Efficient and practical protection of the catechol residue of 3,4-dihydroxy-phenylalanine (DOPA) derivative as acetonide

Article abstract of DOI:10.1055/s-2008-1032164

The acetonide formation of 3,4-dihydroxyphenylalanine (DOPA) derivative was realized under efficient and practical reaction conditions: the reaction of the methyl ester of DOPA in acetone-i-PrOH in the presence of 5 mol% of TsOH afforded the catechol side chain protected DOPA as an acetonide in quantitative yield; the workup procedure is a simple evaporation of the solvents. This methodology allows an access to the reaction in large scale. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032164

SHORT PAPER
693
Efficient and Practical Protection of the Catechol Residue of 3,4-Dihydroxy-
phenylalanine (DOPA) Derivative as Acetonide
A
cetonide Formati
a
on of 3,4-D
d
ihydroxyphe
i
nylalan
m
ine
A. Soloshonok,* Hisanori Ueki
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
E-mail: vadim@ou.edu
Received 27 September 2007; revised 4 December 2007
HO
O
O
Abstract: The acetonide formation of 3,4-dihydroxyphenylalanine
(DOPA) derivative was realized under efficient and practical reac-
tion conditions: the reaction of the methyl ester of DOPA in ace-
tone–i-PrOH in the presence of 5 mol% of TsOH afforded the
catechol side chain protected DOPA as an acetonide in quantitative
yield; the workup procedure is a simple evaporation of the solvents.
This methodology allows an access to the reaction in large scale.
NH2
COOH
acid
NH2
COOH
acetone,
60–70 °C
HO
1
2
Scheme 1
Key words: 3,4-dihydroxyphenylalanine (DOPA), protection, ace-
tonide
In our laboratory, we have investigated the syntheses of
tailor-made amino acids, utilizing alkylations, aldol addi-
tions, and Michael additions of glycine equivalents of
Ni(II) complexes under operationally convenient condi-
tions.11 In the course of the study, we encountered the ne-
cessity of an efficient and practical protection method of
the catechol residue of DOPA as an acetal or ketal. To our
surprise, a literature search revealed that there is no effi-
cient and practical method for the protection of the cate-
chol residue of DOPA as an acetal or ketal. For instance,
although they had attempted various standard methods,
Sever and Wilker mentioned in their recent report12 that
‘Surprisingly, we were unable to prepare acetonide or
diphenylmethylene ketal derivatives of DOPA’. In this ar-
ticle, we would like to present an efficient protection
method of the catechol residue of DOPA derivative as the
acetonide under operationally convenient conditions.
The ubiquitous nature of the naturally occurring amino
acid 3,4-dihydroxyphenylalanine (DOPA, 1) ever fasci-
nates scientists in biological and medicinal fields. One of
the most successful cases is that DOPA is the most suc-
cessful therapeutic agent in the treatment of Parkinson’s
disease.1 In nature, DOPA is derived from post-transla-
tional modification of tyrosine, and is the biosynthetic
precursor of dopamine. It is well known that DOPA is
rarely included in proteins. However, it is detected in ma-
rine mussel adhesive proteins as well as egg-shell precur-
sor proteins,2 and it is postulated that the adhesive and
cohesive properties of mussel adhesive proteins is attrib-
utable to the catechol side chain of DOPA residues.3 On
the other hand, it is well known that many biologically ac-
tive natural products contain DOPA derivatives as a key
structural unit.4 Thus, not only in biological and medicinal
fields but also in the field of synthetic organic chemistry,
DOPA derivatives are regarded as a useful building block
for design and synthesis of biologically active com-
pounds, such as a-Me-DOPA, b3-H-DOPA,5 calpain I in-
hibitor,6 ribasine alkaloids,7 benzazepine derivatives,8
pseudobactin,9 piperonylsyndnone derivatives,10 to men-
tion just a few. However, DOPA (1) itself possesses a car-
boxyl group, an amino group, and a catechol moiety. To
construct such desired useful compounds from DOPA, se-
lective and efficient protection/deprotection steps are cru-
cial. Furthermore, the physical and chemical properties of
unprotected DOPA, which is hardly soluble in most of or-
ganic solvents and is oxidized readily under basic condi-
tions, sometimes make it difficult for us to synthesize
desired compounds. This is why the efficient and practical
synthetic transformation methods of DOPA, including
protection/deprotection, are highly demanded.
As shown in Scheme1, at first, we attempted to protect
DOPA (1) in acetone under acidic conditions (e.g.,
TsOH). However, the conversion of the starting 1 was
27% at most. These poor yields could be attributable to
the low solubility of DOPA in acetone. Therefore, we de-
cided to use HCl salt of DOPA instead of DOPA itself.
The HCl salt of DOPA 3 was prepared easily in quantita-
tive yield by treatment of DOPA (1) with concentrated
HCl.
However, the use of the HCl salt 3 did not improve the
yield of the product 4 even after a long reaction time
(Table1, entries 1 and 2). To improve the solubility of
compound 3, the reaction was performed in MeOH (entry
3), but still low conversion was observed presumably due
to the low reactivity of acetone and/or the evaporation of
acetone at the reaction temperature. To overcome such
drawbacks, we conducted a reaction using dimethoxypro-
pane instead of acetone (entry 4). Although the yield of
the product was improved, still it was not an acceptable
yield. Therefore, we decided to run a reaction in MeOH
using an excess amount of acetone, which functioned both
as a reagent and solvent at the same time (entry 5). This
mixed solvent system worked efficiently and improved
SYNTHESIS 2008, No. 5, pp 0693–0695
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x
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x
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Advanced online publication: 08.02.2008
DOI: 10.1055/s-2008-1032164; Art ID: M07207SS
© Georg Thieme Verlag Stuttgart · New York

