Synthesis of Natural Ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from Cyanosafracin B

Article abstract of DOI:10.1021/jo034547i

The semisynthetic process initially described for the synthesis of 1 (ET-743) has been extended to the preparation of other natural ecteinascidins. For the synthesis of 2 (ET-729) a demethylation of a N-Me intermediate was carried out by a selective oxidation with MCPBA. Other natural ecteinascidins (ET-745, ET-759B, ET-736, ET-637, ET-594) were accessible from key intermediate 25. The described methodologies allow for the preparation of a wide variety of ecteinascidins by procedures that can be easily scaled up.

Full text of DOI:10.1021/jo034547i

Syn th esis of Na tu r a l Ectein a scid in s (ET-729, ET-745, ET-759B,
ET-736, ET-637, ET-594) fr om Cya n osa fr a cin B
Roberto Menchaca, Valent´ın Mart´ınez, Alberto Rodr´ıguez, Natividad Rodr´ıguez, Mar´ıa Flores,
Pilar Gallego, Ignacio Manzanares, and Carmen Cuevas*
Pharma Mar, S. A. C/ Avda de los Reyes, 1.P.I. La Mina-Norte. 28770 Colmenar Viejo, Madrid, Spain
ccuevas@pharmamar.com
Received April 29, 2003
The semisynthetic process initially described for the synthesis of 1 (ET-743) has been extended to
the preparation of other natural ecteinascidins. For the synthesis of 2 (ET-729) a demethylation of
a N-Me intermediate was carried out by a selective oxidation with MCPBA. Other natural
ecteinascidins (ET-745, ET-759B, ET-736, ET-637, ET-594) were accessible from key intermediate
25. The described methodologies allow for the preparation of a wide variety of ecteinascidins by
procedures that can be easily scaled up.
In tr od u ction
as anticancer agents and very attractive synthetic tar-
gets.
The ecteinascidins are marine natural products iso-
lated from the caribbean tunicate Ecteinascidia turbi-
nata1 (see Figure 1). The chemical structure of the
ecteinascidins is formed by two fused tetrahydroisoquino-
line rings linked to a 10-member lactone bridge through
a benzylic sulfide linkage. Most ecteinascidins have an
additional tetrahydroisoquinoline or tetrahydro-â-carbo-
line ring attached to the rest of the structure through a
spiro ring. Their potent antiproliferative activity against
a variety of tumor cells, the scarce availability from
natural sources, and the unique mechanism of action2
have made them attractive candidates for development
The precedents to the synthesis of ecteinascidin 1 (ET-
743), the lead compound that is currently in Phase II
clinical trials in Europe and the United States3 for
ovarian, endometrium, and breast cancer and that has
already shown efficacy in soft tissue sarcomas in three
pivotal phase II trials, are to be found in synthetic work
leading to related molecules such as saframycins, sa-
fracins, and renieramycins4 (see Figure 2). These anti-
microbial compounds isolated from bacterial sources or
marine sponges5 have the same pentacyclic skeleton as
the ecteinascidins but one or two of the aromatic rings
contain a different oxidation pattern, resulting in mono-
or bis-quinone structures.
* Address correspondence to this author. Fax: 341-397-3966.
(1) (a) Rinehart, K. L.; Shield, L. S. Topics in Pharmaceutical
Sciences; Breimer, D. D., Crommelin, D. J . A., Midha, K. K., Eds.;
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II; Seaman, F. C.; Hurley, L. H. J . Am. Chem. Soc. 1997, 119, 5475.
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L. H. Chem. Biol. 2001, 135, 1.
To date, two total syntheses of 1 (ET-743) have been
reported by Corey et al.6 and Fukuyama et al.7 We have
recently reported a semisynthesis of 1 (ET-743)8 more
suitable for large-scale preparation starting from cy-
anosafracin B, an antibiotic of bacterial origin, available
through fermentation of the bacteria Pseudomonas fluo-
rescens.9
(3) (a) Zelek, L.; Yovine, A.; Etienne, B.; J imeno, J .; Taamma, A.;
Marty. M.; Spielmann, M.; Cvitkovic, E.; Misset, J . L. American Society
of Clinical Oncology, 36th Annual Meeting, New Orleans, May 20-
23, 2000; Abstract No. 592. (b) Delaloge, S.; Yovine, A.; Taamma, A.;
Cottu, P.; Riofrio, M.; Raymond, E.; Brain, E.; Marty, M.; J imeno, J .;
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Lynch, T. J .; Fischman, A. J .; Davis, J .; J imeno, J .; Clark, J . W. Clin.
Cancer Res. 2001,7, 231. (e) Delaloge, S.; Yovine, A.; Taamma, A.;
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J .; Misset, J . L.; Marty, M.; Cvitkovic, E. J . Clin. Oncol. 2001, 19, 1248.
(f) Taamma, A.; Misset, J . L.; Riofrio, M.; Guzman, C.; Brain, E.; Lopez
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19, 1256. (g) Villalona-Calero, M. A.; Eckhardt, S. G.; Weiss, G.;
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E.; Kraynak, M.; Lopez-Lazaro, L.; Guzman, C.; Von Hoff, D. D.;
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10.1021/jo034547i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003
J . Org. Chem. 2003, 68, 8859-8866
8859

Menchaca et al.
F IGURE 1. Ecteinascidins isolated from the caribbean tunicate Ecteinascidia turbinata.
The semisynthetic approach provides access not only
to 1 (ET-743) but also to other natural members of the
ecteinascidins family. To extend the scope of the semi-
synthetic route, we report herein syntheses of 2 (ET-729),
3 (ET-745), 4 (ET-759B), 12 (ET-736), 17 (ET-637), and
18 (ET-594) using the key intermediate 2510 as shown
in the retrosynthetic analysis outlined in Scheme 1. As
it was previously described in the semisynthesis of 1 (ET-
743), we envisaged formation of 25 using different
protection and deprotection reactions of the functional
groups of cyanosafracin B, cleavage of the amide bond
by Edman degradation, and transformation of the amino
group into the primary alcohol.8 The synthesis of other
ecteinascidins was accomplished from readily available
intermediate 25.
