A novel and efficient synthesis of DOPA and DOPA peptides by oxidation of tyrosine residues with IBX

Article abstract of DOI:10.1016/j.tetlet.2009.09.034

An efficient route to 3,4-dihydroxylphenylalanine (DOPA) and DOPA peptides was described by oxidation of L-tyrosine and L-tyrosine derivatives with 2-iodoxybenzoic acid (IBX). DOPA was obtained after an situ reduction of the corresponding ortho-quinone with sodium dithionite. Oxidation reactions proceeded in good yields and high chemo- and regio-selectivity. The chirality of the DOPA residue was retained under the reaction conditions. The efficiency and the selectivity of the reaction were successfully tested using recyclable polymer-supported IBX.

Full text of DOI:10.1016/j.tetlet.2009.09.034

Tetrahedron Letters 50 (2009) 6519–6521
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and efficient synthesis of DOPA and DOPA peptides by oxidation
of tyrosine residues with IBX
*
*
Roberta Bernini , Maurizio Barontini, Fernanda Crisante, Maria Cristina Ginnasi, Raffaele Saladino
Dipartimento di Agrobiologia e Agrochimica, Università degli Studi della Tuscia, Via S. Camillo De Lellis snc, 01100 Viterbo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2009
Revised 28 August 2009
Accepted 4 September 2009
Available online 10 September 2009
An efficient route to 3,4-dihydroxylphenylalanine (DOPA) and DOPA peptides was described by oxidation
of -tyrosine and -tyrosine derivatives with 2-iodoxybenzoic acid (IBX). DOPA was obtained after an situ
reduction of the corresponding ortho-quinone with sodium dithionite. Oxidation reactions proceeded in
good yields and high chemo- and regio-selectivity. The chirality of the DOPA residue was retained under
the reaction conditions. The efficiency and the selectivity of the reaction were successfully tested using
recyclable polymer-supported IBX.
L
L
Keywords:
3,4-Dihydroxyphenylalanine (DOPA)
Catechol moiety
Ó 2009 Elsevier Ltd. All rights reserved.
IBX
Polymer-supported IBX (IBX polystyrene)
Regioselective aromatic hydroxylation
The synthesis of unnatural amino acids and peptides is of pivotal
importance for the development of a selective chemical engineering
of proteins.1 According to general methods employed for these
transformations, the amino acids and peptides can be modified at
the backbone of the molecule as well as in their side chains. Back-
bone modifications include changes at any one of thethree repeating
of primary and secondary alcohols,11 benzyl alcohols,12 and b-ami-
no alcohols.13 Among other possible applications of IBX,14 the
ortho-hydroxylation of phenols to catechol derivatives performs
with a regioselectivity similar to that of natural polyphenol oxi-
dases.15 In the last few times, we were involved in the utilization
of IBX for the synthesis of bioactive catechol derivatives, such as
2-(30,40-dihydroxyphenyl)ethanol (hydroxytyrosol) and its lipo-
philic derivatives, useful molecules for cosmetic and pharmaceuti-
moieties, that are NH, CO, and a
-CH bonds.2 Side chain modifications
are in general performed by the oxidation of low redox potential
residues.3–7 In this latter case, a different selectivity is observed
depending on the nature of the oxidant. As for example, the selective
oxidation of methionine (Met), cysteine (Cys), and tryptophan (Trp)
in the presence of other potentially oxidizable residues has been
performed with the methyltrioxorhenium (MTO)/hydrogen perox-
ide catalytic system.8 High redox potential residues, aliphatic side-
chain amino acids, require most powerful oxidants. Thus, leucine
(Leu) and leucine residues are oxidized by dimethyldioxirane
cal applications.16 In
converted to the corresponding catechol derivatives with significa-
tive antioxidant activity.17 Tyrosine (Tyr) is the only
-amino acid
a similar way, guaiacyl lignans were
a
bearing the phenolic moiety. The catechol derivative of Tyr is 3,4-
dihydroxyphenylalanine (DOPA). DOPA is an unusual amino acid
derived from post-translational modification of tyrosine.18 It is
well known that DOPA is rarely included in proteins. However, it
is found in marine biological tissues, including coral reef struc-
tures,19 eggshells,20 seashells21 and adhesives produced by mol-
lusks.22 It has been postulated that the adhesive and cohesive
properties of mussel adhesive proteins in sea water is due to the
catechol moiety present into DOPA and DOPA residues.23 Cross-
linked structures having DOPA residues create hardened matrices
useful as biomaterials.24 Since the late 1960s, DOPA is the most
successful therapeutic agent in the treatment of Parkinson’s dis-
ease.25 It is the building block for design and for the synthesis of
biologically active compounds.26 Thus, research in the design of
novel synthesis of DOPA peptides is a high priority. The recent Let-
ter of Harding prompted us to describe the efficient and selective
ortho-hydroxylation of Tyr and Tyr-containing peptides to corre-
sponding DOPA derivatives with IBX.
