Synthetic studies on ecteinascidin 743: Asymmetric synthesis of the versatile amino acid component

Article abstract of DOI:10.1016/S0040-4039(03)01082-7

The asymmetric synthesis of the modified tyrosine derivative as a basic building block for the ecteinascidin and safracin family of antitumor alkaloids has been achieved in nine steps and 39% overall yield.

Full text of DOI:10.1016/S0040-4039(03)01082-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4635–4639
Synthetic studies on ecteinascidin 743: asymmetric synthesis of
the versatile amino acid component
Wei Jin and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 10 April 2003; revised 26 April 2003; accepted 29 April 2003
Abstract—The asymmetric synthesis of the modified tyrosine derivative as a basic building block for the ecteinascidin and safracin
family of antitumor alkaloids has been achieved in nine steps and 39% overall yield. © 2003 Elsevier Science Ltd. All rights
reserved.
Ecteinascidin (ET)-743 (1), is a natural product isolated
from the marine tunicate Ecteinascidia turbinata,1 and
has been demonstrated to be a highly promising,
exceedingly potent antitumor agent currently in phase
II/III clinical trials.2 The novel structure of ET-743
combined with its meagre availability from natural
sources, and the unique mechanism of action3 have
made this drug a very attractive synthetic target. The
first total synthesis of ET-743 was accomplished by
Corey and co-workers.4 Later Corey, Schreiber and
co-workers prepared a synthetic analogue of ET-743
(phthalascidin, Pt-650) that has virtually the same cyto-
toxicity as the natural product.5 In 2000, a semi-synthe-
sis of Et-743 from cyanosfracin B was described.6 Very
recently, another total synthesis of ET-743 was reported
by Fukuyama and co-workers.7
furnish the alkylation product 10. Further manipula-
tion would involve N-methylation of the amine group
and the phenol protecting group to give amino acid 9.
We have reported separately, the construction of opti-
cally pure b-lactams corresponding to 8 which has been
converted into a pentacyclic intermediate such as 7.14
The synthesis commenced with 3-(benzyloxy)-4-
methoxy-5-methylbenzaldehyde (13),15 which could be
conveniently made in ꢀ10 gram scale batches from
In addition to Et-743 (Fig. 1), the structurally related
safracins,8 saframycins9 and renieramycins10 are also
potent antitumor antibiotics that contain structurally
related amino acid components. We report here, a
potentially general method to synthesize a highly func-
tionalized tyrosine derivative that represents the ‘east-
ern’ sector of Et-743 that may be of potential use for
the asymmetric total synthesis of several members of
this family of natural products and congeners.11 Our
approach is based on the use of the optically pure
oxazinone 12 as template.12,13 Our retrosynthetic strat-
egy for Et-743 is illustrated in Scheme 1.
As shown in Scheme 1, the key amino acid 9 was
envisioned to arise via the coupling of the sodium
enolate of optically active (>99:1 er) oxazinone 1212,13
with the benzyl bromide derivative of aldehyde 11 to
* Corresponding author. E-mail: rmw@chem.colostate.edu
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01082-7

4636
W. Jin, R. M. Williams / Tetrahedron Letters 44 (2003) 4635–4639
Scheme 1.
vanillin in seven steps: (i) HCHO, Me2NH, ethanol
(94%); (ii) Ac2O; conc. HCl; SnCl2 (78%); (iii) AlCl3,
pyridine, CH2Cl2 90%; (iv) TIPS-Cl, Et3N, DMF
(82%); (v) Me2SO4, K2CO3, acetone (88%); (vi) TBAF,
THF (82%); (vii) BnBr, K2CO3, acetone (86%). As
shown in Scheme 2, the aldehyde of 13 was reduced to
the corresponding alcohol (14) by treatment with LAH
in quantitative yield. Alcohol 14 was converted into
benzyl bromide derivative 15 through the agency of
CBr4, Ph3P in 94% yield. Next, 15 was condensed with
the sodium enolate (NaHMDS, THF, −78°C) of oxazi-
none 12 to afford the alkylation product 10 in 79–92%
yield. The O-benzyl group of 10 was removed by
catalytic hydrogenation to give the corresponding phe-
nol 16 in 95% yield, followed by protection as the
O-TBS ether under standard conditions providing 17 in
82% yield.
removed by treatment with TFA in 93% yield affording
the secondary amine 18. In practice, we found it quite
difficult to effect the efficient N-methylation of 18 and
after extensive studies, it was found that the best condi-
tions for this transformation was via reductive amina-
tion using formaldehyde furnishing 19 (NaBH3CN,
HCHO, CH3CN, 77% yield). The chiral auxiliary of 19
was removed by catalytic hydrogenation to provide the
amino acid hydrochloride salt 20.16 Finally, the sec-
ondary amine was protected as the corresponding
Fmoc derivative furnishing 9 in 80% yield for the two
steps.17
Compound 9 should prove to be a versatile amino acid,
which contains the requisite functionality and desired
absolute stereochemistry, for the synthesis of the
ecteinascidins and related alkaloids. Efforts to utilize
this intermediate for the concise asymmetric synthesis
of the ecteinascidin, saframycin as well as safracin
family are currently under study in these laboratories.
The final conversion of 17 into 9 is illustrated in
Scheme 3. The N-t-Boc group of compound 17 was
Scheme 2.