(4) (a) Fukuyama, T.; Sachleben, R. A. J . Am. Chem. Soc. 1982, 104,
4957. (b) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J .
Am. Chem. Soc. 1990, 112, 3712. (c) Kubo, A.; Saito, N.; Yamauchi,
R.; Sakai, S. Chem. Pharm. Bull. 1987, 35, 2158. (d) Kubo, A.; Saito,
N.; Yamato, H.; Kawakami, Y. Chem. Pharm. Bull. 1987, 35, 2525. (e)
Kubo, A.; Saito, N.; Nakamura, M.; Ogata, K.; Sakai, S. Heterocycles
1987, 26, 1765. (f) Kubo, A.; Saito, N.; Yamato, H.; Yamauchi, R.;
Hiruma, K.; Inoue, S. Chem. Pharm. Bull. 1988, 36, 2607. (g) Kubo,
A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. J . Org. Chem.
1988, 53, 4295. (h) Myers, A. G.; Kung, D. W. J . Am. Chem. Soc. 1999,
121, 10828. (i) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J .
Org. Chem. 1999, 64, 3322. (j) Myers, A. G.; Kung, D. W.; Zhong, B.;
Movassaghi, M.; Kwon, S. J . Am. Chem. Soc. 1999, 121, 8401. (k)
Martinez, E. J .; Corey, E. J . Org. Lett. 1999, 1, 75. (l) Martinez, E. J .;
Corey, E. J . Org. Lett. 2000, 2, 993. (m) Saito, N.; Tanitsu, M.; Betsui,
T.; Suzuki, R.; Kubo, A. Chem. Pharm. Bull. 1997, 45, 1120. (n) Zhou,
B.; Edmondson, S.; Padron, J .; Danishefsky, S. J . Tetrahedron Lett.
2000, 41, 2039. (o) Zhou, B.; Guo, J .; Danishefsky, S. J . Tetrahedron
Lett. 2000, 41, 2043. (p) Myers, A. G.; Kung, D. W. Org. Lett. 2000, 2,
3019.
(5) (a) Arai, T.; Takahashi, K.; Kubo, A. J . Antibiot. 1977, 30, 1015.
(b) Arai, T.; Takahashi, K.; Ishiguro, K.; Yazawa, K. J . Antibiot. 1980,
33, 951. (c) Asaoka, T.; Yazawa, K.; Mikami, Y.; Arai, T.; Takahashi,
K. J . Antibiot. 1982, 35, 1708. (d) Lown, J . W.; Hanstock, C. C.; J oshua,
A. V.; Arai, T.; Takahashi, K. J . Antibiot. 1983, 36, 1184. (e) Mikami,
Y.; Takahashi, K.; Yazawa, K.; Hour-Young, C.; Arai, T. J . Antibiot.
1988, 41, 734. (f) Yazawa, K.; Takahashi, K.; Mikami, Y.; Arai, T.;
Saito, N.; Kubo, A. J . Antibiot. 1986, 39, 1639. (g) Fukushima, K.;
Yazawa, K.; Arai, T. J . Antibiot. 1986, 39, 1602.
(8) (a) Cuevas, C.; Pe´rez, M.; Mart´ın, M. J .; Chicharro, J . L.;
Ferna´ndez-Rivas, C.; Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo,
M.; De la Calle, F.; Garc´ıa, J .; Polanco, C.; Rodr´ıguez, I.; Manzanares,
I. Org. Lett. 2000, 2, 2545. (b) Synthetic Process for the Manufacture
of an Ecteinascidin Compound, PCT/GB01/ 02120, WO 01/87895.
(9) Ikeda, Y.; Idemoto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.;
Asao, T.; Munakata, T. J . Antibiot. 1983, 36, 1279.
(10) Compound 25 was obtained from compound 49, an intermediate
in the previously reported semisynthesis of 1 (ET-743).8 See Supporting
Information.
(6) Corey, E. J .; Gin, D. Y.; Kania, R. J . Am. Chem. Soc. 1996, 118,
9202.
(7) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fuku-
yama, T. J . Am. Chem. Soc. 2002, 124, 6552.
8860 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of Natural Ecteinascidins
F IGURE 2. Structures of saframycins, safracins, and renieramycins.
SCHEME 1. Retr osyn th etic An a lysis of 2, 3, 4, 12, 17, a n d 18
Resu lts a n d Discu ssion
intermediate used, which is the key step of the synthetic
plan (Scheme 2).
Syn th esis of 2 (ET-729). The most relevant structural
difference of 2 (ET-729) with other members of the family
is the absence of N-methyl group in the bridgehead
nitrogen of the fused tetrahydroisoquinoline unit. There-
fore, the synthesis of 2 (ET-729) requires a demethylation
reaction of the bridgehead nitrogen of the synthetic
According to Scheme 2, silylation of the primary alcohol
of intermediate 25 under standard conditions and protec-
tion of the phenol with MEMCl in THF, using NaH as
base, furnished 29 in 87% yield. All attempts to ac-
complish the critical N-demethylation of the tertiary
J . Org. Chem, Vol. 68, No. 23, 2003 8861

Menchaca et al.