(DMD) at c-CH bond to obtain the corresponding 4,4-dimethyl-4-
butanolide derivatives without backbone modifications.9
Recently, Harding and co-workers reported the oxidation of
threonine (Thr) residues with 1-hydroxy-1-oxo-1H-1k5-benz[d]-
[1,2]iodoxol-3-one (2-iodoxybenzoic acid, IBX) as a synthetic strat-
egy to incorporate an aldehyde or ketone moiety into a peptide
chain.10 The oxidation of alcohols to corresponding aldehydes
and ketones with IBX reagents has been also described in the case
* Corresponding authors. Tel.: +39 761 357230; fax: +39 761 357242 (R.B.); tel.:
+39 761 357284; fax: +39 761 357242 (R.S.).
E-mail addresses: berninir@unitus.it (R. Bernini), saladino@unitus.it (R. Saladino).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.034

6520
R. Bernini et al. / Tetrahedron Letters 50 (2009) 6519–6521
O
O
OH
HO
HO
OH
a) IBX, THF
OMe
NHBoc
OMe
NHBoc
HO
b) Na2S2O4, H2O
O
O
Boc-Gly-Tyr-OMe
BocHN
OMe
N
H
2
O
O
4
3
Scheme 1. Oxidative conversion of Boc-Tyr-OMe 1 into Boc-DOPA-OMe 2 with IBX/
Na2S2O4 system.
BocHN
HO
OMe
N
H
Firstly we turned our attention on the oxidation of Boc-Tyr-
OMe derivative 1.27 THF appeared to be the most useful solvent.
The oxidation of 1 (1.0 mmol) with a small excess of the oxidant
(1.2 equiv) in THF (8.0 mL) at room temperature followed by
in situ reduction with sodium dithionite (Na2S2O4, 2.0 equiv) in
water (8.0 mL), afforded a quantitative conversion of substrate
after 40 min. Boc-DOPA-OMe derivative 2 was obtained in 95%
yield as the only product (Scheme 1; Table 1, entry 1). No chro-
matographic purifications were needed. The structure of 2 was
unambiguously assigned by comparison with an authentic
sample.28 Compound 2 showed a value of the optical rotatory
Boc-Tyr-Phe-OMe
6
5
OH
O
O
H
N
Boc-Gly-Leu-Tyr-OMe
BocHN
N
H
OMe
O
7
8
OH
OH
OH
OH
power ½a D
tic
-enantiomer.28
In order to further confirm the chirality of Boc-DOPA-OMe
ꢀ
+7.0 (methanol, c 1.0, T = 22 °C) according to an authen-
L
O
O
H
N
BocHN
N
OMe
OH
derivative 2, it was deprotected by HCl-saturated ethyl acetate
and 10% KOH solution in methanol to give free DOPA which was
subjected to chiral HPLC analysis (CHIROBIOTIC T, Aldrich) using
H
O
Boc-Tyr-Tyr-Tyr-OMe
10
9
HO
L-DOPA and D,L
-DOPA as previously reported.29 The
OH
OH
commercial
presence of the peak attributable to
the -DOPA in the HPLC profile of the sample prepared according
L
-DOPA and the absence of
Scheme 2. Oxidative modification of dipeptides 3, 5 and tripeptides 7, 9 with IBX/
D
Na2S2O4 system.
to our procedure confirmed the chirality of the product. These
experimental data demonstrated that the stereochemical integrity
of the final product was not compromised during the oxidative/
the oxidation of tripeptides Boc-Gly-Leu-Tyr-OMe 7 bearing one
reactive Tyr residue, and Boc-Tyr-Tyr-Tyr-OMe 9 bearing three
reactive Tyr residues, was studied. In the case of 7 the Tyr residue
was selectively oxidized to give Boc-Gly-Leu-DOPA-OMe 8 in good
conversion and yield (Table 1, entry 4). The treatment of Boc-Tyr-
Tyr-Tyr-OMe 9 with 1.2 equiv of IBX afforded a complex mixture of
reaction products probably due to a low selectivity in the oxidation
of different Tyr residues. According to this hypothesis, the reaction
repeated in the presence of a large excess of IBX (4.0 equiv) gave
the highly functionalized tripeptides Boc-DOPA-DOPA-DOPA-
OMe 10, in which all Tyr residues are functionalized, in satisfactory
yields (Table 1, entry 5). The shifts of the absorptions of the nine
aromatic protons at 6.26–6.62 ppm in the 1H NMR spectrum of
10 compared to the absorptions of the twelve aromatic protons
at 6.56–6.86 ppm of 9 and the appearance of three new quaternary
carbon atoms in the 13C NMR spectrum of 10 confirmed the as-
signed structure.33
reductive step of Boc-L-Tyr-OMe 1.
