A strategy for total synthesis of complex cardenolides

Full text of DOI:10.1021/jo961209r

6760
J . Org. Chem. 1996, 61, 6760-6761
verification of this general strategy through synthesis of
a cardenolide congener having 8,14 unsaturation.
A Str a tegy for Tota l Syn th esis of Com p lex
Ca r d en olid es
Wei Deng,1a Mark S. J ensen, Larry E. Overman,*
Paul V. Rucker, and J ean-Paul Vionnet1b
Department of Chemistry, 516 Physical Sciences 1,
University of California, Irvine, California 92697-2025
Received J une 27, 1996
The cardiac glycosides (digitalis), which are found in
a variety of plant species, are a large group of steroids
having a sugar residue at the 3â position.2 Cardiac
glycosides display a range of pharmacological activities,
and extracts from leaves of Digitalis lonata are exten-
sively used in the clinical treatment of congestive heart
failure.3 Cardenolides, the genins of cardiac glycosides,
differ from other steroids in having a â-oriented buteno-
lide ring at C17, a cis C/D ring fusion, and a hydroxy
substituent at C14. In addition, most cardenolides also
have a cis A/B ring fusion. The most complex cardeno-
lides, exemplified by strophanthidin (1) and ouabagenin
(2), contain two to four additional sites of oxidation at
A suitably protected A-ring fragment containing oxida-
tion at carbons 5 and 19 was prepared in high enan-
tiopurity as summarized in Scheme 1. Cyclohexenone
3, which is available on a large scale in one step from
1,3-cyclohexanedione,8 was reduced under carefully op-
timized conditions with BH3‚SMe2 in the presence of
oxazaborolidine catalyst 49 to provide the (S)-allylic
alcohol 5 in 98% yield and 92-94% enantiomeric excess
(ee).10,11 It was critical in this reduction to slowly add
BH3‚SMe2 to a cold (-25 °C) solution of 3 and 4 (0.1
equiv) or else significant amounts of the deoxygenated
alkene 6 were produced.12 Acetylation of 5 provided
sensitive acetate 7, which upon conversion to the ketene
silyl acetal derivative underwent smooth Ireland-
Claisen rearrangement at room temperature.13 The silyl
ester product was converted, without purification, to
methyl ester 8 by treatment with KF, K2CO3, and MeI
as a prelude to reduction to the primary alcohol.14 This
sequence for converting 5 to 8 could be accomplished on
a large scale in 77% overall yield. Reduction of 8 then
delivered alcohol 9, whose high ee (91%)15 confirmed that
the key Claisen rearrangement occurred with high ster-
eochemical fidelity. Finally, alcohol 9 was activated for
coupling by conversion to iodide 10.
carbons 1, 5, 11, and 19.2 The high degree of oxidation of
the steroid skeleton and the cis A/B and C/D ring fusions
render complex cardenolides challenging targets for total
synthesis. To date, nearly all synthetic accomplishments
in this area have been partial syntheses from steroid
starting materials.4,5 One of the most attractive features
of palladium-catalyzed methods for carbon-carbon bond
formation are their broad functional group compatibility.6
Attracted by this feature, and the propensity of intramo-
lecular Heck insertions to form cis-fused polycyclic
products, we have been developing a total synthesis
approach to complex cardenolides that features an in-
tramolecular Heck reaction to fashion the B ring and
establish the cis A/B ring fusion (eq 1).7 We report here
The starting material for construction of the C/D
fragment was enone 12, which can be prepared in three
steps and good yield from the (S)-Hajos-Parrish ketone
11 (Scheme 2).16 Protection of the carbonyl group of 1217
followed by reduction of the nitrile with DIBALH gave
aldehyde 13, which was converted to enone 14 in three
routine steps and 68% overall yield from 12. All attempts
(7) (a) For general reviews of the Heck reaction, see: Heck, R. F.
Org. React. (N.Y.) 1982, 27, 345. Meyer, F. E.; de Meijere, A. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379. (b) For recent reviews of aspects
of the intramolecular Heck reaction, see: Overman, L. E. Pure Appl.
Chem. 1994, 66, 1423. Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.;
Liu, F. Chem. Rev. 1996, 96, 365.
(1) Current addresses: (a) Sloan-Kettering Institute for Cancer
Research, 1275 York Ave., New York, NY, 10028. (b) SICPA, 2 Rue
De La Paix, Case Postale 3930, 1002 Lausanne, Switzerland.
(2) Fieser, L. F.; Fieser, M. Steroids; Reinhold: New York, 1959;
Chapter 20.
(3) Thomas, R.; Gray, P.; Andrew, J . Adv. Drug Res. 1990, 19, 312.
(4) (a) For a review of early pioneering partial syntheses see ref 2.
(b) For reviews of recent partial syntheses, see: Hanson, J . R. Nat.
Prod. Rep. 1993, 10, 313 and earlier reviews in this series. (c) For a
recent synthesis of digitoxigenin from an androstane, see: Kabat, M.
M. J . Org. Chem. 1995, 60, 1823.
(5) (a) A total synthesis of digitoxigenin, which represents the first
total synthesis of a cardenolide from nonsteroid starting materials,
has recently been accomplished: Stork, G.; West, F.; Lee, H. Y.; Isaacs,
R. C. A.; Manabe, S. J . Am. Chem. Soc. 1996, 118, in press. (b) For
total synthesis approaches from nonsteroid starting materials, see:
Daniewski, A. R.; Valenta, Z.; White, P. S. Bull. Pol. Acad. Sci., Chem.
