Synthesis of L-3-hydroxy-4-methoxy-5-methylphenylalanol

Article abstract of DOI:10.1055/s-0028-1087548

The L-3-hydroxy-4-methoxy-5-methylphenylalanol, a common subunit of ecteinascidin and safracin family alkaloids, was synthesized from L-tyrosine in eight steps with an overall yield of 50%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087548

466
LETTER
Synthesis of L-3-Hydroxy-4-methoxy-5-methylphenylalanol
Synthesis of
L
-3-H
i
ydroxy
c
-4-methox
o
l
enylala
a
nol s Demoulin, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 17 October 2008
OMe
Abstract: The L-3-hydroxy-4-methoxy-5-methylphenylalanol, a
common subunit of ecteinascidin and safracin family alkaloids, was
synthesized from L-tyrosine in eight steps with an overall yield of
50%.
HO
OH
Me
OAc
H
N
Me
Me
N
OMe
Key words: amino acid, amino alcohol, Friedel–Crafts reaction,
Suzuki–Miyaura reaction
HO
Me
O
S
O
O
O
H2N
The L-3-hydroxy-4-methoxy-5-methylphenylalanol (1,
Figure 1) is a key structural subunit found in ecteinascidin
743 (2)1–4 and a number of other related tetrahydroiso-
quinoline-containing alkaloids.5 Williams and co-workers
reported a concise synthesis of the corresponding amino
acid by way of a diastereoselective alkylation of chiral oxa-
zinone with an appropriate benzylbromide,6 while our
group prepared 1 via a key enantioselective alkylation of
N-(diphenylmethylene)glycine tert-butyl ester.7 Schmidt
and co-workers developed a synthesis of L-3-hydroxy-4-
methoxy-5-methylphenylalanine from L-tyrosine.8 In this
synthesis, the 3-hydroxy group was introduced via a se-
quence of Riemer–Tiemann formylation followed by a
modified Dakin oxidation. Unfortunately, the yield of
Riemer–Tiemann reaction was low (25–30%), reducing
consequently the overall efficiency of this otherwise at-
tractive route. In continuation of our research program
dealing with the synthesis of this family of natural prod-
ucts as well as their analogues,9 we thought to develop an
alternative strategy that is more efficient and is potentially
amenable to large-scale synthesis. We report herein the
elaboration of readily accessible L-tyrosine to 1 featuring
a sequence of Friedel–Crafts acylation–methylation–
Baeyer–Villiger oxidation.
MeO
HO
NH
OH
1
ecteinascidin 743 (2)
Figure 1
failed with trimethylboroxine under standard Suzuki–
Miyaura conditions, but worked well with tetramethyltin
to afford the methylated product 7 in 72% yield under op-
timized conditions [Pd(PPh3)2Cl (0.1 equiv), LiCl (7.0
equiv), DMF, 100 °C, entry 4].11 On the other hand, com-
pound 6 having an ortho methyl ether group participated
in the palladium-catalyzed cross-coupling with both
trimethylboroxine12 and tetramethyltin to afford the cou-
pling product in yields of 85% (entry 5) and 70% (entry
8), respectively.13 While these experiments were per-
formed under microwave-irradiation conditions, we
found that the same reaction occurred with similar effi-
ciency under classic heating conditions,14 albeit with
longer reaction time.
The Baeyer–Villiger oxidation of acetophenone 8 was
best carried out with MCPBA at room temperature.15 Al-
though the reaction took 5–7 days to go to completion, the
transformation is clean and the corresponding acetoxy de-
rivative 9 was isolated in 86% yield.16 Attempt to acceler-
ate the reaction by heating to reflux a dichloromethane
solution leading to the degradation of the starting materi-
als, while other conditions including MCPBA/PTSA (cat-
alytic),17 H2O2/SeO2 (catalytic)18 turned out to be
inefficient. The orthogonally protected L-3-hydroxy-4-
methoxy-5-methylphenylalanine methyl ester (9) was a
key starting material in our synthesis of cribrostatin IV.9b
Finally, concurrent reduction of acetate and methyl ester
with lithium borohydride (LiBH4) furnished amino alco-
hol 10, which upon hydrogenolysis afforded the L-3-
hydroxy-4-methoxy-5-methylphenylalanol (1) in 90%
overall yield.19 The enantiomeric excess of 1 was deduced
to be higher than 95% by comparison of the optical rota-
tion value of 1 with that of the authentic sample synthe-
sized previously.
