A convenient preparation of dityrosine via Miyaura borylation-Suzuki coupling of iodotyrosine derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01081-5

Dityrosine has been prepared from 3-iodo-L-tyrosine derivatives by sequential Miyaura borylation and Suzuki coupling reactions. A tandem borylation-coupling protocol results in improved yields of the dityrosine derivatives. Suitable protecting group strat

Full text of DOI:10.1016/S0040-4039(03)01081-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4895–4898
A convenient preparation of dityrosine via Miyaura
borylation–Suzuki coupling of iodotyrosine derivatives
Craig A. Hutton* and Ojia Skaff
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
Received 12 March 2003; revised 16 April 2003; accepted 25 April 2003
Abstract—Dityrosine has been prepared from 3-iodo-L-tyrosine derivatives by sequential Miyaura borylation and Suzuki coupling
reactions. A tandem borylation–coupling protocol results in improved yields of the dityrosine derivatives. Suitable protecting
group strategies are employed to allow for global deprotection as the final step. © 2003 Elsevier Science Ltd. All rights reserved.
Examples of tyrosine–tyrosine cross-links (Fig. 1) occur
in a plethora of living organisms. Dityrosine (1),1
eases,9 cystic fibrosis,10 atherosclerosis,11 and cataract
formation.12 Dityrosine and isodityrosine units also
occur in the biologically active cyclic peptide RP 66453
(3).13
a
tyrosine dimer formed by 3,3%-biaryl bond formation,
occurs naturally in fungal cell wall proteins,2 insect egg3
and sea-urchin envelopes,4 and vertebrate proteins such
as elastin and collagen.5 In these examples the forma-
tion of dityrosine is believed to accord a strengthening
and/or defensive role to the proteins.6 Dimerisation of
proteins through dityrosine linkages is also necessary
for the proper functioning of proteins such as thyro-
globulin, the precursor to the thyroid hormone, thyr-
oxine.7 Isodityrosine (2), a tyrosine dimer in which the
tyrosine units are linked through a biaryl ether moiety,
occurs in plant cell wall proteins and presumably con-
veys a similar structural/defensive role.8
Formation of tyrosine cross-links in proteins has also
been associated with Alzheimer’s and Parkinson’s dis-
While much effort has been directed towards the syn-
thesis of isodityrosine derivatives, there are few efficient
procedures for the preparation of dityrosine. Malencik1
has reported an enzyme-catalysed oxidative-coupling of
tyrosine to provide dityrosine, albeit in low yield.
Nishiyama and co-workers14 have prepared dityrosine
via electrolysis of a 3,5-diiodotyrosine derivative, again
in low yield. Lygo15 has prepared dityrosine via an
elegant double asymmetric alkylation of a biphenyl
derivative. Zhu and co-workers16 have employed a
related asymmetric alkylation of an arylated tyrosine
derivative to prepare a dityrosine derivative.
The recent development of procedures for the prepara-
tion of biaryl compounds via the Pd-catalysed coupling
of arylboron compounds and aryl halides has enabled
the efficient preparation of biaryls.17 Additionally, the
preparation of arylboronate esters via the coupling of
aryl halides with bis(diol)diboron reagents has enabled
Figure 1.
* Corresponding author. Tel.: +61-2-9351-2752; fax: +61-2-9351-3329;
e-mail: c.hutton@chem.usyd.edu.au
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01081-5

4896
C. A. Hutton, O. Skaff / Tetrahedron Letters 44 (2003) 4895–4898
Scheme 1.
the mild preparation of many arylboronic acid deriva-
tives under mild conditions.18
In their work towards the total synthesis of macrocyclic
peptides, Zhu and co-workers19 have prepared a dity-
rosine-containing cyclic peptide via an intramolecular
borylation–Suzuki coupling, though only under precise
conditions and in moderate yield. Suzuki couplings of
tyrosine-3-boronic acid derivatives have also been used
in the synthesis of the TMC-95 peptides.20 Herein, we
present an efficient preparation of dityrosine via a
Miyaura borylation–Suzuki coupling of 3-iodotyrosine
derivatives.
