Selective synthesis of bissteroidal compounds by multifold Heck reactions

Article abstract of DOI:10.1055/s-2001-12438

Multifold Heck reactions of a hexahydro-1H-indene and a dibromoterephthalaldehyde derivative are used for the synthesis of bissteroidal compounds with a common ring A as simplified analogs of cephalostatins.

Full text of DOI:10.1055/s-2001-12438

560
LETTER
Selective Synthesis of Bissteroidal Compounds by Multifold Heck Reactions
Lutz F. Tietze,* Wolf-Rüdiger Krahnert
Institute for Organic Chemistry, Georg-August University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49-5 51/39 94 76; E-mail: ltietze@gwdg.de
Received 10 January 2001
Abstract: Multifold Heck reactions of a hexahydro-1H-indene and
a dibromoterephthalaldehyde derivative are used for the synthesis
of bissteroidal compounds with a common ring A as simplified an-
alogs of cephalostatins.
Key words: cephalostatin, marine natural products, Heck reaction,
palladium, steroids
In 1988, Petit et al. isolated the unusual dimeric steroid
derivative cephalostatin 1 1 from the marine worm Ceph-
alodosicus Gilchristi.1 It shows a remarkably high cyto-
static activity with a GI50-value of about 2.20 10-9 M in an
in vitro screening against the NCI 60 human cancer cell
line panel. In view of this, synthesis of cephalostatins has
been the focus of a number of recent studies.2 In 1998,
Fuchs et al. have reported the first total synthesis of 1.3
Scheme 1
This approach had the advantage that unsymmetrical ana-
logs of 1 could also be prepared.6
Reaction of 7a with ethylene glycol gave the monoacetal
7b.7 Corey-Fuchs reaction8 followed by selective debro-
mination with Bu3SnH9 selectively furnished the (Z)-2-
bromoethenylbenzene 9 in 80% overall yield. Heck reac-
tion of 9 with the hexahydro-1H-indene 5 afforded the in-
denylethenylbenzene 10 in 41% yield. The bond
formation occurred exclusively at C-4 in 5 with complete
facial selectivity anti to the angular methyl group. Neither
reaction at C-5 nor formation of the homo coupled prod-
Figure 1
uct of 9 or formation of diastereoisomers of 5 was ob-
served.
For the introduction of a second molecule of hexahydro-
1H-indene 5 the acetal moiety in 10 was cleaved and the
obtained aldehyde was transformed into the (Z)-2-bro-
movinylbenzene derivative 11 in 59% yield again using a
sequence of a Corey-Fuchs8 reaction and selective debro-
mination.9 Heck reaction of compound 11 with 5 then
yielded the desired diindenylethenylbenzene 3 (47%)
again in a complete stereo- and regioselective way.
Considering its biological activity and its unusual bisste-
roidal structure as well as the lack of knowledge of its
mode of action, we became interested in the synthesis of
1 and its analogs. Toward this end, we now report a facile
convergent strategy by which a simplified analog of 1, in
which the central octahydrophenazine moiety is replaced
by a benzene ring, can be readily constructed through two-
fold intramolecular Heck reaction4 of the diindenylethen-
ylbenzene 3 (Scheme 1). Retrosynthetic analysis of 3 led
to the tetrafunctionalized benzene 4 and the hexahydro-
1H-indene 5, which can be obtained in a few steps from
the Hajos-Wiechert-Keton 6.5 An intended conversion of
compound 4 with 5 to give the analog 2 in a fourfold Heck
reaction did not work due to the sensitivity of 4. Therefore
9 was used as a substrate for the first Heck reaction, which
was obtained from dibromoterephthalaldehyde 7a via 8.
The following twofold intramolecular Heck reaction of 3
to give analog 2 required a precise control of the reaction
time and temperature. Thus when 3 was reacted with cat-
alytic amounts of the palladacycle 1610 at 130-140 °C for
1.5 hours 2 could be obtained in 80% yield. The conver-
sion proceeded with high selectivity leading to the exclu-
sive formation of the unusual cis-annelation of both the
newly generated rings.
Synlett 2001, No. 4, 560–562 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Selective Synthesis of Bissteroidal Compounds
561
15. The high chemoselectivity in the homogenous hydro-
genation of 2 is probably due to a conformational effect in
2 where the angular 8a- and 16a-methyl groups shielded
the - and -face of the 7,8- and 15,16-double bonds. The
cis-orientation of the rings B, C and E, F in 12 was con-
firmed by a NOESY experiment and the structure of 14 by
X-ray crystallography.11
The present synthesis allows a short and efficient entry to
structural simplified analogs of 1. Application of this
