Synthesis of L,L-cycloisodityrosines by copper(II) acetate-DMAP-mediated intramolecular O-arylation of phenols with phenylboronic acids

Article abstract of DOI:10.1016/S0040-4039(03)01390-X

Two types of cycloisodityrosines, 11 and 13, were synthesized from commercially available chiral tyrosine derivatives through the copper(II) acetate-DMAP-mediated diaryl ether formation of boronotyrosyltyrosines 8 and 10, respectively.

Full text of DOI:10.1016/S0040-4039(03)01390-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5901–5903
Synthesis of
L
, -cycloisodityrosines by copper(II)
L
acetate-DMAP-mediated intramolecular O-arylation of phenols
with phenylboronic acids
Yukio Hitotsuyanagi, Hiroshi Ishikawa, Syunsuke Naito and Koichi Takeya*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 30 April 2003; revised 29 May 2003; accepted 30 May 2003
Abstract—Two types of cycloisodityrosines, 11 and 13, were synthesized from commercially available chiral tyrosine derivatives
through the copper(II) acetate-DMAP-mediated diaryl ether formation of boronotyrosyltyrosines 8 and 10, respectively.
© 2003 Elsevier Ltd. All rights reserved.
Cycloisodityrosines are tyrosyl-tyrosine dipeptide ana-
logues in which one of the two phenoxy groups forms
an ether linkage with the aromatic carbon at the o
position of the other tyrosine, and a few compounds of
this type are known among natural products. There are
two types of cycloisodityrosines. One type of the
cycloisodityrosines, in which an ether linkage is formed
between the hydroxyl oxygen at the z position of the
N-terminus tyrosine and the carbon atom at the o
position of the C-terminus tyrosine, is found in bou-
vardin (1)1 and RA-series antitumor bicyclic peptides2,3
from Rubiaceous plants. The other type of cycloisodity-
rosine, in which the ether linkage is formed between the
carbon atom at the o position of the N-terminus
tyrosine and the hydroxyl oxygen at the z position of
the C-terminus tyrosine, is found in RP 66453 (2) from
Streptomyces sp., possessing a specific binding affinity
to the neurotensin receptor.4
Several synthetic routes to cycloisodityrosines are
known. Total synthesis of cycloisodityrosines involves
construction of a strained 14-membered macrocycle
which requires elaborate work for the preparation of
chiral phenylalanine or tyrosine derivatives and subse-
quent transformations,5–8 whereas preparation of
cycloisodityrosines via degradation of natural RA-VII
(3) into cycloisodityrosine requires a large quantity of
3 as the starting material.9 Such difficulty in the forma-
tion of the cycloisodityrosine unit has hampered
the synthesis of the analogues of those important pep-
tides.
In the present letter, we describe a practical and short
synthetic route to cycloisodityrosines from commer-
cially available tyrosine derivatives by a coupling reac-
tion of arylboronic acids with phenols originally
developed by Chan,10 Evans,11 and Lam.12,13
* Corresponding author. E-mail: takeyak@ps.toyaku.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01390-X

