5 to afford the dipeptide 15. After
removal of the Boc group, the second coupling with 8
furnished the expected tripeptide 16. The TTN oxida-
tion of 16 effected the cyclization, leading to 17 in 63%
yield.6 To introduce a guanidine group, the azide group
was selectively reduced, and coupled with the thiourea
derivative 18. Successively, all of the protecting groups,
as well as halogen atoms were removed stepwise to
afford (3S,4R)-eurypamide A 1.9 However, comparison
Inversion of 19 with the Mitsunobu reaction, followed
by solvolysis, provided 20, which on introduction of an
azide group, and reduction, gave 21 after protection.
Four-step manipulation of the protecting groups
afforded primary alcohol 22 in good yield. Selective
introduction of an azide group was accomplished in five
steps to provide 23. After removal of the cyclic carba-
mate, the resulting alcohol was submitted to oxidation,
followed by coupling with 5 to give the corresponding
dipeptide 24. After TFA treatment,12 the resulting
ammonium salt was coupled with 8 to provide 25.
Among TTN oxidation of 25 and its derivatives, the
TBS derivative 26 provided the desired 27 in 57% yield,
whereas 25 gave spirodienone 28 in 33% yield, and an
acetonide derivative provided no cyclized product.6
Compound 27 was derivatized by essentially the same
procedure as in the case of 17 to afford (3R,4S)-1 ([h]D20
−19.4 (c 0.23, MeOH)), the spectral data of which was
superimposable to those reported.1 Accordingly, the
stereochemistry of eurypamide A 1 should be revised as
shown in Scheme 3.
1
of the H NMR data of the synthetic sample with those
reported, indicated a clear difference in the region of
the methine protones of the dihydroxyarginine moi-
ety,10 while the respective 13C NMR spectra and optical
rotations ([h]D: −17.8 (syn: c 0.23), −21.5 (nat: c 0.23)1
in MeOH) were similar. Faulkner et al. mentioned that
the rigid system of eurypamide A 1 enabled determina-
tion of the stereochemistry with the exception of those
at the C-3 and 4 positions, which should have (3S,4R)-
or (3R,4S)-configuration by chemical and spectroscopic
evidence.1 Although they adopted a more preferred
(3S,4R)-configuration in the molecular modeling calcu-
lation, we expected 1 might possess a more labile
(3R,4S)-stereochemistry. According to this hypothesis,
the corresponding arginine derivative carrying (3R,4S)-
configuration was synthesized from 1911 (Scheme 3).
In conclusion, eurypamides A and B, 1 and 2, were
successfully synthesized by using the TTN-cyclization
of the halogenated diphenol derivatives, 10, 16, and 25,
as key steps. This synthesis enabled the structural revi-
Scheme 3. Reagents and conditions: a. i) iPrO2CꢀNꢁNꢀCO2iPr, p-O2NC6H4CO2H, Ph3P/THF, 90%; ii) NaOMe/MeOH, 80%. b.
i) DEAD, DPPA, Ph3P/THF, 88%; ii) Ph3P/aq. THF; iii) Boc2O, NaHCO3/aq. dioxane, 92%. c. i) H2, Pd(OH)2–C, CaCO3/EtOH;
ii) PivCl·pyr., 53% in two steps; iii) TBSOTf, 2,6-lutidine/CH2Cl2, 89%; iv) DIBAL-H/CH2Cl2, 92%. d. i) NaH/THF, 93%; ii)
Boc2O, DMAP, Et3N/THF, 86%; iii) CSA/MeOH, 75%; iv) MsCl·pyr.; v) NaN3/DMF, 84% in two steps. e. i) Cs2CO3/MeOH,
85%; ii) TEMPO, KBr, NaClO, NaHCO3/aq. acetone; iii) 5, BOP, Et3N/DMF, 85% in two steps. f. i) TBAF, quant; ii)
TFA/CH2Cl2; 8, BOP, Et3N/DMF, 85% in two steps. g. TBSOTf, 2,6-lutidine/CH2Cl2; K2CO3/MeOH, 60%. h. TTN/MeOH–
THF (1:4), 57%. i. i) Ph3P/aq. THF, 76%; ii) 18, HgCl2, Et3N/DMF, 72%; iii) H2, NaOAc, 10% Pd–C/MeOH; iv) TBAF, 70%
in two steps; v) 1 M aq. NaOH/MeOH; iii) TFA/CH2Cl2, quant in two steps.

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M. Ito et al. / Tetrahedron Letters 44 (2003) 7949–7952
sion of 1 to possess (2S,3R,4S)-configuration in the
signals were observed in that of synthetic 2. Selected data
of 2: [h]2D0 −22.1 (c 1.0, MeOH); IR (film) wmax 3407, 1653
cm−1; lH (CD3OD, 400 MHz) 1.14 (3H, d, J=6.4 Hz),
2.66 (1H, t, J=13 Hz), 2.93 (1H, dd, J=5, 15 Hz), 3.20
(1H, d, J=15 Hz), 3.42 (1H, dd, J=4, 13 Hz), 4.16 (2H,
complex), 4.43 (1H, d, J=2.4 Hz), 4.72 (1H, dd, J=4, 13
Hz), 5.94 (1H, d, J=2 Hz), 6.65 (1H, dd, J=2, 8 Hz),
6.83 (1H, d, J=8 Hz), 6.86 (1H, dd, J=2, 8 Hz), 7.02
(1H, dd, J=2, 8 Hz), 7.19 (1H, dd, J=2, 8 Hz), 7.41 (1H,
dd, J=2, 8 Hz); lC (CD3OD, 100 MHz) 19.9, 36.9, 39.8,
53.9, 58.7, 58.8, 69.5, 116.7, 117.0, 122.7, 123.4, 124.5,
124.9, 131.8, 133.0, 135.7, 147.2, 149.7, 154.8, 168.4,
168.5, 170.7. HRFABMS m/z 444.1758, calcd for
C22H26N3O7 (M++H) 444.1771.
dihydroxyarginine residue.
Acknowledgements
This work was supported by Grant-in-Aid for the 21st
Century COE program ‘KEIO Life Conjugate Chem-
istry’, as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science, and Technol-
ogy, Japan. The authors thank Mr. T. Ogamino for his
technical assistance.
8. Yamamoto, Y.; Kirihata, M.; Ichimoto, I.; Ueda, H.
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2.71 (1H, t, J=13 Hz), 2.95 (1H, dd, J=5, 15 Hz), 3.20
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nent in a mixture of 2–4, Faulkner et al. reported no
1
detailed spectroscopic data, with the exception of the H
26 in better yield.
NMR signals (l 1.16, 4.18, and 5.94): the corresponding