A convenient synthesis of C-22 and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins.

Article abstract of DOI:10.1021/ol025580e

A simple transformation of the eight-carbon side chain of a natural spirostan sapogenin into the cephalostatin north 1 spiroketal moiety is described. This methodology, based on an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals,

Full text of DOI:10.1021/ol025580e

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1295-1297
A Convenient Synthesis of C-22 and
C-25 Stereoisomers of Cephalostatin
North 1 Side Chain from Spirostan
Sapogenins
Carmen Betancor,† Raimundo Freire,‡ Ine´s Pe´rez-Mart´ın,‡ Thierry Prange´,§ and
,‡
Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C.,
Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain,
Departamento de Qu´ımica Orga´nica, UniVersidad de La Laguna, Tenerife, Spain,
and LURE, UniVersite´ Paris-Sud, Paris, 91405 Orsay Cedex, France
esuarez@ipna.csic.es
Received January 18, 2002
ABSTRACT
A simple transformation of the eight-carbon side chain of a natural spirostan sapogenin into the cephalostatin north 1 spiroketal moiety is
described. This methodology, based on an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals, permits the synthesis
of C-22 and C-25 stereoisomers of the dioxaspiro[4.4]nonane cephalostatin ring system. The acid-catalyzed isomerization of the spirocenter
in the different isomers is studied.
Several marine alkaloid cephalostatins1 and ritterazines2 are
among the most potent cytotoxins ever isolated from a natural
source.3 They are formed by two steroidal units linked
through a pyrazine ring involving C2 and C3 of each
monomeric unit. In most of the cephalostatins (17 out of
19) the north steroidal eight-carbon side chain has been
transformed into a polyoxygenated (2S,4R,5S,9S)-2-hy-
droxymethyl-2,9-dimethyl-1,6-dioxaspiro[4.4]nonan-4-ol sub-
structure (see, for example, cephalostatin 1).
† Universidad de La Laguna.
‡ Instituto de Productos Naturales y Agrobiolog´ıa.
§ Universite´ Paris-Sud.
(1) (a) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.;
Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S.
J. Am. Chem. Soc. 1988, 110, 2006-2007. (b) Recent publication: Pettit,
G. R.; Tan, R.; Xu, J.-P.; Ichihara, Y.; Williams, M. D.; Boyd, M. R. J.
Nat. Prod. 1998, 61, 955-958 and references therein.
(2) Recent publication: Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J.
Org. Chem. 1997, 62, 4484-4491 and references therein.
(3) Pettit, G. R.; Xu, J.-P.; Williams, M. D.; Christie, N. D.; Doubek, D.
L.; Schmidt, J. M.; Boyd, M. R. J. Nat. Prod. 1994, 57, 52-63.
Their unique structure and biological activity have made
them an important synthetic target. The syntheses of several
10.1021/ol025580e CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/16/2002

