Efficient synthetic approach to potent antiproliferative agent hippuristanol via Hg(II)-catalyzed spiroketalization

Article abstract of DOI:10.1021/ol1019663

Figure Presented. The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)₂-catalyzed oxidation/ spiroketalization of the 3-alkyn-1,7-diol motif.

Full text of DOI:10.1021/ol1019663

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4420-4423
Efficient Synthetic Approach to Potent
Antiproliferative Agent Hippuristanol via
Hg(II)-Catalyzed Spiroketalization
Kontham Ravindar,† Maddi Sridhar Reddy,† Lisa Lindqvist,‡ Jerry Pelletier,‡ and
Pierre Deslongchamps*,†
De´partement de Chimie, UniVersite´ de Sherbrooke, Sherbrooke, QC, J1K 2R1, Canada,
and Department of Biochemistry and Oncology, McIntyre Medical Sciences Building,
McGill UniVersity, Montreal, QC H3G 1Y6, Canada
pierredeslongchamps@omegachem.com
Received August 18, 2010
ABSTRACT
The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in
eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of
a spiroketal unit via Hg(OTf)2-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.
The mechanism of eukaryotic translation initiation has
received increasing attention owing to its potential as an
anticancer drug target. The rate-limiting step of translation
initiation involves the binding of ribosomes to mRNAs
catalyzed by distinct trans-acting factors that differ in their
affinity for different mRNA species. Of note is the eukaryotic
initiation factor (eIF)4A (the prototypical DEAD-box RNA
helicase) which is required to unwind the secondary structure
within the mRNA 5′ untranslated region to prepare the
ribosome landing pad. We have previously identified1
hippuristanol (1), a polyoxygenated steroid from the gorgo-
nian coral Isis hippuris, as a potential candidate to target
the eukaryotic translation initiation factor eIF4A.2 Hip-
puristanol (1) efficiently blocks translation and shows
significant cytotoxic activities against several cultured cell
tumor lines.2 The identification of hippuristanol (1) demon-
strates proof-of-concept that RNA helicases can be selectively
targeted and highlights the anticancer potential of this
approach. There is thus an urgent need for a practical
synthetic route to hippuristanol (1) with the high feasibility
of making analogues with considerable variation in structure
and stereochemistry both for improving the affinity for eIF4A
and for possibly developing inhibitors for other RNA
helicases. Most recently, Yu and co-workers reported the
first synthesis of hippuristanol (1) (from commercially
available hydrocortisone) and showed the importance of
structure and stereochemistry of the spiroketal appendage,3
consistent with what had been previously reported.1 Herein
† Universite´ de Sherbrooke.
(2) (a) Higa, T.; Tanaka, J.-i.; Tsukitani, Y.; Kikuchi, H. Chem. Lett.
1981, 164, 7–1650. (b) Rao, C. B.; Ramana, K. V.; Rao, C. V.; Fahy, E.;
Faulkner, D. J. J. Nat. Prod. 1988, 51, 954–958. (c) Gonzalez, N.; Barral,
M. A.; Rodriquez, J.; Jimenez, C. Tetrahedron 2001, 57, 3487–3497.
(3) Li, W.; Dang, Y.; Liu, J. O.; Yu, B. Chem.sEur. J. 2009, 10356–
10359. Li., W.; Dang, Y.; Liu, J. O.; Yu, B. Biol. Med. Chem. Lett. 2010,
20, 3112–3115.
‡ McGill University.
(1) (a) Bordeleau, M. E.; Mori, A.; Oberer, M.; Lindqvist, L.; Chard,
L. S.; Higa, T.; Wagner, G. J.; Belsham, G.; Tanaka, J.; Pelletier, J. Nat.
Chem. Biol. 2006, 2, 213–220. (b) Lindqvist, L.; Oberer, M.; Reibarkh,
M.; Cencic, R.; Bordeleau, M. E.; Voqt, E.; Marintchev, A.; Tanaka, J.;
Fagotto, F.; Altmann, M.; Wagner, G.; Pelletier, J. PloS One 2008, 3, e1583.
10.1021/ol1019663  2010 American Chemical Society
Published on Web 09/09/2010

we report a practical synthesis of hippuristanol (1) from
commercially available 11-ketotigogenin (5) via unprec-
edented Hg(OTf)2-catalyzed spiroketalization, which can
potentially lead to the synthesis of vast varieties of analogues
for further insights into the structure-activity relationships.
As described in the retrosynthetic analysis in Scheme 1,
the cascade construction of the spiroketal unit of hip-
gave keto diester 10 (via 9) in good yield. Direct hydrolysis
of ester 10 could not be achieved, and all the acidic and
basic conditions proved to be unsuccessful, giving either the
corresponding conjugated methyl ketone or an unidentified
mixture of products. Then, we adopted a round away
procedure for hydrolysis. Thus, vinyl grignard addition to
10 resulted in hydrolytic cleavage of the ester group and
vinylation of the keto group to give diol 11. OsO4-mediated
dihydroxylation of the olefin group in 11 followed by
oxidative cleavage cleanly afforded the requisite ꢀ-hydroxy
ketone 4.
Scheme 1. Retrosynthetic Analysis of Hippuristanol (1)
Synthesis of an alkyne coupling partner is depicted in
Scheme 3. The known diol 127 was oxidized with PDC to
give hydroxy aldehyde 13. Homologation of 13 under various
conditions of Corey-Fuchs8 and Ohira-Bestmann9 protocols
proved to be unfruitful revealing the substrate’s high
sensitivity in basic conditions. The Miwa protocol10 using
excess TMSCHN2 in combination with substoichiometric
nBuLi at reduced temperatures produced the desired product
but in low yield, and the resulting alkyne was protected as
its THP ether 14. Unsatisfied with the yield, we have
developed a slightly longer but convenient route to 14 from
diol 12. Thus, the primary and tertiary hydroxyl groups of
12 were protected as TBDPS and THP ethers, respectively,
in standard conditions to obtain 15, which upon treatment
with TBAF relieved the primary hydroxyl group to give
alcohol 16. Oxidation of alcohol 16 with TPAP-NMO gave
aldehyde 17 which under Miwa’s conditions cleanly fur-
nished alkyne 14 in 85% yield (Scheme 3).
Completion of the synthesis of hippuristanol (1) is
described in Scheme 4. Addition of lithiated alkyne 14 to
ꢀ-hydroxy ketone 4 yielded exclusively the desired and
expected Cram’s product 3 in excellent yield.11 The stage
was now set for the key cascade sequence, oxidation of
alkyne, hemiketalization, deprotection of THP ether, and
spiroketalization. Unprecedented, exposure of semiprotected
3-alkyn-1,7-diol 3 to Hg(OTf)2 in aqueous acetonitrile at
room temperature,12 within no time, cleanly furnished
directly the desired ketal 18 which on debenzylation with
lithium in liquid ammonia resulted in 22-epi-hippuristanol
(2) as a major diastereomer (22S/22R, 99.9:0.1) in 82%
overall yield (Scheme 4). Stereochemistry of the spiroketal
unit of both 18 and 22-epi-hippuristanol (2) was confirmed
by the appearance of spirocarbon 13C signals above δ 118
(122.53 and 118.66, respectively).2b,c Further, the analytical
puristanol (1) and/or 22-epi-hippuristanol (2) can be achieved
from suitably functionalized 3-alkyn-1,7-diol intermediate
3. This intermediate comes from ꢀ-hydroxy ketone 4 which
is readily available from 11-ketotigogenin (5)4 through
Marker’s degradation along with some functional group
manipulations.
As depicted in Scheme 2, our synthesis starts with 11-
ketotigogenin (5), which is commercially available and can
also be obtained in bulk quantity from hecogenin acetate (6).4
We have also prepared 5 on a moderate scale, using a slightly
modified procedure which is described in the experimental
section (Supporting Information). To begin the synthesis of
hippuristanol (1), the hydroxyl group at C3 of 11-ketotigo-
genin (5) was inverted under Mitsunobu conditions5 to afford
the 3R-benzoate which upon treatment with LiAlH4 under-
went reductive removal of the benzoyl group and a highly
stereocontrolled reduction of the 11-keto group to yield
3R,11ꢀ-diol 7. Dibenzyl derivative 8 was then obtained under
standard conditions. Following Marker’s degradation,6 treat-
ment of 8 successively with pyridine hydrochloride in acetic
anhydride followed by CrO3 in acetic acid and sodium acetate
(6) (a) Dauben, W. G.; Fonken, G. J. J. Am. Chem. Soc. 1954, 76, 4618–
4619. (b) Kemp, S. J.; Ph. D. Thesis, University of California, Berkeley,
1995. (c) Yamamoto, K.; Heathcock, C. H. Org. Lett. 2000, 2, 1709–1712.
(d) Kongkathip, N.; Kongkathip, B.; Noimai, N. Synth. Commun. 2006,
865–874.
(4) (a) McCarthy, P. A.; DeNinno, M. P.; Morehouse, L. A.; Chandler,
C. E.; Bangerter, F. W.; Wilson, T. C.; Urban, F. J.; Walinsky, S. W.;
Cosgrove, P. G.; Duplantier, K.; Etienne, J. B.; Fowler, M. A.; Lambert,
J. F.; O’Donnell, J. P.; Pezzullo, S. L.; Watson, H. A.; Wilkins, R. W.;
Zaccaro, L. M.; Zawistoski, M. P. J. Med. Chem. 1996, 39, 1935–1937.
(b) DeNinno, M. P.; McCarthy, P. A.; Duplantier, K. C.; Eller, C.; Etienne,
J. B.; Zawistoski, M. P.; Bangerter, F. W.; Chandler, C. E.; Morehouse,
L. A.; Sugarman, E. D.; Wilkins, R. W.; Woody, H. A.; Zaccaro, L. M.
J. Med. Chem. 1997, 40, 2547–2554.
(7) Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. Eur. J. Org. Chem.
2003, 3958–3968.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
(9) (a) Muller, S.; Liepold, B.; Roth, G.; Bestmann, H. J. Synlett 1996,
06, 521–522. (b) Toth, G.; Liepold, B.; Muller, S.; Bestmann, H. J. Synthesis
2004, 1, 59–62.
(10) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107–108.
(11) (a) Hedtmann, U.; Klintz, R.; Hobert, K.; Frelek, J.; Vlahov, I.;
Welzel, P. Tetrahedron 1991, 47, 3753–3772. (b) Kerb, U.; Wiechert, R.
Tetrahedron Lett. 1968, 40, 4277–4280.
(5) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380–2382. (b) Mitsunobu, O. Synthesis 1981, 1–28. (c) Hughes, D. L.
Org. React. 1992, 42, 335–656.
(12) (a) Yamamoto, H.; Imagawa, H. Synlett 2009, 7, 1175–1179. (b)
Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617–1661.
Org. Lett., Vol. 12, No. 19, 2010
4421

Scheme 2. Synthesis of Key Intermediate 4
Scheme 3. Synthesis of Alkyne Intermediate 14
Scheme 4. Synthesis of Hippuristanol (1)
data of our 22-epi-hippuristanol (2) was in good agreement
with that of the literature.3 The mechanistic sequence that
we presume for the completely stereocontrolled cascade
spiroketalization is depicted in Scheme 5. Oxymercuration
of the triple bond in 3 involving the 16-hydroxyl group
presumably led to intermediate A which on olefin isomer-
ization (to give B) followed by demercuration formed cyclic
enol ether C.12 Protonation of C to produce D, followed by
ketalization, furnished the cyclic ketal 18. The reason for
the exclusive formation of one isomer at the end of the
cascade process might be due to approach of the hydroxyl
group in D from the less hindered R-side (anti to the
neighboring tertiary hydroxyl group at C21), or the other
isomer of 18 formed in the reaction might be converted to
18 due to the acidic (and protic) nature of the reaction
medium (vide infra).
value of spirocarbon (115.61) in 13C NMR confirmed the
inversion of the spirocenter. Surprisingly, in contrast to the
previous reports,3 we observed that hippuristanol (1) (both
synthetic and natural product) quickly isomerized in CDCl3
to 22-epi-hippuristanol (2), and hence it was necessary to
take 1H and 13C NMRs in the CCl4/C6D6 (9:1) solvent system.
Data of synthetic material were in good agreement with those
of the natural product as well as with the reported data.3
Ultimately, the 22-epi-hippuristanol (2) was converted to
hippuristanol (1) using PPTS in CHCl3 (aprotic system) at
room temperature in a good yield of 87% (brsm). Initial
observation of the Rf value on TLC and lowering of the δ
4422
Org. Lett., Vol. 12, No. 19, 2010

complete isomerization to 22-epi-hippuristanol (2). Of course,
upon treatment of 22-epi-hippuristanol (2) under the same
aqueous acidic conditions, no isomerization occurred. The
existence of hippuristanol (1) and 22-epi-hippuristanol (2)
in equilibrium is thus possible only in aprotic acidic medium.
This indicates that the conversion of 3 to 18 is a thermody-
namically controlled process. In addition, the appearance of
hipppuristanol (1) along with epi-hippuristanol (2) in aprotic
acidic medium is likely due to the presence of an intramo-
lecular hydrogen bond with the neighboring tertiary hydrox-
yl group at C20 with one of the spiroketal oxygens. In
conclusion, an efficient synthesis of hippuristanol (1) has
been achieved from readily available 11-ketotigogenin (5)
through an unprecedented Hg(OTf)2-catalyzed cascade
spiroketalization. This novel spiroketal synthesis via the facile
coupling of readily available acetylenic intermediates with
hydroxy ketones should allow the preparation of hip-
puristanol analogues for further biological studies. Further
study on structure-activity relationships of hippuristanol (1)
and its analogues and the extension of the spiroketalization
method are in progress and will be reported shortly.
Scheme 5. Proposed Mechanism for Cascade Spiroketalization
The 22-epi-hippuristanol (2) was inactive, while synthetic
hippuristanol (1) inhibited translation to an extent similar to
the natural compound.
To further understand the complete stereocontrolled for-
mation of dibenzyl epi-hippuristanol (18), we treated hip-
puristanol (1) under the same reaction conditions (Hg(OTf)2,
H2O (3 equiv), and CH3CN) and found that it underwent a
Acknowledgment. We thank NSERC for funding.
Supporting Information Available: Experimental section
and physical and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1019663
Org. Lett., Vol. 12, No. 19, 2010
4423