694
V. A. Soloshonok, H. Ueki
SHORT PAPER
Table 1 Reaction Conditions Tested for the Acetonide Formation of the HCl Salt of DOPA
TsOH (0.5 equiv),
additive
HO
HO
O
O
NH2⋅HCl
⋅HCl
NH2
60–70 °C, 6 h
COOH
COOH
4
3
Entry
Additive
Solvent
acetone
acetone
MeOH
MeOH
Yield (%)
1
none
15
27
26
46
71
65
78
79
2a
3b
4c
5
none
none
none
none
acetone–MeOH (1:1)
acetone
6
MgSO4
Na2SO4
4 Å MS
7
acetone
8
acetone
a The reaction was run for 15 h.
b The reaction was conducted with 2 equiv of acetone.
c The reaction was conducted with 2 equiv of dimethoxypropane.
Table 2 Reaction Conditions Tested for the Acetonide Formation of
the yield dramatically up to 71%. Presumably, the higher
solubility of compound 3 in the co-solvent MeOH and the
excess amount of ‘reagent’ acetone could have accelerat-
ed the reaction rate. As an alternative method, inspired by
the report from Hu and Messersmith,13 reactions were
conducted in the presence of dehydrating reagents (entries
6–9). It was proved that dehydrating reagents worked as
good as the mixed solvent system. However, we decided
to keep optimizing the reaction conditions without dehy-
drating reagents since dehydrating reagents are not effi-
cient and practical in large scale reaction. Unfortunately,
in spite of numerous attempts, we could not obtain better
results; for example, we have conducted several reactions
with Dean–Stark device, but formation of unknown by-
products was observed. Therefore, we decided to modify
the starting compound to the methyl ester of DOPA, and
the HCl salt of methyl ester of DOPA 5 was prepared by
treatment of unprotected DOPA (1) with SOCl2 in MeOH
(isolated yield: >99%).
the HCl Salt of DOPA Methyl Estera
HO
O
NH2⋅HCl
COOMe
TsOH
NH2
⋅HCl
80 °C, 17 h
HO
O
COOMe
5
6
Entry TsOH
(equiv)
Solvent
Solventb
Yield
(%)
1
2
3
4
0.1
acetone–MeOH (1:1)
acetone
MeCN
i-PrOH
i-PrOH
i-PrOH
>99
>99
>99
86
0.1
0.05
0.01
acetone
acetone
a All reactions are conducted with Dean–Stark device. The purity of
the product is >90%.
b For the purpose of azeotropic removal of water.
Since this reaction is controlled by equilibria, we conduct-
ed the reaction with a Dean–Stark device. To our satisfac-
tion, the application of the methyl ester 5 improved the
while the deceleration of the reaction rate was observed in
the case of the reaction with 1 mol% TsOH (entry 4).
yield of compound 6 up to >99%, even in the presence of In summary, a very simple, efficient and practical protec-
the smaller amount of the acid catalyst (Table2, entry 1). tion method of DOPA has been developed. Especially, we
The workup procedure is quite simple: just removal of have realized the first simple, efficient and practical pro-
solvents afforded the desired product (any further purifi- tection method of catechol side chain of DOPA. The for-
cation step is not necessary), and it allows us to access the mation of the acetonide of methyl ester of DOPA was
reaction in larger scale. To make the reaction system sim- realized in acetone–i-PrOH in the presence of 5 mol% of
pler and more practical, the reaction was preformed using TsOH. The workup procedure is a simple evaporation of
i-PrOH as a co-solvent, and it furnished the desired prod- the solvents. The purity of the product is enough high to
uct in quantitative yield (entry 2). Next, we investigated use for further reaction without any purification step. This
the effect of the amount of the acid catalyst TsOH. The de- method does not require any special technique and/or re-
creasing of the catalyst to 5 mol% did not effect on the action conditions, and allows us to conduct the reaction in
complete consumption of the starting compound (entry 3), large scale for practical purpose. Also, this efficient cate-
Synthesis 2008, No. 5, 693–695 © Thieme Stuttgart · New York

