Synthetic study on ecteinascidin 743 starting from D-glucose

Article abstract of DOI:10.1055/s-1999-3161

During the course of synthetic study on ecteinascidin 743 (1), key intermediate 5 was prepared. Stereocontrolled synthesis of 5 from D-glucose was accomplished using incorporation of two nitrogen atoms and stereoselective addition of a phenol to an imine

Full text of DOI:10.1055/s-1999-3161

LETTER
1103
Synthetic Study on Ecteinascidin 743 Starting from D-Glucose
Atsushi Endo, Toshiyuki Kann, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, CREST, The Japan Science and Technology Corporation (ST),
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax+81-3-5802-8694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 14 April 1999
selective synthesis of this key intermediate, employing the
incorporation of two nitrogen atoms into D-glucose and
the addition of phenol to an imine.
Abstract: During the course of synthetic study on ecteinascidin 743
(1), key intermediate 5 was prepared. Stereocontrolled synthesis of
5 from D-glucose was accomplished using incorporation of two ni-
trogen atoms and stereoselective addition of a phenol to an imine as
key steps.
Our synthesis began with epoxide 6, available on multi-
gram scale from inexpensive D-glucose in five steps
(Scheme 2).8 Upon treatment with p-toluenesulfonamide
and Cs2CO3, epoxide 6 underwent smooth ring opening
followed by mesylation to give 7. Acidic hydrolysis of ac-
etonide 7 afforded a 3:2 mixture of diastereomers at the
anomeric position. Subsequent treatment with SnCl4 fur-
nished the desired a-isomer 8.9 Base-induced ring closure
of mesylate 8 and subsequent protection as a TBS ether
provided aziridine 9.
Key words: ecteinascidin 743, D-glucose, bicyclo [3.3.1] system,
imine
The ecteinascidins were isolated by Rinehart and co-
workers from the marine tunicate Ecteinascidia turbina-
ta.1,2 Their novel structure and extremely potent antitumor
activities have promoted extensive studies.3,4,5 The first of
these compounds to advance to clinical trials was ectein-
ascidin 743 (1). In this communication, we report our syn-
thetic approach to 1. We plan to construct this compound
from the pentacyclic framework 2, which is common to all
ecteinascidins (Scheme 1). An intramolecular ortho-addi-
tion of the phenol to an aldehyde will provide the B-ring
of 2.6 The C-ring should be accessible from amino alde-
hyde 3, since a similar ring closure was demonstrated in
our total synthesis of saframycin A.7 The dialdehyde 3
will be prepared by oxidative cleavage of the diol 4, which
should be readily derived from 5. The pentacycle 5 bears
four chiral centers at C1, C3, C11, and C13 as well as the ar-
omatic A- and E-rings of 1. Described herein is a stereo-
The Grignard reagent 13, precursor for the E-ring, was
prepared from 3-methylcatechol (10) in six steps (Scheme
3). Selective protection of 10 by TsCl, bromination of the
resulting phenol, and methylation gave bromide 11. After
the phenol protecting group of 11 was changed from the
tosylate to a MOM ether, the bromide 12 was converted to
Grignard reagent 13 by treatment with Mg in THF.
A copper-catalyzed ring opening of the aziridine 9 by
freshly prepared 13 gave 14 (Scheme 4). Following pro-
tection of sulfonamide 14 with the Boc group and cleav-
age of the TBS ether, the second nitrogen atom was
incorporated by conversion of the alcohol to a triflate and
Synlett 1999, No. 07, 1103–1105 ISSN 0936-5214 © Thieme Stuttgart · New York

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A. Endo et al.
LETTER
treatment with lithium azide, to yield 15. This displace-
ment did not proceed in the case of the b-anomer.10 After
sequential removal of the MOM ether and the BOC group,
regioselective bromination of the phenol provided p-bro-
mide 16. This bromide prevented any formation of the un-
wanted tetrahydroisoquinoline isomer in the next step.
The bicyclo [3.3.1] system was constructed by treating the
methoxy acetal 16 with TFA-H2O. The cyclization pro-
ceeded through an iminium-ion intermediate to afford 17
as a single isomer.11
Conversion of 17 into amino diol 18 was accomplished by
a three-step sequence involving protection of the phenol
as a methyl ether, deprotection of the benzyl ether, and hy-
drogenolysis of the azide group. The dehydrooxazinone
ring was introduced into 18 by regioselective aminolac-
tonization and subsequent Pb(OAc)4 oxidation of the
amine to provide acylimine 19. A TFA-induced intermo-
lecular addition of phenol 2012 to 19 provided 5. The reac-
tion occurred at the sterically less hindered convex face of
the tetracyclic imine 19 with complete diastereoselectivi-
ty. The stereochemistry at C1 of 5 was confirmed by 2D
NOESY spectroscopy. The strong NOE observed be-
tween the C3 and C5 protons proves that the E-ring must
occupy the b-face of the tetracyclic system. Therefore, 5
possesses the desired R configuration at C1 (Scheme 5).
References and Notes
(1) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.;
Kreifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem.
1990, 55, 4512.
(2) Sakai, R.; Jares-Erijman, E. A.; Manzanares, I.; Elipe, M. V.
S.; Rinehart, K. L. J. Am. Chem. Soc. 1996, 118, 9017.
(3) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, A. H. -J. Proc.
Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
In summary, we have successfully synthesized the key in-
termediate 5 from D-glucose with complete stereoselec-
tivty at four chiral centers.
Synlett 1999, No. 07, 1103–1105 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Study on Ecteinascidin 743 Starting from D-Glucose
(10) A similar difference of reactivity in the methyl D-
1105
(4) Guan, Y.; Sakai, R.; Rinehart, K. L.; Wang, A. H. -J.
J. Biomol. Struct. Dyn. 1993, 10, 793.
(5) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996,
118, 9202.
(6) Intramolecular ortho-addition of a phenol to an aldehyde
succeeded in the following simple model.
(7) For previous work on the synthesis of the saframycins:
(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) Saito,
N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org.
Chem. 1989, 54, 5391.
glucofuranoside derivatives has been reported: Fleet, G. W. J.;
Smith, P. W. Tetrahedron 1987, 43, 971.
(11) A similar Pictet-Spengler cyclization via an acyliminium was
performed in the total synthesis of the saframycins; ref 7b.
Cyclization proceeded exclusively to give the desired product.
(12) We prepared phenol 20 from 3,4-(methylenedioxy)phenol in
four steps: i) MOMCl, iPr2NEt, CH2Cl2, (91%); ii) n-BuLi,
(MeO)3B, THF; H2O2, (92%); iii) TMSCl, NaI, CH3CN,
(86%); iv) TsCl, iPr2NEt, CH2Cl2, (56%).
(8) Epoxide 5 was prepared from D-glucose in five steps through
a known procedure: Methods in Carbohydrate Chemistry,
Vol. II 190, Academic Press, New York 1963.
(9) Martin, O. R.; Kurz, K. G.; Rao, S. P. J. Org. Chem. 1987, 52,
2922.
Article Identifier:
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