of these natural products and analogues have been achieved,4
but despite efforts by several research groups, the mechanism
of action of these compounds remains unknown.5
Scheme 1a
Taking into account the SAR correlation of cephalostatins
and OSW-1,6 a related cholestane glycoside isolated from a
terrestrial plant, it was hypothesized that the active inter-
mediate might be an oxycarbenium ion located at rings E or
F and originated by opening of the dioxaspiro grouping.7
We can deduce from this that the stereochemistries at C-22,
C-23, and C-25, which doubtless have a strong influence on
the stability of the dioxaspiro[4.4]nonane system, may also
influence the activity of cephalostatins.
With these ideas in mind, we decided to develop a simple
methodology to permit the synthesis of all possible isomers
of this system by modification of the steroidal side chain of
a spirostan sapogenin, the key step being an intramolecular
hydrogen abstraction reaction (IHA) promoted by alkoxy
radicals.8 In previous papers from this laboratory, we have
demonstrated the utility of IHA reactions in the synthesis of
dioxaspiro[4.4]nonane ring systems in the carbohydrate
field.9
The synthesis starts with 3-methoxy-23-oxotigogenin (2)
(Scheme 1) prepared using a previously described procedure
by oxidation of 3-methoxytigogenin (1) with NaNO2/BF3‚
Et2O.10 The reduction of 2 with L-Selectride gave a mixture
of alcohols 3 and 4 (72%, 1.7:1) from which the alcohol 3
with the correct natural orientation (23R) could be obtained
in moderate yield. The reduction of 2 with NaBH4 afforded
preferentially the non-natural isomer 4 (91%, 19:1). In these
preliminary studies we decided to continue with the natural
diastereoisomeric alcohol 3. The regio- and stereoselective
opening reaction of the tigogenin dioxaspiro[5.4]decane
system present in 3 was accomplished with Ph2SiH2/TiCl4
to give diol 5 in 67% yield.11
a Reagent and conditions: (a) NaNO2, BF3‚Et2O, AcOH, rt, 1 h,
68%; (b) NaBH4, EtOH, rt, 1 h, 91% (3/4 ratio 5:95) or L-Selectride,
THF, -20 °C, 2 h, 72% (3/4 ratio 63:37); (c) Ph2SiH2, TiCl4,
CH2Cl2, -20 °C, 1.5 h, 67%; (d) pivaloyl chloride, Py, CH2Cl2, rt,
24 h, 96%; (e) tBuMe2SiOTf, CH2Cl2, Et3N, rt, 3 h, 81%; (f) KOH,
MeOH, 50 °C, 24 h, 92%; (g) (i) o-NO2PhSeCN, n-Bu3P, THF, rt,
0.5 h, 99%, (ii) H2O2, THF, rt, 3 h, 92%; (h) (i) OsO4, Py, CH2Cl2,
rt, 1.5 h, (ii) Ac2O, py, rt, 99% (10/11 ratio 1:2).
Conversion of 5 to the monoprotected primary alcohol 8
was accomplished by a protection-deprotection sequence
involving formation of the primary pivalate 6 (96%),
silylation with TBSOTf (81%), and hydrolysis of pivalate 7
with KOH/MeOH (92%). Nitrophenylselenenylation of the
primary alcohol in 8 followed by oxidative elimination
furnished alkene 9 in 92% yield. Osmylation of the double
bond and subsequent acetylation afforded tertiary alcohols
10 and 11 (99%, 1:2).12
The IHA reaction was carried out by separately treating
compounds 10 and 11 with (diacetoxyiodo)benzene and
iodine under irradiation with two 80 W tungsten-filament
lamps at 50 °C. Alcohol 10 afforded a mixture of the
dioxaspirocycles 12 and 13 (83%, 28:72) while alcohol 11
gave compounds 17 and 18 (83%, 33:67) (Scheme 2). The
desired diols 14, 15 and 19, 20 (Scheme 2) were subsequently
obtained by hydrolysis of the silyl and acetate protective
groups, the structures of which were determined by extensive
1H and 13C NMR 1D and 2D studies including DEPT, COSY,
HMBC, HSQC, and NOESY experiments and confirmed by
X-ray crystallography analysis of compounds 15 and 20. The
(4) (a) Dro¨gemu¨ller, M.; Jautelat, R.; Winterfeld, E. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1572-1574. (b) LaCour, T. G.; Guo, C.; Bhandaru, S.;
Boyd, M. R.; Fuchs, P. L. J. Am. Chem. Soc. 1998, 120, 692-707. (c)
Dro¨gemu¨ller, M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeld, E. Eur.
J. Org. Chem. 1998, 2811-2831. (d) Kim, S.; Sutton, S. C.; Guo, C.;
LaCour, T. G.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121, 2056-2070. (e)
Jeong, J. U.; Guo, C.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121, 2071-
2084. (f) For a short review, see: Ganesan, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 611-615.
(5) LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett. 2000,
2, 33-36.
(6) (a) Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 1099-1102.
(b) Deng, S.; Yu, B.; Lou, Y.; Hui, Y. J. Org. Chem. 1999, 64, 202-208.
(c) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369-3370.
(7) (a) Guo, C.; LaCour, T. G.; Fuchs, P. L. Bioorg., Med. Chem. Lett.
1999, 9, 419-424. (b) Guo, C.; Fuchs, P. L. Tetrahedron. Lett. 1998, 39,
1099-1102.
(8) (a) Majetich, G. Tetrahedron 1995, 51, 7095-7129. (b) Feray, L.;
Kuznetsov, N.; Renaud, P. In Hydrogen Atom Abstraction; Renaud, P., Sibi,
M. P., Eds.; Radicals in Organic Synthesis, Vol. 2. Wiley-VCH: Weinheim,
2001; pp 246-278. (c) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc.
ReV. 2001, 30, 94-103.
(9) (a) Mart´ın, A.; Salazar, J. A.; Sua´rez, E. J. Org. Chem. 1996, 61,
3999-4006. (b) Dorta, R. L.; Mart´ın, A.; Salazar, J. A.; Sua´rez, E.; Prange´,
T. J. Org. Chem. 1998, 63, 2251-2261.
(10) (a) Barton, D. H. R.; Sammes, P. G.; Taylor, M. V.; Werstiuk, E.
J. Chem. Soc. C 1970, 1977-1981. (b) Gonza´lez, A. G.; Freire, R.; Garc´ıa-
Estrada, M. G.; Salazar, J. A.; Sua´rez, E. Tetrahedron 1972, 28, 1289-
1297. (c) Gonza´lez, A. G.; Freire, R.; Garc´ıa-Estrada, M. G.; Salazar, J.
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(12) For studies on the diastereoselective osmylation of a related olefin
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1296
Org. Lett., Vol. 4, No. 8, 2002