Our synthesis of 1 from L-tyrosine is shown in Scheme 1.
The Friedel–Crafts reaction of L-tyrosine (3) with acetyl
chloride in the presence of AlCl3 (4 equiv) afforded 3-
acetyltyrosine10 which, without purification, was N-pro-
tected leading to 4 in 79% overall yield. Iodination of 4
with iodine in the presence of silver sulfate occurred con-
currently with the esterification of the free carboxylic acid
to provide L-N-Cbz-3-acetyl-5-iodotyrosine methyl ester
(5). The phenol group of 5 was subsequently O-methylat-
ed to afford 6. Methylation of aryliodides 5 and 6 was next
investigated using the Stille and Suzuki–Miyaura reac-
tions. The results are summarized in Table 1. As can be
seen, cross-coupling of 5 having an ortho hydroxy group
SYNLETT 2009, No. 3, pp 0466–0468
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087548; Art ID: G33308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of L-3-Hydroxy-4-methoxy-5-methylphenylalanol
467
O
OH
containing alkaloids has already been demonstrated. We
believed that the synthesis of 1 and 9 described herein is
the most efficient one reported to date. With the easy ac-
cess of 1, we are now envisaging the synthesis of ana-
logues of ecteinascidin 743 (2), a complex marine natural
product recently being approved by the European Com-
mission as an anticancer drug.
OH
O
OR
I
a,b
c
e
COOH
COOH
NH2
COOMe
NHCbz
NHCbz
5 R = H
6 R = Me
d
3
4
OMe
O
OR
O
Acknowledgment
OMe
HO
Me
OH
Me
O
Me
f
g
Financial supports from CNRS and ICSN are gratefully acknowled-
ged. N.D. thanks ICSN for a doctoral fellowship.
COOMe
NHCbz
COOMe
NHCbz
References and Notes
NHCbz
7 R = H
(1) Total synthesis: (a) Corey, E. J.; Gin, D. Y.; Kania, R. S.
J. Am. Chem. Soc. 1996, 118, 9202. (b) Endo, A.;
Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T.
J. Am. Chem. Soc. 2002, 124, 6552. (c) Chen, J.; Chen, X.;
Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87.
(2) Formal total synthesis: (a) Zheng, S.; Chan, C.; Furuuchi,
T.; Wright, B. J. D.; Zhou, B.; Guo, J.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2006, 45, 1754. (b) Fishlock, D.;
Williams, R. M. J. Org. Chem. 2008, 73, 9594.
9
10
8 R = Me
OMe
HO
Me
h
OH
NH2
1
(3) Semisynthesis: Menchaca, R.; Martínez, V.; Rodríguez, A.;
Rodríguez, N.; Flores, M.; Gallego, P.; Manzanares, I.;
Cuevas, C. J. Org. Chem. 2003, 68, 8859.
Scheme 1 Synthesis of 1 from L-tyrosine. Reagents and conditions:
a) AlCl3 (4 equiv), nitrobenzene, r.t., then AcCl, 100 °C; b) CbzOSu,
dioxane, aq NaHCO3, 79% over two steps; c) I2, AgSO4, MeOH, r.t.;
d) K2CO3, MeI, DMF, r.t., 91% over two steps; e) Pd(PPh3)4, K2CO3
(2 equiv), BHT cat., TMB (1.5 equiv), dioxane, MW irradiation,
100 °C, 2 h, 85%; f) MCPBA, CH2Cl2, r.t., 5–7 d, 86%; g) LiBH4,
THF–MeOH, r.t., 97%; h) Pd/C, H2, MeOH, 100%.