SCHEME 2. Syn th esis of 2 (ET-729)a
a
Conditions: (a) TBDPSCl, imidazole, DMAP, DMF; (b) MEMCl, NaH, THF; (c) MCPBA, TEA, TFAA, CH2Cl2; (d) HSnBu3, AcOH,
(PPh3)2PdCl2, CH2Cl2; (e) (PhSeO)2O, CH2Cl2; (f) Cs2CO3, AllylBr, DMF; (g) TBAF, THF; (h) L-cysteine derivative, EDC‚HCl, DMAP,
DIPEA, CH2Cl2; (i) DMSO; Tf2O, DIPEA, t-BuOH, tert-butyltetramethyl guanidine, Ac2O, CH2Cl2; (j) p-TsOH, CHCl3; (k) N-methyl-
pyridinium-4-carboxaldehyde iodide, DBU, oxalic acid; (l) 3-hydroxy-4-methoxyphenylethylamine, silica gel, EtOH; (m) HSnBu3,
(PPh3)2PdCl2, AcOH, CH2Cl2; (n) AgNO3, CH3CN-H2O.
amine under different conditions described in the litera-
mitted to desilylation under standard conditions to give
34 in 68% yield. Next, esterification of the resulting
alcohol with (R)-N-[(tert-butoxy)carbonyl-S-(9-fluorenyl-
methyl)]cysteine and subsequent cyclization gave the 10-
membered lactone bridge intermediate 36 via formation
of the exo quinone methide followed by nucleophilic
addition of the deprotected cysteine and further acety-
lation of the phenoxide ion. Simultaneous removal of the
Boc and MEM protecting groups with p-TsOH in CHCl3
afforded compound 27b in 71% yield. Next, transamina-
tion and introduction of the dopamine moiety by Pictet-
Spengler reaction gave intermediate 38 in excellent yield.
Deprotection of the allyl protecting group and replace-
ment of CN by OH with AgNO3 in a mixture of CH3CN-
H2O gave 2 (ET-729) in high yield, which had identical
data upon comparison with that of a natural sample.
ture such us I2/CaO,11 vinyl chloroformate,12 tert-butyl
hydroperoxide/RuCl2(PPh3)2,13 or RuCl3/H2O2
led to
14
undesired products or unaltered starting material. By
contrast demethylation in CH2Cl2 with MCPBA, TEA,
and TFAA15 afforded 30 in 85% yield. With compound
30 in hand, deprotection of the allyl group, oxidation of
the phenol, and subsequent protection with allyl bromide
of the bridgehead amine furnished 33, which was sub-
(11) Acosta, K.; Cessac, P.; Rao, N.; Kim, H. K. J . Chem. Soc., Chem
Commun. 1988, 110, 8256.
(12) Olofson, R. A.; Schnur, R. C.; Bunes, I.; Pepe, J . P. Tetrahedron
Lett. 1997, 1567.
(13) (a) Murahashi S.-I.; Naota, T.; Yonemura, K. J . Am. Chem. Soc.
1988, 110, 8256. (b) Ostovic, D.; Knobler, C. B.; Bruice, T. C. J . Am.
Chem. Soc. 1987, 109, 3444.
(14) Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato, T. Tetra-
hedron Lett. 1992, 33, 6991.
(15) Gesson, J . P.; J acquesy, J . C.; Mondon, M. Synlett 1990, 669.
Syn th esis of Oth er Na tu r a l Ectein a scid in s. The
8862 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of Natural Ecteinascidins
SCHEME 3. Syn th esis of 17 (ET-637)a
a
Conditions: (a) L-cysteine derivative, EDC‚HCl, DMAP, DIPEA, CH2Cl2; (b) MEMCl, NaH, THF; (c) HSnBu3, AcOH, (PPh3)2PdCl2,
CH2Cl2; (d) (PhSeO)2O, CH2Cl2; (e) DMSO; Tf2O, DIPEA, t-BuOH, tert-butyltetramethyl guanidine, Ac2O, CH2Cl2; (f) p-TsOH, CHCl3; (g)
Ac2O, CH2Cl2; (h) CuCl, THF-H2O.
SCHEME 4. Syn th esis of 18 (ET-594)a
synthesis of other natural ecteinascidins that retain the
N-Me group can be achieved from the common interme-
diate 27a . From this compound the preparation of 17
(ET-637) and 18 (ET-594) involves two additional steps
while four steps produce 3 (ET-745) and 4 (ET-759B). For
the synthesis of 12 (ET-736) the tryptamine moiety needs
to be introduced to give the tetrahydro â-carboline ring.
Following the synthetic route (Scheme 3), we first
prepared the common intermediate 27a by esterification
a
of 25 with protected L-cysteine to obtain 40 in 93% yield.
Protection of the phenol with MEMCl and deprotection
of the allyl group gave compound 42, which was then
oxidized to 43 in good yield. Cyclization of 43 under the
conditions developed by Corey6 furnished 44. Treatment
of 44 with acid to effect simultaneous deprotection of the
Boc and MEM groups gave intermediate 27a in excellent
yield. With compound 27a in hand, 17 (ET-637) was
obtained in 72% yield by acetylation with Ac2O without
base to avoid protection of the free phenol. Substitution
of the CN group by OH was better performed in this case
with CuCl in a mixture of THF-H2O since the reaction
failed when carried out under the standard conditions
with AgNO3.
Conditions: (a) N-methylpyridinium-4-carboxaldehyde iodide,
DBU, oxalic acid; (b) CuCl, THF-H2O.
For the synthesis of 4 (ET-759B) (Scheme 5), we
followed the same sequence that we defined previously
for the synthesis of ET-743. We introduced the dopamine
residue through a Pictet-Spengler reaction to give 7 (ET-
770), followed by oxidation of the sulfide with MCPBA
to give compound 47 as single isomer in 90% yield. The
synthesis of 4 (ET-759B) was finally completed by treat-
ment of 47 with AgNO3. The reduction of 1 (ET-743) with
sodium cyanoborohydride proceeded smoothly to give 3
(ET-745) in 77% yield.
