Synthetic studies on ecteinascidin-743: Constructing a versatile pentacyclic intermediate for the synthesis of ecteinascidins and saframycins

Article abstract of DOI:10.1021/ol034575n

(Matrix presented) The asymmetric synthesis of a highly functionalized pentacyclic tetrahydroisoquinoline relevant to the ecteinascidin, saframycin, safracin, and renieramycin family of antitumor alkaloids is described.

Full text of DOI:10.1021/ol034575n

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2095-2098
Synthetic Studies on Ecteinascidin-743:
Constructing a Versatile Pentacyclic
Intermediate for the Synthesis of
Ecteinascidins and Saframycins
Wei Jin, Sammy Metobo, and Robert M. Williams*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
rmw@chem.colostate.edu
Received April 1, 2003
ABSTRACT
The asymmetric synthesis of a highly functionalized pentacyclic tetrahydroisoquinoline relevant to the ecteinascidin, saframycin, safracin, and
renieramycin family of antitumor alkaloids is described.
Ecteinascidin (ET)-743 (1) is a natural product isolated from
the marine tunicate Ecteinascidia turbinata,1 which 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 the meager
availability from natural sources and the unique mechanism
of action of this drug3 have made this substance a very
attractive and important synthetic target.
In addition to Et-743, the structurally related safracins,8
saframycins,9 and renieramycins10 are also potent antitumor
antibiotics that contain densely functionalized tetrahydroiso-
(2) (a) Zelek, L.; Yovine, A.; Etienne, B.; Jimeno, J.; Taamma, A.;
Mart´ın, C.; Spielmann, M.; Cvitkovic, E.; Misset, J. L. Ecteinacidin-743 in
taxane/Antracycline pretreated advanced/metastatic breast cancer patients:
preliminary results with the 24 h continuous infusion Q3 week schedule,
presented at the American Society of Clinical Oncology, 36th Annual
Meeting, New Orleans, May 20-23, 2000; Abstract number 592. (b)
Delaloge, S.; Yovine, A.; Taamma, A.; Cottu, P.; Riofrio, M.; Raymond,
E.; Brain, E.; Marty, M.; Jimeno, J.; Cvitkovic, E.; Misset, J. L. Prelim-
inary evidence of activity of Ecteinacidin-743 (ET-743) in heavily pre-
treated patients with bone and soft tissue sarcomas, presented at the
American Society of Clinical Oncology, 36th Annual Meeting, New Orleans,
May 20-23, 2000; Abstract number 2181. (c) Le Cesne, A.; Judson, I.;
Blay, J. Y.; Radford, J.; an Oosterom, A.; Lorigan, P.; Rodenhuis, E.;
Donato Di Paoula, E.; Van Glabbeke, M.; Jimeno, J.; Verweij, J. Phase II
of ET-743 in advance soft tissue sarcoma in adult: a STBSG-EORTC
trial, presented at the American Society of Clinical Oncology, 36th
Annual Meeting, New Orleans, May 20-23, 2000; Abstract number 2182.
(d) Aune G. J.; Furuta T.; Pommier Y. Anti-Cancer Drugs 2002, 13, 545-
555.
The first total synthesis of ET-743 was accomplished by
Corey and co-workers.4 Later, Corey, Schreiber, and co-
workers prepared a simpler synthetic analogue of ET-743
(phthalascidin, Pt-650) that exhibited virtually the same
cytotoxity as the natural product.5 In 2000, a semisynthesis
of Et-743 from cyanosfracin B was described,6 and more
recently, a total synthesis of ET-743 was accomplished by
Fukuyama and co-workers.7
(1) (a) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson,
G. R.; Perun, T. J.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.;
Seigler, D. S. J. Nat. Prod. 1990, 53, 771-792. (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, 4512-4515. (c) Wright, A. E.; Forleo, D.
A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O.
J. J. Org. Chem. 1990, 55, 4508-4512. (d) Guan, Y.; Sakai, R.; Rinehart,
K. L.; Wang, A. H.-J. J. Biomol. Struct. Dyn. 1993, 10, 793-818.
(3) (a) Jin, S.; Gorfajn, B.; Faircloth, G.; Scotto, K. W. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 6775-6779 (b) Minuzzo, M.; Marchini, S.; Broggini,
M.; Faircloth, G.; D’Incalci, M.; Mantovani, R. Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 6780-6784.
(4) Corey, E. J.; Gin, D. Y.; Kania, R. J. Am. Chem. Soc. 1996, 118,
9202-9203.
(5) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl.
Acad. Sci. U.S.A. 1999, 96, 3496-3501.
10.1021/ol034575n CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/17/2003

