A short enantioselective synthesis of protected L-3-hydroxy-4-methoxy-5- methyl phenylalanine and its corresponding aldehyde - A common subunit of ecteinascidin-743, safracin and congeners

Article abstract of DOI:10.1055/s-2004-817763

An asymmetric synthesis of appropriately protected L-3-hydroxy-4-methoxy-5- methyl phenylalanine from 3-methyl-catechol is described featuring a key enantioselective alkylation step.

Full text of DOI:10.1055/s-2004-817763

LETTER
729
A Short Enantioselective Synthesis of Protected L-3-Hydroxy-4-methoxy-5-
methyl Phenylalanine and its Corresponding Aldehyde – A Common Subunit
of Ecteinascidin-743, Safracin and Congeners
Synthesis of
L
-3-Hydro
i
xy-4-m
c
ethoxy-5-m
h
ethyl Pheny
a
lalanine
C
o
ë
rrespondin
l
g Aldehyde De Paolis, Xiaochuan Chen, 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 13 November 2003
have already described a concise synthesis of enantiomer-
Abstract: An asymmetric synthesis of appropriately protected L-3-
hydroxy-4-methoxy-5-methyl phenylalanine from 3-methyl-cate-
chol is described featuring a key enantioselective alkylation step.
ically pure macrolactone 5 from sesamol.10 Reported
herein is an asymmetric synthesis of L-amino acid 6 and
amino aldehyde 7. The key step of this synthesis is the
enantioselective alkylation of N-(diphenylmethylene)
glycine tert-butyl ester 8 by 3-tolylsulfonyloxy-4-meth-
oxy-5-methyl benzyl bromide 9 under phase transfer cat-
alytic conditions.11–13 A synthesis of this amino acid
wherein the key operation is a diastereoselective alkyla-
tion of chiral oxazinone has very recently been communi-
cated by the group of Williams.9a Besides being
enantioselective, our synthesis started from 3-methyl cat-
echol, instead of vanillin, that considerably shortened the
synthesis of the substituted benzyl bromide 9.
Key words: amino acid, Ecteinascidin 743, phase transfer catalyst,
glycine template, L-DOPA derivative.
Ecteinascidin 743 (Et 743, 1, Figure 1), which has been
isolated from the Caribbean tunicate Ecteinascidia turbi-
nate, possesses potent cytotoxic activity against a variety
of tumor cell lines in vitro and against several rodent tu-
mors and human tumor xenografts in vivo.1 It is currently
in phase II/III clinicals trials as an anticancer agent.
Whilst the Et 743 is structurally related to the safracin (2a,
2b) class of antibiotics,2 the presence of a 1,4-bridged 10-
membered macrolactone in 1 made its synthesis even
more challenging.3 To date, two total syntheses of Et 743
(1) have been accomplished by Corey,4 Fukuyama,5 and a
semi synthesis from cyanosafracin B (2b) has been real-
ized by Cuevas et al.6 Other original contributions have
been reported from the group of Kubo,7 Danishefsky,8 and
Williams.9
OMe
Me
OMe
HO
AllO
HO
OAc
O
OAll
H
N
1
S
N
S
N
O
NHAlloc
O
CN
NHTroc
CN
O
O
O
O
O
3
4
NHTroc
OMe
OMe
OAll
OH
OMe
HO
HO
R1O
OAc
O
O
S
NH
H
N
H
N
O
O
Me
N
Me
N
O
O
R2
S
TrocHN
NHR3
O
MeO
O
OH
O
O
X
6 R1 = tosyl, R2 = OH, R3 = H
7 R1 = allyl, R2 = H, R3 = Alloc
HN
O
Me
5
O
MeO
HO
NH
NH2
OMe
R1O
2a Safracin B, X = OH
2b Cyanosafracin B, X = CN
1 Ecteinascidin 743
Ph
Ph
N
COOtBu
+
Figure 1
9
Br
8
Scheme 1 Retrosynthesis of Et 743 (1)
Our group is working on a convergent synthetic approach
in which the tetrahydroisoquinoline with a 1,4-bridged
10-membered macrocycle 5 and amino acid 6/or amino
aldehyde 7 are projected to be the key intermediates. We
The synthesis of substituted benzyl bromide 9 is described
in Scheme 2. Regioselective mono-protection of 3-methyl
catechol (10) with tosyl chloride5b followed by methyla-
tion provided compound 12. The tosylation was conduct-
ed at lower temperature with a slight default in tosyl
chloride to avoid bis-tosylation. Formylation of 12 with
SYNLETT 2004, No. 4, pp 0729–0731
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817763; Art ID: G31303ST
© Georg Thieme Verlag Stuttgart · New York