According to the previously reported mechanism, the oxidation
reaction with IBX probably proceeded with an ionic pathway.15b,c
In particular, the regioselectivity of the ortho-hydroxylation of 1
is a consequence of an intramolecular delivery of an oxygen atom
from the iodine(V) center of the k5-iodanyl intermediate to the
most nucleophilic and congested ortho-site on the phenol with
concomitant reduction into a more stable k3-iodanyl orthoquinol
monoketal. It is interesting to note that the IBX/Na2S2O4 system
mimed the activity of naturally occurring mushroom tyrosinase
(EC 1.14.18.1).30
On the basis of the efficiency observed in the oxidation of 1, we
extended the IBX procedure to a panel of selected Tyr-containing
dipeptides and tripeptides bearing amino acids with different ali-
phatic or aromatic side-chain residues (Scheme 2).
The oxidation of Boc-Gly-Tyr-OMe 3 with IBX afforded Boc-Gly-
DOPA-OMe 4 in good conversion and yield (Table 1, entry 2),
besides a low amount of unreacted substrate. In a similar way,
treatment of Boc-Tyr-Phe-OMe 5 gave the corresponding Boc-
DOPA-Phe-OMe 6 in satisfactory conversion and yield (Table 1,
entry 3). The transformations reported were found to be selective,
and the possible oxidation of the benzylic position31 in phenylala-
nine (Phe) residue as well as that of the amide group32 in the back-
bone were not observed in our experimental conditions. Finally,
As selected examples, the stereochemical integrity of peptides 4
and 10 was confirmed by comparison of the optical rotatory power
with authentic samples after the deprotection procedure described
above [Gly-
DOPA-
-DOPA: found ½a D
T = 25 °C).34
L
-DOPA: found ½a D
ꢀ
+46.0, reported +46.07°;
+13.7, reported +13.76 (1 M HCl, c 1.0,
L-DOPA-L-
L
ꢀ
In view of the technological applications of the IBX procedure
for the oxidative conversion of tyrosine derivatives into DOPA res-
idues, we worked under heterogeneous conditions using polymer-
supported IBX, specifically IBX polystyrene already applied suc-
cessfully by us for the synthesis of hydroxytyrosol.35 We tested
the oxidation of Boc-Tyr-OMe derivative 1, the selected model
compound. Good results in terms of conversion of substrate and
yield of 2 were obtained with an excess of the oxidant (2.1 mmol,
conversion: 95%, yield: 90%). Recycling experiments proceeded
with success. When the substrate disappeared (1 h), the polymeric
reagent was recovered by filtration and the remaining solution was
treated with Na2S2O4. IBX polystyrene was regenerated as was pre-
Table 1
Experimental data of oxidations depicted in Schemes 1 and 2
Entry
Substrate
Product
Conv. (%)
Yield (%)
1
2
3
4
5
1
3
5
7
9
2
4
6
8
10
>98
90
88
85
80
95
85
84
80
75

R. Bernini et al. / Tetrahedron Letters 50 (2009) 6519–6521
6521
Table 2
8. Lazzaro, f.; Crucianelli, M.; De Angelis, F.; Neri, V.; Saladino, R. Tetrahedron Lett.
2004, 45, 9237.
Experiment of recycling of IBX polystyrene in the oxidation of 1
9. Saladino, R.; Mezzetti, M.; Mincione, E.; Torrini, I.; Paglialunga Paradisi, M.;
Mastropietro, G. J. Org. Chem. 1999, 64, 8468.
Entry
Run
Conv. (%)
Yield (%)
10. Abeysinghe, P. M.; Han, Y.; Harding, M. M. Tetrahedron Lett. 2009, 50, 2601.
11. (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019; (b) De
Munari, S.; Frigerio, M.; Santagostino, M. J. Org. Chem. 1996, 61, 9272.
12. Sorg, G.; Mengel, A.; Jung, G.; Rademann, J. Angew. Chem., Int. Ed. 2001, 40,
4395.
13. (a) Ocejo, W.; Vicario, J. L.; Carrillo, L.; Reyes, E. Synlett 1995, 2110; (b) Chen, J.