W. Jin, R. M. Williams / Tetrahedron Letters 44 (2003) 4635–4639
4637
Scheme 3.
Acknowledgements
3. (a) Jin, S.; Gorfajn, B.; Faircloth, G.; Scotto, K. W. Proc.
Natl. Acad. Sci. USA 2000, 97, 6775–6779; (b) Minuzzo,
M.; Marchini, S.; Broggini, M.; Faircloth, G.; D’Incalci,
M.; Mantovani, R. Proc. Natl. Acad. Sci. USA 2000, 97,
6780–6784.
4. (a) Corey, E. J.; Gin, D. Y.; Kania, R. J. Am. Chem. Soc.
1996, 118, 9202–9203; (b) Martinez, E. J.; Corey, E. J.; Owa,
T. Chem. Biol. 2001, 8, 1151–1160; (c) Takebayashi, Y.;
Pourquier, P.; Zimonjic, D. B.; Nakayama, K.; Emmert,
S.; Ueda, T.; Urasaki, Y.; Kanzaki, A.; Akiyama, A.-I.;
Popescu, N.; Kraemer, K. H.; Pommier, Y. Nature Med.
2001, 7, 961–966; (d) Zewail-Foote, M.; Li, V.-S.; Kohn,
H.; Bearss, D.; Guzman, M.; Hurley, L. H. Chem. Biol.
2001, 8, 1033–1049.
We appreciate financial support of this work by
National Institutes of Health (Grant CA85419). Mass
spectra were obtained on instruments supported by the
NIH Shared Instrumentation Grant GM49631.
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10, catalog c33,181–3.