730
M. De Paolis et al.
LETTER
OMe
OMe
CHO
OH
OR
OMe
a
Me
OTs
HO
Me
OH
Me
OTs
c
HO
a,b
c
d
6
11, R = H
12, R = Me
b
HO
10
HO
13
NH2
NHAlloc
18
OMe
OMe
17
d
Me
OTs
Me
OTs
e
OMe
OMe
AllO
AllO
e
OH
Br
14
9
OHC
HO
NHAlloc
NHAlloc
Scheme 2 Reagents and conditions: a) TsCl, Et3N, CH2Cl2, –70 °C;
b) MeI, K2CO3, acetone, 55 °C, 84% for two steps; c) TiCl4 in CH2Cl2,
Cl2CHOCH3, 0 °C → r.t., 85%; d) NaBH4, MeOH–THF–H2O
(1:1:0.1), 0 °C, quantitative; e) PBr3, toluene–CH2Cl2, (4:1), 0 °C →
r.t., 96%
19
7
Scheme 4 Reagents and conditions: a) LiBH4, MeOH, Et2O, r.t.; b)
aq 2 N NaOH, EtOH, reflux; c) AllocCl, sat. aq NaHCO3, CH2Cl2, r.t.
then K2CO3, MeOH–H2O (10:1), r.t.; d) Allyl bromide, K2CO3, ace-
tone, reflux; 60–65% overall yield from 6; e) Swern oxidation, 92%.
a,a-dichloromethyl methyl ether in the presence of titani-
um chloride (1 M in CH2Cl2) provided 13 in 85% yield as
the only isolable regioisomer.14 The presence of a tosyl-
oxy function at C-3 might account for the observed high
regioselectivity. Reduction of aldehyde 13 to alcohol 14
(NaBH4, MeOH–THF–H2O) followed by bromination
(PBr3, toluene–CH2Cl2 = 4:1) furnished 9 in 96% overall
yield. This 5-step synthesis of 9 compared favorably to the
previous 9-step synthesis starting from vanillin.9a
of ester to alcohol followed by N-protection as allyl car-
bamate afforded amino alcohol 18. Selective allylation of
phenol followed by Swern oxidation of the remaining pri-
mary alcohol provided then the expected amino aldehyde
7.15 The overall yield of this 5-step sequence is about
55%. Both amino ester 6 and amino aldehyde 7 could be
considered as versatile building blocks in the synthesis of
ecteinascidin and safracin family alkaloids.
The (S) configuration of amino ester 6 was assigned by
taking the Corey-Lygo empiric model in account. To fur-
ther prove this assignment, both (S)- and (R)-O-methyl-
mandelic amide 20 and 21 were synthesized (Figure 2).
OMe
OMe
TsO
TsO
H2N
a
b
8 + 9
H
N
The calculated chemical shift differences [dArCH2 (20–21)
=
BocHN
–0.08 ppm; dTBDMSOCH2 (20–21) = 0.09 ppm] are in accord
with the S configuration of the amino alcohol, hence that
COOtBu
O
COOtBu
16
6
1
of the amino ester 6.16 In addition, analysis of H NMR
spectra of compounds 21 and 22 indicated that the de of
20 and 21, and hence the ee of their precursor 6, is higher
than 90%.