quinoline ring systems constituted from similar amino acid
components. As part of a program directed toward efficient,
asymmetric total syntheses of these substances and mecha-
nistically inspired analogues for biochemical and biological
evaluation,11 we report here a potentially general and concise
Scheme 1. Retrosynthetic Analysis of Et-743
chiral amino phenol 9 would be subjected to a Pictet-
Spengler reaction to form tetrahydroisoquinoline 8 that
embodies all the requisite functionality to tackle the planned
asymmetric synthesis of Et-743 and bioxalomycin. We have
previously reported a racemic model study along these lines11
and now describe an asymmetric approach that specifically
provides the western half of Et-743 in the optically pure form.
In a separate report, we described the asymmetric synthesis
of the amino acid component (18).12 Herein, we describe an
asymmetric synthesis of the tetrahydroisoquinoline 8 that
represents the “Western” sector of Et-743 and the coupling
of these two fragments culminating in the construction of
the pentacyclic core of the ecteinascidin, saframycin, and
related alkaloids.
As shown in Scheme 2, the Staudinger reaction13 was
accomplished by condensing benzylamine with aldehyde 10
in refluxing benzene to afford the corresponding imine in
quantitative yield. The ketene of the optically pure acid
chloride 12 was prepared at -78 °C by the addition of
triethylamine and the benzyl imine obtained from 10 was
added and the reaction warmed to 0 °C, which afforded, after
workup, â-lactam 13 in excellent yield.
Figure 1. Structures of Et-743, safracins, saframycin A, and
jorumycin.
method to construct densely functionalized pentacyclic
tetrahydroisoquinoline ring systems that represent the “west-
ern” sector of Et-743 that should prove useful for the
asymmetric total synthesis of several members of this family
of natural products and congeners. Our approach is based
on the use of sequential asymmetric Staudinger and Pictet-
Spengler cyclization reactions.11
Our retrosynthetic strategy for Et-743 is illustrated in
Scheme 1. It was anticipated that the Staudinger reaction
between an imine derived from aldehyde 10 and a chiral
N-protected ketene would afford the cis-relationship at C-3
and C-4 (ecteinascidin numbering). After removal of the
chiral auxiliary and deprotection of the phenolic residue, the
(6) 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,
16, 2545-2548.
(7) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T, J. Am. Chem. Soc. 2002, 124, 6552-6554.
(8) (a) Ikeda, Y.; Idemoto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.;
Asao, T.; Munakata, T. J. Antibiot. 1983, 36, 1279-1283. (b) Ikeda, Y.;
Matsuki, H.; Ogawa, T.; Munakata, T. J. Antibiot. 1983, 36, 1284-1289.
(9) Arai, T.; Takahashi, K.; Kubo, A.; Nakahara, S. Experientia 1980,
36, 1025-1026.
Reductive removal of the chiral auxiliary and the benzyl
ether was accomplished by hydrogenolysis over Pd(OH)2 to
afford the corresponding amino phenol, which upon treatment
with methylglyoxylate afforded 14 in 84% yield as a single
stereoisomer.14 The relative stereochemistry of this substance
was determined by comparison of 1H NMR coupling
constants to a related racemic substance for which an X-ray
crystal structural analysis on a Pictet-Spengler cyclization
(10) (a) Frincke, J. M.; Faulkner, D. J. J. Am. Chem. Soc. 1982, 104,
265-269. (b) He, H.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5822-5824.
(c) Davidson, B. S. Tetrahedron Lett. 1992, 33, 3721-3724. (d) Parameswa-
ran, P. S.; Naik, C. G.; Kamat, S. Y.; Pramanik, B. N. Ind. J. Chem. 1998,
37B, 1258-1263. (e) Fontana, A.; Cavaliere, P.; Wahidulla, S.; Naik, C.
G.; Cimino, G. Tetrahedron 2000, 56, 7305-7308.
(12) Jin, W.; Williams, R. M. Unpublished results.
(13) Matsui, S.; Hashimoto, Y.; Sago, K. Synthesis 1998, 1161-1166.
(14) It should be noted that the free phenol was found to be essential
for a successful Pictet-Spengler cyclization reaction to proceed. Related
substrates containing the methylenedioxy moiety or simple aryl methyl ethers
failed to afford the corresponding Pictet-Spengler products.
(11) Herberich B.; Kinugawa M.; Vazquez A.; Williams, R. M.
Tetrahedron Lett. 2001, 42, 543-546.
2096
Org. Lett., Vol. 5, No. 12, 2003