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Y. Hitotsuyanagi et al. / Tetrahedron Letters 44 (2003) 5901–5903
Commercially obtained 3-iodo-
L
-tyrosine (4) was N-
common pyridine-based ligands for copper(II) ion, did
not enhance the yield of 11, either (entries 4–6). When
more basic 4-picoline (entry 7) or 4-(dimethyl-
amino)pyridine (DMAP) (entry 8) was employed, the
yield of 11 was improved to 36 and 45%, respectively,
protected with a Boc group, and then methylated with
(trimethylsilyl)diazomethane14 to afford protected iodo-
tyrosine 5 in 96% yield from 4. Reaction of 5 with
bis(pinacolato)diboron using PdCl2(dppf) as a catalyst
afforded a mixture of cyclic arylboronate 6 and boronic
acid 7. After treating the mixture with sodium perio-
date to convert 6 to 7,15 7 was obtained in 83% yield
from 5 (Scheme 1). Compound 7 was N-deprotected
Table 1. Cyclization of dipeptide 8a
and coupled with Boc- -tyrosine to afford dipeptide 8
L
Entry
Amine
Concentration
(M)
Products (%)
in 83% yield. When hydrolyzed, 7 afforded acid 9 in
90% yield, which by subsequent coupling reaction with
L
-tyrosine methyl ester gave dipeptide 10 in 85% yield
11
12
(Scheme 2).
1
2
3
Pyridine
Triethylamine
N,N-Diisopropylethyl 0.025
amine
3,5-Dichloropyridine 0.025
2,2%-Dipyridyl
1,10-Phenanthroline 0.025
4-Picoline
4-(Dimethylamino)-
pyridine
0.025
0.025
29
5
4
29
65
72
When a dichloromethane solution of 8 (0.025 M) was
treated with 1 equiv. of copper(II) acetate and 5 equiv.
of pyridine11 in the presence of powdered 4 A molecular
,
4
5
6
7
8
6
4
12
36
45
33
75
39
28
5
sieves for 48 h at room temperature, desired cycloisodi-
tyrosine 116g and the protodeborylated product 12 were
obtained both in 29% yield (Table 1, entry 1). When 5
equiv. of triethylamine10,11 was used as the base, the
reaction gave 11 and 12 in 5 and 65% yield, respectively
(entry 2). Production of the protodeborylated product
is a known side reaction when the boronic acid pos-
sesses an ortho-hetero atom.11 To suppress the forma-
tion of 12, several related amines were examined for
their effect on the reaction. The use of N,N-diisopropyl-
ethylamine gave a similar result as triethylamine (entry
3). The use of 3,5-dichloropyridine, a less basic pyridine
derivative, or 2,2%-dipyridyl and 1,10-phenanthroline,
0.025
0.025
0.025
9
4-(Dimethylamino)-
pyridine
4-(Dimethylamino)-
pyridine
0.013
56
55
6
4
10
0.0063
a The reactions were carried out by using 1 equiv. of Cu(OAc)2, 5
,
equiv. of amine and powdered 4 A molecular sieves in CH2Cl2 for
48 h at room temperature.
Scheme 1. Reagents and conditions: (i) Boc2O, Et3N, H2O, rt; (ii) (trimethylsilyl)diazomethane, MeCN–MeOH (9:1), rt; 96% (two
steps); (iii) bis(pinacolato)diboron, KOAc, PdCl2(dppf), DMSO, 80°C; (iv) NaIO4, NH4OAc, acetone–H2O (1:1), 83% (two steps).
Scheme 2. Reagents and conditions: (i) 4 M HCl–dioxane, rt; Boc-Tyr, EDC, HOBt, Et3N, CHCl3, rt, 83%; (ii) Cu(OAc)2, amine,
,
powdered 4 A MS, CH2Cl2, see Table 1; (iii) LiOH, THF–MeOH–H2O (3:3:1), rt, 90%; (iv) Tyr-OMe·HCl, EDC, HOBt, Et3N,
,
CHCl3, 85%; (v) Cu(OAc)2, DMAP, powdered 4 A MS, CH2Cl2, 0.013 M, 35%.