Br
O
N
H
N
O
H
15
OTBDMS
H
N
Scheme 3 Reagents and conditions: a) 15 (10%), CsOH·H2O,
CH2Cl2, –78 °C then after work up THF–H2O–AcOH (1:1:1), 85%; b)
N-Boc-D-Ala, EDCI, HOBt, DMF, r.t., 87%, dr = 10:1.
OMe H
OTBDMS
OMe
20
Following Corey’s procedure, alkylation of N-(diphenyl-
methylene) glycine tert-butyl ester 8 with 9 in the pres-
O
H
OTBDMS
ence of
a
catalytic amount of O-9-allyl-N-(9¢-
N
H
anthracenylmethyl)cinchonidium bromide 15 (0.1 equiv)
afforded, after chemoselective hydrolysis of the imine
function (THF–H2O–AcOH), the amino ester 6 in 85%
overall yield. The enantiomeric purity of this compound
was determined to be higher than 90% by its transforma-
tion to the dipeptide 16.
OMe H
OTBDMS
OMe
21
Figure 2
While compound 6 is ready to couple with macrolactone
5 to advance the total synthesis, an alternative coupling
partner for 5 would be the amino aldehyde 7. The trans-
formation of 6 to 7 is shown in the Scheme 4. Reduction
In conclusion, we have developed a short asymmetric syn-
thesis of a protected L-3-hydroxy-4-methoxy-5-methyl
phenylalanine (6) and the corresponding aldehyde (7).
Key steps are: a) the regioselective tosylation of catechol,
Synlett 2004, No. 4, 729–731 © Thieme Stuttgart · New York

LETTER
Synthesis of L-3-Hydroxy-4-methoxy-5-methyl Phenylalanine Corresponding Aldehyde
731
(8) (a) Zhou, B.; Edmondson, S.; Padron, J.; Danishefsky, S. J.
Tetrahedron Lett. 2000, 41, 2039. (b) Zhou, B.; Guo, J.;
Danishefsky, S. J. Tetrahedron Lett. 2000, 41, 2043.
(c) Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4,
43.
(9) (a) Jin, W.; Williams, R. M. Tetrahedron Lett. 2003, 44,
4635. (b) Jin, W.; Metobo, S.; Williams, R. M. Org. Lett.
2003, 5, 2095.
(10) De Paolis, M.; Chiaroni, A.; Zhu, J. Chem. Commun. 2003,
2896.
(11) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
which ensures the regioselective formylation of the aro-
matic ring and, b) the efficient enantioselective alkylation
under phase transfer conditions. We are pursuing the total
synthesis of Et 743 and related natural products using the
advanced intermediates 5 and 7.
Acknowledgment
We thank CNRS for financial support. A doctoral fellowship from
the ‘Ministère de l’Enseignement Supérieur et de la Recherche’ to
M. De Paolis is gratefully acknowledged.
(12) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595.
References
(13) For an earlier contribution, see: O’Donnell, M. J.; Bennett,
W. D. J. Am. Chem. Soc. 1989, 111, 2353.
(14) Sinhababu, A. K.; Gosh, A. K.; Borchardt, R. T. J. Med.
Chem. 1985, 28, 1273.
(1) (a) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.;
Shield, L. S.; Seigler, D. S. J. Nat. Prod. 1990, 53, 771.
(b) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.;
Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org.
Chem. 1990, 55, 4508. (c) Suwanborirux, K.; Charupant,
K.; Amnuoypol, S.; Pummangura, S.; Kubo, A.; Saito, N. J.
Nat. Prod. 2002, 65, 935.