(4) Other synthetic approaches: (a) Saito, N.; Kamayachi, H.;
Tachi, M.; Kubo, A. Heterocycles 1999, 51, 9. (b)Saito,N.;
Tachi, M.; Seki, R.; Kamayachi, H.; Kubo, A. Chem. Pharm.
Bull. 2000, 48, 1549. (c) Vincent, G.; Lane, J. W.; Williams,
R. M. Tetrahedron Lett. 2007, 48, 3719. (d) Tang, Y.-F.;
Liu, Z.-Z.; Chen, S.-Z. Tetrahedron Lett. 2003, 44, 7091.
(e) González, J. F.; Salazar, L.; Cuesta, E.; Avendaño, C.
Tetrahedron 2005, 61, 7447. (f) Chen, X.; Chen, J.;
De Paolis, M.; Zhu, J. J. Org. Chem. 2005, 70, 4397.
(g) Aubry, S.; Pellet-Rostaing, S.; Fenet, B.; Lemaire, M.
Tetrahedron Lett. 2006, 47, 1319. (h) Chandrasekhar, S.;
Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098.
(i) Ceballos, P. A.; Péres, M.; Cuevas, C.; Francesch, A.;
Manzanares, I.; Echavarren, A. M. Eur. J. Org. Chem. 2006,
1926. (j) Chang, Y.-A.; Sun, T.-H.; Chiang, M. Y.; Lu, P.-J.;
Huang, Y.-T.; Liang, L.-C.; Ong, C. W. Tetrahedron 2007,
63, 8781. (k) Obika, S.; Yasui, Y.; Yanada, R.; Takemoto,
Y. J. Org. Chem. 2008, 73, 5206.
(5) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(6) Jin, W.; Williams, R. M. Tetrahedron Lett. 2003, 44, 4635.
(7) De Paolis, M.; Chen, X.; Zhu, J. Synlett 2004, 729.
(8) Schmidt, E. W.; Nelson, J. T.; Fillmore, J. P. Tetrahedron
Lett. 2004, 45, 3921.
(9) (a) Chen, J.; Chen, X.; Willot, M.; Zhu, J. Angew. Chem. Int.
Ed. 2006, 45, 8028. (b) Chen, X.; Zhu, J. Angew. Chem. Int.
Ed. 2007, 46, 3962. (c) Wu, Y.-C.; Liron, M.; Zhu, J. J. Am.
Chem. Soc. 2008, 130, 7148.
Table 1 Palladium-Catalyzed Methylation of Aryliodide 5 and 6a
EntryR
‘MeM’
Catalyst
Solvent, base
Yield
(%)b
1
2
3
4
5
6
7
8
H
H
H
H
(MeBO)3 Pd(PPh3)4
dioxane, K2CO3
0c
36
71
72
Me4Sn
Me4Sn
Me4Sn
Pd(OAc)2, Ph3P DMF
Pd(PPh3)2Cl2
Pd(PPh3)4
DMF
DMF
Me (MeBO)3 Pd(PPh3)4
dioxane, K2CO3 85c
Me Me4Sn
Me Me4Sn
Me Me4Sn
Pd(OAc)2, Ph3P DMF 31
Pd(PPh3)2Cl2
Pd(PPh3)4
DMF
DMF
64
70
a General conditions: 5 (6)/‘MeM’ = 1:1.5, Pd catalyst (0.1 equiv),
c 0.25 M, MW irradiation.
b Isolated yield.
c Suzuki–Miyaura reaction was performed in the presence of 2,6-di-
tert-butyl-4-methylphenol (BHT).20
(10) (a) Boger, D. L.; Yohannes, D. J. Org. Chem. 1987, 52,
5283. (b) Heinrich, M. R.; Steglich, W. Tetrahedron 2003,
59, 9231.