4638
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15. (a) Synthesis of this aldehyde could also be achieved in
four steps for small scale (1ꢀ2 g) from commercial
available isovanillin: (i) NaH, DMF; MOM-Br 95%; (ii)
nBuLi, N-methylpiperazine, THF; nBuLi; MeI 40%; (iii)
MsOH, CH2Cl2/H2O; (iv) BnBr, K2CO3, acetone 81% for
two steps; (b) Sinhababu, A. K.; Borchardt, R. T. Synth.
Commun. 1983, 13, 677–683. The synthesis of 13 as
described in the text is prepared according to the follow-
ing scheme.
6.93 (1H, s), 7.09–7.49 (9H, m). 13C NMR (100 MHz)
(DMSO-d6, 373 K) l DMSO: 13.5, 15.0, 27.2, 57.9, 59.2,
59.7, 70.3, 77.5, 80.0, 113.9, 123.8, 125.8, 126.7, 126.9,
127.2, 127.3, 127.6, 127.8, 130.8, 131.2, 134.2, 136.7,
146.1, 151.0, 167.8, 169.5. IR (NaCl, neat): 3032, 2931,
1754, 1697, 1588, 1494, 1453, 1382, 1331, 1233, 1161,
1085, 1010, 738, 702 cm−1. HRMS (FAB+) calcd for
C37H39NO6: 593.2777; found: 593.2781. [h]2D5 +22.5 (c
0.71, CH2Cl2).
1
Compound 16: H NMR (400 MHz) (DMSO-d6, 373 K)
l DMSO: 1.08–1.47 (9H, broad), 2.20 (3H, s), 3.16–3.19
(1H, broad), 3.34–3.39 (1H, m), 3.47–3.51 (1H, m), 3.73
(3H, s), 5.01 (1H, broad), 5.08 (1H, broad), 5.38 (1H,
broad), 6.56–6.59 (3H, m), 6.69 (1H, s), 6.85–6.86 (2H, d,
J=6.4 Hz), 7.08–7.26 (6H, m). 13C NMR (100 MHz)
(DMSO-d6, 373 K) l DMSO: 15.0, 17.8, 27.2, 55.6, 58.8,
59.6, 77.4, 80.0, 115.3, 115.4, 121.8, 125.7, 126.7, 126.9,
127.2, 127.6, 130.4, 131.0, 134.2, 145.1, 149.4, 167.9. IR
16. This amino acid salt is soluble in ether, and it thus
proved expedient to take the crude salt on directly for the
next step without further purification.
(NaCl, neat): 3399, 2977, 2933, 1754, 1697, 1590, 1497,
1454, 1386, 1357, 1301, 1161, 1119, 1060, 1003, 736, 702
cm−1. HRMS (FAB+) calcd for C30H33NO6: 503.2308,
found: 503.2307. [h]2D5 +37.8 (c 1.27, CH2Cl2).
17. All new compounds gave satisfactory spectroscopic and
analytical data consistent with the assigned structures.
1
Compound 17: H NMR (400 MHz) (DMSO-d6, 373 K)
1
Alcohol 14: H NMR (300 MHz) l CDCl3: 1.95 (1H, s),
l DMSO: 0.17–0.18 (6H, s), 1.00 (9H, s), 1.05–1.50 (9H,
broad), 2.22 (3H, s), 3.19–3.22 (1H, broad), 3.37–3.42
(1H, broad), 3.73 (3H, s), 4.99 (1H, broad), 5.08 (1H,
broad), 5.30 (1H, broad), 6.56–6.58 (2H, d, J=6.8 Hz),
6.66 (1H, s), 6.73 (1H, s), 6.83–6.84 (2H, d, J=4.8 Hz),
7.10–7.25 (6H, m). 13C NMR (100 MHz) (DMSO-d6, 373
K) l DMSO: −5.2, 15.1, 17.4, 25.1, 27.2, 58.9, 77.5, 80.1,
119.4, 119.5, 124.2, 125.7, 126.8, 127.0, 127.3, 127.7,
131.3, 134.1, 147.7, 148.2, 167.82. IR (NaCl, neat): 3032,
2927, 2856, 1757, 1702, 1585, 488, 1454, 1380, 1357, 1254,
1162, 1116, 1067, 1011, 838, 784, 701 cm−1. HRMS
(FAB+) calcd for C36H47NO6Si: 617.3173; found:
617.3169. [h]2D5 +22.1 (c 1.09, CH2Cl2).
2.32 (3H, s), 3.88 (3H, s), 4.60 (2H, s), 5.15 (2H, s), 6.82
(1H, s), 6.89–6.90 (1H, d, J=1.8 Hz), 7.37–7.52 (5H, m).
13C NMR (75 Hz) l CDCl3: 16.1, 60.4, 65.3, 70.7, 110.7,
121.8, 127.3, 127.9, 128.6, 132.1, 136.4, 137.1, 147.1,
151.8. IR (NaCl, neat) 3396, 2932, 2872, 2827, 1591,
1495, 1433, 1325, 1230, 1143, 1089, 1008, 737, 697 cm−1
.
HRMS (FAB+) calcd for C16H18O3: 258.1256; found:
258.1249.
1
Bromide 15: H NMR (300 MHz) l CDCl3: 2.33 (3H, s),
3.91 (3H, s), 4.49 (2H, s), 5.17 (2H, s), 6.89–6.90 (1H, d,
J=2.1 Hz), 6.92–6.93 (1H, d, J=2.4 Hz), 7.39–7.54 (5H,
m). 13C NMR l CDCl3: 15.1, 33.3, 59.3, 69.8, 111.7,
123.0, 126.4, 127.0, 127.6, 131.4, 131.9, 135.9, 147.0,
150.77. IR (NaCl, neat): 3031, 2932, 2828, 1589, 1493,
Compound 18: 1H NMR (400 MHz) l CDCl3: −0.01
(3H, s), 0.02 (3H, s), 0.90 (9H, s), 1.23 (1H, broad), 2.15
(3H, s), 3.12–3.17 (2H, m), 3.68 (3H, s), 4.15–4.18 (1H,
dd, J=4.0 Hz, 9.2 Hz), 4.60 (1H, d, J=3.6 Hz), 5.55–
5.56 (1H, d, J=3.6 Hz), 6.49–6.50 (1H, d, J=2.0 Hz),
6.62 (1H, d, J=1.6 Hz), 6.85–6.88 (4H, m), 7.11–7.23
(6H, m). 13C NMR (100 MHz) l CDCl3: −4.6, 16.1, 18.3,
25.8, 29.8, 38.5, 56.7, 58.3, 59.9, 85.3, 120.0, 124.6, 127.3,
127.7, 127.8, 128.2, 128.4, 132.4, 132.9, 135.1, 136.8,
148.8, 149.0, 170.6. IR (NaCl, neat): 3325, 2955, 2929,
1434, 1333, 1287, 1211, 1150, 1090, 1008, 738, 698 cm−1
.
HRMS (FAB+) calcd for C16H17O2Br: 320.0419; found:
320.0418.
1
Compound 10: H NMR (400 MHz) (DMSO-d6, 373 K)
l DMSO: 1.16–1.41 (9H, broad), 2.23 (3H, s), 3.27–3.30
(3H, d, J=16 Hz), 3.41–3.46 (1H, m), 3.77 (3H, s), 5.04
(1H, broad), 5.14 (3H, s), 5.4 (1H, broad), 6.59–6.61 (2H,
d, J=7.2 Hz), 6.78 (1H, s), 6.86–6.87 (2H, d, J=5.6 Hz),