Finally, to synthesize 12 (ET-736) we introduced the
tetrahydro-â-carboline ring into compound 46 under
milder conditions than those usually employed for Pic-
tet-Spengler reaction.16 Thus, treatment of 46 with the
Ecteinascidin 18 (ET-594) was obtained from 27a by
transamination reaction with the pyridiniumcarboxal-
dehyde iodide, DBU, and oxalic acid to give 46, followed
by replacement of CN by OH under the same conditions
used to prepare 17 (ET-637) (Scheme 4).
(16) Cox, E. D.; Cook, J . M. Chem Rev. 1995, 95, 1797.
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Menchaca et al.
SCHEME 5. Syn th esis of 4 (ET-759B) a n d 3 (ET-745)a
a
Conditions: (a) 3-hydroxy-4-metoxyphenethylamine, silica gel, EtOH; (b) MCPBA, CH2Cl2; (c) AgNO3, CH3CN-H2O; (d) NaCNBH3,
AcOH, CH3CN.
SCHEME 6. Syn th esis of 12 (ET-736)a
MHz, CDCl3) δ 7.55 (d, J ) 6.3 Hz, 2H), 7.45-7.28 (m, 8H),
6.70 (s, 1H), 6.14-6.02 (m, 1H), 5.81 (d, J ) 1.2 Hz, 1H), 5.67
(d, J ) 1.2 Hz, 1H), 5.43-5.35 (m, 2H), 5.26 (m, 2H), 5.03 (br
s, 1H), 4.73 (br s, 1H), 4.68 (m, 1H), 4.22-4.09 (m, 3H), 3.81
(br s, 2H), 3.73 (s, 3H), 3.61 (dd, J ) 2.2, 10.0 Hz, 1H), 3.53
(br s, 4H), 3.46-3.28 (m, 2H), 3.34 (s, 3H), 2.97 (d, J ) 17.8
Hz, 1H), 2.25 (s, 3H), 2.11 (s, 3H), 1.95 (dd, J ) 11.7, 15.4 Hz,
1H), 0.94 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 157.13, 148.8,
147.1, 144.9, 139.4, 135.9, 135.6, 133.9, 133.6, 133.2, 132.5,
130.1, 130.0, 128.7, 127.9, 127.8, 125.6, 120.9, 119.8, 117.7,
113.9, 111.8, 101.4, 98.4, 74.5, 71.8, 70.0, 68.6, 60.7, 60.1, 59.2,
55.3, 50.1, 48.4, 30.2, 27.0, 26.0, 25.3, 21.3, 19.2, 16.2, 14.4,
9.5. MS (EI+) calcd for C48H57N3O8Si (M + H) 832.4, found
832.3.
a
Conditions: (a) AcOH; (b) AgNO3, CH3CN-H2O.
Com p ou n d 39. To a solution of intermediate 38 (30 mg,
0.038 mmol), (PPh3)2PdCl2 (3 mg, 0.003 mmol), and acetic acid
(11 mL, 0.188 mmol) in anhydrous CH2Cl2 (1 mL, 0.04 M) at
23 °C was added dropwise HSnBu3 (36 mL, 0.13 mmol). The
reaction mixture was stirred at 23 °C for 20 min. Then, the
reaction mixture was poured onto a chromatography column
(eluent mixtures of CH2Cl2/methanol with a gradient from
100/0 to 30:1) to afford intermediate 39 (12 mg, 42%) as a pale
yellow solid. Some starting material (17 mg) was recovered
contaminated with traces of tin byproducts. Rf 0.22 (CH2Cl2/
methanol 20:1). Mp 186-188 °C. IR (KBr, cm-1) 3420, 1740,
tryptamine in acetic acid as solvent provided compound
48 in good yield, which was transformed into 12 (ET-
736) by reaction with AgNO3 (Scheme 6).
In summary we have demonstrated that the semisyn-
thetic process developed to synthesize 1 (ET-743) is a
versatile methodology that allows the preparation of a
large number of natural ecteinascidins. Particularly
significant is the smooth demethylation of the intermedi-
ate 29 that could allow the preparation of a wide variety
of new N-derivatives of the ectainascidins difficult to
obtain from the natural source.
1
1520, 1450, 1210. H NMR (300 MHz, CDCl3) δ 6.62 (s, 1H),
6.47 (s, 1H), 6.44 (s, 1H), 6.06 (d, J ) 1.2 Hz, 1H), 5.98 (d, J
) 1.2 Hz, 1H), 5.03 (d, J ) 11.5 Hz, 1H), 4.57 (br s, 1H), 4.50
(d, J ) 5.1 Hz, 1H), 4.34 (s, 1H), 4.20 (d, J ) 2.4 Hz, 1H), 4.12
(dd, J ) 2.2, 11.5 Hz, 1H), 3.85 (d, J ) 9.0 Hz, 1H), 3.78 (s,
3H), 3.62 (s, 3H), 3.52 (d, J ) 4.6 Hz, 1H), 3.15-2.95 (m, 3H),
2.77 (m, 1H), 2.60 (m, 1H), 2.46 (m, 1H), 2.35 (d, J ) 14.9 Hz,
1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.15 (d, J ) 14.9 Hz, 1H), 2.04
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 172.8, 172.1, 145.9, 145.6,
144.8, 144.5, 143.0, 141.6, 140.4, 131.5, 129.8, 129.4, 125.8,
124.6, 121.6, 121.3, 118.3, 114.33, 114.2, 109.9, 102.1, 64.8,
61.5, 60.7, 60.2, 59.2, 59.0, 55.4, 48.8, 47.9, 42.1, 39.9, 29.0,
28.3, 20. 7, 16.0, 10.0. MS (EI+) calcd for C39H40N4O10S (M +
H) 757.2, found 757.3.