(2) (a) Ikeda, Y.; Shimada, Y.; Honjo, K.; Okumoto, T.;
Munakata, T. J. Antibiot. 1983, 36, 1290. (b) Saito, N.;
Harada, S.; Yamashita, M.; Saito, T.; Yamaguchi, Y.; Kubo,
A. Tetrahedron 1995, 51, 8213.
(3) For a recent review, see: Scott, J. D.; Williams, R. M. Chem.
Rev. 2002, 102, 1669.
(4) (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc.
1996, 118, 9202. (b) Corey, E. J.; Gin, D. Y. Tetrahedron
Lett. 1996, 37, 7163.
(5) (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2545.
(b) Endo, A.; Kann, T.; Fukuyama, T. Synlett 1999, 7, 1103.
(6) Cuevas, C.; Pérez, M.; Martin, M. J.; Chicharro, J. L.;
Fernandez-Rivas, C.; Flores, M.; Francesch, A.; Gallego, P.;
Zarzuelo, M.; De La Calle, F.; Garcia, J.; Polanco, C.;
Rodriguez, I.; Manzanares, I. Org. Lett. 2000, 2, 2545.
(7) (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.
(15) Compound 6. [a]D23 +13 (c = 0.8, CHCl3). IR (CHCl3): 3382,
3034, 2981, 2938, 1725, 1598, 1495, 1370, 1293, 1218, 1178
cm–1. 1H NMR (250 MHz, CDCl3, 293 K): d = 7.76 (d, J =
7.6 Hz, 2 H), 7.32 (d, J = 7.5 Hz, 2 H), 6.90 (br s, 1 H), 6.79
(br s, 1 H), 3.67 (s, 3 H), 3.48 (dd, J = 7.3, 5.5 Hz, 1 H), 2.88
(dd, J = 13.7, 5.5 Hz, 1 H), 2.67 (dd, J = 13.7, 7.3 Hz, 1 H),
2.44 (s, 3 H), 2.19 (s, 3 H), 1.42 (s, 9 H). 13C NMR (75 MHz,
CDCl3, 293 K): 174.0, 149.3, 145.1, 142.2, 133.1, 132.8,
130.4, 129.5, 129.2, 128.5, 128.4, 121.8, 81.2, 60.5, 56.0,
40.2, 28.1, 27.9, 21.6, 15.9. MS (ESI+): m/z = 436.2 [M +
H]+, 458.3 [M + Na]+, 474.2 [M + K]+. HRMS (ESI+): m/z
[M + H+] calcd for C22H30O6S: 436.1794; found: 436.1789.
Compound 7. [a]D23 +22 (c = 1, CHCl3). IR (CHCl3): 3426,
3024, 2933, 2830, 1716, 1590, 1496, 1343, 1232, 1087, 1007
cm–1. 1H NMR (300 MHz, CDCl3, 293 K): 9.52 (s, 1 H), 6.56
(m, 2 H), 5.96 (ddd, J = 17.7, 12.5, 7.2 Hz, 1 H), 5.82 (m, 1
H), 5.33 (ddt, J = 16.8, 1.7, 1.6 Hz, 1 H), 5.17 (m, 4 H), 4.47
(m, 4 H), 4.46 (m, 1 H), 3.80 (s, 3 H), 2.98 (dd, J = 14.0, 6.5
Hz, 1 H), 2.89 (dd, J = 14.0, 6.8 Hz, 1 H), 2.21 (s, 3 H). 13
C
NMR (75 MHz, CDCl3, 293 K): 199.2, 155.8, 151.6, 146.7,
133.2, 132.5, 132.3, 130.6, 123.8, 118.0, 117.5, 112.7, 69.4,
65.9, 60.9, 60.1, 35.2, 15.9. MS (ESI+): m/z = 334.2 [M +
H]+.
(16) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem.
1994, 59, 4202. (b) Helmchen, G.; Sauber, K. Tetrahedron
Lett. 1972, 3873.
Synlett 2004, No. 4, 729–731 © Thieme Stuttgart · New York