Scheme 2.
Iodotyrosine derivatives 6a–c were prepared as shown
in Scheme 1. L-Tyrosine benzyl ester p-toluenesulfonate
4 (commercially available or easily prepared from
L-
tyrosine21) was N-protected by treatment with Cbz-Cl.
Treatment of 5a with iodomethane or benzyl bromide
gave the O-methyl and O-benzyl derivatives, 5b and 5c,
respectively, in excellent yields. Iodination of 5a–c with
iodine/silver sulfate then gave the iodotyrosine deriva-
tives 6a–c. Alternatively, 4-O-benzyl iodotyrosine
Scheme 3.
isolated in 23% yield and iodotyrosine 6a recovered in
23% yield. This result indicates that protodeborylation
of the tyrosine-3-boronate 9a to give 5a is competitive
with the Suzuki coupling reaction. Accordingly, opti-
mum conditions employed an excess (2 equiv.) of
boronate 9a with respect to the aryl iodide 6a, yielding
the dityrosine derivative 10a in 29% yield.
derivative 6c could be prepared from 3-iodo-
(7) as shown in Scheme 2.
L-tyrosine
Conversion of the iodotyrosine derivatives 6a–c to the
corresponding pinacolboronates 9a–c was performed
under standard Miyaura conditions (bis(pinaco-
lato)diboron (8), Pd(dppf)Cl2, KOAc, DMSO, 80°C, 24
h, Scheme 3). All reactions proceeded to 100% conver-
sion, giving the pinacol boronates as the only detectable
products. Purification of the O-Me and O-Bn deriva-
tives 9b and 9c was achieved by chromatography on
silica, furnishing the pure boronates in 82% and 85%
isolated yield. Purification of the phenol 9a by chro-
matography on silica gave low to moderate yields of the
boronate, together with variable amounts of the corre-
sponding boronic acid, indicating that partial hydroly-
sis of the pinacol boronate was occurring on silica.
Accordingly, the crude boronate 9a was used directly in
the following step without purification.
Suzuki coupling of the O-methyl and O-benzyl
boronates 9b and 9c with the corresponding iodides 6b
and 6c was more successful, giving the protected dity-
rosine derivatives 10b and 10c in 88% and 56% yield,
respectively (Scheme 4). Optimum conditions again
employed 2 equiv. of the boronate with respect to the
iodide, with K2CO3 as the base.
As the dityrosine derivatives 10a–c are symmetrical
biaryls, we also investigated the direct conversion of
iodotyrosine derivatives 6a–c to dityrosine derivatives
in a one-pot borylation–coupling procedure. In theory,
treatment of an aryl iodide with 0.5 equiv. of bis(pina-
colato)diboron (8) under standard Suzuki-coupling
conditions should result in 50% of the iodide being
transformed to the corresponding boronate, which then
couples with the remaining iodide to give the symmetri-
cal biaryl product. In practice, optimisation of the
amount of the diboron reagent is required for each
Suzuki coupling of iodotyrosine derivative 6a with the
corresponding tyrosine-3-boronate 9a required triethyl-
amine as the base (use of K2CO3 gave no coupled
product), and gave the protected dityrosine derivative
10a in only low yield. Employing a 1:1 ratio of iodide
6a and boronate 9a gave the dityrosine derivative 10a
in only 19% yield, with the tyrosine derivative 5a

C. A. Hutton, O. Skaff / Tetrahedron Letters 44 (2003) 4895–4898
4897
Scheme 4.
iodide due to the differing relative rates of conversion
of the iodide to the boronate intermediate, protode-
borylation, and Suzuki coupling (Table 1).
