Synthesis of a cyclic diaryl ether derivative under solid-phase conditions

Article abstract of DOI:10.1016/S0040-4039(01)01240-0

The TTN phenolic oxidation, along with the N-protective group of the corresponding tripeptide derivatives, was examined to accomplish construction of a cyclic isodityrosine derivative under solid-phase conditions. The desired cyclization was effected under the TTN (thallium(III) trinitrate)/NMP-MeOH conditions to give the corresponding 17-membered ring lactam 12.

Full text of DOI:10.1016/S0040-4039(01)01240-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6311–6313
Synthesis of a cyclic diaryl ether derivative under solid-phase
conditions
Kazuhiko Nakamura,b Hisa Nishiyaa and Shigeru Nishiyamaa,*
aDepartment of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
bNational Institute of Advanced Industrial Science and Technology, Higashi 1-1, Tsukuba 305-8566, Japan
Received 4 June 2001; accepted 6 July 2001
Abstract—The TTN phenolic oxidation, along with the N-protective group of the corresponding tripeptide derivatives, was
examined to accomplish construction of a cyclic isodityrosine derivative under solid-phase conditions. The desired cyclization was
effected under the TTN (thallium(III) trinitrate)/NMP–MeOH conditions to give the corresponding 17-membered ring lactam 12.
© 2001 Elsevier Science Ltd. All rights reserved.
Isodityrosine-related natural products are known not
only as components of the plant cell wall but also as
bioactive substances isolated from a wide range of
natural origins. Based on molecular-based consider-
ation, their prominent activities are apparently arise
from the rigid stereochemistry of the peptide chains
strongly supported by the diaryl ethers.1,2 From exten-
sive chemical investigation of these molecules, the
assembly of the diaryl ether moieties may be a crucial
step in synthesis of the isodityrosine-class natural prod-
ucts. Along with such effective methods as the Ullmann
reactions and SNAr reactions,3 our phenolic oxidation
by employing thallium(III) salts has been recognized as
a standard methodology (Scheme 1).4,5
ethers in high yields, owing to easy tendency of pheno-
lic oxidation to polymerization. 2) More than stoichio-
metric amounts of poisonous thallium(III) salts are
usually required for syntheses of the cyclization of
halogenated phenols. Accordingly, work-up of the reac-
tion mixture involves troublesome procedures to obtain
the oxidation products. The solid-phase synthesis might
provide a possible solution to these problems by
anchoring molecules to prevent polymerization,6–8 by
washing out excess reagents from the substrate-loaded
resin, along with the feasibility of providing libraries for
effective screening of leads of new chemotherapeutic
agents. Such motivation prompted us to investigate the
solid-phase chemistry of the phenolic oxidation.9
However, some problems may be incurred with our
methodology: 1) difficulties of construction of diaryl
At the outset, the cyclic isodityrosine derivative 6, was
synthesized as a reference by the usual solution proce-
dure (Scheme 2). Successive peptide-chain elongation
was commenced by coupling of dibromo-L-tyrosine
methyl ester 1 with the isoleucine derivative 2, leading
to 3. After deprotection of the Boc group in the N-ter-
TTN
minal, further connection with diiodo- -tyrosine (4)
L
Br
provided the tripeptide substrate 5 for the oxidation.
Upon treatment of 5 with TTN in THF–MeOH, the
desired cyclization effectively proceeded to afford the
cyclic diaryl ether 615 in 66% yield. The direction of the
cyclization was unambiguously determined by the mass
spectrum that exhibited a molecular ion possessing two
bromines and one iodine.10 Since 6 was obtained by the
solution procedure, this peptide skeleton would be syn-
thesized on an appropriate resin. Base-labile Fmoc
groups are adopted as N-protective groups to carry out
the repeated peptide elongation on resin. Although
I
I
Br
Br
Br I
OH
OH
TTN = thallim trinitrate
Scheme 1.
O
OH
Keywords: isodityrosine; diaryl ether; thallium trinitrate; phenolic
oxidation; solid-phase reaction.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01240-0

6312
K. Nakamura et al. / Tetrahedron Letters 42 (2001) 6311–6313
Br
I
OH
Br
HO
Br
HO
O
I
i
ii, iii
Br
Br
Br
O
O
H
N
BocHN
N
H3N
CO2Me
CO2Me
CO2H
N
CO2Me
H
BocHN
1
H
3
O
5
iv
I
I
BocHN
HO
I
OH
CO2H
Br
O
2
BocHN
4
Br
O
H
N
N
CO2Me
BocHN
H
O
6
Scheme 2. Reagents and conditions: (i) Boc-
L-isoleucine (2), DCC, HOBt, NMM/THF (63%); (ii) TFA/CH2Cl2; (iii) Boc-diiodo-L-
tyrosine (4), BOP, Et3N/DMF (84% in two steps); (iv) TTN/THF–MeOH (8:1) (66%).
MeOH is the best solvent for the TTN oxidation, lack
of swelling of resin in this solvent would interfere with
the smooth solid-phase reaction. Accordingly, combina-
tions of MeOH with CH2Cl2, DMF, and NMP, known
as effective solvents for resin swelling, were inspected to
acquire the expected cyclization of 7 prepared by essen-
tially the same procedure as in the case of 5 (Scheme 3).
Upon comparison of the solvent pairs, the NMP–
MeOH provided the best results in the conversion of 7
into 8 (entry 3).
to the resin 11: the loading amount was confirmed to be
65% of the theoretical amount after cleavage of the
linkage under AcOH–TFE/CH2Cl2 conditions. Conse-
quently, the tripeptide 11 in hand was submitted to the
TTN oxidation, followed by switching the N-protective
group to an acetyl group, reduction,13 cleaving from the
resin, and methylation to give the desired cyclic isodity-
rosine 1215 in 17% yield as the sole oxidation product.14
In conclusion, the TTN oxidation of ortho,ortho-
dihalogenated phenols was demonstrated under the
solid-phase conditions to develop safe and effective
methodology for production of isodityrosine-class
bioactive molecules, as well as to aim at production of
a screening library of isodityrosine congeners. Opti-
mization of the reaction conditions is in progress.
Based on these findings, the solid-phase synthesis of 12
was initiated with loading of Fmoc-dibromo-L-tyrosine
(9) (0.3 equiv. mol) onto the trityl resin (1 equiv. mol),12
leading to 10 in 81% yield (Scheme 4). Successive
peptide-chain elongation afforded the tripeptide bound
I
I
OH
OH
HO
Br
Br
O
I
TTN
solvent
Br
Br
O
O
H
H
N
N
N
N
CO2Me
CO2Me
FmocHN
FmocHN
H
H
O
O
7
8
yields of the oxidation (%)
entries
solvent
1
2
3
DMF - MeOH (10 : 1)
CH2Cl2 - MeOH (10 : 1)
NMP - MeOH (10 : 1)
19
33
49
Scheme 3.