W. Jin, R. M. Williams / Tetrahedron Letters 44 (2003) 4635–4639
4639
2857, 1738, 1584, 1489, 1336, 1253, 1226, 1180, 1070,
1254, 1176, 1146, 1070, 1012, 839, 783, 712, 697 cm−1
.
1012, 838, 783, 699 cm−1. HRMS (FAB+) calcd for
C31H40NO4Si: 518.2727; found: 518.2719. [h]2D5 +55.4 (c
0.70, CH2Cl2).
HRMS (FAB+) calcd for C32H42NO4Si: 532.2883; found:
532.2861. [h]2D5 −40.5 (c 1.11, CH2Cl2).
1
Compound 9: H NMR (300 Hz) l CDCl3 0.14 (6H, s),
1
0.99 (9H, s), 2.18 (3H, s), 2.87 (3H, s), 2.6–3.3 (4H, m),
3.66 (3H, s), 4.14–4.37 (3H, m), 4.64–4.93 (1H, m), 6.48
(1H, s), 6.59–6.64 (1H, s), 7.25–7.54 (6H, m), 7.72–7.76
(2H, dd, J=3.0 Hz, 7.5 Hz), 8.04 (1H, s); 13C NMR (75
MHz) l −4.3, 16.3, 18.5, 25.9, 31.9, 32.6, 34.4, 36.9, 47.3,
59.9, 60.9, 68.1, 119.3, 120.0, 124.0, 124.9, 125.1, 127.1,
127.7, 132.3, 132.4, 141.3, 144.0, 148.6, 163.0, 174.8; IR
(neat, film): 2954, 2929, 2857, 1682, 1598, 1451, 1322,
1142, 839 cm−1; HRMS calcd for C33H41NO6Si: 575.2703,
found: 575.2697. [h]D −40.8 (c 0.5, CH2Cl2).
Compound 19: H NMR (400 MHz) l CDCl3: 0.18 (3H,
s), 0.20 (3H, s), 1.03 (9H, s), 2.27 (3H, s), 2.39 (3H, s),
3.03–3.23 (2H, dd, J=4.0 Hz, 13.2 Hz), 3.76 (3H, s),
3.97–4.01 (2H, m), 5.06 (1H, s), 6.71 (1H, s) 6.74 (1H, s),
6.78–6.79 (2H, d, J=7.2 Hz), 6.86–6.87 (2H, d, J=5.2
Hz), 7.10–7.19 (6H, m). 13C NMR (100 MHz) l CDCl3:
−4.5, −4.4, 16.2, 18.4, 25.9, 29.8, 37.4, 39.7, 60.0, 64.7,
67.4, 81.7, 121.0, 125.5, 126.1, 127.8, 127.9, 128.0, 128.2,
129.4, 132.0, 132.6, 134.3, 135.9, 148.4, 148.8, 171.7. IR
(NaCl, neat): 2930, 2857, 1744, 1585, 1489, 1351, 1315,