Com p ou n d 2 (ET-729). To a solution of intermediate 39
(12 mg, 0.016 mmol) in MeCN (0.66 mL) and water (0.44 mL,
0.015 M, final concentration) at 23 °C was added AgNO3 (81
mg, 0.47 mmol). The reaction mixture was stirred at 23 °C for
23 h protected from light. The reaction was diluted with CH2-
Cl2, a saturated solution of NaHCO3, and a saturated solution
of sodium chloride. The aqueous phase was extracted with CH2-
Cl2 and the combined organic layers were dried over Na2SO4
and filtered and the solvent was eliminated under reduced
pressure. The crude was purified by flash chromatography
(eluent CH2Cl2/methanol in gradient from 100/0 to 3:1) to
afford the final product 2 (ET-729) (8.3 mg, 70%) as a white
solid. Rf 0.07 (CH2Cl2/methanol 95:5). [R]22D -51.6 (c 0.1, CH2-
Cl2). Mp 179-181 °C. IR (KBr, cm-1) 3650, 1720, 1650, 1420,
1200. 1H NMR (300 MHz, CD3OD) δ 6.59 (s, 1H), 6.44 (s, 1H),
6.40 (s, 1H), 6.13 (s, 1H), 6.02 (s, 1H), 5.20 (d, J ) 11.2 Hz,
1H), 4.73 (s, 1H), 4.58 (d, J ) 4.9 Hz, 2H), 4.26 (d, J ) 2.4 Hz,
Exp er im en ta l Section
Gen er a l Meth od s. Reagents obtained from commercial
suppliers were used without further purification unless oth-
erwise noted. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded in CDCl3 or CD3OD at 300 and 75 MHz,
respectively. All air- and water-sensitive reactions were per-
formed in flame-dried glassware under a positive pressure of
argon. Analytical thin-layer chromatography was performed
on silica gel 60 plates. Silica gel chromatography was per-
formed with the indicated solvents on silica gel (type 60A,
170-400 mesh).
Com p ou n d 30. To a solution of intermediate 29 (2.51 g,
0.003 mol) in anhydrous CH2Cl2 (25 mL, 0.12 M) at -20 °C
under Argon atmosphere was added m-CPBA (1.33 g, 0.006
mol). The solution was warmed to -10 °C and stirred for 25
min. TEA (4.14 mL, 0.03 mol) was added and the reaction
mixture was warmed to 0 °C. Finally TFAA (6.29 mL, 0.045
mol) was added dropwise and the solution was stirred at 0 °C
for 30 min. After this time water was added and the aqueous
phase was extracted with CH2Cl2. The combined organic phase
was dried over Na2SO4 and filtered and the solvent was
eliminated under reduced pressure. The crude was purified
by flash column chromatography (eluent mixtures of ethyl
acetate/hexane in gradient from 1:4 to 6:1 and final washing
with methanol) to afford intermediate 30 (2.1 g, 85%) as a
yellow solid. Rf 0.19 (ethyl acetate/hexane 1:1). Mp 92-94 °C.
IR (KBr, cm-1) 3560, 2890, 1690, 1410, 1100. 1H NMR (300
8864 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of Natural Ecteinascidins
1H), 4.13 (dd, J ) 2.2, 11.5 Hz, 1H), 3.80 (br d, J ) 8.5 Hz,
1H), 3.73 (s, 3H), 3.67 (d, J ) 4.6 Hz, 1H), 3.59 (s, 3H), 3.22-
3.02 (m, 3H), 2.78 (m, 1H), 2.59 (m, 1H), 2.42 (m, 2H), 2.31 (s,
3H), 2.30 (s, 3H), 2.05 (m, 1H), 2.04 (s, 3H). 13C NMR (75 MHz,
CD3OD) δ 173.5, 170.3, 148.1, 147.0, 146.9, 146.9, 145.0, 142.7,
141.9, 132.0, 129.3, 125.8, 122.8, 122.4, 121.4, 116.3, 115.9,
111.6, 103.5, 90.9, 65.5, 61.8, 60.4, 58.2, 57.2, 55.8, 47.3, 43.1,
40.7, 28.8, 27.8, 20.5, 16.1, 9.4. MS (EI+) calcd for C38H41N3O11S
(M + H) 748.2, found 748.1.
Hz, 1H), 5.12 (d, J ) 11.7 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H),
4.55-4.36 (m, 3H), 4.17-4.11 (m, 4H), 3.77 (s, 3H), 3.75 (s,
3H), 3.58 (d, J ) 4.8 Hz, 1H), 3.47 (s, 4H), 3.19 (s, 2H), 3.07
(s, 3H), 2.87-2.54 (m, 6H), 2.31 (s, 3H), 2.30 (s, 3H), 2.28 (s,
3H), 2.23 (s, 3H), 2.18-2.05 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H),
2.05 (s, 3H), 1.98 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 187.3,
170.2, 170.1, 168.9, 160.8, 148.0, 147.3, 146.3, 143.2, 143.1,
141.8, 141.3, 141.2, 141.0, 131.4, 131.3, 129.8, 129.6, 122.0,
121.9, 121.2, 121.0, 120.9, 117.9, 117.2, 115.5, 114.7, 102.2,
102.1, 102.0, 82.2, 81.8, 63.4, 60.5, 60.4, 58.1, 58.0, 57.9, 56.4,
56.2, 55.1, 55.0, 51.4, 41.6, 41.5, 37.0, 31.8, 29.9, 24.3, 24.0,
22.9, 20.7, 20.6, 20.5, 16.0, 15.9, 14.3, 9.9, 9.8. MS (EI+) calcd
for C30H32N2O10S (M - H2O + H) 595.1, found 595.5.