which afforded the phenolic amine 20 in 80% isolated yield.
Exposure of 20 to LiBEt3H in THF at 0 °C remarkably
furnished the desired pentacyclic compound 24 directly in
one step in 49% yield.
Scheme 2. Asymmetric Staudinger Sequence
Scheme 3
product has been secured.15 As expected, on the basis of our
previous racemic study, the relative stereochemistry of 14
at C-1 possessed the undesired anti-configuration.
Epimerization of the anti-carbomethoxy group of 14 with
DBU in THF at room temperature afforded a 75% yield of
the desired syn-isomer 15 plus 25% of recovered 14, which
could be readily separated and recycled. The secondary amine
of 15 was selectively protected by treatment with Boc2O in
ethanol and reduction of the carbomethoxy group to the
corresponding alcohol was accomplished by treatment with
LiBH4-MeOH in refluxing ether in excellent yield to
afforded 16 in 78% yield. Benzyl protection of both the
primary alcohol and the phenol was achieved by treatment
with NaH and BnBr in the presence of a catalytic amount
nBn4NI. Next, the Boc group was removed by treatment with
TMSOTf and lutidine to afford the tetrahydroisoquinoline
17 in 55% isolated yield.
The conversion of 20 into 24 is envisioned to proceed by
initial partial reduction of the â-lactam to the amine-
coordinated lithium complex 21 that obviates over-reduction
of the incipient aldehyde. Extensive experience on related
compounds in our hands and a search of the literature has
revealed that the reduction of â-lactams directly to aldehydes
is a synthetically challenging reaction for which few good
solutions exist.17 Elimination of benzylamine occurs spon-
taneously under the reaction conditions to afford the R,â-
unsaturated aldehyde 22 that subsequently suffers cyclization
of the secondary amine on the aldehyde to generate the key
iminium ion species 23. Regioselective intramolecular Pic-
tet-Spengler cyclization finally affords the pentacyclic
compound 24 without contamination of the alternative
regioisomer.18 The pentacyclic compound 24 contains the
olefinic moiety at C3-C4 (saframycin numbering) that is
flexibly poised for either saturation to the saframycins and
related compounds or functionalization at C-4 for closure
of the sulfur-containing macrocyclic ring of the ecteinasci-
The amino acid was converted into the corresponding acid
chloride by treatment with oxalyl chloride and then coupled
to the amine in the presence of DMAP to afford the peptide
19 in 84% yield.16 Both the Fmoc and TBS protecting groups
were removed in a single operation by treatment with TBAF,
(15) The relative stereochemistry of model compound i was secured by
X-ray analysis, confirming the trans-configuration at the C-1 position.
Comparison of 1H NMR data of the pre-Pictet-Spengler â-lactam used to
prepare i to that of 21 was used to establish the relative stereochemistry of
21.
(16) The coupling with the acid chloride 18 in the presence of DMAP
did not lead to detectable racemization.
(17) A search of the literature did not reveal any general methods for
the reduction of â-lactams to aldehydes. For a pertinent reference, see:
Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita, M.; Abe, R.
J. Org. Chem. 1991, 56, 5263-5277.
(18) In the Pictet-Spengler reaction, the regioselectivity of the observed
1
product was secured by H NMR nOe studies.
Org. Lett., Vol. 5, No. 12, 2003
2097

dins.19 The retention of the oxidation state of the C-4 carbon
atom (saframycin numbering) from the initial tricyclic
â-lactam should prove to be very versatile, particularly for
the ecteinascidins, since this was a difficult problem in the
Corey total synthesis approach,4 as well as the semisynthetic
approach to the ecteinascidins that was based on benzylic
C-4 oxidation of saframycin.6
intermediate and the approach outlined for the concise
asymmetric synthesis of the ecteinascidin, saframycin fami-
lies, and related alkaloids are currently under study in these
laboratories.
Acknowledgment. We gratefully acknowledge financial
support by the National Institutes of Health (Grant CA85419).
In summary, the optically pure, densely functionalized
pentacyclic tetrahydroisoquinoline 24 was prepared in 12
steps, with an overall yield of 12%. Efforts to utilize this
Supporting Information Available: Complete spectro-
scopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) All new compounds gave satisfactory spectroscopic and analytical
data consistent with the assigned structures (see Supporting Information).
OL034575N
2098
Org. Lett., Vol. 5, No. 12, 2003