Total synthesis of ecteinascidin 743

Article abstract of DOI:10.1021/ja408034x

A straightforward synthesis of ecteinascidin 743 was accomplished from readily available l-glutamic acid as a single chiral source. Our novel synthesis features a concise and convergent approach for construction of the B-ring, consisting of a sequence involving a stereoselective Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho substitution of the phenol by an aldehyde.

Full text of DOI:10.1021/ja408034x

Subscriber access provided by Georgetown University | Lauinger and Blommer Libraries
Communication
Total Synthesis of Ecteinascidin 743
Fumiki Kawagishi, Tatsuya Toma, Tomohiko Inui, Satoshi Yokoshima, and Tohru Fukuyama
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja408034x • Publication Date (Web): 03 Sep 2013
Downloaded from http://pubs.acs.org on September 5, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Total Synthesis of Ecteinascidin 743
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fumiki Kawagishi,†, ‡ Tatsuya Toma,† Tomohiko Inui,† Satoshi Yokoshima,‡ Tohru Fukuyama*,‡
†Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
Supporting Information Placeholder
nitrile was hydrolyzed to furnish carboxamide 10. Hofmann
ABSTRACT: A straightforward synthesis of ecteinascidin
rearrangement followed by hydrolysis afforded amine 11.
743 was accomplished from readily available L-glutamic acid
as a single chiral source. Our novel synthesis features a con-
Scheme 1. Retrosynthesis
cise and convergent approach for construction of the B-ring,
consisting of a sequence of a stereoselective Heck reaction
between a diazonium salt and an enamide, oxidative cleavage
of the resulting alkene and intramolecular ortho substitution of
the phenol by an aldehyde.
Ecteinascidin 743 (1, Scheme 1), a tetrahydroisoquinoline
alkaloid, was isolated from the Caribbean tunicate Ecteinas-
cidia turbinata by Rinehart and coworkers.1 This alkaloid
attracted strong interest as a potential anticancer agent due to
its combination of strong cytostatic properties and antitumor
activity2,3 and has recently been approved for the treatment of
soft tissue sarcoma and ovarian cancer. However, only minute
quantities of ecteinascidin 743 are available from the marine
sources. While several total syntheses have been reported to
date,4,5 they are not amenable to scale up for manufacturing
purposes. Ecteinascidin 743 is currently provided by a long-
step semisynthesis from cyanosafracin B.6 There is, however,
an urgent need for more efficient synthesis of the natural
product from readily available chemicals due to the increasing
demand. Since our first-generation total synthesis was reported
in 2002,4b we have made continued efforts to establish a prac-
tical synthetic pathway that could meet the demand for ectein-
ascidin 743. Herein we disclose an interim report of our novel
approach for the robust synthesis of ecteinascidin 743.
Scheme 2
As shown in our retrosynthesis in Scheme 1, the ten-
membered cyclic sulfide in 1 would be generated according to
our published strategy4b from alcohol 2, a key intermediate
with the pentacyclic core structure. Construction of the B-ring
could be achieved via an intramolecular ortho substitution of
the phenol with an aldehyde. Intermediate 3 bearing two alde-
hyde moieties would be derived from dihydropyrrole 4. Given
the aryl group on the less hindered side, stereoselective intro-
duction of the aryl group in 4 would be achieved via a Heck
reaction between diazonium salt 5 and enamide 6.7
Our synthesis commenced with preparation of amine 11 as
the precursor for diazonium salt 5 (Scheme 2). Oxidation of
known phenol 75e,8 with PhI(OAc)2 in methanol gave dienone
8, which was treated with sodium cyanide to afford nitrile 9.
Reagents and conditions: (a) PhI(OAc)2, MeOH, 0 °C; (b)
After benzylation of the phenolic hydroxy group, the resulting
NaCN, DMF-H2O, 0 °C to rt, 37% (2 steps); (c) BnBr, K2CO3,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
6
7
8
9
DMF, rt; (d) aq H2O2, K2CO3, DMSO, rt; (e) PhI(OAc)2, KOH,
MeOH, 0 °C; (f) LiOH, EtOH-H2O, reflux, 83% (4 steps).