Y. Hitotsuyanagi et al. / Tetrahedron Letters 44 (2003) 5901–5903
5903
the production of 12 being effectively reduced in the
latter. When the concentration of the starting
dichloromethane solution of 8 was diluted to 0.013 M,
the yield of 11 increased to 56% (entry 9). However,
further dilution of the starting material (0.0063 M) did
not give further increase in the yield of 11 (entry 10).16
Although this type of cycloisodityrosine is known to
readily epimerize at the C-terminus chiral center,6e–g,7b
under these reaction conditions, apparently no epimer-
ization took place: no epimerized cycloisodityrosine
was separated.17
7. (a) Beugelmans, R.; Bigot, A.; Bois-Choussy, M.; Zhu, J.
J. Org. Chem. 1996, 61, 771–774; (b) Bigot, A.; Beugel-
mans, R.; Zhu, J. Tetrahedron 1997, 53, 10753–10764; (c)
Bigot, A.; Dau, M. E. T. H.; Zhu, J. J. Org. Chem. 1999,
64, 6283–6296; (d) Boisnard, S.; Carbonnelle, A.-C.; Zhu,
J. Org. Lett. 2001, 3, 2061–2064; (e) Boisnard, S.; Zhu, J.
Tetrahedron Lett. 2002, 43, 2577–2580.
8. Poupardin, O.; Ferreira, F.; Genet, J. P.; Greck, C.
Tetrahedron Lett. 2001, 42, 1523–1526.
9. Hitotsuyanagi, Y.; Hasuda, T.; Matsumoto, Y.;
Yamaguchi, K.; Itokawa, H.; Takeya, K. Chem. Commun.
2000, 1633–1634.
In the same manner, dipeptide 10 was cyclized by using
its dichloromethane solution at 0.013 M to afford 1318
in a moderate yield of 35%, which constitutes the
cycloisodityrosine moiety of RP 66453 (2) (Scheme 2).
10. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933–2936.
11. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937–2940.
12. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941–2944.
13. This method of diaryl ether formation was applied to the
synthesis of (S,S)-isodityrosine, but the reaction was
Our methods described above provide shorter routes
for the preparation of the two types of cycloisodityrosi-
nes from commercially available chiral tyrosine deriva-
tives. Thus, it is now possible to obtain sufficient
quantities of cycloisodityrosines, which will facilitate
the analogue syntheses of bouvardin (1), RA-VII (3)
and RP 66453 (2) for their structure–activity relation-
ship studies and designing of more promising antitumor
peptide analogues or of neurotensin antagonists.
carried out between protected 4-borono-
and a -DOPA derivative. Jung, M. E.; Lazarova, T. I. J.
Org. Chem. 1999, 64, 2976–2977.
L-phenylalanine
L
14. Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. Chem.
Pharm. Bull. 1984, 32, 3759–3760.
15. Coutts, S. J.; Adams, J.; Krolikowski, D.; Snow, R. J.
Tetrahedron Lett. 1994, 35, 5109–5112.
16. Representative reaction procedure—To a solution of dipep-
References
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,
added DMAP (51.0 mg, 0.417 mmol) and powdered 4 A
molecular sieves (200 mg), and the mixture was stirred at
room temperature for 30 min. Copper(II) acetate (15.3 mg,
0.0842 mmol) was added to the mixture, and the mixture
was stirred at room temperature for 48 h. The mixture was
filtered, and the filtrate was diluted with CHCl3 (30 mL).
The CHCl3 solution was washed successively with 5%
aqueous KHSO4 (10 mL) and brine (10 mL), dried over
MgSO4 and filtered. The solvent was removed in vacuo,
and the residue was separated by HPLC (ODS, MeOH–
H2O, 55:45) to afford cycloisodityrosine 11 (21.9 mg, 56%,
[h]2D1 +53°, c 0.25, CHCl3; lit.6g [h]D25 +57°, c 0.6, CHCl3)
and peptide 12 (2.2 mg, 6%).
3. Itokawa, H.; Takeya, K.; Hitotsuyanagi, Y.; Morita, H. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
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17. The epimer of 11 is less polar than 11 and more polar than
peptide 12 (the data not shown). Thus, if present, the
epimer of 11 should have been separated by ODS-HPLC
under the conditions described in Ref. 16.
18. Data for 13: colorless prisms, mp 96–99°C (from isopropyl
ether), [h]2D1 +145° (c 0.10, CHCl3), H NMR (500 MHz,
1
CDCl3, 313 K) l 7.43 (dd, 1H, J=8.3, 2.1 Hz), 7.22 (dd,
1H, J=8.3, 2.5 Hz), 7.08 (dd, 1H, J=8.3, 2.1 Hz), 6.88 (dd,
1H, J=8.3, 2.5 Hz), 6.78 (d, 1H, J=8.2 Hz), 6.58 (dd, 1H,
J=8.2, 1.5 Hz), 6.52 (br s, 1H), 5.01 (m, 1H), 4.78 (d, 1H,
J=1.5 Hz), 4.40 (br t, 1H, J=8 Hz), 4.06 (br s, 1H), 3.95
(s, 3H), 3.79 (s, 3H), 3.61 (d, 1H, J=15.6 Hz), 3.57 (dd,
1H, J=13.4, 5.1 Hz), 2.64 (dd, 1H, J=13.4, 12.3 Hz), 2.56
(dd, 1H, J=15.6, 6.8 Hz), 1.45 (s, 9H); 13C NMR (125
MHz, CDCl3, 313 K) l 171.68 (s), 171.14 (s), 158.15 (s),
155.85 (s), 152.90 (s), 147.20 (s), 134.38 (s), 133.40 (d),
130.15 (d), 128.02 (s), 125.63 (d), 123.41 (d), 123.37 (d),
116.32 (d), 112.60 (d), 81.06 (s), 56.28 (q), 53.52 (d), 53.23
(d), 52.53 (q), 38.51 (t), 33.07 (t), 28.29 (q).