J.; Aduda, V. Synth. Commun. 2007, 37, 3493.
14. See for example: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–
1178; (b) Hypervalent Iodine in Organic Synthesis; Varvoglis, A., Ed.; Academic
Press: London, 1997; (c) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121–145; (d)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
1
2
3
4
5
6
7
8
9
9
1
2
3
4
5
6
7
8
9
95
95
95
94
95
75
72
70
72
70
90
88
90
89
88
72
70
68
70
68
10
15. (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T. R. R. Org. Lett.
2002, 4, 285; (b) Ozanne, A.; Pouységu, L.; Depernet, D.; Francois, B.; Quideau,
S. Org. Lett. 2003, 5, 2903; (c) Quideau, S.; Pouysegu, L.; Deffieux, D.; Ozanne, A.;
Gagnepian, J.; Fabre, I.; Oxoby, M. ARKIVOC 2003, 6, 106.
16. (a) Bernini, R.; Mincione, E.; Barontini, M.; Crisante, F. It. Pat., MI2007A001110,
2007.; (b) Bernini, R.; Mincione, E.; Barontini M.; Crisante, F. PCT 2008/110908,
2008.; (c) Bernini, R.; Mincione, E.; Barontini, M.; Crisante, F. J. Agric. Food Chem.
2008, 56, 8897–8904; (d) Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett.
2008, 10, 3457–3460.
17. Bernini, R.; Barontini, M.; Mosesso, P.; Pepe, G.; Willför, S. M.; Sjöholm, R. E.;
Eklund, P. C.; Saladino, R. Org. Biochem. 2009, 7, 2367.
18. Longo, R.; Castellani, P.; Tibolla, M. Phytochemistry 1974, 13, 167.
19. Waite, J. H.; Jensen, R. A.; Morse, D. E. Biochemistry 1992, 31, 5733.
20. Rzepecki, L. M.; Waite, J. H.. In Bioorganic Marine Chemistry; Scheuer, P. J., Ed.;
Springer: New York, 1991; Vol. 4, pp 120–148.
viously reported35 and reused in oxidations after adding fresh sub-
strate. As shown, IBX polystyrene was used for at least five cycles
of oxidation without loss of efficiency to give 2 (Table 2, runs 1–
5). With the sixth recycling experiment, conversions and yields de-
creased but no side-chain products were isolated demonstrating
that the oxidations proceeded again with an high chemo- and re-
gio-selectivity (Table 2, runs 6–10).
In summary, IBX and IBX polystyrene were efficient reagents in
the oxidative conversion of tyrosine and tyrosine derivatives into
DOPA and DOPA residues. The stereochemical integrity of the final
product was not compromised during the reactions. Usually, DOPA
peptides are prepared under solid phase synthesis that sometimes
requires complex reaction conditions. To the best of our knowledge
this is the first example of an one-pot synthesis of DOPA peptides
starting from already available substrates. This procedure opens a
novel way for the synthesis of modified proteins having DOPA res-
idues in their structure.
21. Waite, J. H. Comp. Biochem. Physiol. 1990, 97B, 19.
22. (a) Deming, T. J. Curr. Opin. Chem. Biol. 1999, 3, 100; (b) Vrreland, V.; Waite, J.
H.; Epstein, L. J. Phycol. 1998, 34, 1.
23. (a) Dalsin, J. L.; Hu, B.-H.; Lee, B. P.; Messersmith, P. B. J. Am. Chem. Soc. 2003,
125, 4253; (b) Waite, J. H.; Tanzer, M. L. Science 1981, 212, 1038.
24. (a) Bhattacharjee, H. R.; Unger, P. D.; Swerdloff, M. d.; Sedgwick, r. D.; Gabriel,
M.; Brambilla, R.; Hindeanlang, D. M.; Williams, J. I. Polym. Mat. Sci. Eng. 1988,
59, 110; (b) Wang, J.; liu, C.; Lu, X.; Yin, M. Biomaterials 2007, 28, 3456.
25. (a) Mendis, T.; Suchowersky, O.; lang, A.; Gauthier, S. Can. J. Neur. Sci. 1999, 26,
89; (b) Hornykiewicz, O. Amino Acids 2002, 23, 65.
26. See for example: (a) Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.;
Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2005, 16, 857; (b)
Wells, G. J.; Tao, M.; Josef, K. A.; Bihovsky, R. J. J. Med. Chem. 2001, 44, 3488; (c)
Paleo, M. r.; Dominguez, D.; Castedo, L. Tetrahedron 1994, 50, 3627.