K3PO4, 1,4-dioxane, 100 °C, 92%; (h) HCl, EtOAc, rt; ClCO2Me,
NaHCO3, H2O, 0 °C, 91%; (i) L-Selectride®, THF, –42 °C; (j)
CSA, toluene, reflux, 55% (2 steps); (k) aq KOH, 1,4-dioxane, rt;
MOMCl, 0 °C, 95%.
We next focused on construction of the enamide unit
(Scheme 3). L-glutamic acid, chosen as an inexpensive, readi-
ly available, and reliable chiral source, was converted to N,N’-
diacetylated diketopiperazine 13.9 Perkin condensation of 13
with aldehyde 14 proceeded stereoselectively to give 15. After
introduction of a Boc group at the lactam, cleavage of the ben-
zyl group and stereoselective reduction of the double bond
were simultaneously carried out to furnish 16. Hydrazinolysis
of the acetyl group in 16 followed by selective reduction of the
imide carbonyl group with sodium borohydride afforded 17.
Upon treatment of 17 with TFA, the N-acyliminium ion-
mediated cyclization reaction proceeded smoothly, and subjec-
tion of the product to PhNTf2 under basic conditions afforded
bis-triflate 18 in 88% yield. Suzuki-Miyaura coupling of 18
with trimethylboroxine took place selectively at the less hin-
dered triflate to produce 19 in 92% yield. After the Boc group
was switched to a methoxycarbonyl group, partial reduction of
the ester moiety in 20 with L-Selectride® and subsequent de-
hydration of the resulting hemiaminal under acidic conditions
afforded enamide 21. The Tf group was replaced with a MOM
group in a one-pot process to afford 22.
With the requisite units in hand, we next investigated con-
struction of the B-ring (Scheme 4). After treatment of amine
11 with tert-butyl nitrite and BF3·OEt2,10 the resulting diazoni-
um salt was reacted with enamide 22 in the presence of a pal-
ladium catalyst to perform the crucial Heck reaction. As ex-
pected, the reaction occurred exclusively from the less hin-
dered face of the enamide to produce coupling product 23
with the desired stereo- and regiochemistry. It should be noted
that this crucial intermolecular Heck reaction was carried out
on a multi-gram scale in an excellent yield. An osmium-
mediated dihydroxylation of the resulting, highly hindered
double bond in 23 was accomplished by using K3[Fe(CN)6] as
a co-oxidant in the presence of quinuclidine and methanesul-
fonamide.11,12,13 Oxidative cleavage of the resulting 1,2-diol
with H5IO6 formed a dialdehyde, which underwent facile hy-
dration to afford 25. Although partial epimerization occurred
during the oxidative cleavage of the diol, the crude product
could be purified by recrystallization from methanol to give 25
as a single diastereomer.14 Hydrogenolysis of the benzyl ether
in 25 gave phenol 26. Heating 26 in m-xylene promoted lib-
eration of the dialdehyde, which was trapped intramolecularly
by the electron-rich A-ring moiety to furnish 27.15 Subsequent
reduction of 27 with Red-Al® afforded 28 in 76% yield over
the 2 steps. Treatment of 28 with KCN in acetic acid induced
cleavage of the oxazolidine ring, forming aminonitrile 29.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3
Having established an efficient and robust synthetic route
toward the pentacyclic core skeleton of the target molecule,
we then undertook a study to construct the ten-membered cy-
clic sulfide. Condensation of the primary hydroxy group in 29
with cysteine derivative 304b followed by selective cleavage of
the S-acetyl group with hydrazine furnished thiol 31 in good
yield. Upon treatment of 31 with TFA, the cyclic sulfide for-
mation occurred presumably via the generation of an ortho
quinone methide to give, after acetylation of the phenolic hy-
droxy group, compound 32 in 55% yield. Sequential cleavage
