A new approach to the synthesis of l-3-hydroxy-4-methoxy-5-methyl-phenylalanine derivatives from l-tyrosine

Article abstract of DOI:10.1016/j.tetasy.2009.12.024

A practical procedure to regioselectively install a methyl group and a phenolic hydroxyl group onto l-tyrosine was developed. By using this approach, protected l-3-hydroxy-4-methoxy-5-methyl-phenylalanine and l-3-hydroxy-4-methoxy-5-methyl-phenylalanol, which are utilized in efficient syntheses of the relevant tetrahydroisoquinoline alkaloids, were prepared conveniently with high yield.

Full text of DOI:10.1016/j.tetasy.2009.12.024

Tetrahedron: Asymmetry 21 (2010) 39–42
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new approach to the synthesis of L-3-hydroxy-4-methoxy-5-methyl-
phenylalanine derivatives from L-tyrosine
*
Ruijiao Chen, Deguang Zhu, Zuoqiang Hu, Zhiming Zheng, Xiaochuan Chen
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical procedure to regioselectively install a methyl group and a phenolic hydroxyl group onto
Received 30 October 2009
Accepted 15 December 2009
Available online 3 February 2010
L-tyrosine was developed. By using this approach, protected
L-3-hydroxy-4-methoxy-5-methyl-phen-
ylalanine and -3-hydroxy-4-methoxy-5-methyl-phenylalanol, which are utilized in efficient synthe-
L
ses of the relevant tetrahydroisoquinoline alkaloids, were prepared conveniently with high yield.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Tetrahydroisoquinoline alkaloids and their derivatives,1 notably
exemplified by ecteinascidin 743 1 (Et 743)2–5 which is a highly
promising antitumor drug, have attracted particular attention in
synthetic chemistry due to their biological activities. As an impor-
tant sector contained in quite a few members of the tetrahydroiso-
quinoline family including ecteinascidins, renieramycins and
OMe
Me
OMe
Me
HO
HO
OAc
OAc
OH
H
H
Me
N
N
S
N
O
N
O
O
S
MeO
saframycins 1–4 (Fig. 1),
ylalanine derivatives might be conveniently used to asymmetric
total syntheses of these alkaloids. For example, -3-hydroxy-4-
L-3-hydroxy-4-methoxy-5-methyl-phen-
O
OH
OH
O
MeO
HO
L
O
NH
NH2
2 Ecteinascidin 597
OMe
methoxy-5-methyl-phenylalanol 5 was a common intermediate
in the quite efficient syntheses of Et 743 13c and Et 597 26 devel-
oped by Zhu et al., while its corresponding amino acids 6 were
the important coupling partners in the convergent syntheses of
cribrostatin 4 37 and Et 743.4b Therefore, a highly efficient synthe-
sis for the preparation of moieties 5 and 6 is necessary for the re-
lated total syntheses.
1 Ecteinascidin 743
OMe
HO
O
O
O
O
H
N
OH
O
N
Me
O
N
Me
N
Two synthetic routes to
L-3-hydroxy-4-methoxy-5-methyl-
MeO
MeO
phenylalanine derivatives, based on a diastereoselective alkylation
and an enantioselective alkylation, respectively, have been re-
ported by Williams et al.8 and Zhu et al.9 Subsequently, the
O
O
CN
O
NH
O
O
O
Schmidt protocol which employs L-tyrosine 7 to prepare 5 and 6
H
seems more economic and has received more attention.10 Unfortu-
nately, the low yield in the Riemer–Tiemann reaction (25–30%) de-
creases the overall efficiency of the attractive approach. Very
3 Renieramycin H
4 Saframycin A
(Cribrostatin 4)
OMe
OMe
HO
recently Zhu described a more efficient conversion of
L-tyrosine
HO
to 5.11 Herein, we report an alternative route to 5 and 6 from
L
-
tyrosine, in which the key methylation was achieved by a sequence
involving selective hydroxymethylation/ionic hydrogenation in-
stead of the procedures via iodination/Stille or Suzuki reaction in
the two former syntheses.10,11 Therefore, this strategy removes
CO2H
NHP
OH
NH2
5
6
Figure 1. Several tetrahydroisoquinoline alkaloids 1–4 and their common struc-
tural sectors 5–6.
* Corresponding author. Tel./fax: +86 28 85413712.