from the 22S-diol 19 toward the more stable 22R-compound
20. One interesting observation was that even under pro-
longed reaction time neither 19 nor 20 yielded the corre-
sponding dioxaspiro[4.5] compound 21 to any appreciable
extent, in contrast to the series possessing the natural
stereochemistry. These findings are in agreement with the
results of a MM2 study,14 compounds 14 and 19 being the
highest steric energy isomers in the respective series while
compounds 15 and 20 are more stable (∆E14,15 ) 5 kcal/
mol; ∆E19,20 ) 2.6 kcal/mol).
Scheme 2. IHA Reaction from Compounds 10 and 11a
In conclusion, we have prepared four of eight possible
isomers of the target molecule and their reactivity toward
acid catalysts has been studied. The usefulness of the IHA
reaction to construct the different stereoisomers of this
steroidal dioxaspiro[4.4]bicyclic ring system has been dem-
onstrated.15 The methodology is especially useful when a
specific stereochemistry is required at the spirocenter since
thermodynamically less stable isomers can also be obtained.
Although we are conscious that the conclusions obtained
from this simple model cannot be fully extrapolated to the
natural products,16 it is interesting to note that the greatest
acid-catalyzed reactivity corresponds to a compound with
the natural stereochemistry.
Acknowledgment. This work was supported by Inves-
tigation Programmes BQU2000-0650 and BQU2001-1665
of the Direccio´n General de Investigacio´n, Spain. I.P.-M.
thanks the Cooperativa Farmace´utica de Tenerife (CO-
FARTE), Spain, for a fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds. An X-ray
crystallographic file (CIF) for compounds 15 and 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reagents and conditions: (a) PhI(OAc)2, I2, cyclohexane, hν,
50 °C, 3.5 h, 83% (12/13 ratio 28:72); (b) (i) TBAF, THF, rt, (ii)
KOH, MeOH, rt; (c) PhI(OAc)2, I2, cyclohexane, hν, 55 °C, 7 h,
83% (18/19 ratio 33:67).
OL025580E
(22S,23R,25S)-diol 14 possesses the stereochemistry of the
natural product. Compounds 14 and 19 appear to be the
products of kinetic control whereas 15 and 20 are the
thermodynamic products. The stability of these compounds
was determined by following the evolution of the acid-
catalyzed rearrangement through a C-22 oxycarbenium ion.
Compound 14 was transformed into the 22R-isomer 15 and
both 14 and 15 finally led to the dioxaspiro[4.5]decane 16
under prolonged hydrochloric acid treatment (Scheme 2).13
In the 25R series the equilibrium is also strongly displaced
(13) The diol dissolved in CHCl3 was treated with an undetermined
catalytic amount of HCl (some gas taken with a Pasteur pipet from the
headspace of a concentrated HCl bottle).
(14) Molecular mechanics calculations were performed using the AM-
BER* all-atom force field and the GB/SA solvation model for CHCl3 as
implemented in version 7.0 of the MacroModel and BatchMin packages.
(15) Shortly before submitting this Letter we became aware of the studies
by Prof. P. L. Fuchs in the ASAP section of this journal (Lee, S.; LaCour,
T. G.; Lantrip, D.; Fuchs, P. L. Org. Lett. 2002, 4, 313-316. Lee, S.; Fuchs,
P. L. Org. Lett. 2002, 4, 317-318) where IHA reactions are used to prepare
related dioxaspiro compounds.
(16) The 14,15-double bond and the 17R-hydroxyl group may have a
strong influence on the stability of the dioxaspiro ring system.
Org. Lett., Vol. 4, No. 8, 2002
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