Synthesis of new DOPA derivative from l-tyrosine for construction of bioactive compound

Article abstract of DOI:10.14233/ajchem.2013.14893

A practical synthetic method of new DOPA derivative was developed with L-tyrosine as starting material. The new DOPA analogue could be used in building bioactive compounds.

Full text of DOI:10.14233/ajchem.2013.14893

Asian Journal of Chemistry; Vol. 25, No. 16 (2013), 9407-9408
http://dx.doi.org/10.14233/ajchem.2013.14893
NOTE
Synthesis of New DOPA Derivative from L-Tyrosine for Construction of Bioactive Compound
1,*
1
2
1
DEQUN SUN , PEIHONG WAN , GUOQING ZHANG and MIN LUO
1Marine College, Shandong University (Weihai), No. 180, Wenhua West Road, Weihai 264209, P.R. China
2Institute of microbiology, Chinese Academy of Sciences, Beijing 100101, P.R. China
*Corresponding author: E-mail: dequn.sun@sdu.edu.cn
(Received: 3 December 2012;
Accepted: 27 September 2013)
AJC-14189
A practical synthetic method of new DOPA derivative was developed with L-tyrosine as starting material. The new DOPA analogue could
be used in building bioactive compounds.
Key Words: Bioactive compound, L-DOPA analogue, Synthesis, L-Tyrosine.
OH
OH
OH
OBn
DOPA and its analogues have been useful unit in many
biologically active natural products, such as the inhibitor of
FPTase, pepticinnamin E1, OF4949-I2 (Fig. 1).
CHO
CHO
(Boc)2O, Et3N
6eq NaOH, 2eq H2O
K2CO3/BnBr
dioxane/H2O
92%
CHCl3, reflux/4hr
64%
COOH
CHCl3/MeOH
reflux/4hr
COOH
COOH
COOH
71%
H2N
BocHN
BocHN
BocHN
4
5
3
OCH3
6
HO
OBn
OMe
1) 2.5eq 30% H2O2
4% (PhSe)2
OR
O
Cl
O
7: R=CHO
8: R=H
CH Cl ,
2
18hr
2
Me
N
O
O
O
H
N
2) NH3/MeOH/1hr
78%
O
COOH
N
O
NH
H
N
N
O
Me
O
HN
H2N
BocHN
COONH2
Fig. 2
R2
O
OH
OF4949-I
2
2/1 chloroform/methanol, reflux 4 h), which may cause
racemization as well.
Pepticinnamin E
1
Fig. 1
Wilcoxen6 reported an another synthetic method of O-
benzylation L-DOPA derivative from L-tyrosine based on the
conditions described by Boger5 by utilizing warm conditions
(2.5equiv of BnBr, 2.5equiv of K2CO3, 0.1 equiv of Et4NI,
DMF, 25 ºC) to minimize possible racemization. However no
efficient methods have been report to prepare O-methylated,
N-methylated L-DOPA analogue even they are very useful
building block for the total synthesis of many biological
active natural compounds.
Many methods have been reported for preparation of
DOPA analogue3, such as traditional Schollköpf method for
preparation of chiral amino acid; the improved synthesis of
selectively protected L-DOPA derivatives from L-tyrosine,
via Reimer-Tiemann to obtain compound 5 and Dakin
reaction and Baeyer-Villiger oxidation to obtain selectively
O-benylation L-DOPA derivatives 7 reported by Jung and
Lazarova4 (Fig. 2):
Herein, we reported an efficient method for synthesis O-
methylation, N-methylation chlorinated L-DOPA derivative,
which could be utilized as key intermediate in the total
synthesis of natural products and their derivatives, such as
analogues of pepticinnamin E 1. In our prior study of total
synthesis of pepticinnamin E, we obtained the novel DOPA
analogue through catalytic hydrogenation of the dehydroamino
acids (DDAA)7. In this paper, we report the other strategy to
In above procedure, the compound 5 was prepared accor-
ding to Reimer-Tiemann process, such reaction had to run
refluxing in solution of sodium hydroxide (6 equive) in water
and chloroform for 4 h, so risking in substantial racemization
(15-20 %) according to the report of Boger5 even under the
reaction conditions (2 equive of K2CO3, acetone, 60 ºC); further-
more, the O-benzylation of tyrosine phenol in compound 5
also need vigorous reaction conditions (4.4 equive of K2CO3,

9408 Sun et al.
Asian J. Chem.
obtain new DOPA analogue by starting from nature amino
acid. We employed L-tyrosine as starting material via synthetic
strategy based on Baeyer-Villiger oxidation, methylation under
Coggins's condition8 and finally chlorination by Cl2 gas in
dichloromethane to give new DOPA analogue 16 (Fig. 3).
Preparation of L-N-methyl-3-hydroxy-4-methoxy-6-
chlorophenylalanine methyl ester 16: To a stirred solution of
compound 15 (0.24 g, 1 mmol) in dichloromethane was
bubbled chlorine at 0 ºC until 15 was converted completed
showed by TLC plate. The yellow reaction solution was
concentrated at 0 ºC to give slight yellow oil, which was
chromato-graphed to yield final product 16 as pale yellow oil,
107 mg, yield 39.1 %. 1H NMR (CDCl3, 400 Hz) δ ppm: 6.82
(s, 1H, Ar-H), 6.79(s, 1H, Ar-H), 3.85(s, 3H, COOMe), 3.68
(s, 3H, OMe), 3.63-3.48 (m, 1H, CH), 3.05-2.93 (m, 2H, CH2),
2.39 (s, 3H, NMe).
OH
OH
OH
COCH3
COCH3
CH3COCl/AlCl3
80.1%
SOCl2/MeOH
100%
CbzCl/Na2CO3
Et2O/H2O
88.8%
COOCH3
COOH
COOH
NH2. HCl
NH2
NH2
3
9
10
OCH3
COCH3
OCH3
OH
OCOCH3
REFERENCES
COCH3
Sat.NaHCO3
MeOH/H2O
MeI/NaH
m-CPBA
CH2Cl2
85.4%
(two steps)
THF/DMF
62%
1. (a) S. Omura and H. Tomoda, Pure Appl. Chem., 66, 2267 (1994); (b)
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(Tokyo), 46, 229 (1993).
COOCH3
NCbz
COOCH3
COOCH3
Me
MeNCbz
13
NHCbz
11
12
OCH3
OH
OCH3
OH
OCH3
OH
gas
2. L. Ciasullo, A. Casapullo, A. Cutignano, G. Bifulco, C. Debitus, J.
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H2, Pd/C
Cl2
CH3OH
100%
CH2Cl2
Cl
COOCH3
COOCH3
COOCH3
NHMe
15
NHMe
16
MeNCbz
14
Fig. 3
8. J.R. Coggins and N.L. Benoiton, Can. J. Chem., 49, 1968 (1971).
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Melting points were determined with an electrothermal
digital melting point apparatus and were uncorrected. Optical
rotation were recorded on a Perkin-Elmer Model 341 polari-
meter, at the sodium D line. NMR and spectra were run either
on Bruker-200 and Bruker-300 or on Varian-400.
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1547 (2003).
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Compound 99, 109, 119a, 125, 1310, 147, 1511 were prepared
based on the procedures reported in literatures.