E-mail address: chenxc@scu.edu.cn (X. Chen).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.024

40
R. Chen et al. / Tetrahedron: Asymmetry 21 (2010) 39–42
OH
OMe
OH OH
OH
OMe
OMe
OH
CbzCl, NaOH
HCHO
Borax, NaOH
Et3SiH, TFA
CH2Cl2
Me2SO4, K2CO3
CH3CN
+
9
CO2H
NH2
CO2Me
CO2H
NHCbz
CO2H
NHCbz
CO2Me
NHCbz
13
NHCbz
7
8
12
9
OMe
OMe
OH
OMe
HO
CHO
Me2SO4, K2CO3
CH3CN
Et3SiH, TFA
CH2Cl2
Cl2CHOCH3
TiCl4, CH2Cl2
1) mCPBA, CH2Cl2
11
2) LiBH4, THF
CO2Me
NHCbz
OH
NHCbz
CO2H
NHCbz
10
CO2Me
NHCbz
11
15
14
2) LiOH,
1) mCPBA,
CH2Cl2
Pd/C, CH3OH
H2O/CH3OH/THF
Scheme 1. Synthesis of 11 from L-tyrosine via the primary methylation procedure.
OMe
OMe
HO
HO
the need for expensive reagents and harsh reaction conditions. This
will greatly improve the ease of synthesis and the overall yield of
these complex natural alkaloids.
CO2H
NHCbz
OH
2. Results and discussion
NH2
5
6
Our initial attempts at the methylation of
lined in Scheme 1. -Tyrosine 7 was N-protected with CbzCl in
aqueous NaOH solution affording
-N-Cbz-tyrosine 812 in 80% yield.
L-tyrosine are out-
Scheme 2. Modified methylation approach to 11 and its conversion to 5 and 6.
L
L
The base-promoted phenolic aldol condensation between 8 and
formaldehyde in the presence of Na2B4O7 was achieved smoothly
to generate the desired mono-hydroxymethylated product 9 in
85% yield. Here Na2B4O7 is necessary for the reaction to prevent
considerable bishydroxymethylation of 8 by chelating with 9.13
Ionic hydrogenation,14 a widely used method for the hydrogena-
tion of benzyl alcohols with electron-rich aromatic ring was then
employed in the conversion of the hydroxymethyl group in 9 to
its corresponding methyl group. After investigation of various
reagents and conditions, the optimized hydrogenation was carried
out in CH2Cl2 using TFA (12 equiv) and Et3SiH (3 equiv) for 16–24 h
16
of TiCl4 worked well with high regioselectivity to produce L-N-
Cbz-3-formyl-4-methoxy-5-methyl-phenylalanine methyl ester
14 in 92% yield. By stirring a mixture of the formylation product
14 and mCPBA in CH2Cl2 for only 12 h, we observed a complete
and clean conversion of 14 to the resulting formate ester, which
was partly hydrolyzed to the corresponding phenol in situ. In con-
trast, for the acetylation counterpart of 14, the Baeyer–Villiger oxi-
dation required 5–7 days to proceed thoroughly.11 Without further
purification, the mixture of the formate ester and the phenol was
reduced with lithium borohydride to its amino alcohol 15 in 80%
yield after two steps. Following Zhu’s procedure, removal of the
Cbz- protecting group in 15 by Pd-catalyzed hydrogenolysis pro-
to furnish
Compound 10 was subjected to the esterification and the etherifi-
cation in one-pot to produce -N-Cbz-3-methyl-4-methoxy-phen-
L-N-Cbz-3-methyl-tyrosine 10 in 70–80% yield.
duced
L-3-hydroxy-4-methoxy-5-methyl-phenylalanol 5, whose
L
physical and spectroscopic characteristics ([
a
]D, IR, 1H/13C NMR)
ylalanine methyl ester 11. However, the presence of a free
carboxylic acid in 9 and 10 complicated the TLC detection and
chromatographic purification.
Thus, we switched the reaction sequence in the methylation as
shown in Scheme 2. Treatment of 9 with excessive Me2SO4 and
were consistent with that of the authentic sample in the litera-
ture.11 Treatment of 14 with mCPBA followed by hydrolysis in
aqueous LiOH17 gave the corresponding amino acid 6.
3. Conclusion
K2CO3 generated a mixture of L-N-Cbz-3-hydroxymethyl-4-meth-
oxy-phenylalanine methyl ester 12 and its corresponding methyl
ether 13 in a ratio of 1:3. Both 12 and 13 showed higher activity
than 9 in the subsequent hydrogenation. In particular, the hydro-
genation of 13 was easily accomplished within 6 h and gave the
desired 11 in 97% yield under the same conditions as that of 9. This
improvement in the reaction velocity and yield is attributed to the
benzylic methoxy group in 13 being a better leaving group than the
hydroxyl group in 9 under the hydrogenation conditions. To sim-
plify the experimental procedures, the crude products 13 and 12
were utilized in the next reduction without any further purification
to generate compound 11 in an excellent yield of 92%.