(11) (a) Hudgens, T. L.; Turnbull, K. D. Tetrahedron Lett. 1999,
40, 2719. (b) For a comprehensive review, see: Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(12) (a) Gray, M.; Endrews, I. P.; Hook, D. F.; Kitteringham, J.;
Voyle, M. Tetrahedron Lett. 2000, 41, 6237. (b) For a
review, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
In summary, we reported a concise synthesis of ortho-
gonally protected L-3-hydroxy-4-methoxy-5-methyl-phenyl-
alanine (9) and L-3-hydroxy-4-methoxy-5-methylphenyl-
alanol (1) from L-tyrosine (3). The synthesis is racemiza-
tion-free and is highly efficient. Indeed 1 was obtained in
eight steps from 3 with a 50% overall yield.21 The utility
of 9 and 1 in total syntheses of tetrahydroisoquinoline-
Synlett 2009, No. 3, 466–468 © Thieme Stuttgart · New York

468
N. Demoulin, J. Zhu
LETTER
3.62 and 3.67 (rotamers, 3 H), 3.01 (dd, J = 14.1, 5.8 Hz,
(13) Conversion of 6 into 8 by Suzuki–Miyaura Reaction
To a solution of the iodoester (6, 250 mg, 0.49 mmol),
K2CO3 (138 mg, 1 mmol, 2 equiv), Pd(PPh3)4 (56 mg, 0.05
mmol, 0.1 equiv), and BHT (15 mg, 0.05 mmol, 0.1 equiv)
in degassed dioxane (2.0 mL), TMB (204 mL, 184 mg, 1.5
equiv) was added dropwise under argon. After being heated
at 100 °C under microwave conditions for 2 h (Microwave
heating with a Discover microwave reactor from CEM.
Irradiation power: 20 W; ramp time: 5 min, 100 °C), the
mixture was filtered over Celite and purified by flash column
chromatography (heptane–EtOAc, 9:1 to 7:3) to afford the
desired product 8 (172 mg, 0.42 mmol, 85%) as a yellow oil;
[a]D28.4 +43 (c 2.0, CHCl3). IR: 3340, 2950, 1715, 1697,
1681, 1518, 1435, 1354, 1257, 1213, 1177, 1058, 1003, 738,
697 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.20–7.37 (m, 5
H), 7.16 (d, J = 2.2 Hz, 1 H), 7.04 (d, J = 2.2 Hz, 1 H), 5.22
(br d, J = 7.9 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H), 5.05 (d,
J = 12.2 Hz, 1 H), 4.60 (br m, 1 H), 3.67–3.73 (m, 6 H), 3.07
(dd, J = 14.0, 5.3 Hz, 1 H), 2.99 (dd, J = 14.0, 6.1 Hz, 1 H),
2.57 (s, 3 H), 2.24 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
200.6, 171.8, 157.0, 155.6, 135.8, 133.2, 132.4, 128.6,
128.3, 128.1, 67.0, 61.8, 54.8, 52.4, 37.4, 30.5, 16.1. MS
(ESI+, MeOH): m/z = 422.1 [M + Na]+. HRMS (ESI+,
MeOH): m/z [M + Na]+ calcd for C22H25NO6Na: 422.1580;
found: 422.1570.
1 H), 2.94 (dd, J = 14.1, 6.6 Hz, 1 H), 2.20 (s, 3 H), 2.25 (s,
3 H). 13C NMR (75 MHz, CDCl3): d = 172.0, 169.0, 155.6,
149.0, 143.6, 136.4, 133.7, 131.7, 129.4, 128.5, 128.1,
128.0, 121.7, 67.0, 60.5, 54.9, 52.3, 37.4, 20.8, 16.0. MS
(ESI+, MeOH): m/z = 438.1 [M + Na]+. HRMS (ESI+,
MeOH): m/z [M + Na]+ calcd for C22H25NO7Na: 438.1529;
found: 438.1488.
(17) Bovicelli, P.; Antonioletti, R.; Barontini, M.; Borioni, G.;
Bernini, R.; Mincione, E. Tetrahedron Lett. 2005, 46, 1255.
(18) Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.;
Olivares, L. Z.; Maldonado, L. A. Synth. Commun. 1995, 25,
2121.