DirectconversionoftheO-methyliodotyrosinederivative
6b to the corresponding dityrosine derivative 10b was
most efficient with 0.75 equiv. of the diboron reagent 8
(entry 6), providing a 54% yield of 10b. Conversion of
the O-benzyl iodotyrosine derivative 6c to dityrosine
derivative10cwasachievedin70%yieldusing0.95e2quiv.
of the diboron reagent 8 (entry 10).22 In most cases low
yields of the tyrosine derivatives 5a–c were isolated as a
result of protodeborylation of the intermediate boronates
9a–c. The requirement of increasing amounts of diboron
reagent 8 in the optimised one-pot couplings of the
iodotyrosine derivatives 6a, 6b and 6c, respectively,
suggests that the steric bulk of the ortho-substituent
affects the relative rate of the borylation step to a greater
extent than the Suzuki coupling step.
Treatment of iodophenol 6a with 0.5 equiv. of
diboron reagent 8 gave dityrosine derivative 10a
(Scheme 5) in 47% yield (entry 1). Increasing the
amount of the diboron reagent 8 did not greatly
affect the yield (entries 2, 3), indicating that the
increase in available boronate intermediate is offset by
a decrease in the amount of iodide remaining. Again,
coupling of the phenol 6a required triethylamine as
the base for the Suzuki coupling to proceed—use of
K2CO3 gave a 1:1 mixture of iodide 6a and boronate
9a (entry 4).
Scheme 5.
Table 1. One-step conversion of iodotyrosine derivatives to dityrosine derivativesa
Entry
R
Equivalents of
Recovered
Yield of tyrosine
Yield of dityrosine
bis(pinacolato)diboron (8)
iodide 6 (%)
derivative 5 (%)
derivative 10 (%)
1b
2b
3b
4
5
6
7
8
9
10
H
H
H
H
Me
Me
Me
Bn
Bn
Bn
0.5
0.6
15
8
3
50
53
7
0
11
7
10
5
8
0
0
11
14
14
15
20
47
45
38
0
16
54
21
35
41
70
0.75
0.75
0.5
0.75
0.85
0.75
0.85
0.95
0
a Conditions: iodide (6), bis(pinacolato)diboron (8), Pd(dppf)Cl2·CH2Cl2 (0.03 equiv.), K2CO3 (4 equiv.), DMSO, 80°C, 48 h.
b NEt3 (4 equiv.) added after 24 h.

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C. A. Hutton, O. Skaff / Tetrahedron Letters 44 (2003) 4895–4898
With the formation of the protected dityrosine deriva-
tives optimised, deprotection was required to furnish
dityrosine. Hydrogenolysis of compounds 10a and 10c
would provide a one-step global deprotection, whereas
deprotection of 10b would require a further step to
remove the methyl ether groups. Hence, deprotection of
10b was not investigated. Additionally, compound 10c
was prepared in 58% yield from 4 (or 56% from iodoty-
rosine 7), whereas preparation of 10a was less efficient
(32% yield from 4). Accordingly, dityrosine (1) was
prepared by treatment of 10c with palladium-on-char-
coal under an atmosphere of hydrogen. Dityrosine (1)
was isolated in quantitative yield, and was purified by
reverse-phase HPLC for characterisation purposes.23
14. Nishiyama, S.; Kim, M. H.; Yamamura, S. Tetrahedron
Lett. 1994, 35, 8397.
15. Lygo, B. Tetrahedron Lett. 1999, 40, 1389.
16. Boisnard, S.; Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2001,
3, 2061.
17. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
18. Ishiyama, T.; Murate, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508.
19. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477.
20. (a) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2002, 41, 512; (b) Kaiser, M.; Groll, M.; Renner, C.;
Huber, R.; Moroder, L. Angew. Chem., Int. Ed. 2002, 41,
780; (c) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 1967; (d) Ma, D.; Wu, Q. Tetrahedron Lett.
2001, 42, 5279.
21. Yamamoto, Y.; Nakamura, H.; Fujiwara, M. J. Org.
In summary, we have developed an efficient prepara-
tion of dityrosine that employs a mild, one-pot
Miyaura-borylation–Suzuki-coupling reaction. The
optimum procedure furnishes dityrosine in four steps
Chem. 1998, 63, 7529.