The phenol group ortho to the methoxyl in 11 was then func-
tionalized via formylation followed by Baeyer–Villiger oxidation.
Treatment of 11 under Vilsmeier–Haack conditions15 led only to
the decomposition of the reactants and we failed to observe any
trace amounts of the formylation products. Fortunately, the formy-
In conclusion, we have developed a novel and short access to
L
-3-hydroxy-4-methoxy-5-methyl-phenylalanine derivatives, by
which the two representative compounds, 5 and 6 were obtained from
-tyrosine in eight steps with an overall 46% yield and in seven steps
with an overall 51% yield, respectively. This economically efficient
and robustsynthesis maypromote its employment to the total synthe-
ses of related natural alkaloids and their analogues accordingly.
L
4. Experimental
4.1. General
IR spectra were recorded on a NEXUS 670 spectrophotometer.
1H NMR spectra were recorded on Bruker AV II-400 (400 MHz),
and AV II-600 (600 MHz) with TMS as the internal standard. Data
are reported as follows: chemical shift, integration, multiplicity
lation of 11 with a,a-dichloromethyl methyl ether in the presence

R. Chen et al. / Tetrahedron: Asymmetry 21 (2010) 39–42
41
(s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), cou-
1006, 749, 698 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d (ppm) 10.32
pling constants (Hz). 13C NMR data were collected on Bruker AV
II-400 (100 MHz) with complete proton decoupling. Chemical
shifts are reported in parts per million (ppm) from the tetrameth-
ylsilane with the solvent resonance as an internal standard. Optical
rotations were measured on AUTOPOL V automatic polarimeter at
room temperature. Anhydrous CH2Cl2 and anhydrous CH3CN were
distilled from CaH2 before use. All reagents were obtained from
commercial suppliers unless otherwise stated.
(1H, s), 7.42 (1H, s), 7.25–7.37 (5H, m), 7.19 (1H, s), 5.31 (1H, d,
J = 8.0 Hz), 5.12 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.3 Hz), 4.63
(1H, m), 3.85 (3H, s), 3.73 (3H, s), 3.13 (1H, dd, J = 13.9, 5.5 Hz),
3.03 (1H, dd, J = 13.9, 6.0 Hz), 2.28 (3H, s); 13C NMR (100 MHz,
CDCl3): d (ppm) 15.5, 37.4, 52.5 54.8, 63.1, 67.0, 126.9, 128.1,
128.2, 128.5, 129.0, 132.1, 132.6, 136.2, 138.4, 155.6, 160.9,
171.7, 190.0; MS (ESI+) m/z: (M+Na)+ 408.1; HRMS (ESI+): m/z
[M+Na]+ calcd for C21H23NO6Na: 408.1423; found: 408.1418.
4.2.
L
-N-Benzyloxycarbonyl-3-hydroxymethyl-tyrosine 9
-N-benzyloxycarbonyl-tyrosine (5.30 g, 16.70 mmol),
4.5. L-N-Benzyloxycarbonyl-3-hydroxy-4-methoxy-5-methyl-
phenylalanol 15
A mixture of
L
borax (12.80 g), 1 M sodium hydroxide (33 mL) solution, and H2O
(111 mL) was stirred for 30 min at room temperature, and aqueous
formaldehyde (5 mL, 37% solution, 67 mmol) was added in one por-
tion. After the reaction was stirred at 40 °C for 5 days, the cooled reac-
tion mixture was acidified with 3 M hydrochloric acid to pH 2. The
suspension was extracted with ethyl acetate (3 ꢀ 100 mL). The latter
organic phases were combined, and dried (Na2SO4). After concentra-
tion under reduced pressure, the residue was purified by column chro-
To a solution of the compound 14 (0.42 g, 1.10 mmol) in CH2Cl2
(10 mL), mCPBA (98.4%; 0.28 g, 1.65 mmol) was added. After the
reaction was stirred overnight at rt, the reaction mixture was di-
luted with aqueous solution of sodium bicarbonate and extracted
with ethyl acetate (3 ꢀ 40 mL). The combined extracts were
washed with aqueous solution of sodium bicarbonate, brine, dried
(Na2SO4), filtered, and the solvent evaporated in vacuo. The crude
was taken up in anhydrous THF (11 mL), and LiBH4 (92 mg,
2.20 mmol) was added under argon atmosphere. The resulting
mixture was stirred overnight at rt, and methanol (1 mL) was
added. Then the solvent was evaporated and the residue was di-
luted with H2O (50 mL), extracted with ethyl acetate (3 ꢀ 30 mL),
and dried (Na2SO4). After concentration and column chromatogra-
phy, the amino alcohol 15 (0.32 g, 80%, over two steps) was iso-
matography on silica gel to give 9 (4.90 g, 85%); ½a D27
¼ þ11 (c 0.99,
ꢁ
AcOH); 1H NMR (400 MHz, DMSO-d6): d (ppm) 12.80 (1H, br. s), 9.20
(1H, s), 7.58 (1H, d, J = 8.3 Hz), 7.24–7.43 (5H, m), 7.18 (1H, s), 6.92
(1H, d, J = 7.9 Hz), 6.66 (1H, d, J = 8.1 Hz), 4.99 (1H, d, J = 12.7 Hz),
4.96 (1H, d, J = 12.7 Hz), 4.45 (2H, s), 4.10 (1H, m), 2.95 (1H, dd,
J = 13.8, 4.2 Hz), 2.72 (1H, dd, J = 13.8, 10.3 Hz).
