Enantioselective synthesis of saframycin A and evaluation of antitumor activity relative to ecteinascidin/saframycin hybrids.

Article abstract of DOI:10.1021/ol990553i

[formula: see text] A short synthesis of saframycin A is described which begins with a readily available intermediate previously utilized for the total synthesis of ecteinascidin 743. A key step in this synthesis is the use of 1-fluoro-3,5-dichloropyridin

Full text of DOI:10.1021/ol990553i

ORGANIC
LETTERS
1999
Vol. 1, No. 1
75-77
Enantioselective Synthesis of
Saframycin A and Evaluation of
Antitumor Activity Relative to
Ecteinascidin/Saframycin Hybrids
Eduardo J. Martinez and E. J. Corey*
HarVard UniVersity, Department of Chemistry and Chemical Biology,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received April 1, 1999
ABSTRACT
A short synthesis of saframycin A is described which begins with a readily available intermediate previously utilized for the total synthesis
of ecteinascidin 743. A key step in this synthesis is the use of 1-fluoro-3,5-dichloropyridinium triflate to oxidize a phenolic ring to a 1,4-
benzoquinone unit while simultaneously cleaving a methoxymethyl ether of a different phenolic ring to the corresponding phenol (4 f 5). The
common intermediate (2) for the synthesis of saframycin A (1) and ecteinascidin 743 also allowed the synthesis of two hybrids of these
structures (6 and 7). Whole cell bioassays for antitumor activity using lung, colon, melanoma, and prostate-derived tumor cell lines allowed
a clear correlation of structure with biological activity in this series.
Ecteinascidin 743,1 an exceedingly potent antitumor agent
which is currently undergoing phase II clinical trials, has
recently been synthesized by a process2 that is being applied
for the preparation of clinical material. This paper describes
a short synthesis of the structurally related antitumor agent
saframycin A (1)3 from an intermediate which was utilized
in the synthesis of ecteinascidin 743, thus making available
a common route for producing both saframycin- and ectein-
ascidin-type compounds. Syntheses of both racemic and
natural forms of saframycin A have previously been re-
ported.4 In addition, we describe herein the synthesis of two
structural hybrids of ecteinascidins and saframycins and the
evaluation of antitumor activity for these substances relative
to ecteinascidin 743 (Et 743) and saframycin A.
(1) (a) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson,
G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L.
S.; Seigler, D. S.; Li, L. H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.;
Ga¨de, G. J. Nat. Prod. 1990, 53, 771. (b) Rinehart, K. L.; Sakai, R.; Holt,
T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield,
L. S. Pure Appl. Chem. 1990, 62, 1277. (c) 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) Wright, A. E.; Forleo, D. A.;
Gunawardana, P. G.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J.
Org. Chem. 1990, 55, 4508. (e) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang,
A. H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456. (f) Sakai, R.; Jares-
Erijman, E. A.; Manzanares, I.; Elipe, M. V. S.; Rinehart, K. L. J. Am.
Chem. Soc. 1996, 118, 9017.
(2) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118,
9202.
10.1021/ol990553i CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