K. Nakamura et al. / Tetrahedron Letters 42 (2001) 6311–6313
6313
Scheme 4. Reagents and conditions: (i) i-Pr2NEt/CH2Cl2, 81%; (ii) 30% piperidine/DMF; Fmoc-
L
-isoleucine, HATU, i-Pr2NEt/
DMF; (iii) 30% piperidine/DMF; Fmoc-diiodo-L-tyrosine, HATU, i-Pr2NEt/DMF, 65% from 10 after acid hydrolysis (AcOH–
TFE/CH2Cl2); (iv) (a) TTN/NMP–MEOH (10:1), (b) 30% piperidine, (c) Ac2O, i-Pr2NEt, (d) NaBH4, (e) 10% AcOH, (f)
TMSCHN2, 17% from 11.
Acknowledgements
11), a substrate for K-13, L-tyr-L-tyr-L-tyr involving a
ClꢀI pair, provided a considerable amount of the product
cyclized by the undesired direction. Accordingly, the
structure of the oxidation product should be carefully
inspected by means of mass spectrometry.
The authors are financially supported by a Grant-in-
Aid for Scientific Research (C) from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan, as well as Keio Gijyuku Academic Development
Funds.
11. Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahedron
Lett. 1989, 30, 379–382.
12. The 2-chlorotritylchloride resin was purchased from Nov-
abiochem: loading, 1.3 mmol/g; polymer matrix, copoly-
mer of styrene–1% DVB, 100–200 mesh.
13. This step was required to eliminate the remaining oxi-
dant.
References
1. Bugg, T. H. D.; Walsh, C. T. Nat. Prod. Rep. 1992, 9,
14. Upon using the Wang resin, (4-bromomethyl)-
phenoxymethyl polystylene, the tripeptide was obtained
in lower yield than in the case of the trityl resin, probably
owing to the acidic phenol group of the tyrosine residue
that might take part in the loading reaction. Although 12
accompanied no unexpected oxidation products, cleavage
of the substrate from the resin under the acidic TTN
reactions, might result in the low yield.
15. Selected data of the cyclic products. Compound 6: IR
(film) 1660 cm−1; lH (CDCl3) 0.89 (6H, complex), 1.08
(1H, m), 1.26 (1H, m), 1.49 (9H, s), 1.76 (1H, m), 2.52
(1H, t, J=13 Hz), 2.71 (1H, dd, J=3.2, 14.2 Hz), 3.30
(1H, dd, J=6.1, 14.2 Hz), 3.41 (1H, dd, J=4.1, 13.2 Hz),
3.85 (3H, s), 4.33 (1H, m), 4.41 (1H, dd, J=4.3, 9.6 Hz),
4.93 (1H, ddd, J=4.1, 8.4, 12.8 Hz), 5.26 (1H, d, J=7.1
Hz), 5.74 (1H, d, J=1.7 Hz), 6.00 (2H, complex), 6.11
(1H, s), 7.07 (1H, d, J=1.7 Hz), 7.30 (1H, d, J=1.9 Hz),
7.63 (1H, d, J=1.9 Hz). FAB-MAS. Found: m/z
853.9951. Calcd for C30H37O8N379Br81BrI, 885.9975 (M+
H). Compound 12: IR (film) 1742, 1638 cm−1; lH
(CDCl3) 0.89 (6H, complex), 2.01 (3H, d, J=4.3 Hz),
3.86 (3H, s), 4.91 (1H, m), 5.72 (1H, d, J=2.2 Hz), 7.08
(1H, d, J=2.2 Hz), 7.29 (1H, d, J=1.6 Hz), 7.61 (1H, d,
J=1.6 Hz). FAB-MAS. Found: m/z 809.9732. Calcd for
C28H33O7N379Br81BrI, 809.9712 (M+H).
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6. This effect is known as pseudo-dilution. See: Bourne, G.
T.; Meutermans, W. D. F.; Alewood, P. F.; McGeary, R.
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9. A part of this investigation was presented in the 79th
Annual Meeting of the Chemical Society Japan, Kobe,
2001 (abst. 1G3 33).
10. In general, the ether linkage is constructed at the halogen
substituent possessing a lower oxidation potential (ex.
iodo group in 5). However, it is possible that stereochem-
ical strain interferes with this selection. For instance (Ref.