lated as a pale yellow oil; ½a D27
ꢁ
¼ ꢂ23 (c 1.1, CHCl3); IR (neat)
4.3.
L
-N-Benzyloxycarbonyl-3-methyl-4-methoxy-
m
max: 3340, 2933, 1696, 1501, 1452, 1264, 1233, 1052, 740,
phenylalanine methyl ester 11
698 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d (ppm) 7.25–7.37 (5H, m),
6.64 (1H, s), 6.52 (1H, s), 6.00 (1H, s), 5.12 (1H, d, J = 7.4 Hz), 5.07
(2H, s), 3.88 (1H, s), 3.76 (3H, s), 3.60 (2H, m), 2.71 (2H, d,
J = 2.7 Hz), 2.23 (3H, s); MS (ESI+) m/z: (M+Na)+ 368.1.
To a solution of compound 9 (0.56 g, 1.62 mmol) in dry CH3CN
were added (CH3)2SO4 (0.46 mL, 4.85 mmol) and anhydrous K2CO3
(0.67 g, 4.85 mmol), and the resulting mixture was stirred at 60 °C
for 5 h. The solvent removed in vacuo, and the water (20 mL) was
added. The mixture was extracted with ethyl acetate (3 ꢀ 25 mL).
The combined organic layer was dried with Na2SO4, filtered, and
the solvent evaporated in vacuo affording a mixture of 12 and 13.
The mixture was dissolved in dry CH2Cl2 (16 mL), and Et3SiH
(0.78 mL, 4.86 mmol) and CF3COOH (1.20 mL) were added under ar-
gonatmosphere. Theresultingmixture wasstirredovernightatroom
temperature, basified with the diluted aqueous solution of sodium
bicarbonate to pH 7, and extracted with ethyl acetate (3 ꢀ 40 mL).
The combined organic layer was dried with Na2SO4, filtered, and
the solvent evaporated in vacuo. The residue was purified by column
chromatography on silica gel to afford 11 as a yellow oil (0.58 g, 92%
4.6. L-N-Benzyloxycarbonyl-3-hydroxy-4-methoxy-5-methyl-
phenylalanine 6
To a solution of compound 14 (0.24 g, 0.61 mmol) in CH2Cl2
(6 mL), mCPBA (98.4%; 0.16 g, 0.92 mmol) was added. After the reac-
tion was stirred overnight at rt, the reaction mixture was diluted
with aqueous solution of sodium bicarbonate and extracted with
ethyl acetate (3 ꢀ 30 mL). The combined extracts were washed with
aqueous solution of sodium bicarbonate, brine, dried (Na2SO4), fil-
tered, and the solvent evaporated in vacuo. The crude was taken
up in a mixture of H2O/CH3OH/THF (1:3:1, 6 mL), and LiOH (77 mg,
1.84 mmol) was added. The resulting mixture was stirred overnight
at room temperature. Then the solvent was evaporated and the res-
idue was diluted with H2O (50 mL), extracted with ethyl acetate
(3 ꢀ 30 mL), and dried (Na2SO4). After concentration and column
chromatography, the compound 6 (0.22 g, 88% over two steps) was
over two steps); ½a D26
ꢁ
¼ þ49 (c 0.99, CHCl3); IR (neat)
m
max: 3355,
2956, 1724, 1506, 1446, 1392, 1255, 1009, 827, 753, 700 cmꢂ1
;
1H
NMR (400 MHz, CDCl3): d (ppm) 7.25–7.37 (5H, m), 6.87 (2H, m),
6.71 (1H, d, J = 8.1 Hz), 5.20 (1H, d, J = 8.0 Hz), 5.12 (1H, d,
J = 12.3 Hz), 5.07 (1H, d, J = 12.3 Hz), 4.60 (1H, m), 3.79 (3H, s), 3.72
(3H, s), 3.02 (2H, m), 2.16 (3H, s); MS (ESI+) m/z: (M+Na)+ 380.1.