Com p ou n d 45. To a solution of compound 27a 8 (520.8 mg,
0,84 mmol) in CH2Cl2 (17 mL, 0.05M) at 23 °C was added acetic
anhydride (0.08 mL, 0.88 mmol). The reaction was stirred for
30 min and then quenched with a saturated aqueous solution
of NaHCO3. The aqueous layer was extracted with CH2Cl2 and
the combined organic layer was dried over Na2SO4 and filtered
and the solvent was eliminated under reduced pressure. The
crude was purified by flash chromatography (hexane/EtOAc,
1:2, 2:5, 1:3) affording pure compound 45 in 96% yield. Rf 0.2
Com p ou n d 47. To a solution of 78 (ET-770) (45 mg, 0.058
mmol) in CH2Cl2 (3 mL, 0.03 M) at 0 °C was added m-CPBA
(15.1 mg, 0.087 mmol). The reaction was stirred at 0 °C for 30
min. Then a saturated aqueous solution of NaHCO3 was added
and then the aqueous phase was extracted with CH2Cl2. The
organic layers were dried over Na2SO4 and the solvent was
eliminated under reduced pressure. The crude was purified
by flash column chromatography (eluent: ethyl acetate/hexane
3:1) to afford compound 47 (45.6 mg, 90%). Rf 0.18 (ethyl
acetate/hexane 2:1). Mp 190-192 °C. IR (KBr, cm-1) 3300,
(Hexane/ethyl acetate 2:3). Mp 205-207 °C. IR (KBr, cm-1
)
1
3360, 1720, 1450, 1200. H NMR (300 MHz, CDCl3) δ 6.56 (s,
1H), 6.09 (d, J ) 1.3 Hz, 1H), 6.00 (d, J ) 1.3 Hz, 1H), 5.78 (s,
1H), 5.52 (br d, J ) 9.0 Hz, 1H), 5.02 (d, J ) 11.8 Hz, 1H),
4.58 (ddd, J ) 4.3, 6.4, 9.0 Hz, 1H), 4.53 (br s, 1H), 4.27-4.25
(m, 2H), 4.19-4.15 (m, 2H), 3.77 (s, 3H), 3.44-3.43 (m, 2H),
2.92-2.90 (m, 2H), 2.36-2.02 (m, 2H), 2.36 (s, 3H), 2.30 (s,
3H), 2.16 (s, 3H), 2.02 (s, 3H), 1.88 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 170.5, 168.8, 168.4, 148.1, 145.8, 143.1, 141.0, 140.3,
130.7, 129.9, 129.0, 120.3, 119.0, 117.9, 113.5, 102.0, 61.3, 60.3,
60.2, 59.3, 58.9, 54.7, 54.5, 51.9, 41.8, 41.4, 32.4, 23.7, 22.8,
20.4, 16.0, 9.5. MS (EI+) calcd for C33H36N4O9S (M + H) 665.2,
found 665.2.
1
1680, 1520, 1450. H NMR (300 MHz, CDCl3) δ 6.63 (s, 1H),
6.51 (s, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 6.05 (s, 1H), 6.00 (s,
1H), 4.66 (d, J ) 4.5 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.30-
4.28 (m, 1H), 4.19 (s, 1H), 4.07 (s, 1H), 3.82 (s, 1H), 3.73 (d, J
) 4.2 Hz, 1H), 3.65 (d, J ) 15.0 Hz, 1H), 3.60 (s, 3H), 3.43 (d,
J ) 15.0 Hz, 1H), 3.04-2.95 (m, 2H), 2.88-2.81 (m, 1H), 2.72-
2.55 (m, 3H), 2.48-2.41 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.23
(s, 3H), 2.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 172.0, 169.2,
148.2, 146.8, 146.3, 145.1, 144.8, 142.3, 140.8, 130.8, 129.6,
129.5, 124.5, 122.6, 120.2, 120.0, 117.8, 114.6, 111.8, 109.5,
102.4, 70.9, 67.8, 61.8, 61.7, 60.9, 60.6, 60.0, 55.3, 54.9, 54.7,
41.9, 40.0, 29.9, 29.1, 25.0, 21.0, 16.2, 10.3. MS (EI+) calcd
for C40H42N4O11S (M + Na) 809.2, found 809.3.
Com p ou n d 17 (ET-637). To a solution of 1 equiv of 45 (512
mg) in THF/H2O 4:1 (0.03M) at 23 °C was added 10 equiv of
CuCl. The reaction was stirred for 24 h protected from light.
After this time, the reaction was quenched with a saturated
aqueous solution of NH4Cl, diluted with CH2Cl2, and washed
twice with saturated aqueous solutions of NaHCO3 and NH4-
Cl. The aqueous layers were extracted with CH2Cl2, and the
organic layers were dried over Na2SO4. Flash chromatography
(CH2Cl2/MeOH 50:1, 35:1, 20:1, 15:1, 10:1, 7:1) yielded pure
compound 17 (ET-637) (75%). Rf 0.28 (CH2Cl2:MeOH 30:1).