27. Chemical purchased from Aldrich Company (Milan, Italy). The optical rotatory
Acknowledgments
Work supported by Ministero dell’Università e della Ricerca Sci-
entifica e Tecnologica and by PNR-FIRB is acknowledged.
power ½aꢀD +51.0 (methanol, c 1.0, T = 22 °C) was according to that reported in
the literature: Oswald, C. L.; Carrillo-Marquez, T.; Caggiano, L.; Jackson, R. F. W.
Tetrahedron 2008, 64, 681.
28. Aubry, S.; Pellet- Rostaing, S.; Lamaire, M. Eur. J. Org. Chem. 2007, 5212.
29. Liu, Z.; Hu, Bi.-H.; Messersmith, P. B. Tetrahedron Lett. 2008, 49, 5519. and
references cited therein.
30. Marumo, K.; Waite, J. H. Biochim. Biophys. Acta, Protein Struct. Mol. Enzym. 1986,
872, 98.
References and notes
1. (a) Offord, R. E. Protein Eng. 1987, 1, 151; (b) Gaetner, H. F.; Offord, R. E.; Cotton,
R.; Timms, D.; Camble, R.; Rose, K. J. Biol. Chem. 1994, 269, 7224; (c) Mutter, M.
Angew. Chem., Int. Ed. Engl. 1985, 24, 639; (d) Mutter, M.; Vuilledumier, S.
Angew. Chem., Int. Ed. Engl. 1989, 28, 535.
2. (a) Ranganathan, D.; Vaish, N. K.; Shah, K. J. Am. Chem. Soc. 1994, 116, 6545; (b)
Bol, K. M.; Liskamp, R. M. J. Tetrahedron Lett. 1991, 32, 5401.
3. Junheim, L. N.; Shepherd, T. A.; Baxter, A. J.; Burgess, J.; Hatch, S. D.;
Lubbenusen, P.; Wiskerchen, M.; Muesling, M. A. J. Med. Chem. 1996, 39, 96.
4. (a) Blondelle, S. E.; Perez-Paya, E.; Allicotti, G.; Foored, B.; Houghten, R. A.
Biophys. J. 1995, 69, 6304; (b) Chowdhury, S.; Eshraghi, J.; Wolfe, H.; Forde, D.;
Hlavac, A. G.; Johnston, D. Anal. Chem. 1995, 67, 390.
5. Ranganathan, S.; Ranganathan, D.; Bhattacharyya, D. J. Chem. Soc., Chem.
Commun. 1995, 67, 390.
6. (a) Ranganathan, S.; Ranganathan, D.; Bhattacharyya, D. J. Tetrahedron Lett.
1991, 32, 5615; (b) Veda, J.; Ozawa, T.; Miyazaki, M.; Fujiwara, Y. J. Inorg.
Biochem. 1994, 55, 123.
31. Nicolau, K. C.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2001, 123, 3183.
32. (a) Nicolau, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126,
5192; (b) Nicolau, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44,
5992.
33. Spectroscopic data of Boc-DOPA-DOPA-DOPA-OMe 10. 1H NMR (200 MHz,
CDCl3):
d 1.37 (9H, s, (CH3)3C), 2.67–2.82 (6H, m, ArCH2), 3.56 (3H, m,
COOCH3), 4.21–4.52 (3H, m, CH2CHNH), 6.26–6.62 (9H, m, Ar-H). 13C NMR
(200 MHz, CDCl3): d 28.0 (CH3)2CH), 36.6 (CH2), 36.9 (CH2), 37.1 (CH2), 52.2
(CH), 53.6 (CH), 54.3 (OCH3), 60.5 (CH3CHCH2), 80.64 (C(CH3)3), 115.2 (Ar),
115.8 (Ar), 116.1 (Ar), 120.7 (Ar), 127.3 (Ar), 127.7 (Ar), 127.9 (Ar), 129.6 (Ar),
143.6 (Ar), 144.1 (Ar), 144.3 (Ar), 144.4 (Ar), 155.9 (NHCOOCH), 170.8
(NHCOCH2), 171.5 (NCOCH2), 172.2 (CO).
34. Felix, A. M.; Winter, D. P.; Wang, S.-S.; Kulesha, I. D.; Pool, W. R.; Hane, D. l.;
Sheppard, H. J. Med. Chem. 1974, 17, 422.
7. Grammer, J. C.; Loo, J. A.; Edmonds, C. G.; Cremo, C. R.; Yount, R. G. Biochemistry
1996, 35, 15582.
35. Bernini, R.; Mincione, E.; Crisante, F.; Barontini, M. Tetrahedron Lett. 2009, 50,
1307. and Synfacts 2009, 5, 571.