A synthetic approach towards stoloniferones: Synthesis of 11-acetyl-24-desmethyl-stoloniferone C

Article abstract of DOI:10.1016/S0040-4039(00)02306-6

The synthesis of 11α-acetoxy-5β,6β-epoxycholest-2-en-1-one, a compound containing the nuclear functionalities of the stoloniferones, is described starting from dihydrocholesterol.

Full text of DOI:10.1016/S0040-4039(00)02306-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1575–1577
A synthetic approach towards stoloniferones: synthesis of
11-acetyl-24-desmethyl-stoloniferone C
Marcello Di Filippo, Irene Izzo, Sandra Raimondi, Francesco De Riccardis* and Guido Sodano*
Dipartimento di Chimica, Universita` di Salerno, Via S. Allende, Baronissi-84081, Salerno, Italy
Received 12 September 2000; revised 7 December 2000; accepted 14 December 2000
Abstract—The synthesis of 11a-acetoxy-5b,6b-epoxycholest-2-en-1-one, a compound containing the nuclear functionalities of the
stoloniferones, is described starting from dihydrocholesterol. © 2001 Published by Elsevier Science Ltd.
The Okinawan soft coral Clavularia viridis is a marine
invertebrate from which a remarkable array of bioac-
tive secondary metabolites has been obtained. Among
them the clavulones,1 powerful antitumor prostanoids,
the stoloniolides,2 structurally unique steroids, the
stoloniferones,3 such as the cytotoxic stoloniferon C 1
and its acetylated derivative 2,4 can be listed. It is
interesting to point out that most of the steroids iso-
lated from Clavularia viridis4,5 possess an epoxy-enone
moiety, which is a current feature in some withanolides6
and has been known as an important partial structure
of cytotoxic solanoceus plant products.7
dihydrocholesterol 4 was converted into the expected
cholest-9(11)-en-3a-ol 6 via a three step process (77%
overall yield from 4 to 6).
Standard benzylation of 6 gave the D9(11)-steroidal ether
7. This was subjected to a highly stereoselective hydro-
boration-oxidation reaction9 (d.r.>95%, 1H NMR analy-
sis, 86% yield) to give the monobenzylated diol 8. The
equatorial nature of the alcoholic function at C-11 was
confirmed through unambiguous rationalization of the
1H NMR data of 8 which showed, for the C-11 methine
proton, a ddd (J=10.5, 10.5, 5.2 Hz) at l 3.91.
Described herein is the synthesis of 11a-acetoxy-5b,6b-
epoxycholest-2-en-1-one 3, that is the 11-acetyl-24-
Silylation of the hindered C-11 hydroxy group with
tert-butyldimethylsilyl trifluoromethanesulfonate and
Pd-mediated debenzylation at C-3 afforded the monosi-
lylated diol 9 (83%, two steps).
desmethylstoloniferone
C
13 or the 24-desmethyl
analogue of the cytotoxic steroid 2.4
The synthesis of compound 3 began with the stereose-
lective functionalization of the C ring (Scheme 1). This
was easily achieved using the Breslow remote function-
alization methodology.8 Thus, commercially available
For the A and B ring functionalization we planned
to follow a well established procedure10a including a
selective quadruple dehydrogenation of 9, transforma-
tion of the resulting trienone in the 11a-[(tert-butyl-
dimethylsilyl)oxy]-cholest-5-en-1a,3b-diol following the
Barton method,10 and final elaboration of the re-
quired a,b-unsaturated ketone and b-epoxide function-
alities.
Keywords: Clavularia viridis; stoloniferones; marine metabolites;
steroids; cytotoxins.
* Corresponding authors.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02306-6