Com p ou n d 4 (ET-759B). To a solution of compound 47 (45
mg, 0.057 mmol) in a mixture of CH3CN/H2O (6 mL/ 2 mL,
0.007 M) at 23 °C was added AgNO3 (287.1 mg, 1.71 mmol).
The reaction mixture was protected from light and stirred for
24 h. The reaction was then diluted with CH2Cl2 and quenched
with a 1:1 mixture of saturated aqueous solutions of NaHCO3
and brine. The aqueous phase was extracted with CH2Cl2, the
organic layers were dried over Na2SO4, and the solvent was
eliminated under reduced pressure. The crude was purified
by flash column chromatography to afford 4 (ET-759B) (23.2
mg, 52%) as a pale yellow solid. Starting material (18.7 mg,
[R]22 -13.6 (c 0.1, CH2Cl2). Mp 151-153 °C. IR (KBr, cm-1
)
D
1
3400, 1750, 1650, 1190. H NMR (300 MHz, CDCl3) δ 6.57 (s,
1H), 6.07 (d, J ) 1.5 Hz, 1H), 5.96 (d, J ) 1.5 Hz, 1H), 5.79
(br s, 1H), 5.60 (br d, J ) 8.7 Hz, 1H), 5.15 (d, J ) 10.2 Hz,
1H), 4.77 (s, 1H), 4.56 (m, 1H), 4.46-4.43 (m, 2H), 4.15 (d, J
) 3.3 Hz, 1H), 4.09 (dd, J ) 2.1, 11.4 Hz, 1H), 3.77 (s, 3H),
3.49-3.47 (m, 1H), 3.23-3.20 (m, 1H), 2.91-2.76 (m, 2H),
2.31-2.11 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H), 2.01
(s, 3H), 1.89 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.4, 168.8,
168.5, 148.0, 145.6, 143.0, 141.0, 140.7, 131.5, 128.8, 120.9,
120.6, 118.9, 115.2, 112.7, 101.8, 81.5, 61.6, 60.2, 57.7, 57.4,
55.9, 55.0, 52.1, 52.0, 41.3, 32.4, 23.6, 22.9, 20.5, 16.1, 9.5. MS
(EI+) calcd for C32H37N3O10S (M - H2O + H) 638.2, found
638.1.
42%) was also recovered. Rf 0.36 (CH2Cl2/MeOH 8:0.5). [R]22
D
-148.3 (c 0.1, CH2Cl2). Mp 176-178 °C. IR (KBr, cm-1) 3300,
1
1710, 1400, 1250, 1100. H NMR (300 MHz, CDCl3) δ 6.65 (s,
1H), 6.48 (s, 1H), 6.43 (s, 1H), 6.20 (s, 1H), 6.04 (s, 1H), 5.97
(s, 1H), 4.78 (s, 1H), 4.70 (d, J ) 10.8 Hz, 1H), 4.55 (d, J ) 4.5
Hz, 1H), 4.36 (d, J ) 3.3 Hz, 1H), 4.21 (dd, J ) 1.8, 10.8 Hz,
1H), 4.07-3.98 (m, 1H), 3.83 (s, 3H), 3.77 (d, J ) 4.5 Hz, 1H),
3.69-3.63 (m, 1H), 3.61 (s, 3H), 3.46 (d, J ) 4.5 Hz, 1H), 3.22
(d, J ) 7.5 Hz, 1H), 3.06-2.82 (m, 4H), 2.66-2.43 (m, 4H),
2.31 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.04 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 171.9, 169.3, 148.0, 146.9, 145.0, 144.7,
142.2, 141.0, 130.7, 130.1, 129.6, 124.9, 123.0, 120.9, 120.1,
114.6, 113.7, 109.5, 102.2, 82.9, 67.9, 63.1, 61.8, 60.5, 57.7, 57.6,
55.9, 55.3, 55.1, 41.7, 40.0, 29.9, 29.2, 24.7, 21.0, 16.1, 14.3,
10.2. MS (EI+) calcd for C39H43N3O12S (M - H2O + H) 760.8,
found 760.2.
Com p ou n d 3 (ET-745). To a solution of 18 (ET-743) (75
mg, 0.1 mmol) in acetonitrile (5 mL, 0.02 M) at 23 °C were
added acetic acid (85 mL, 0.3 mmol) and NaCNBH3 (166 mg,
2.65 mmol). The solution was stirred at 23 °C for 30 min. Then
a saturated aqueous solution of NaHCO3 was added and then
aqueous phase was extracted with CH2Cl2. The organic layers
were dried over Na2SO4 and the solvent was eliminated under
reduced pressure. The resulting crude was purified by flash
column chromatography (CHCl3/EtOAc/MeOH 49:49:2) to af-
Com p ou n d 18 (ET-594). To a solution of compound 468
(100 mg, 0.16 mmol) in a mixture THF/H2O (4.26 mL/ 1.06
mL, 0.03 M) at 23 °C was added CuCl (79.5 mg, 0.80 mmol).
The reaction was protected from light and stirred for 24 h.
The reaction was then diluted with CH2Cl2 and quenched with
a saturated aqueous solution of ammonium chloride. The
aqueous phase was decanted and the organic phase was
washed with a saturated aqueous solution of NaHCO3. The
aqueous phase was extracted with CH2Cl2, the organic layers
were combined and dried over Na2SO4, and the solvent was
eliminated under reduced pressure. The crude was purified
by flash chromatography (eluent CH2Cl2/MeOH 60:1) to afford
18 (ET-594) (70 mg, 71%) as a yellow solid. Rf 0.44 (CH2Cl2/
MeOH 60:1). [R]22D -44.7 (c 0.1, CH3OH). Mp 188-190 °C. IR
(KBr, cm-1) 3450, 2950, 1720, 1650, 1420, 1150. 1H NMR (300
MHz, CDCl3) δ 6.53 (s, 1H), 6.49 (s, 1H), 6.07 (s, 1H), 6.05 (s,
1H), 5.98 (s, 1H), 5.94 (s, 1H), 5.71 (s, 2H), 5.18 (d, J ) 11.1
J . Org. Chem, Vol. 68, No. 23, 2003 8865

Menchaca et al.