of the MOM and Alloc protecting groups furnished 33, which
was identical to the intermediate of our previous synthesis,
and was converted into ecteinascidin 743 (1) via the published
3-step sequence.4b
Reagents and conditions: (a) Ac2O, 130 °C, 80%; (b) 14, t-
BuOK, THF, –78 to 0 °C; DBU, 0 °C; (c) Boc2O, DMAP, THF, rt,
quant (2 steps); (d) H2 (750 psi), Pd/C, EtOAc, rt; (e)
H2NNH2·H2O, THF, rt; evaporation; NaBH4, MeOH, 0 °C, 57%
(2 steps); (f) TFA, CF3CH2OH, rt; evaporation; PhNTf2, DMAP,
Cs2CO3, MeCN, rt, 88%; (g) trimethylboroxine, Pd(PPh3)4,
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
3
Scheme 4
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reagents and condition: (a) BF3·OEt2, t-BuONO, THF, –15 to 0 °C; 22, Pd2(dba)3, NaOAc, MeCN-THF, 0 °C to rt; (b) OsO4,
K3[Fe(CN)6], K2CO3, quinuclidine·HCl, MeSO2NH2, t-BuOH, H2O, rt, 93% (2 steps); (c) H5IO6, THF, 0 °C, 87%; (d) H2, Pd/C, MeOH,
rt; (e) m-xylene, 120 °C; Red-Al®, –42 to 60 °C, 76% (2 steps); (f) KCN, AcOH, rt, 98%; (g) 30, EDCI·HCl, DMAP, CH2Cl2, rt, 92%; (h)
H2NNH2·H2O, MeCN, rt, 85%; (i) TFA, CF3CH2OH, 25 °C; toluene, evaporation; Ac2O, pyridine, rt, 55%; (j) TFA, CH2Cl2, rt, 64%; (k)
(Ph3P)2PdCl2, AcOH, n-Bu3SnH, CH2Cl2, rt, 95%.
In conclusion, a straightforward synthesis of ecteinascidin
743 has been accomplished in 28 steps and 1.1% overall yield
from readily available L-glutamic acid as a single chiral source.
Corresponding Author
* fukuyama@ps.nagoya-u.ac.jp
Our novel synthesis features a concise and convergent ap-
proach for construction of the B-ring, consisting of a sequence
ACKNOWLEDGMENT
This work is dedicated to Professor Robert M. Williams of Colo-
rado State University on the occasion of his 60th birthday. The
authors are grateful to the financially supports by JSPS
KAKENHI Grant Numbers 20002004 and 25221301, Astellas
Foundation for Research on Metabolic Disorders, the Sumitomo
Foundation, and the Tokyo Biochemical Research Foundation.
F.K. is, and T.T. and T.I. were research fellows of JSPS.
of a stereoselective Heck reaction between a diazonium salt
and an enamide, oxidative cleavage of the resulting alkene and
intramolecular ortho substitution of the phenol by an aldehyde.
Other highlights of the synthesis include a straightforward
method to access a functionalized diketopiperazine by Perkin
condensation, facile construction of the bicyclo[3.3.1] system
by an N-acyliminium ion-mediated cyclization, and a regiose-
lective Suzuki-Miyaura coupling. We are currently exploring a
more practical synthetic route that could be applied on a man-
ufacturing scale to supply ecteinascidin 743 for clinical use.
REFERENCES
(1)
(a) Holt, T. G. Ph.D. Dissertation, University of Illinois,
Urbana-Champaign 1986. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N.
L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org.
Chem. 1990, 55, 4512. (d) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, A.
H. J. Proc. Natl. Acad. Sci. 1992, 89, 11456. (d) Wright, A. E.; Forleo, D.
A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; Mcconnell, O.
J. J. Org. Chem. 1990, 55, 4508. (e) Sakai, R.; Jares-Erijman, E. A.;
Manzanares, I.; Elipe, M. V. S.; Rinehart, K. L. J. Am. Chem. Soc. 1996,
118, 9017.
ASSOCIATED CONTENT
Supporting Information. Experimental details, characterization
data, and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
6
7
8
9
(2)
(a) Pommier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.;
Mazumder, A.; Kohn, K. W. Biochemistry 1996, 35, 13303. (b) Moore,
B. M.; Seaman, F. C.; Hurley, L. H. J. Am. Chem. Soc. 1997, 119, 5475.
(c) Moore, B. M.; Seaman, F. C.; Wheelhouse, R. T.; Hurley, L. H. J. Am.