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M. Di Filippo et al. / Tetrahedron Letters 42 (2001) 1575–1577
Scheme 1. (a) 1.2 equiv. of m-iodobenzoic acid, 1.8 equiv. of PPh3, 1.8 equiv. of DEAD, THF, rt, 12 h, 100%; (b) 0.3 equiv. of
(C6H5CO)2O2, 1 equiv. SO2Cl2, CCl4, reflux, 2 h, then 10% KOH in MeOH, reflux, 2 h, 77%; (c) 4 equiv. of NaH, 4 equiv. of
BnBr, 0.5 equiv. of TBAI, THF, reflux, 16 h, 84%; (d) 3 equiv. catechol borane, 0.7 equiv. of LiBH4, THF, 0°C, 3 h then
NaOH/H2O2, 50°C, 12 h, 86%; (e) 2 equiv. of lutidine, 1.5 equiv. of TBSOTf, THF, 0°C, 1 h, 97%; (f) H2/Pd, EtOH:AcOH
(200:1), 12 h, 86%.
The dehydrogenation of the monosilylated diol 9
(Scheme 2) proved particularly difficult to achieve. The
recent palladium-catalysed method, with allyl diethyl
phosphate (ADP) and sodium carbonate,11 gave no
reaction. The use of 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ),12 furnished acceptable yields of the
expected trienone 10 (40–45% yield) only when the
reaction was performed with an excess of the oxidant (7
equivalents) and refluxing the reaction mixture in diox-
ane for 48 h.13 Treatment of 10 with alkaline hydrogen
peroxide gave stereoselectively only the expected a-
epoxydienone 11 whose stereochemistry was confirmed
by comparison with literature data.14
1a,3a,11a-triol 1315 was obtained. This was shown to
be epimeric at C-3 with the previously reported
cholesta-4,6-dien-1a,3b-diol.16 Finally a catalytic 1,4-
addition of hydrogen yielded the key intermediate
cholest-5-en-1a,3a,11a-triol 14, which was shown to be
epimeric at C-3 with the 24-methylene-cholesta-
1a,3b,11a-triol, isolated by Djerassi from the soft coral
Sinularia dissecta.17
Additional confirmation of the C-3 epimeric relation-
ship in 14 and the natural sterol was obtained by
acetylating 14 (pyridine/Ac2O, overnight, 91% yield)
and comparing the 1H NMR spectral data of the
3b,11a-diacetylated natural sterol 15, synthesized by
Djerassi,17 with the 3a,11a-diacetylated synthetic sterol
16 (3b,11a-diacetylated natural; 3h-H: l 5.00, m;
3a,11a-diacetylated synthetic; 3i-H: l 5.10, bs).
Birch reduction of 11, in order to obtain the expected
1a,3b-diol 12, which is a common practice at this
stage,10 invariably induced extensive decomposition of
the starting material. We attributed this unexpected
failure to the presence of the C-11 functionality. Desily-
lation of the secondary alcohol at C-11, to reduce the
steric hindrance on C-1, did not prove useful.
The diacetate 16 was subjected to a pyridinium dichro-
mate oxidation to provide the ketone 17 in 75% yield
(Scheme 4). The latter was easily transformed into the
2,5-dien-1-one 18, using Al2O3 in refluxing benzene.18
Epoxidation of 18 with m-CPBA18 gave a 1:1.6 mixture
of two isomeric19 5,6-epoxides, which were separated by
flash chromatography. The minor and less polar
product was the desired 5b,6b target epoxide 3.20
In view of these discouraging results we turned our
attention to a different two step reductive method
(Scheme 3). Thus, on treating the a-epoxydienone 11
with lithium aluminium hydride, cholesta-4,6-dien-
Scheme 2. (a) 7 equiv. DDQ, dioxane, reflux, 48 h, 40–45%; (b) H2O2/NaOH, MeOH, 36 h, 60%.
Scheme 3. (a) 6 equiv. LiAlH4, THF, reflux; (b) H2/Pt, EtOH, rt, 6 h, 30%, two steps.

M. Di Filippo et al. / Tetrahedron Letters 42 (2001) 1575–1577
1577
,
Scheme 4. (a) 2 equiv. of PDC, 3 A molecular sieves, CH2Cl2, rt, 6 h, 75%; (b) Al2O3, benzene, reflux, 80%; (c) 2 equiv. MCPBA,
0.1 equiv. NaHCO3, CH2Cl2, 0°C, 5 h, 3 (28%); 19 (45%).
In summary the synthesis of A/B/C rings of stolonifer-
ones has been reported for the first time. In vitro
biomimetic studies on the formation of stoloniolides2
are currently underway.
5640–5642.
12. This method works relatively well when D4- or D5-3-alco-
hols or ketones are used as starting materials; see: Organic
Reactions in Steroid Chemistry; Fried, J.; Edwards, J. A.,
Eds.; Van Nostrand Reinhold Company: New York, 1972;
Vol. 1, pp. 308–316.
13. When different reaction conditions were used extensive
decomposition or the presence of the 11a-[(tert-
Acknowledgements
butyldimethylsilyl)oxy]-cholesta-1,4-diene-3-one
invariably observed.
14. (a) Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe, T.;
Curci, R. J. Org. Chem. 1992, 57, 2182–2184; (b) Oshida,
J.; Okamoto, M.; Azuma, S. Tetrahedron: Asymmetry
1999, 10, 2337–2342. See also Ref. 16.
were
This work has been supported by the MURST (PRIN
‘Chimica dei Composti Organici di Interesse
Biologico’).
15. Triol 13: [h]=+67 (c=1.0, CHCl3); EIMS, m/z: 562 [M]+;
1H NMR (CDCl3, 400 MHz): l 5.98 (1H, dd, J=9.8, 2.2
Hz, H-6), 5.68 (1H, d, J=4.9 Hz, H-4), 5.60 (1H, bd, J=9.8
Hz, H-7), 4.21 (1H, bs, H-1), 4.09 (1H, bs, H-3), 4.02 (1H,
ddd, J=10.5, 10.5, 4.9 Hz, H-11), 0.97 (3H, s, H-19), 0.92
(3H, d, J=6.4 Hz, Me-21), 0.85 (6H, d, J=6.6 Hz, Me-26
and Me-27), 0.74 (3H, s, H-18); 13C NMR (CDCl3, 100
MHz): l 140.9, 130.4, 129.4, 125.0, 71.9, 67.6, 63.3, 55.8,
53.3, 51.1, 49.9, 43.4, 40.9, 39.4, 35.9, 35.6, 35.2, 32.5, 28.2,
27.9, 23.8, 23.7, 22.8, 22.5, 18.5, 17.8, 12.9.
16. Mitra, M. N.; Norman A. W.; Okamura, W. H. J. Org.
Chem. 1974, 39, 2931–2933. The reason for the opposite
stereoselectivity found for the LiAlH4 reduction of the
carbonyl at C-3 could be explained considering the effect
of the hindered silyl protecting group at C-11 on the
conformation of the A ring.
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