1984, 32, 29. Stork, G.; Mook, R. J . Am. Chem. Soc. 1983, 105, 3720.
Daniewski, A. R.; Kabat, M. M.; Masnyk, M.; Wicha, J .; Wojciechowska,
W. J . Org. Chem. 1988, 53, 4855. Ruel, R.; Deslongchamps, P. Can. J .
Chem. 1992, 70, 1939. Rawal, V. H.; Iwasa, S. Abstracts of Papers;
204th National Meeting of the American Chemical Society, Washing-
ton, DC; American Chemical Society: Washington, 1992; ORGN 35.
(6) Tsuji, J . Palladium Reagents and Catalysts. Innovations in
Organic Synthesis; J ohn Wiley: New York, 1995.
(8) Smith, A. B., III; Dorsey, B. D.; Ohba, M.; Lupo, A. T., J r.;
Malamas, M. S. J . Org. Chem. 1988, 53, 4314.
(9) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh,
V. K. J . Am. Chem. Soc. 1987, 109, 7925. (b) Mathre, D. J .; Thompson,
A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J . D.; Corley, E. G.;
Grabowski, E. J . J . J . Org. Chem. 1993, 58, 2880. (c) Nikolic, N. A.;
Beak, P. Org. Synth. 1997, 94, in press.
(10) New compounds were fully characterized by 1H and 13C NMR,
IR, and MS analysis, while elemental composition was confirmed by
combustion analysis or high-resolution mass spectrometry.
(11) Determined by GLC analysis on a Cyclodex B capillary column.
(12) The ee of 5 was 96-98% when 0.5 equiv of oxazaborolidine 4
was employed.
(13) (a) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J .
Org. Chem. 1980, 45, 48. (b) For a recent review of the Ireland-Claisen
rearrangement, see: Pereira, S.; Srebnik, M. Aldrichim. Acta 1993,
26, 17.
(14) Ito, Y.; Higuchi, N.; Murakami, M. Tetrahedron Lett. 1988, 29,
5151.
(15) Determined by 1H NMR analysis of the Mosher ester deriva-
tive: Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(16) (a) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1984, 63, 26. (b)
Hajos, Z. G.; Parrish, D. R.; Oliveto, E. P. Tetrahedron 1968, 24, 2039.
(c) Caine, D.; Kotian, P. L. J . Org. Chem. 1992, 57, 6587.
S0022-3263(96)01209-1 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 20, 1996 6761
Sch em e 1
Sch em e 3
Sch em e 2
yield. The conjugated diene 18 (λmax 274 nm) was quite
sensitive to acid and, for example, was converted to
s-trans isomer 19 (λmax 251 nm) when left overnight in
unpurified CHCl3. The structure of pentacycle 18 was
secured by reaction with N-phenylmaleimide at 100 °C
to provide endo Diels-Alder adduct 20. This material
yielded crystals (mp 95-97 °C) suitable for X-ray analy-
sis, thus allowing unambiguous confirmation of the
expected cis stereochemistry of the A/B ring fusion.20
In summary, we have shown that an intramolecular
Heck reaction can be employed to form the basic skeleton
of complex cardenolides. Pentacycle 18 displays a cis A/B
ring fusion and oxidation at C5 and C19 along with
unsaturation at carbons 1, 11, and 14 that could conceiv-
ably be employed to incorporate additional oxidation
characteristic of complex cardenolides. The lability of the
diene moiety of 18, however, suggests that it would be
preferable to incorporate C14 oxygenation prior to the
central Heck reaction. The results of our investigations
of this latter strategy will be reported in due course.
Ack n ow led gm en t. This research was supported by
NIH NIGMS Grant No. GM-30859. We also thank NIH
for a NRSA postdoctoral fellowship for M.S.J . (HL-
09186) and the Swiss National Research Foundation for
a postdoctoral fellowship for J .-P.V. NMR and mass
spectra were determined at Irvine using instruments
acquired with the assistance of NSF and NIH shared
instrumentation programs. We are grateful to Drs.
J oseph Ziller and J ohn Greaves for their advice and
assistance with X-ray and mass spectrometric analyses.
to directly couple an enolate derivative of 14 with iodide
10 gave the desired dienone 16 in low yield. However,
the lithium salt of 1,1-dimethylhydrazone derivative 15
reacted smoothly with iodide 10 to provide 16 in 71%
yield after cleavage of the hydrazone group.18
Dienone 16 then was converted into trienyl triflate 17
in 83% yield by treatment with KHMDS and N-phenyl-
triflamide (Scheme 3). Triflate 17 initially was exposed
to Heck cyclization conditions that we had employed in
an earlier model study (10 mol % Pd(dppb) and excess
KOAc in N,N-dimethylacetamide at 120 °C).19 These
conditions provided none of the desired Heck product;
however, when the reaction was performed at 75 °C, a
single pentacyclic product 18 was isolated in 65-70%
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic and analytical data for new com-
pounds reported in Schemes 1-3 (11 pages).
J O961209R
(17) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(18) Corey, E. J ., Pearce, H. L. J . Am. Chem. Soc. 1979, 101, 5841.
(19) Laschat, S.; Narjes, F.; Overman, L. E. Tetrahedron 1994, 50,
347.
(20) Crystallographic data for this intermediate have been deposited
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.