SHORT PAPER
Acetonide Formation of 3,4-Dihydroxyphenylalanine
695
(3) (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.
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chemists in the preparation of many biologically active
compounds.
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General laboratory techniques used in this study were as previously
1
reported.11i The new compound was characterized by H NMR
and 13C NMR (300 MHz and 75.4 MHz, respectively) (Varian-
300), and HRMS (Micromass, ESI Q-TOF). The melting point
(mp) is uncorrected and was obtained in an open capillary. All re-
agents and solvents, unless otherwise stated, are commercially
available and were used as received.
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Acetonide of DOPA Methyl Ester (6)
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To a flask attached with a Dean–Stark device containing DL-3-(3,4-
dihydroxyphenyl)alanine methyl ester hydrochloride (5; 4.95 g, 20
mmol) and acetone (20 mL) acetone was added p-toluenesulfonic
acid monohydrate (0.19 g, 1.0 mmol) and an excess amount of
i-PrOH for azeotropic removal of H2O. The mixture was stirred at
80 °C for 17 h. After removal of the solvents under vacuum, the de-
sired product 6 was obtained in quantitative yield (the purity of the
product is >95%, since they contain a small amount of TsOH); mp
227.6 °C (dec.).
1H NMR (D2O): d = 1.49 (3 H, s), 1.66 (3 H, s), 3.00 (1 H, dd,
J = 17.0, 12.5 Hz), 3.14 (1 H, dd, J = 17.0, 5.28 Hz), 3.81 (3 H, s),
4.41 (1 H, dd, J = 12.4, 5.28 Hz), 6.50–6.80 (3 H, m).
13C NMR (CD3OD): d = 28.0, 28.8, 29.8, 52.3, 54.1, 60.3, 112.6,
116.0, 121.0, 129.5, 146.5, 146.7, 170.3.
(11) For alkylations, see: (a) Soloshonok, V. A.; Yamada, T.;
Ueki, H.; Moore, A. M.; Cook, T. K.; Arbogast, K. L.;
Soloshonok, A. V.; Martin, C. H.; Ohfune, Y. Tetrahedron
2006, 62, 6412. (b) Soloshonok, V. A.; Ellis, T. K. Synlett
2006, 533. (c) Soloshonok, V. A.; Ueki, H.; Ellis, T. K.
Tetrahedron Lett. 2005, 46, 941. (d) Ellis, T. K.; Martin, C.
H.; Tsai, G. M.; Ueki, H.; Soloshonok, V. A. J. Org. Chem.
2003, 68, 6208. See, for aldol additions: (e) Soloshonok, V.
A.; Avilov, D. V.; Kukhar’, V. P.; Meervelt, L. V.;
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(f) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.;
Tararov, V. I.; Saveleva, T. F.; Churkina, T. D.; Ikonnikov,
N. S.; Kochetkov, K. A.; Orlova, S. A.; Pysarevsky, A. P.;
Struchkov, Y. T.; Raevsky, N. I.; Belokon, Y. N.
Tetrahedron: Asymmetry 1995, 6, 1741. See, for Michael
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L.; Kukhar, V. P. Zh. Org. Khim. 1987, 23, 2308; Chem.
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5795.
HRMS: m/z calcd for C13H18NO4 [M – Cl–]: 252.1236; found:
252.1143.
Acknowledgment
This work was supported by Ajinomoto Company (Tokyo, Japan).
References
(1) For leading references, see the historical review article:
Hornykiewicz, O. Amino Acids 2002, 23, 65.
(2) Structure, Cellular Synthesis and Assembly of Biopolymers;
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Synthesis 2008, No. 5, 693–695 © Thieme Stuttgart · New York