(19) Conversion of 10 into 1 by Hydrogenolysis
To a solution of the amino alcohol 10 (3.8 g, 11.0 mmol) in
anhyd MeOH (60 mL), Pd/C (400 mg) was added. The
mixture was degassed and flushed several times with H2.
The reaction was stirred at r.t. under H2 for 2 h. Filtration
over Celite and concentration under vacuum gave the final
product 1 (2.3 g, 100%) as a pale yellow oil; [a]D27.4 –15 (c
1.0, MeOH). IR: 3346, 2928, 1585, 1435, 1316, 1216, 1142,
1047, 1000, 860, 822 cm–1. 1H NMR (300 MHz, CD3OD):
d = 6.56 (d, J = 2.0 Hz, 1 H), 6.49 (d, J = 2.0 Hz, 1 H), 3.69
(s, 3 H), 3.56 (dd, J = 11.1, 4.0 Hz, 1 H), 3.39 (dd, J = 11.1,
6.7 Hz, 1 H), 3.12 (br m, 1 H), 2.65 (dd, J = 13.6, 6.8 Hz, 1
H), 2.52 (dd, J = 13.6, 7.2 Hz, 1 H), 2.17 (s, 3 H). 13C NMR
(75 MHz, CD3OD): d = 149.8, 144.8, 133.3, 131.5, 122.1,
114.7, 63.2, 59.1, 54.2, 37.1, 14.7. MS (ESI+, MeOH):
m/z = 212.1 [M + H]+, 234.1 [M + Na]+. HRMS (ESI+,
MeOH): m/z [M + Na]+ calcd for C22H25NO7Na: 234.1106;
found: 234.1101.
(14) For a recent example from our group showing the distinct
difference of thermal and microwave-assisted Suzuki–
Miyaura reaction, see: Lépine, R.; Zhu, J. Org. Lett. 2005, 7,
2981.
(15) Chen, C.; Zhu, Y.-F.; Wilcoxen, K. J. Org. Chem. 2000, 65,
2574.
(16) Conversion of 8 into 9 by Baeyer–Villiger Oxidation
To a solution of the accetophenone (8, 40.0 mg, 1.0 mmol)
in CH2Cl2 (1 mL), MCPBA (70%; 50 mg, 2.0 mmol, 2.0
equiv) was added. After being stirred at r.t. for 5 d, the
reaction mixture was diluted with aq Na2CO3 and extracted
with CH2Cl2. The combined extracts were washed with aq
Na2CO3, brine and dried (Na2SO4). Evaporation of the
volatile under reduced pressure afforded the desired acetate
9 (35.7 mg, 86%) as a pale yellow oil; [a]D28.4 +37 (c 1.0,
CHCl3). IR: 3332, 2950, 1715 (br), 1519, 1493, 1435, 1230,
1199, 1045, 1004, 738, 697 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.20–7.37 (m, 5 H), 6.78 (br s, 1 H), 6.66 (br s,
1 H), 5.49 (br d, J = 8.0 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H),
5.04 (d, J = 12.2 Hz, 1 H), 4.58 (br m, 1 H), 3.69 (s, 3 H),
(20) We found that addition of BHT led to more reproducible
results on this coupling reaction; BHT may suppress the
oxidation of palladium species by adventurous oxygen and
extend consequently the catalytic cycle. See: (a) McKean,
D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org.
Chem. 1987, 52, 422. (b) Cooper, C. B.; MacFarland, J. W.;
Blair, K. T.; Fontaine, E. H.; Jones, C. S.; Muzzi, M. L.
Bioorg. Med. Chem. Lett. 1994, 4, 835.
(21) On a fifty-gram scale, we used Stille coupling for the
conversion of 6 into 8 due to the price difference between
tetramethyltin (Aldrich: 50 mL, 145 €) and trimethyl-
boroxine (Aldrich: 5 g, 116 €). The overall yield in this case
is about 41%.
Synlett 2009, No. 3, 466–468 © Thieme Stuttgart · New York

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