Scheme 1. Synthesis of Saframycin A (1)
The pathway to saframycin A from the Et 743 intermediate
in methylene chloride in the presence of a catalytic amount
of PdCl2(PPh3)2. A novel oxidation was used to convert the
phenol 4 to the corresponding 1,4-benzoquinone. Although
1-fluoro-3,5-dichloropyridinium triflate is generally used as
a reagent for electrophilic fluorination,7 it can serve also as
an electron acceptor and as such effects the oxidation of
phenol 4 to 1,4-benzoquinone and the concomitant cleavage
of the methoxymethyl (MOM) protecting group to form 6
in a single step under mild conditions (CH2Cl2 solution at 0
°C for 2 h). One possible explanation of the facile MOM
protecting group cleavage which is consistent with the
isolation of phenol 5 rather than its further oxidation product-
(s) is the occurrence of the sequence:
2 is outlined in Scheme 1. The phenolic function of 2 was
protected as the allyl ether, and the tert-butyldiphenylsilyl
group was cleaved with tetra-n-butylammonium fluoride to
generate a primary alcohol which was converted via the
corresponding tosylate (toluenesulfonic anhydride, diisopro-
pylethylamine, and 4-(dimethylamino)pyridine) to the azide
3 by displacement using LiN3 as nucleophile in dimethyl-
formamide at 70 °C. The azide 3 was transformed into the
phenolic pyruvamide 4 by the sequence (1) reduction of azide
to primary amine with dithiothreitol and triethylamine in
methanol at 23 °C,5,6 (2) N-acylation with pyruvyl chloride
and 4-(dimethylamino)pyridine in CH2Cl2, and (3) deallyla-
tion by treatment with tri-n-butyltin hydride and acetic acid
(a) ROCH2OCH3 f ROCHFOCH3
(3) (a) Arai, T.; Takahashi, K.; Kubo, A. J. Antibiot. 1977, 30, 1015.
(b) Arai, T.; Takahashi, K.; Nakahara, S.; Kubo, A. Experientia 1980, 36,
1025. For reviews on the saframycins, see: (a) Arai, T.; Kubo, A. In The
Alkaloids Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press:
New York, 1983; Vol. 21, Chapter 3. (b) Remers, W. A. In The Chemistry
of Antitumor Antibiotics; Wiley: New York, 1988; Vol. 2, Chapter 3.
(4) (a) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am.
Chem. Soc. 1990, 112, 3712. (b) Myers, A. G.; Kung, D. Book of Abstracts,
216th National Meeting of the American Chemical Society, Boston, MA;
American Chemical Society, Washington, DC, 1998; Abstract ORGN0501.
(5) (a) Staros, J. V.; Bayley, H.; Standring, D. N.; Knowles, J. R.
Biochem. Biophysic. Res. Commun. 1978, 80, 568. (b) Bayley, H.; Standring,
D. N.; Knowles, J. R. Tetrahedron Lett. 1978, 39, 3633.
(b) ROCHFOCH3 + H2O f ROH + HCOOCH3
Such a pathway implies that 1-fluoro-3,5-dichloropyridinium
triflate might be a generally useful reagent for the selective
cleavage of MOM ethers. This point is under investigation
and will be reported separately.
(7) (a) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,
27, 4465. (b) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.;
Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563. (c) Lal, G. S.;
Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737.
(6) Hydrogen sulfide in pyridine was less effective for the azide f amine
reduction, see: Adachi, T.; Yamada, Y.; Inoue, I. Synthesis 1977, 45.
76
Org. Lett., Vol. 1, No. 1, 1999

Selective O-methylation of 5 to form 6 was carried out
using trimethylsilyldiazomethane (which was far more ef-
ficacious than diazomethane itself). Catalytic oxidation of 6
in a THF solution using dioxygen and a catalytic amount of
cobalt bis-salicylidineethylenediamine complex (salcomine)
provided saframycin A (1) cleanly.8
The antitumor activities of 1, 6, 7, Et 743, and phthalas-
cidin (Pt 650, the most active of a series of synthetic Et 743
analogues)9 were determined using four human cancer cell
lines with the results shown in Table 1. A number of
The A-ring monoquinone 6 can be regarded as a penta-
cyclic hybrid of ecteinascidin and saframycin structures. In
connection with the correlation of antitumor activity of
saframycin and ecteinascidin type compounds with this
structure, we decided to evaluate compound 6 and also the
alternative Et 743-saframycin hybrid 7, which has the
Table 1. Antiproliferative Activities of Et 743, Saframycin A, and
Analogues (IC50 (nM))
A-549
(lung)
HCT 116
(colon)
A 375
PC-3
compd
(melanoma)
(prostate)
7
6
1
16
>180
430
3.4
47
39
1.2
26
30
3.6
44
27
Et 743
Pt 650
1.0
0.95
0.50
0.38
0.15
0.17
0.70
0.55
important points emerge from these data. It is clear that
saframycin A is at least 2 orders of magnitude less active
than ecteinascidin 743 or phthalascidin. Comparison of the
A-ring monoquinone 6 and the analogous nonquinone
structure 7 reveals that a quinoid A-ring lowers potency
relative to the benzenoid A-ring counterpart by about 10-
fold. These results underscore the importance of the ben-
zenoid A-ring to the superior antitumor activity of Et 743
and Pt 650.
characteristic saframycin A appendage on ring B but is
nonquinoid at rings A and E. This compound was readily
prepared from phenol 4 in 64% overall yield by acetylation
(Ac2O, DMAP in CH2Cl2 at 23 °C) and MOM ether cleavage
(4:1:1 CF3CO2H-H2O-THF at 23 °C for 11 h).
Acknowledgment. This work was assisted by a grant
from the National Institutes of Health and a graduate student
fellowship from Schering Plough.
(8) De Jonge, C. R. H. I.; Hageman, H. J.; Hoentjen, G.; Mus, W. J.
Organic Syntheses; Wiley: New York, 1988; Collect Vol. VI, p 412.
(9) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl.
Acad. Sci. U.S.A. 1999, 96, 3496.
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