ford 3 (ET-745) (15.8 mg, 64%). Rf 0.17 (CHCl3/EtOAc/MeOH
49:49:2). [R]22D -73.4 (c 0.1, CH2Cl2). Mp 219-221 °C. IR (KBr,
cm-1) 3400, 1750, 1680, 1200. 1H NMR (300 MHz, CDCl3) δ
6.61 (s, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 6.00 (d, J ) 1.2 Hz,
1H), 5.95 (d, J ) 1.2 Hz, 1H), 5.10 (d, J ) 11.4 Hz, 1H), 4.50
(br s, 1H), 4.38 (d, J ) 3.9 Hz, 1H), 4.09 (d, J ) 9.3 Hz, 1H),
3.79 (s, 3H), 3.60 (s, 3H), 3.38-3.21 (m, 3H), 3.17-2.81 (m,
5H), 2.71 (m, 1H), 2.52 (m, 2H), 2.41 (d, J ) 13.8 Hz, 1H),
2.33 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.12 (m, 1H), 2.02 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 172.4, 168.19, 147.7, 144.8,
144.6, 144.50, 142.6, 141.0, 139.7, 131.6, 128.6, 126.1, 122.1,
120.5, 118.5, 115.4, 114.5, 112.6, 109.9, 101.4, 64.2, 64.0, 62.2,
60.8, 60.0, 55.0, 42.4, 41.7, 40.7, 39.3, 31.4, 29.5, 28.5, 25.4,
AgNO3 (30 equiv, 619 mg). The reaction mixture was protected
from light and stirred for 24 h at 23 °C. The mixture was
diluted with a 1:1 mixture of saturated aqueous solutions of
brine and NaHCO3 and stirred for 10 min. After dilution with
CH2Cl2, the organic layer was separated and dried over Na2-
SO4. Purification by flash chromatography afforded pure
compound 12 (ET-736) (85.4 mg) in 92% yield. Rf 0.5 (CH2Cl2:
MeOH 8:1). [R]22 -19.3 (c 0.1, CH2Cl2). Mp 170-172 °C. IR
D
(KBr, cm-1) 3600, 1720, 1520, 1150, 1100. 1H NMR (300 MHz,
CDCl3) δ 7.70 (s, 1H), 7.38 (d, J ) 7.8 Hz, 1H), 7.24 (d, J ) 7.8
Hz, 1H), 7.08 (t, J ) 8.1 Hz, 1H), 7.00 (t, J ) 7.2 Hz, 1H), 6.67
(s, 1H), 6.20 (d, J ) 1.2 Hz, 1H), 5.99 (d, J ) 1.2 Hz, 1H), 5.74
(s, 1H), 5.20 (d, J ) 11.4 Hz, 1H), 4.82 (s, 1H), 4.34-4.38 (m,
3H), 4.16-4.10 (m, 2H), 3.81 (s, 3H), 3.49 (d, J ) 4.5 Hz, 1H),
3.22-3.13 (m, 2H), 3.00 (d, J ) 18.0 Hz, 1H), 2.88-2.79 (m,
2H), 2.71-2.52 (m, 3H), 2.37 (s, 3H), 2.28-2.24 (m, 1H), 2.25
(s, 3H), 2.19 (s, 3H), 2.05 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 171.4, 168.7, 147.8, 145.4, 142.8, 141.0, 140.6, 135.4, 131.2,
130.9, 129.0, 126.8, 121.8, 121.3, 120.9, 119.1, 118.3, 118.1,
115.5, 112.8, 110.8, 110.1, 101.7, 81.9, 62.3, 61.8, 60.2,57.6,
57.4, 55.8, 54.9, 42.1, 41.2, 39.7, 39.2, 31.5, 23.5, 22.6, 21.5,
20.5, 15.8, 14.0, 9.6. MS (EI+) calcd for C40H42N4O9S (M - H2O
+ H) 737.8, found 737.2.
22.4, 20.3, 15.6, 13.9, 9.4. MS (EI+) calcd for C39H43N3O10
(M + H) 746.3, found 746.2.
S
Com p ou n d 48. To a solution of 1 equiv (75 mg) of 468 in
acetic acid (1.5 mL) at room temperature was added tryptamine
(3.5 equiv, 67.8 mg). The reaction mixture was stirred for 24
h and then the acetic acid was evaporated. NaHCO3 saturated
aqueous solution was added and the mixture was extracted
with CH2Cl2. The organic layers were dried over Na2SO4. Flash
chromatography afforded pure compound 48 (90 mg) in 99%
yield. Rf 0.4 (hexane/ethyl acetate 2:3). Mp 215-217 °C. IR
(KBr, cm-1) 3650, 3400, 1710, 1520, 1200. 1H NMR (300 MHz,
CDCl3) δ 7.74 (s, 1H), 7.38 (d, J ) 7.5 Hz, 1H), 7.25 (d, J ) 6.9
Hz, 1H), 7.08 (t, J ) 7.2 Hz, 1H), 7.00 (t, J ) 7.2 Hz, 1H), 6.66
(s, 1H), 6.22 (d, J ) 1.2 Hz, 1H), 6.02 (d, J ) 1.2 Hz, 1H), 5.79
(s, 1H), 5.08 (d, J ) 11.7 Hz, 1H), 4.55 (s, 1H), 4.32 (s, 1H),
4.27 (d, J ) 3.9 Hz, 1H), 4.21 (s, 1H), 4.19 (d, J ) 11.7 Hz,
1H), 3.81 (s, 3H), 3.44-3.40 (m, 2H), 3.18-2.78 (m, 4H), 2.71-
2.51 (m, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.06 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 171.7, 168.9, 148.2, 145.9,
143.2, 141.3, 140.5, 135.7, 130.8, 130.6, 129.5, 127.0, 122.2,
120.9, 120.8, 119.5, 118.6, 118.4, 113.8, 111.1, 110.5, 102.2,
62.5, 61.5, 60.8, 60.5, 59.7, 55.9, 54.8, 42.1, 41.7, 40.0, 39.5,
29.9, 24.0, 21.7, 20.8, 16.1, 9.9. MS (EI+) calcd for C41H41N5O8S
(M - H2O + H) 763.8, found 764.2.
Ack n ow led gm en t. This paper is dedicated to Prof.
Kenneth L. Rinehart who discovered the Ecteinascidins
family. We thank Prof. Antonio M. Echavarren (Uni-
versidad Auto´noma de Madrid) for his continuous advice
and support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Com p ou n d 12 (ET-736). To a solution of 1 equiv (94 mg)
of 48 in a mixture of CH3CN/H2O (3:2) (6.5 mL) was added
J O034547I
8866 J . Org. Chem., Vol. 68, No. 23, 2003