method to different arenes and indenes should enable the
preparation of symmetrical as well as unsymmetrical
cephalostatin analogs, that are not accessible from natural
steroids.
Typical procedure for the preparation of 2: A solution of 3
(100 mg, 1.43 10-4 mol), nBu4NOAc (215 mg, 7.14 10-4 mol)
and trans-di( -acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalla-
dium(II)10 16 in DMF/CH3CN/H2O (1/1/0.2, 5 mL) was heated for
1.5 h at 130-140 °C in a preheated oil bath. After cooling, water
(15 mL) was added and the reaction mixture was extracted with
Et2O (2 20 mL). The organic phase was washed with brine and
dried over Na2SO4. Removal of the solvent and chromatographic
purification (pentane/CH2Cl2 = 5/1) yielded 2 (60 mg, 80%) as a co-
lourless oil. [ ]D20 = -39.0 (c = 0.2 in CHCl3); 1H NMR (500 MHz,
CDCl3, 25 °C): = 0.9 (s, 3H; CH3), 1.1 (s, 9H; OC(CH3)3), 1.4 -
1.6 (m, 3H; CHa, CH2), 1.7 -1.9 (m, 2H; CHb, CHa), 2.6 -2.7 (m, 1H;
3
3
CHb), 3.5 (dd, 1H, J (H,H) = 8.7 Hz, J (H,H) = 6.6 Hz; CH), 3.7
(dd, 1H, 3J (H,H) = 5.6 Hz, 3J (H,H) = 4.4 Hz; CH), 5.8 (dd, 1H, 3J
(H,H) = 9.6 Hz, 3J (H,H) = 5.9 Hz; CH), 6.0 (d, 1H, 3J (H,H) = 8.7
Hz; CH), 6.1 (dd, 1H, 3J (H,H) = 10.0 Hz, 3J (H,H) = 4.4 Hz, CH),
6.3 (d, 1H, 3J (H,H) = 9.6 Hz; CH), 6.9 (s, 1H, Aryl-CH); 13C NMR
(75 MHz, CDCl3, 25 °C): = 14.9 (CH3), 22.8 (CH2), 28.7
(OC(CH3)3), 31.9 (CH2), 33.9 (CH), 37.5 (CH), 41.8 (CH), 44.7 (C),
72.3 (OC(CH3)3), 76.2 (CH), 125.0 (Aryl-CH), 125.3 (Vinyl-CH),
128.8 (Vinyl-CH), 129.2 (Vinyl-CH), 131.8 (Aryl-C), 134.6 (Aryl-
C), 135.9 (Vinyl-CH); HRMS: calculated for C38H50O2 (M+):
538.3810, found: 538.3810.
Acknowledgement
Scheme 2 [a] 2 equiv CBr4, 4 equiv PPh3, CH2Cl2, -20 °C, 0.5 h;
[b] 10 equiv HOCH2CH2OH, pTsOH, toluene, reflux, 1.5 h, 81%
(two steps); [c] 4 mol% Pd(PPh3)4, 1.1 equiv HSnBu3, toluene, r.t., 1
h, 98%; [d] 9/5 = 4/1, 10 mol% Pd(OAc)2, 20 mol% PPh3, 8 equiv
nBu4NOAc, DMF/CH3CN/H2O = 1/1/0.2, 60 °C, 16 h, 41%; [e]
80% HOAc, 80 °C, 2 h, 74%; [f] 2 equiv CBr4, 4 equiv PPh3,
CH2Cl2, 0 °C, 0.5 h, 90%; [g] 4 mol% Pd(PPh3)4, 1.1 equiv HSnBu3,
toluene, r.t., 2 h, 88%; [h] 11/5 = 1/2, 10 mol% Pd(OAc)2, 20 mol%
PPh3, 1 equiv nBu4NCl, 2.5 equiv K2CO3, DMF/CH3CN/H2O = 1/1/
0.2, 60 °C, 5 h, 47%; [i] 5 mol% 16, 5 equiv nBu4NOAc, DMF/
CH3CN/H2O = 1/1/0.2, 130-140 °C, 1.5 h, 80%; [j] 10 mol% 10%
Pd/C, H2, 3 bar, EtOAc, r.t., 16 h, 80%; [k] 2 equiv TMSI, CH2Cl2,
r.t., 18 h, 90%; [l] 10 mol% (PPh3)3RhCl, H2, 3 bar, EtOAc/
MeOH = 1/1, r.t., 13 h, 70%; [m] 2 equiv TMSI, CH2Cl2, r.t., 18 h,
77%.
We thank the Deutsche Forschungsgemeinschaft (Sonderfor-
schungsbereich 416) and the Fonds der Chemischen Industrie for fi-
nancial support. We also thank Schering AG and Degussa AG for
generous gifts of chemicals.
References and Notes
(1) a) Petit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.;
Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.;
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6828. b) Drögemüller, M.; Flessner, T.; Jautelat, R.; Scholz,
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L. J. Am. Chem. Soc. 1998, 120, 692.
The bissteroidal arene 2 could be further manipulated in
several ways. Hydrogenation with 10% Pd on charcoal led
to analog 12, which was transformed into the diol 13 using
trimethyliodosilane (TMSI). On the other hand, hydro-
genation of 2 using the Wilkinson catalyst yielded analog
14, which was again deprotected with TMSI to give diol
(4) a) Nöbel, T.; Spescha, M.; Tietze, L. F. Angew. Chem. Int. Ed.
Engl. 1996, 35, 2259. b) Nöbel, T.; Spescha, M.; Tietze, L. F.
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L. F. Tietze, W.-R. Krahnert
LETTER
(11) Crystallographic data for 14 have been deposited with the
(6) Winterfeldt, E. Pure Appl. Chem. 1999, 71, 1095.
(7) 7b was obtained in 35% yield by reaction of 2,5-dibromo-
terephthalaldehyde 7a with catalytic amounts of p-TsOH and
1 equiv ethyleneglycol in toluene under reflux together with
26% of the diacetal.
(8) a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 14, 3769.
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Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC-148318. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax +44 1223 336 033;
deposit@ccdc.cam.ac.uk).
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Article Identifier:
1437-2096,E;2001,0,04,0560,0562,ftx,en;G00401ST.pdf
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Synlett 2001, No. 4, 560–562 ISSN 0936-5214 © Thieme Stuttgart · New York