22. Representative procedure: To a solution of 6c (200 mg,
0.32 mmol), Pd(dppf)Cl2·CH2Cl2 (8 mg, 0.01 mmol) and
K2CO3 (178 mg, 1.29 mmol) in DMSO (5 mL) was added
8 (78 mg, 0.31 mmol). The mixture was stirred under N2
at 80°C for 48 h. The mixture was diluted with water (30
mL), extracted with ethyl acetate (2×30 mL) and the
combined extracts were washed with 20% aq. NaCl (2×30
mL), dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed on silica eluting with 1:2:2
ether/DCM/hexanes to give the protected dityrosine 10c
and 39% yield from 3-iodo-L-tyrosine. The methods
developed should be extendable to the preparation of
higher oligomers of tyrosine and work in this area is
currently underway in our laboratories.
References
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(111 mg, 70%): H NMR (300 MHz, CDCl3) l 7.36–7.11
(30H, m), 6.98 (2H, m), 6.92 (2H, dd, J=1.9, 8.3 Hz),
6.78 (2H, d, J=8.3 Hz), 5.23 (2H, br d, J=7.9 Hz),
5.14–4.99 (8H, m), 4.90 (4H, s), 4.65 (2H, m), 3.05–3.02
(4H, m); 13C NMR (100 MHz, CDCl3) l 171.5, 155.7,
155.4, 137.4, 136.3, 135.2, 132.6, 129.3, 128.6, 128.5,
128.4, 128.3, 128.1, 128.0, 127.6, 127.4, 126.6, 113.2, 70.3,
67.1, 66.9, 55.0, 37.8; MS (ESI) m/z 1011 (M+Na+,
100%), 921 (32%).
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Data for 10b: H NMR (400 MHz, CDCl3) l 7.31–7.25
(20H, m), 6.97–6.93 (4H, m), 6.78 (2H, d, J=8.2 Hz),
5.28 (2H, br d, J=8.0 Hz), 5.12–5.09 (8H, m), 4.68 (2H,
m), 3.65 (6H, m, OMe), 3.06–3.01 (4H, m); 13C NMR
(100 MHz, CDCl3) l 172.1, 156.7, 156.4, 136.9, 135.8,
133.3, 129.9, 129.3, 129.2, 129.1, 129.0, 128.8, 128.7,
127.8, 127.6, 112.0, 67.8, 67.6, 56.3, 55.6, 37.9; MS (ESI)
m/z 859 (M+Na+, 100%).
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1
Data for 10a: H NMR (400 MHz, CDCl3) l 7.30–7.23
(20H, m), 6.94–6.92 (4H, m), 6.85 (2H, d, J=8.2 Hz),
6.03 (2H, br s), 5.32 (2H, br d, J=8.2 Hz), 5.17 (2H, d,
J=12.2 Hz), 5.13 (2H, d, J=12.2 Hz), 5.03 (2H, d,
J=12.2 Hz), 4.97 (2H, d, J=12.2 Hz), 4.70 (2H, m), 3.14
(2H, dd, J=4.5, 13.7 Hz), 2.84 (2H, dd, J=7.6, 13.7 Hz);
13C NMR (100 MHz, CDCl3) l 171.4, 155.7, 152.8,
136.0, 134.9, 131.5, 131.1, 128.6, 128.6, 128.5, 128.4,
128.2, 128.0, 127.9, 122.9, 116.8, 67.4, 67.0, 55.1, 38.2;
MS (ESI) m/z 831 (M+Na+, 100%).
1
23. Data for 1: H NMR (300 MHz, D2O/DCl) l 7.02 (2H,
br d, J=8.3 Hz), 6.92 (2H, br s), 6.79 (2H, d, J=8.3 Hz),
4.13 (2H, m), 3.11 (2H, dd, J=5.6, 14.7 Hz), 2.98 (2H,
dd, J=7.4, 14.7 Hz), in accordance with literature values
(Refs. 14 and 15).