isolated as a red oil; ½a D27
ꢁ
¼ þ41 (c 1.1, CHCl3); IR (neat) mmax
:
3339, 3032, 2394, 1712, 1500, 1447, 1233, 1055, 1001, 737,
698 cmꢂ1 1H NMR (400 MHz, CDCl3): d (ppm) 7.21–7.34 (5H, m),
;
4.4.
L
-N-Benzyloxycarbonyl-3-formyl-4-methoxy-5-methyl-
6.59 (1H, s), 6.46 (1H, s), 5.45 (1H, d, J = 8.1 Hz), 5.10 (1H, d,
J = 12.2 Hz), 5.05 (1H, d, J = 12.4 Hz), 4.62 (1H, m), 3.70 (3H, s), 3.03
(1H, dd, J = 14.0, 5.3 Hz), 2.94 (1H, dd, J = 14.0, 6.4 Hz), 2.18 (3H, s);
13C NMR (100 MHz, CDCl3): d (ppm) 15.8, 37.2, 54.7, 60.5, 67.3,
114.4, 123.5, 128.1, 128.2, 128.5, 131.2, 132.0, 136.1, 144.7, 148.9,
156.2, 175.7; MS (ESI+) m/z: (M+Na)+ 382.1; HRMS (ESI+): m/z
[M+Na]+ calcd for C19H21NO6Na: 382.1267; found: 382.1278.
phenylalanine methyl ester 14
To a solution of compound 11 (1.04 g, 2.91 mmol) in dry CH2Cl2
(11 mL), TiCl4 (0.77 mL, 6.98 mmol) and Cl2CHOCH3 (0.32 mL,
3.49 mmol) were added at ꢂ30 °C under an argon atmosphere.
After stirring for 1 h, ice-cold water (30 mL) was added and stirred
at rt for 1 h. The mixture was extracted with ethyl acetate
(3 ꢀ 50 mL). The combined organic layer was dried with Na2SO4,
filtered, and the solvent evaporated in vacuo. The crude material
was purified by column chromatography on silica gel to afford 14
4.7. L-3-Hydroxy-4-methoxy-5-methyl-phenylalanol 5
A mixture of compound 15 (0.13 g, 0.38 mmol) and 10% Pd/C
(17 mg) in anhydrous methanol (3.80 mL) was stirred at rt under
an H2 atmosphere. After completion of the reaction (monitoring
as a yellow oil (1.03 g, 92%); ½a D27
¼ þ63 (c 1.1, CHCl3); IR (neat)
ꢁ
m
max: 3314, 2954, 2866, 1748, 1692, 1541, 1259, 1214, 1058,

42
R. Chen et al. / Tetrahedron: Asymmetry 21 (2010) 39–42
F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512–4515; (c) Rinehart, K. L.
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¼ ꢂ17 (c 0.99, CH3OH); IR (neat) max: 3347, 2925, 1589,
1456, 1330, 1234, 1144, 1050, 1006, 863 cmꢂ1 1H NMR
5 (77 mg, 97%);
½
a 2D7
ꢁ
m
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(600 MHz, CD3OD): d (ppm) 6.57 (1H, s), 6.53 (1H, s), 3.74 (3H,
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3.03 (1H, br. m), 2.65 (1H, dd, J = 13.5, 6.2 Hz), 2.44 (1H, dd,
J = 13.5, 7.7 Hz), 2.23 (3H, s); 13C NMR (100 MHz, CD3OD): d
(ppm) 149.6, 144.5, 134.3, 131.2, 122.0, 114.6, 65.0, 59.0, 54.0,
38.5, 14.6; MS (ESI+) m/z: (M+Na)+ 234.1; HRMS (ESI+): m/z
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Acknowledgments
This work was supported by grants from the National Natural
Science Foundation of China (No. 20802045), the National Basic Re-
search Program of China (973 Program, No. 2012CB833200), the
Youth Foundation of Sichuan University and the Setup Foundation
of Sichuan University. We also thank Sichuan University Analytical
and Testing Center for NMR analysis.
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