Chem. Soc. 1998, 120, 9975. (d) Moore, B. M.; Seaman, F. C.;
Wheelhouse, R. T.; Hurley, L. H. J. Am. Chem. Soc. 1998, 120, 2490. (e)
Seaman, F. C.; Hurley, L. H. J. Am. Chem. Soc. 1998, 120, 13028. (f)
Zewail-Foote, M.; Hurley, L. H. J. Med. Chem. 1999, 42, 2493. (g)
Garcia-Nieto, R.; Manzanares, I.; Cuevas, C.; Gago, F. J. Med. Chem.
2000, 43, 4367. (h) Garcia-Nieto, R.; Manzanares, I.; Cuevas, C.; Gago,
F. J. Am. Chem. Soc. 2000, 122, 7172. (i) Zewail-Foote, M.; Hurley, L. H.
J. Am. Chem. Soc. 2001, 123, 6485. (j) Marco, E.; Garcia-Nieto, R.;
Mendieta, J.; Manzanares, I.; Cuevas, C.; Gago, F. J. Med. Chem. 2002,
45, 871. (k) Marco, E.; David-Cordonnier, M.-H.; Bailly, C.; Cuevas, C.;
Gago, F. J. Med. Chem. 2006, 49, 6925.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3)
(a) Gajate, C.; An, F. Y.; Mollinedo, F. J. Biol. Chem. 2002,
277, 41580. (b) Minuzzo, M.; Ceribelli, M.; Pitarque-Marti, M.; Borrelli,
S.; Erba, E.; diSilvio, A.; D'Incalci, M.; Mantovani, R. Mol. Pharmacol.
2005, 68, 1496.
(4)
(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.
C.; Chen, X. C.; Bois-Choussy, M.; Zhu, J. P. J. Am. Chem. Soc. 2006,
128, 87. (d) Zheng, S. P.; Chan, C.; Furuuchi, T.; Wright, B. J. D.; Zhou,
B.; Guo, J.; Danishefsky, S. Angew. Chem. Int. Ed. 2006, 45, 1754. (e)
Fishlock, D.; Williams, R. M. J. Org. Chem. 2008, 73, 9594. (f) Imai, T.;
Nakata, H.; Yokoshima, S.; Fukuyama, T. Synthesis 2012, 44, 2743.
(5)
For syntheteic studies toward ecteinascidin 743, see: (a) Endo,
A.; Kan, T.; Fukuyama, T. Synlett 1999, 1999, 1103. (b) Zhou, B. S.;
Guo, J. S.; Danishefsky, S. J. Org. Lett. 2002, 4, 43. (c) De Paolis, M.;
Chiaroni, A.; Zhu, J. Chem. Commun. 2003, 2896. (d) De Paolis, M.;
Chen, X. C.; Zhu, J. P. Synlett 2004, 2004, 729. (e) Chen, X. C.; Chen, J.
C.; De Paolis, M.; Zhu, J. P. J. Org. Chem. 2005, 70, 4397. (f) Chen, X.;
Chen, J.; Zhu, J. Synthesis 2006, 2006, 4081. (g) Enomoto, T.; Yasui, Y.;
Takemoto, Y. J. Org. Chem. 2010, 75, 4876.
(6)
(a) Cuevas, C.; Perez, M.; Martin, M.; Chicharro, J.;
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. (b) Menchaca, R.; Martínez, V.; Rodríguez, A.;
Rodríguez, N.; Flores, M.; Gallego, P.; Manzanares, I.; Cuevas, C. J. Org.
Chem. 2003, 68, 8859.
(7)
Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C.
R. D. Org. Lett. 2003, 5, 305.
(8)
M.; Chichirau, A.; Chepelev, L. L. J. Org. Chem. 2003, 68, 7023.
(9)
(10)
(11)
766.
(12)
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J.
Org. Chem. 1992, 57, 2768.
(13)
not determine the stereochemistry.
(14)
ring was difficult to reproduce.
(15)
isomers.
Hussain, H. H.; Babic, G.; Durst, T.; Wright, J. S.; Flueraru,
Weigl, M.; Wünsch, B. Tetrahedron 2002, 58, 1173.
Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55,
Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
While diol 24 was obtained as a single diastereomer, we could
Without recrystallization at this stage, construction of the B-
This aldehyde could be isolated as a 5:1 mixture of the
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment