Synthesis of the antiproliferative agent hippuristanol and its analogues via Suárez cyclizations and Hg(II)-catalyzed spiroketalizations

Article abstract of DOI:10.1021/jo102054r

A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was identified as a suitable and economical starting material for this work, and substrate-controlled stereoselection was obtained throughout the construction of the key spiroketal unit. Suárez cyclization was first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as the most convenient strategy.(Figure Presented)

Full text of DOI:10.1021/jo102054r

pubs.acs.org/joc
Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues
ꢀ
via Suarez Cyclizations and Hg(II)-Catalyzed Spiroketalizations
Kontham Ravindar,† Maddi Sridhar Reddy,† Lisa Lindqvist,‡ Jerry Pelletier,‡ and
Pierre Deslongchamps*,†
†
‡
ꢀ
ꢀ
Departement de Chimie, Universite de Sherbrooke, Sherbrooke, QC, Canada, J1K 2R1, and Department of
Biochemistry and Oncology, McIntyre Medical Sciences Building, McGill University, Montreal, QC,
Canada, H3G 1Y6
Pierre.Deslongchamps@USherbrooke.ca
Received October 19, 2010
A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was
identified as a suitable and economical starting material for this work, and substrate-controlled stereo-
ꢀ
selection was obtained throughout the construction of the key spiroketal unit. Suarez cyclization was
first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as
the most convenient strategy.
Introduction
Recently, there has been much interest in targetting protein
translation initiation as an anticancer therapy.2d Indeed, the
use of other eIF4A activity modulators, such as silvestrol, has
shown striking activity in preclinical mouse lymphoma
models.2e Clearly, inhibiting eIF4A with hippuristanol may
provide similar activity, and thus, there is a large unmet need
to develop an easy access to hippuristanol and its analogues.
While our efforts were under progress, Yu and co-workers
reported a synthesis of hippuristanol and a few closely related
analogues in order to study the effect of stereochemistry and
substitution pattern on spiroketal appendage in relation to the
biological activity.3 We, most recently, disclosed our synthetic
route to hippuristanol via an unprecedented Hg(OTf)2-
catalyzed cascade spiroketalization.4 Herein, we give a full
account of the synthetic efforts on hippuristanol and some
Hippuristanol (1), a steroid isolated from coral Isis hippuris,
has been identified as a selective and potent inhibitor of eu-
karyotic initiation factor(eIF)4A RNA-binding activity that
can be used to distinguish between eIF4A-dependent and
eIF4A-independent modes of translation initiation in vitro
and in vivo.1 It was also shown that poliovirus replication was
delayed when infected cells were exposed to hippuristanol.2
(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.
(c) Lindqvist, L.; Oberer, M.; Reibarkh, M.; Cencic, R.; Bordeleau, M.-E.; et al.
PLoS One 2008, 3, e1583.
(2) (a) Higa, T.; Tanaka, J.-i.; Tsukitani, Y.; Kikuchi, H. Chem. Lett.
1981, 1647–1650. (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. (d) Mills,
J. R.; Hippo, Y.; Robert, F.; Chen, S. M.; Malina, A.; Lin, C. J.; Trojahn, U.;
Wendel, H. G.; Charest, A.; Bronson, R. T.; Kogan, S. C.; Nadon, R.;
Housman, D. E.; Lowe, S. W.; Pelletier, J. Proc. Natl. Acad. Sci. U.S A. 2008,
105, 10853–10858. (e) Bordeleau, M. E. J. Clin. Invest. 2008, 118, 2651–2660.
(3) Li, W.; Dang, Y.; Liu, J. O.; Yu, B. Chem.;Eur. J. 2009, 15, 10356–
10359. Li, W.; Dang, Y.; Liu, J. O.; Yu, B. Bioorg. Med. Chem. Lett. 2010, 20,
3112–3115.
(4) Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps, P.
Org. Lett. 2010, 12, 4420–4423.
DOI: 10.1021/jo102054r
r
Published on Web 01/26/2011
J. Org. Chem. 2011, 76, 1269–1284 1269
2011 American Chemical Society

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ꢀ
SCHEME 1. Retrosynthetic Analysis of Hippuristanol and Analogues via Suarez Cyclization
SCHEME 2. Synthesis of 11-Ketotigogenin 5 from Hecogenin Acetate 6
ꢀ
analogues via the Suarez cyclization and the Hg(OTf)2-
catalyzed cascade spiroketalization.
MeOH to get hecogenin, which, on exposure to TBSOTf and
TEA in CH2Cl2, afforded TBS enol ether 7. OsO4-catalyzed
dihydroxylation of 7 produced the 11-R-hydroxy-12-one 8,
which was rearranged to 12-β-hydroxy-11-one 9 using NaOH
in tBuOH/H2O (1:1). Acylation of 9 with Ac2O in pyridine
and reductive cleavage of the resulting R-ketoacetate using
calcium in liquid NH3 cleanly afforded 3-OTBS-11-ketoti-
gogenin 10. TBS deprotection of 10 afforded the 11-ketoti-
gogenin 5, which was obtained in 40% overall yield from 6
through seven steps.
Results and Discussion
In the initial retrosynthetic analysis, as described in Scheme 1,
we envisioned the synthesis of hippuristanol and its analo-
ꢀ
gues (2, 3, and 4) from the suitable intermediate A via Suarez
cyclization.5 11-Ketotigogenin 56 was considered the best
choice of material to derive intermediate A as it contains the
favorable steric rigidity as well as suitable groups. Though
11-ketotigogenin is commercially available, it could be easily
obtained from the cost-effective and commercially available
plant-derived steroid material hecogenin acetate 6.6
The reaction of 5 under Mitsunobu conditions7 (BzOH,
DIAD, TPP) gave the corresponding inverted benzoate,
which, on exposure to LiAlH4 in THF, underwent reductive
deprotection of the C3-benzoyl group and exclusive stereo-
selective reduction of the C11-keto group to produce diol 11
having the desired stereochemistry (see Scheme 3).
Thus, our synthetic efforts were begun from hecogenin
acetate, as shown in Scheme 2. Though there is literature pre-
cedent for the bulk synthesis of 11-ketotigogenin 5 from
hecogenin acetate 6,6 we adopted a slightly modified and
practical approach to overcome the difficulty associated with
selective bromination of the later at the C11 position. Thus,
hecogenin acetate 6 was hydrolyzed using K2CO3 in THF-
Having converted the A and C rings suitable for hippur-
istanol 1 and its analogues, the stage was set for working on
ꢀ
the E and F rings. Initially, we wanted to evaluate the Suarez
cyclization before introducing a methyl group at C24 and a
hydroxyl group at C20. Also, we were interested to study the
effect of these two groups on the biological activity by
synthesizing 20-deshydroxy-24-desmethylhippuristanol and
its 22-epimer. Accordingly, protection of 11 as its dibenzoate
12, followed by reductive opening of the cyclic spiroketal of
12 using NaCNBH3 in AcOH8, cleanly yielded the alcohol
(5) (a) Betancor, C.; Freire, R.; Perez-Martin, I.; Prange, T.; Suarez, E.
Tetrahedron 2005, 61, 2803–2814. (b) Phillips, S. T.; Shair, M. D. J. Am.
Chem. Soc. 2007, 129, 6589–6598.
(6) (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. (c) Zhou, L. B.; Chen, T. H.; Bastow, K. F.;
Shibano, M.; Lee, K. H.; Chen, D. F. J. Nat. Prod. 2007, 70, 1263–1267.
(7) (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.
(8) Basler, S.; Brunck, A.; Jautelat, R.; Winterfeldt, E. Helv. Chim. Acta
2000, 83, 1854–1880.
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SCHEME 3. Synthesis of 20-Deshydroxy-24-desmethylhippuristanol 18 and Its 22-Epimer 19
13. Conversion of the hydroxyl group in 13 using TPP, I2,
and imidazole, followed by DBU-mediated elimination of
the resulting iodide, produced olefin 14 in 70% yield in two
steps. Introduction of the tertiary hydroxyl group at C25 to
obtain 15 was easily achieved by oxymercuration and demer-
curation5b using Hg(OAc)2 and NaBH4 in aqueous THF.
leading to complete degradation of the E ring.11 Regioselec-
tive reductive opening of epoxide 22 using NaCNBH3 in
AcOH8 produced alcohol 23 as a mixture of C22-epimers.
Though separable, we took forward the mixture as such as
this epimeric center will be eventually destroyed. Thus, kine-
tic dehydration of 23 using SOCl2 in pyridine gave exoolefin
24. Oxidative cleavage of the exoolefinic group in 24 using
OsO4, followed by NaIO4, and treatment of the resulting
ketone 25 with MeMgBr resulted in both the hydrolysis of
the acetate group as well as the exclusive substrate-controlled
addition of the methyl group to the ketone group to furnish
inverted alcohol 26. The primary hydroxyl group of 26 was
eliminated via iodination to get olefin 27, which, on oxymer-
curation and demercuration,5b produced ditertiary alcohol
ꢀ
In the standard Suarez cyclization conditions (PhI(OAc)2, I2,
hexanes/CH2Cl2),5 alcohol 15 neatly underwent cyclic keta-
lization to afford ketals 16 and 17 in a 1:2.8 ratio in 82%
yield. Benzoyl groups in 16 and 17 were removed through
reduction using LiAlH4 to afford 20-deshydroxy-24-des-
methylhippuristanol 18 and its 22-epimer 19 in 83% and
88% yields, respectively. The stereochemistry was assigned
on the basis of the analogy of the data (Rf values, 13C spectra,
and sensitivity to acidic and basic mediums) from previous
similar work (vide infra). Compounds 18 and 19 were found
to be biologically inactive by comparison with hippuristanol
(1), indicating the importance of the role of hydroxyl and
methyl groups at C20 and C24, respectively.
ꢀ
28. Exposure of 28 to standard Suarez cyclization condi-
tions5 cleanly furnished the diastereomeric spiroketal mix-
ture (4.5:5.5, R/S), which, on separation and subjection to
debenzylation, furnished 24-desmethylhippuristanol 3 and
its 22-epimer 4. In our hands, these isomers of hippuristanol
were devoid of biological activity; Yu and co-workers re-
ported also that these isomers were much less biologically
active compared with the natural product.3
We next turned our attention to introduce the C20-hydro-
xyl group to obtain 24-desmethylhippuristanol and its 22-
epimer. Protection of 11 as its dibenzylether 20 was carried
out in standard conditions, and regioselective opening of the
spiroketal in 20, as a part of Marker’s degradation,9 was
We then tried to introduce the missing methyl group at
C24 from intermediate 20 (via oxidation of C23), followed by
the same reaction sequence described in Scheme 5. Oxidation
of C23 of the hecogenin congeners is well-documented.12 We
achieved using Py HCl in refluxing Ac2O to obtain enol
3
ether 21 (see Scheme 4). A clean and stereospecific epoxida-
tion of 21 using dimethyldioxirane10 afforded epoxide 22.
The same transformation using mCPBA proved unfruitful,
followed the same conditions (BF3 OEt2, NaNO2, AcOH)
3
for the oxidation of 20 to 29, but the yield of the product was
unsatisfactory due to side reactions through the deprotection
of benzyl groups. The same oxidation of 12 (obtained from
benzoylation of 11) cleanly yielded 23-ketone 29a. After
several failures with LDA and KHMDS, LiHMDS was
found suitable for methylation of ketone 29a to get 30 as a
(9) (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, CA,
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.
(10) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S. J. Am. Chem. Soc. 2006,
128, 1792–1793.
(11) Jastrzebska, I.; Katrynski, K. S.; Morzycki, J. W. ARKIVOC 2002,
iX, 46–54.
(12) Iglesias-Arteaga, M. A.; Gil, R. P.; Martinez, C. S. P.; Manchado,
F. C. J. Chem. Soc., Perkin Trans. 1 2001, 261–266.
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SCHEME 4. Synthesis of 24-Desmethylhippuristanol 3 and Its 22-Epimer 4
1:2 diastereomeric mixture in favor of the equatorial isomer.
The 24-S isomer was converted to the 24-R isomer using
NaOMe in refluxing MeOH, and the hydrolysis of the C3-
benzoate group took place concurrently with the isomeriza-
tion and provided S6. Surprisingly, the anticipated reductive
decarbonylation of 30 and S6 were unsuccessful through
Wolff-Kishner and modified Wolff-Kishner (Huang-
Minlon) conditions.13 We obtained only the corresponding
reduced product triol, which was characterized by the deri-
vitization to its triacetate 31. We then subjected 29 to Wolff-
Kishner reaction conditions to get, to our surprise, the de-
carbonylated product 20 cleanly. When we tried the same
reduction on 29a, the reduction was also observed with
concomitant hydrolysis of the benzoate groups to give back
11. A literature example supports the formation of reduction
product 31 from 30 under alcoholic KOH conditions.14 If the
reduction of 30 to 32 worked well, our next sequence of
reactions, as described from 20 to 3 or 4 as in Scheme 4,
would have led to hippuristanol (1) through intermediate 33.
Because of failure of direct deoxygenation of 30 together
with the low yield of oxidation of 20 to 29 and unwanted
deprotections during the isomerization of 30, we were forced
to seek a new approach to produce the spiroketal and not con-
sider alternative methods for deoxygenation of 30 through
reduction andelimination reactions. Therefore, weconsidered
the new retrosynthetic analysis(depicted inScheme 6) withthe
degradation and elimination of the E ring completely, and
reconstruct with all prerequisites. Accordingly, we envisioned
the construction of the E and F rings of hippuristanol via
spiroketalization of suitably constructed intermediates 34 or
35. Regioselective spiroketalization of 34 with the assistance of
C16-OH was anticipated with the support of some relevant
literature. Intermediates 34 and 35 were convergently expected
from hydroxy ketone 37 through the Cram’s addition of
organometallates of 36 and 38, respectively. Intermediate 37
would be easily obtained from 21 via Marker’s degradation.9
Thus, a new synthetic route began by the oxidative de-
gradation of 21 to 39 using CrO3 in AcOH (see Scheme 7).9
However, addition of lithiated 3815 to the ketodiester 39 did
not result in the expected addition product, but only the
conjugated ketone 40 through the elimination of the side-
chain ester. Much of the literature also shows that the con-
geners of 39 are very sensitive to both acidic and basic condi-
tions, resulting in the conjugated ketones like 40. We then
decided to hydrolyze the ester side chain prior to addition of
the required moiety to the ketone group. The direct hydrolysis
of 39 proved to be insurmountable, in both acidic and basic
conditions, leading to either the corresponding conjugated
(15) Tsuji, M.; Yokoyama, S.; Tachibana, Y.; Ikekawa, N. Bull. Chem.
Soc. Jpn. 1990, 63, 2233–2238.
(13) (a) Huang-Minlon J. Am. Chem. Soc. 1949, 71, 3301–3303.
(b) Callow, R. K.; Massy-Beresford, P. N. J. Chem. Soc. 1957, 4482–4488.
(14) Fisher, H.; Zeile, K.; Liebigs J. Ann. Chem. 1929, 468, 98.
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SCHEME 5. Efforts toward the Synthesis of Hippuristanol 1 and Its 22-Epimer 2 via Suarez Cyclization
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SCHEME 6. New Retrosynthetic Analysis of Hippuristanol 1 and Its 22-Epimer 2 via Spiroketalization
methyl ketone 40 or decomposition (Table 1). We then
adopted a roundabout procedure for hydrolysis. Thus, vinyl
Grignard addition to 39 resulted in alkylative cleavage of the
ester group and vinylation of the keto group to give diol 41.
OsO4-mediated dihydroxylation of the olefin group in 41,
followed by oxidative cleavage, cleanly afforded the requisite
β-hydroxy ketone 37. Another parallel practical way was
evaluated for 37 via 40.3 Thus, conjugated ketone 40 was
synthesized in high yield from 39 using basic alumina (Al2O3)
in benzene. Enone 40 on exposure to N-bromoacetamide
(NBA) in aqueous acetone/THF underwent bromohydrox-
ylation to give 16β-hydroxy-17R-bromide, which, on im-
mediate treatment with Bu3SnH/Et3B, resulted in radical
mediated debrominated product 37. Again, the addition of
lithiated 38 to hydroxy ketone 37 proved to be unsuccessful
(to give 42), though the excess of reagent was added. This
failure could be due to the Thorpe-Ingold effect (gem
dialkyl effect), as described in a literature precedent by Smith
et al.16 Hence, we decided to slightly alter the strategy by
choosing a coupling partner, which is less sterically hindered.
This strategy is described in Scheme 8. Initially, we con-
structed 24-desmethylhippuristanol 3 using the known al-
kyne partner 43.17 Pleasingly, addition of lithiated 43 to
ketone 37 cleanly furnished the propargyl alcohol 44 as a
(16) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365–377.
(17) Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. Eur. J. Org. Chem.
2003, 3958–3968.
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SCHEME 7. Some Synthetic Efforts for the Coupling of 38 and for the Preparation of 37
TABLE 1. Efforts on the Hydrolysis of 39 to 37
entry
conditions
result
1
2
3
4
5
K2CO3, MeOH, rt
K2CO3, MeOH/THF (1:1), rt
1 N HCl, THF, rt
40% AcOH, THF, 45 °C
PLE (pig liver esterase), phosphate buffer (pH = 7.0), Et2O, rt
enone (40)
enone (40)
decomposition
decomposition
starting material þ decomposition
SCHEME 8. Synthesis of 24-Desmethylhippuristanol 3 and Its 22-Epimer 4 via Hg(II)-Catalyzed Spiroketalization
single diastereomer. The exclusive formation of a single iso-
mer must be due to the hydroxyl group mediated chelate sta-
bilization of the Cram’s intermediate, as shown in Scheme 8.
At this stage, our aim was the regioselective hydration of 44
at C22 over C23 with the assistance of C16-OH, as described
in a recent literature precedent, and later OTHP deprotec-
tion would lead to spiroketalization. Unprecedentedly, ex-
posure of semiprotected 3-alkyn-1,7-diol 44 to Hg(OTf)2 in
aqueous acetonitrile18 at room temperature, within no time,
cleanly furnished directly the desired spiroketal 45 (in 8:2
22S/22R diastereomers) in a cascade manner. The mechan-
istic sequence of this cascade reaction is detailed in our com-
munication.4 Intermediate 45, on debenzylation with lithium
in liquid ammonia, resulted in 24-desmethylhippuristanol
(3) and 24-desmethyl-22-epi-hippuristanol (4) in 83% yield
(Scheme 8).3
With the above promising results, we then targeted the
synthesis of hippuristanol (1). The suitable alkyne coupling
partner 36 was synthesized from known diol 46 as shown in
Scheme 9. Diol 4619 was oxidized with PDC to give hydroxy
aldehyde 47, which, on homologation under various condi-
tions of Corey-Fuchs20 and Ohira-Bestmann21 protocols,
proved to be unfruitful, revealing the substrate’s high sensi-
tivity to basic conditions. The Miwa protocol22 using excess
(19) Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. Eur. J. Org. Chem.
2003, 3958–3968.
(20) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
(21) (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.
(18) (a) Yamamoto, H.; Imagawa, H. Synlett 2009, 7, 1175–1179.
(b) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661.
(22) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107–108.
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SCHEME 9. Completion of the Synthesis of Hippuristanol 1
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 36. Unsatisfied with the yield, we developed a slightly
longer, but convenient, route to 36 from diol 46. Thus, the
primary and tertiary hydroxyl groups of 46 were protected as
TBDPS and THP ethers, respectively, in standard conditions
to obtain 48, which, upon treatment with TBAF, relieved the
primary hydroxyl group to give alcohol 49.15 Oxidation of
alcohol 49 with TPAP-NMO gave aldehyde 50, which, under
Miwa’s conditions, cleanly furnished alkyne 36 in 85% yield.
Now, the stage was set for the completion of the synthesis
of hippuristanol (1). Addition of lithiated alkyne 36 to hy-
droxy ketone 37 yielded exclusively the desired and expected
Cram’s product 34 in excellent yield.23 As was observed
above, exposure of semiprotected 3-alkyn-1,7-diol 34 to
Hg(OTf)2 in aqueous acetonitrile4 at room temperature
cleanly furnished the desired spiroketal 51, which, on deben-
zylation with lithium in liquid ammonia, resulted in 22-epi-
hippuristanol (2) as a single diastereomer in 82% overall
yield. Stereochemistry of the spiroketal unit of both 51 and
22-epi-hippuristanol (2) was confirmed by the appearance of
C22 spirocarbon 13C NMR signals above δ 118 (122.53 and
118.66, respectively).2b,c Further, the analytical data of our
22-epi-hippuristanol (2) were in good agreement with those
of the literature.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 value of C22 spirocarbon (δ 115.61) in
13C NMR confirmed the inversion of the spirocenter. The
remaining analytical data of the synthetic material were in
good agreement with those of the natural product as well as
with the reported data.3
Conclusion
In conclusion, an efficient synthesis of hippuristanol (1)
and some of the close analogues has been achieved from rea-
dily available hecogenin acetate through an unprecedented
ꢀ
Hg(OTf)2-catalyzed cascade spiroketalization. Suarez cycli-
zation was well studied for the synthesis of hippuristanol and
was successfully applied for some of its analogues, that is, 20-
deshydroxy-24-desmethylhippuristanol (both C22-epimers)
and 24-desmethylhippuristanol (both C22-epimers). It has
been revealed that the C20-OH and C24-methyl groups are
important for the biological activity of hippuristanol. This
novel construction of spiroketal motifs via the facile cou-
pling of readily available acetylenic intermediates with hy-
droxy ketones, followed by Hg(II) treatment, should allow
the preparation of hippuristanol analogues for further bio-
logical studies. Overall, our successful synthetic sequence
produced hippuristanol (1) in 5.54% overall yield from 11-
ketotigogenin 5 in 12 steps, compared with Yu’s synthesis in
3.6% overall yield in 16 steps from hydrocortisone. Further
study on the structure-activity relationships of hippurista-
nol and its analogues and the extension of the spiroketaliza-
tion method are in progress and will be reported shortly.
Experimental Section
General Procedures. All reactions were performed under a
nitrogen atmosphere with oven (80 °C) or flame-dried glass-
ware. Tetrahydrofuran (THF) and ether were distilled from
sodium-benzophenone under a nitrogen atmosphere immedi-
ately prior to use. Dichloromethane, toluene, N,N-dimethylfor-
mamide, and acetonitrile were freshly distilled over calcium
(23) (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.
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hydride under an argon atmosphere. For the NMR spectra
assignments, the following abbreviations were used: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; ABq, AB quartet; and
br, broad. Chemical shifts are reported in values relative to the
solvent used (CHCl3: 7.26 ppm for 1H NMR and 77.0 ppm for
13C NMR) as an internal standard. Optical rotations were
measured at the sodium D line (589 nm) with a 1.00 dm path
length cell. Infrared spectra were recorded as neat liquid films,
and only the most significant absorption bands are reported
(in cm-1). Experimental procedures for all the new compounds
and known compounds without published experimental proce-
dures are described below. Compounds that are not presented in
the main text are numbered starting from S1.
NaOH (0.599 g, 14.9 mmol), and the mixture was refluxed (80-
90 °C) for 12 h. After completion of the reaction, tert-BuOH was
removed under reduced pressure, and then more water was ad-
ded and extracted with CH2Cl2. The crude product was dried
over anhydrous Na2SO4 and concentrated under vacuum. Pur-
ification of the crude product by flash chromatography (5%
EtOAc/hexanes) using silica gel afforded the isomerized ketol 9
(1.08 g, 90%) as a white solid. Rf = 0.5 (SiO2, 10% EtOAc/
hexanes); mp 274-276 °C; [R]D -32.8 (c = 1.0, CHCl3); H
NMR (CDCl3, 300 MHz): δ 4.57-4.43 (m, 1H), 3.84-3.75 (m,
1H), 3.66-3.43 (m, 3H), 3.43-3.28 (m, 1H), 2.45-2.30 (m, 1H),
2.25-2.05 (m, 2H), 1.93-0.75 (m, 20H), 1.05 (d, 3H, J = 7.13
Hz), 1.04 (s, 3H), 0.88 (s, 9H), 0.79 (d, 3H, J = 6.58 Hz), 0.56 (s,
3H), 0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz): δ 210.7, 109.4,
84.3, 80.5, 71.6, 66.8, 62.8, 60.5, 52.9, 50.0, 44.9, 42.4, 38.0, 37.1,
35.7, 35.2, 32.6, 31.5, 31.3, 30.9, 30.1, 28.7, 27.9, 25.9, 18.2, 17.1,
13.3, 12.4, 11.3, -4.6; IR (NaCl): cm-1 2931.4, 2852.5, 1690.1,
1446.9, 1374.6, 1059.1; HRMS (ESI) m/z calcd for C33H56O5Si
[M]þ 560.3897, found 560.3896 ( 0.0017.
20
1
Hecogenin S1: Hecogenin acetate 6 (2.0 g, 4.231 mmol) was
first dissolved in THF (15 mL) by stirring for 15 min at rt.
MeOH (10 mL) and powdered K2CO3 (1.17 g, 8.46 mmol) were
then added sequentially, and the reaction mixture was stirred at
rt for 12 h. After completion, the reaction was filtered through
Celite and washed with EtOAc, CH2Cl2, and 5% MeOH in
CH2Cl2. Purification by flash chromatography (30/70% EtOAc/
hexanes) using a small band of silica gel afforded hecogenin S1 as
a white solid (1.73 g, 95%). The product was confirmed by the
comparison of its spectroscopic data with the literature.6a,c
TBS Enol Ether 7: To a mixture of Et3N (2.0 mL) and CH2Cl2
(2.0 mL) was added tert-butyldimethylsilyl trifluoromethane-
sulfonate (7.85 mL, 29.72 mmol) dropwise at 0 °C. To this mix-
ture was added hecogenin (1.60 g, 3.71 mmol) in anhydrous
CH2Cl2 at the same temperature. The mixture was warmed to
room temperature and stirred at this temperature for 24 h. It was
then quenched with isopropanol (2.0 mL) and H2O (10 mL) at
0 °C. It was then diluted with CH2Cl2, washed with brine solu-
tion, and dried over Na2SO4. Purification by flash chromatog-
raphy (5% EtOAc/hexanes) using silica gel gave TBS enol ether
7 (1.96 g, 80%) as a white solid. Rf = 0.8 (SiO2, 10% EtOAc/
3-OTBS-11-ketotigogenin 10: To the ketol 9 (1.0 g, 1.78
mmol) in a single-neck, round-bottom flask was added pyridine
(5 mL), followed by Ac2O (5 mL), and the reaction mixture was
refluxed at 135 °C for 2.5 h. After completion of the reaction, the
contents were cooled to 0 °C and cold water and EtOAc were
added. It was then extracted with EtOAc (3 ꢀ 10 mL), and
combined extracts were washed with water and brine solution,
dried over anhydrous Na2SO4, and concentrated under vacuum.
Purification by silica gel column chromatography (5% EtOAc/
hexanes) afforded the corresponding acetate S2 (910 mg, 85%)
as a white solid. Rf = 0.45 (SiO2, 10% EtOAc/hexanes); mp
232-235 °C; [R]D20 -51.8 (c = 0.7, CHCl3); 1H NMR (CDCl3,
300 MHz): δ 4.82-4.67 (m, 1H), 4.57-4.41 (m, 1H), 3.59-3.42
(m, 2H), 3.42-3.23 (m, 1H), 2.40-2.24 (m, 1H), 2.22-1.98 (m,
2H), 2.15 (s, 3H), 1.97-0.64 (m, 20H), 1.03 (s, 3H), 0.93 (d, 3H,
J = 7.13 Hz), 0.87 (s, 9H), 0.79 (d, 3H, J = 6.58 Hz), 0.72 (s,
3H), 0.03 (s, 6H); 13C NMR (CDCl3, 75 MHz): δ 203.9, 170.1,
109.3, 85.8, 80.4, 71.7, 66.9, 63.1, 60.0, 54.2, 47.8, 44.9, 42.3,
37.9, 36.6, 35.6, 35.2, 32.6, 31.5, 31.2, 30.8, 30.1, 28.7, 27.9, 25.9,
20.7, 18.3, 17.1, 13.5, 12.4, 12.4, -4.4, -4.6; IR (NaCl): cm-1
2931.4, 2852.5, 1742.7, 1716.4, 1453.5, 1368.0, 1052.5; HRMS
(ESI) m/z calcd for C35H58O6Si [M]þ 602.4002, found 602.4003
( 0.0018. Calcium (96.2 mg, 22.9 mmol) was placed in a flask
topped with a dry ice condenser. The system was flushed with
argon. The flask was cooled to -78 °C and the condenser filled
with a dry ice/acetone mixture. Ammonia was condensed until
no further calcium was seen. The cooling bath was removed, and
the system was allowed to equilibrate to the refluxing tempera-
ture (-33 °C). THF (5 mL) was added to disperse the newly
formed reagent, followed by a slow addition of a solution of the
above acetate S2 (500 mg, 2.29 mmol). A cautious addition is
needed to ensure a regular and smooth ammonia reflux. The
reaction mixture was then stirred at -33 °C for 20 min, carefully,
and bromobenzene was slowly added at -33 °C to quench the
reaction, followed by water. Ammonia was allowed to evapo-
rate under a stream of air. To the reaction mixture was added
water and a small amount of aqueous NH4Cl (2 mL), and it was
extracted with EtOAc, dried over anhydrous Na2SO4, filtered,
concentrated under reduced pressure, and purified by silica gel
column chromatography (6% EtOAc/hexanes) to afford the
ketone 10 (910 mg, 86%) as a white solid. Rf = 0.6 (SiO2, 20%
20
1
hexanes); mp 190-193 °C; [R]D -46.3 (c = 1.0, CHCl3); H
NMR (CDCl3, 300 MHz): δ 4.51 (d, 1H, J = 1.64 Hz), 4.47-
4.37 (m, 1H), 3.62-3.42 (m, 2H), 3.42-3.31 (m, 1H), 2.11-1.81
(m, 3H), 1.78-0.77 (m, 20H), 1.04 (d, 3H, J = 7.13 Hz), 0.93 (s,
9H), 0.90 (s, 3H), 0.88 (s, 9H), 0.78 (d, 3H, J = 6.58 Hz), 0.75 (s,
3H), 0.17 (s, 3H), 0.14 (s, 3H), 0.05 (s, 6H); 13C NMR (CDCl3, 75
MHz): δ 159.4, 109.0, 100.68, 80.8, 72.1, 66.8, 58.1, 56.1, 53.8,
46.3, 44.6, 42.9, 38.6, 36.6, 36.3, 33.4, 31.9, 31.7, 30.7, 30.4, 30.3,
29.2, 28.9, 26.1, 26.0, 18.6, 18.4, 18.3, 17.2, 14.0, 13.0, -3.7,
-4.2, -4.6; IR (NaCl): cm-1 2955.7, 2925.0, 1472.0, 1370.5,
1252, 1084; HRMS (ESI) m/z calcd for C39H70O4Si2 [M]þ
658.4812, found 658.4818 ( 0.0020.
11-Hydroxy-12-ketone 8: To a stirred solution of silyl enol
ether 7 (1.5 g, 2.27 mmol) in THF/water (3:1, 10 mL) were added
4-methylmorpholine-N-oxide (0.533 g, 4.55 mmol), followed by
a solution of OsO4 in H2O (4% in H2O, 0.01 mL, 0.455 mmol).
The resulting solution was stirred for 5 h at room temperature.
The mixture was as such concentrated without further workup
and subjected to silica gel column chromatography (7% EtOAc/
hexanes) to afford the R-hydroxy ketone 8 as a white solid (1.092 g,
86%). Rf = 0.6 (SiO2, 10% EtOAc/hexanes); mp 225-228 °C;
[R]D20 -16.2 (c = 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
4.41-4.30 (m, 2H), 3.95 (d, 1H, J = 2.74), 3.54 (sept, 1H, J =
4.94 Hz), 3.52-3.43 (m, 1H), 3.40-3.27 (m, 1H), 2.70-2.60 (m,
1H), 2.20-2.05 (m, 2H), 2.03-1.86 (m, 1H), 1.83-0.83 (m,
25H), 1.05 (d, 3H, J = 7.13 Hz), 0.88 (s, 9H), 0.79 (d, 3H, J =
6.03 Hz), 0.04(s,6H);13C NMR (CDCl3, 75MHz): δ213.6, 109.1,
79.3, 73.1, 71.4, 67.0, 63.5, 55.7, 53.6, 45.0, 42.1, 38.9, 38.0,
37.9, 34.3, 32.0, 31.7, 31.4, 31.3, 30.1, 28.8, 28.7, 25.9, 18.3, 17.1,
15.4, 13.3, 12.6, -4.5, -4.6; IR (NaCl): cm-1 2955.7, 2935.0,
1708, 1462, 1063; HRMS (ESI) m/z calculated for C29H47O5Si
[M - C4H9]þ 503.3193, found 503.3196 ( 0.0015.
20
EtOAc/hexanes); mp 235-238 °C; [R]D -22.3 (c = 1.0,
1
CHCl3); H NMR (CDCl3, 300 MHz): δ 4.54-4.42 (m, 1H),
3.59-3.42 (m, 2H), 3.42-3.27 (m, 1H), 2.48-2.36 (m, 1H), 2.23
(s, 2H), 2.17-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.90-0.71 (m,
20H), 1.01 (s, 3H), 0.93 (d, 3H, J = 7.13 Hz), 0.87 (s, 9H), 0.78
(d, 3H, J = 6.58 Hz), 0.70 (s, 3H), 0.04 (s, 6H); 13C NMR
(CDCl3, 75 MHz): δ 210.1, 109.2, 80.6, 71.8, 67.0, 64.6, 60.7,
57.7, 55.8, 45.0, 44.4, 41.8, 38.1, 37.0, 35.9, 35.1, 32.8, 31.7, 31.3,
12-Hydroxy-11-ketone 9: To the ketol 8 (1.2 g, 2.14 mmol) in
tert-BuOH (5 mL) and water (5 mL) was added powdered
1276 J. Org. Chem. Vol. 76, No. 5, 2011

Ravindar et al.
JOCArticle
31.2, 30.2, 28.7, 28.1, 25.9, 17.1, 14.2, 12.2, -4.5, -4.6; IR
(NaCl): cm-1 2918.3, 2852.5, 1690.1, 1453.5; HRMS (ESI) m/z
calcd for C33H56O4Si [M]þ 544.3901, found 544.3902 ( 0.0016.
11-Ketotigogenin 5: The TBS ether 10 (900 mg, 1.651 mmol)
was placed in a flame-dried, two-neck, round-bottom flask,
under an argon atmosphere. To this was added anhydrous THF
(8 mL), and the mixture was cooled to 0 °C. TBAF (1.0 M in THF,
3.30 mL, 3.30 mmol) was then added slowly at the same tempera-
ture. The cooling bath was removed, and the system was allowed
to stir at room temperature for 8 h. After complete conversion, the
reaction mixture was as such concentrated and flashed on silica gel
column chromatography (30-60% EtOAc/hexanes) to affordthe
11-ketotigogenin 5 (654 mg, 92%) as a white solid. Rf = 0.25
(SiO2, 60% EtOAc/hexanes); mp 220-223 °C; [R]D20 -27.5 (c =
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 4.55-4.42 (m, 1H),
3.65-3.41 (m, 2H), 3.41-3.27 (m, 1H), 2.54-2.39 (m, 1H), 2.24
(s, 2H), 2.18-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.91-0.66 (m,
20H), 1.03 (s, 3H), 0.94 (d, 3H, J = 7.13 Hz), 0.79 (d, 3H, J = 6.58
Hz), 0.71 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 210.2, 109.2,
80.6, 70.9, 66.9, 64.5, 60.7, 57.7, 55.7, 44.8, 44.3, 41.8, 37.6, 37.0,
36.0, 35.1, 32.7, 31.3, 30.2, 28.7, 28.0, 17.1, 14.2, 12.1; IR (NaCl):
cm-1 3272.7, 2925.0, 1702.8, 1447.2, 1048.3; HRMS (ESI) m/z
calcd for C27H42O4 [M]þ 430.3083, found 430.3084 ( 0.0013.
3-Benzoate S3: The hydroxy ketone 5 (600 mg, 1.39 mmol)
was weighed in a flame-dried, round-bottom flask, connected to
an argon supply, dissolved in anhydrous THF (5 mL), and cool-
ed to 0 °C. Benzoic acid (BzOH, 169 mg, 1.39 mmol) and tri-
phenylphosphine (TPP, 438 mg, 1.67 mmol) were added to the
reaction mixture. After 5 min, diisopropyl-azodicarboxylate
(DIAD, 0.34 mL, 1.67 mmol) was added at the same tempera-
ture. The mixture was allowed to stir at rt for 1.5 h. It was then
concentrated as such (without any workup) and subjected to
silica gel column chromatography (12% EtOAc/hexanes) to
afford the corresponding benzoate S3 (685 mg, 93%) as a white
solid. Rf = 0.8 (SiO2, 30% EtOAc/hexanes); mp 160-162 °C;
[R]D20 -20.8 (c = 0.8, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
8.10-7.99 (m, 2H), 7.61-7.37 (m, 3H), 5.26 (br s, 1H),
4.56-4.42 (m, 1H), 3.48 (dd, 1H, J = 10.97, 3.84 Hz), 3.36 (t,
1H, J = 10.97 Hz), 2.35 (dd, 1H, J = 13.17, 3.84 Hz), 2.26 (s,
2H), 2.18-2.04 (m, 1H), 2.02-0.84 (m, 20H), 1.08 (s, 3H), 0.94
MHz): δ 109.3, 80.6, 68.1, 66.8, 66.4, 62.8, 58.2, 57.9, 48.5, 41.6,
39.9, 39.6, 36.3, 35.3, 32.5, 31.8, 31.5, 31.3, 31.1, 30.3, 28.8, 28.6,
27.9, 19.2, 17.1, 14.5, 14.3; IR (NaCl): cm-1 3441.5, 2930.1,
1452, 1048.3; HRMS (ESI) m/z calcd for C27H44O4 [M]þ
432.3239, found 432.3244 ( 0.0013.
Dibenzoate 12: To the diol 11 (560 mg, 1.29 mmol) in an-
hydrous pyridine (25 mL) under argon at room temperature was
added DMAP (31.5 mg, 0.25 mmol), followed by benzoic an-
hydride (2.29 g, 12.96 mmol). The reaction mixture was refluxed
(∼125 °C bath temperature) for 6 h, cautiously quenched with
ice water at 0 °C, extracted with CH2Cl2, and washed with
aqueous NaHCO3 solution. The organic fractions were dried
over anhydrous Na2SO4 and filtered using sintered funnel, and
solvents were removed under vacuum. Purification of the crude
product by silica gel column chromatography (5% EtOAc/hex-
anes) afforded the dibenzoate 12 (680 mg, 82%) as a white solid.
Rf = 0.65 (SiO2, 15% EtOAc/hexanes); 1H NMR (CDCl3, 300
MHz): δ 8.18-8.01 (m, 4H), 7.65-7.39 (m, 6H), 5.65 (s, 1H),
5.23 (s, 1H), 4.49-4.37 (m, 1H), 3.52-3.41 (m, 1H), 3.41-3.29
(m, 1H), 2.28-2.02 (m, 3H), 1.97-0.81 (m, 22H), 0.98 (s, 3H),
0.95 (s, 3H), 0.91 (d, 3H, J = 6.58 Hz), 0.77 (d, 3H, J = 6.03 Hz);
13C NMR (CDCl3, 75 MHz): δ 165.9, 165.3, 132.9, 132.7, 129.7,
129.5, 128.5, 128.4, 109.4, 80.6, 70.3, 66.8, 62.8, 57.6, 57.1, 44.4,
41.6, 41.3, 39.6, 35.9, 33.1, 32.4, 31.9, 31.5, 31.3, 30.2, 28.7, 27.7,
26.1, 19.1, 17.1, 14.7, 14.4; IR (NaCl): cm-1 2953, 2931, 1736,
1091, 1025; HRMS (ESI) m/z calcd for C41H52O6 [M]þ 640.3764,
found 640.3771 ( 0.0019.
Primary Alcohol 13: To a solution of compound 12 (500 mg,
0.76 mmol) in acetic acid (2 mL) was added NaCNBH3 (96 mg,
1.52 mmol). After 1.5 h, the mixture was quenched carefully with
saturated aqueous sodium bicarbonate solution (15 mL) and
then was extracted with CH2Cl2 (3 ꢀ 10 mL). The organic layer
was washed with brine and dried over Na2SO4, and solids were
removed by filtration. The solvent was removed in vacuo, and
the crude material was purified by flash chromatography
(30-45% EtOAc/hexanes) to provide the alcohol 13 (352 mg,
92%) as an oil. Rf = 0.25 (40% EtOAc/hexanes); 1H NMR (300
MHz, CDCl3): δ 8.12-8.02 (m, 4H), 7.64-7.41 (m, 6H), 5.68-
5.62 (m, 1H), 5.23 (brs, 1H), 4.38-4.26 (m, 1H), 3.50-3.37 (m,
1H), 3.36-3.25 (m, 1H), 2.24-0.91 (m, 34H), 0.87 (d, 3H, J =
7.13 Hz); 13C NMR (75 MHz, CDCl3): δ 165.9, 165.6, 132.8,
132.7, 129.7, 129.5, 128.4, 128.2, 90.4, 83.0, 70.3, 68.1, 65.6, 57.9,
57.1, 44.2, 41.3, 40.2, 38.0, 35.6, 33.0, 32.4, 31.9, 30.4, 30.0, 27.6,
25.8, 19.4, 18.8, 16.6, 14.7; IR (NaCl): cm-1 3521, 2952, 1736,
1734; HRMS (ESI) m/z calcd for C41H54O6 [M]þ 642.3920,
found 642.3920 ( 0.0019.
(d, 3H, J = 6.58 Hz), 0.79 (d, 3H, J = 6.03 Hz), 0.72 (s, 3H); 13
C
NMR (CDCl3, 75 MHz): δ 210.1, 165.8, 132.7, 131.1, 129.5,
128.3, 109.2, 80.6, 70.4, 66.9, 64.5, 60.8, 57.7, 55.8, 44.4, 41.8,
40.3, 36.9, 35.6, 32.7, 32.2, 31.9, 31.2, 30.2, 28.7, 27.6, 26.1, 17.2,
17.1, 14.2, 11.1; IR (NaCl): cm-1 2954.5, 2922.7, 1708, 1452,
1273.0, 114.8; HRMS (ESI) m/z calcd for C34H46O5 [M]þ
534.3345, found 534.3344 ( 0.0016.
Iodide S4: To a solution of alcohol 13 (350 mg, 0.54 mmol) in
CH2Cl2 (10mL) wasaddedPh3P (430 mg, 1.6 mmol) and imidazole
(148 mg, 2.1 mmol) at room temperature and I2 (274 mg, 1.08
mmol) at 0 °C. The contents were stirred at rt for 3 h. When TLC
showed the completion of the reaction, the reaction mixture was
quenched with Na2S2O3 solution and extracted with CH2Cl2
(3 ꢀ 8 mL). Combined extracts were washed with brine and con-
centrated to remove solvent. The residue was flashed on silica
(20% EtOAc/hexanes) to get iodide S4 (320 mg, 79%) as an oil.
Rf = 0.6 (40% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ
8.10-8.03 (m, 4H), 7.62-7.43 (m, 6H), 5.68-5.63 (m, 1H),
5.28-5.22 (m, 1H), 4.37-4.28 (m, 1H), 3.55-3.25 (m, 1H), 3.22
(dd, 1H, J = 9.33, 3.84 Hz), 3.12 (dd, 1H, J = 9.33, 5.48 Hz),
Diol 11: The keto-ester S3 (650 mg, 1.21 mmol) was placed in
a flame-dried, two-neck, round-bottom flask under argon.
Anhydrous THF (5 mL) was added, and the system was cooled
to -10 °C (ice þ NaCl mixture bath). LiAlH4 (2.0 M in THF,
3.0 mL, 7.30 mmol) was added slowly and cautiously at -10 °C.
After 30 min of stirring at -10 °C slowly, the mixture was
allowed to reflux for 1.5 h. The reaction mixture was then cooled
to -10 °C and quenched with a minimum amount of cold water
(4 mL), cautiously and very slowly. After the completion of
quenching, to the reaction mixture was added EtOAc (10 mL),
and it was allowed stir for 2.5 h at rt, then filtered on Celite using
EtOAc and CH2Cl2. The filtrate was dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. Purification
of the crude product by column chromatography (50% EtOAc/
hexanes) using silica gel afforded the diol 11 (451 mg, 86%) as a
white solid. Rf = 0.35 (SiO2, 30% EtOAc/hexanes); mp 247-
250 °C; [R]D20 -53.3 (c = 1.0, CHCl3); 1H NMR (CDCl3, 300
MHz): δ 4.39 (q, 1H, J = 7.13 Hz), 4.30 (br s, 1H), 4.04 (br s,
1H), 3.54-3.26 (m, 2H), 2.12-1.96 (m, 1H), 1.95-1.76 (m, 4H),
1.75-0.72 (m, 20H), 1.03 (s, 3H), 0.99 (s, 3H), 0.96 (d, 3H, J =
6.58 Hz), 0.78 (d, 3H, J = 6.03 Hz); 13C NMR (CDCl3, 75
2.26-2.80 (m, 3H), 1.96-1.80 (m, 2H), 1.75-0.92 (m, 32H); 13
C
NMR (75 MHz, CDCl3): δ165.9, 165.4, 133.9, 133.6, 132.9, 132.7,
132.2, 132.0, 129.8, 129.5, 128.7, 128.5, 128.4, 128.3, 90.2, 83.0,
70.2, 65.6, 57.9, 57.1, 44.2, 41.6, 38.0, 35.8, 34.8, 33.6, 33.1, 32.4,
31.8, 30.8, 27.6, 25.8, 20.4, 19.4, 18.8, 17.6, 14.8; IR (NaCl): cm-1
2931.0, 2853.4, 1738, 1736, 1452.4, 1089.2, 1063.6; HRMS (ESI)
m/z calcd for C41H53IO5 [M]þ 752.2938, found 752.2938 ( 0.0022.
Olefin 14: To a solution of the above iodide S4 (300 mg, 0.39
mmol) in DMF (5 mL) was added DBU at rt, and the contents
J. Org. Chem. Vol. 76, No. 5, 2011 1277

Ravindar et al.
JOCArticle
were stirred at 80-90 °C for 4 h. When TLC showed the com-
pletion of the reaction, the contents were cooled to rt and diluted
with water and extracted with EtOAc (3 ꢀ 8 mL). The combined
extracts were washed with water and brine and concentrated to
remove solvent. The residue was chromatographed on silica
(15% EtOAc/hexanes) to get olefin 14 (228 mg, 88%) as a yellow
oil. Rf = 0.5 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3): δ 8.12-8.04 (m, 4H), 7.62-7.43 (m, 6H), 5.70-5.64
(m, 1H), 5.28-5.23 (m, 1H), 4.70-4.65 (m, 1H), 4.38-4.30 (m,
1H), 3.38-3.30 (m, 1H), 2.28-0.94 (m, 36H); IR (NaCl): cm-1
2952, 1736, 1734, 1457.4, 1089, 1058; HRMS (ESI) m/z calcd for
C41H52O5 [M]þ 624.3815, found 624.3815 ( 0.0018.
Tertiary Alcohol 15: Tetrahydrofuran (1 mL) was added to a
solution of mercury(II) acetate (140 mg, 0.44 mmol) in water
(0.8 mL). The flask was wrapped in aluminum foil to exclude
light, and then a solution of olefin 14 (110 mg, 0.17 mmol) in
tetrahydrofuran (1 mL) was added to the solution of mercury(II)
acetate. After stirring at 23 °C for 16 h, NaBH4 (133 mg, 5.0
mmol) was added in portions over 5 min, and the solution was
stirred for 3 h. The reaction mixture was diluted with brine
(2 mL) and was extracted with ethyl acetate (4 ꢀ 3 mL). The
solution was dried over Na2SO4, the solids were removed by
filtration, and the solvent was removed in vacuo. The crude ma-
terial was purified by flash chromatography (25-50% EtOAc/
hexanes) to afford tertiary carbinol 15 (60 mg, 53%) along with
40% starting material (44 mg). Rf = 0.2 (40% EtOAc/hexanes);
1H NMR (300 MHz, CDCl3): δ 8.10-8.02 (m, 4H), 7.62-7.42
(m, 6H), 5.68-5.62 (m, 1H), 5.26-5.21 (m, 1H), 4.38-4.28 (m,
1H), 3.38-3.28 (m, 1H), 2.68 (brs, 1H), 2.28-2.04 (m, 3H),
1.96-0.92 (m, 36H); 13C NMR (75 MHz, CDCl3): δ 165.8,
165.4, 132.9, 132.8, 129.8, 129.5, 128.5, 128.3, 90.8, 83.1, 70.3,
70.0, 65.4, 58.0, 57.1, 44.1, 41.4, 40.9, 40.0, 38.0, 35.8, 33.1, 32.4,
32.3, 31.9, 29.8, 28.9, 27.9, 27.8, 25.9, 19.3, 18.6, 14.8; IR (NaCl):
cm-1 3410.8, 2930.1, 2848.3, 1447.2, 1094.3, 1058.5; HRMS
(ESI) m/z calcd for C41H54O6 [M]þ 642.3920, found 642.3920 (
0.0019.
contents were slowly heated to reflux for 1 h. After cooling to
room temperature, the mixture was slowly quenched with water
and the solids were filtered off. The filtrate was concentrated,
and the residue was chromatographed (33% EtOAc/hexanes) to
get diol 18 (11 mg, 83%) as a white solid. Rf = 0.25 (40%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ 4.25-4.28 (m,
1H), 4.16-4.00 (m, 2H), 2.24-0.78 (m, 39H); 13C NMR (75
MHz, CDCl3): δ 119.3, 77.1, 76.4, 67.1, 65.4, 59.9, 57.2, 56.0,
47.8, 38.9, 37.2, 35.9, 35.3, 34.3, 31.6, 31.0, 30.7, 30.0, 28.7, 28.3,
28.2, 27.6, 27.3, 26.9, 18.6, 14.6, 13.2; IR (NaCl): cm-1 3441.5,
2930.1, 1452, 1048.3; HRMS (ESI) m/z calcd for C27H44O4 [M]þ
432.3239, found 432.3244 ( 0.0013.
3,11-Dihydroxy-spiroketal 19: The preparation of 19 from 17
followed the same procedure as that described for the conver-
sion of 16 to 18. The yield of 19 was 88%. Rf = 0.3 (40% EtOAc/
1
hexanes); H NMR (300 MHz, CDCl3): δ 4.44 (dd, 1H, J =
15.3, 7.6 Hz), 4.30 (brs, 1H), 4.04 (brs, 1H), 2.13-0.76 (m, 39H);
13C NMR (75 MHz, CDCl3): δ 120.0, 82.0, 80.3, 68.1, 66.3, 62.4,
58.1, 57.8, 48.6, 39.9, 39.7, 38.3, 37.0, 36.2, 35.3, 33.6, 32.5, 31.8,
31.0, 30.2, 28.6, 28.4, 27.9, 19.0, 14.6, 14.3; IR (NaCl): cm-1
3442, 2930, 1452, 1049; HRMS (ESI) m/z calcd for C27H44O4
[M]þ 432.3239, found 432.3244 ( 0.0018.
Dibenzyl Ether 20: To a suspension of NaH (60% dispersion
in mineral oil, 248 mg, 6.240 mmol) in anhydrous THF (5 mL)
under argon at 0 °C was added diol 11 (450 mg, 1.040 mmol) in
anhydrous THF (2 mL), and the mixture was stirred for 30 min
at 0 °C and for 30 min at rt. The mixture was then cooled again
to 0 °C, and TBAI (768 mg, 2.08 mmol) was added, followed
by benzylbromide (0.310 mL, 2.60 mmol). The reaction mixture
was refluxed for 10 h, cautiously quenched with cold water at
0 °C, extracted with Et2O, and washed with brine solution. The
organic fractions were dried over anhydrous Na2SO4 and fil-
tered using a sintered funnel, and solvents were removed under
vacuum. Purification of the crude product by silica gel column
chromatography (6% EtOAc/hexanes) afforded the dibenzyl
ether 20 (541 mg, 85%) as a low-melting white foamy solid. Rf =
0.75 (SiO2, 10% EtOAc/hexanes); mp 65-68 °C; [R]D20 -16.3
(c = 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.43-7.27 (m,
10H), 4.69-4.18 (ABq, 2H, J = 11.52 Hz), 4.48 (q, 2H, J =
13.17 Hz), 4.44-4.33 (m, 1H), 3.90 (br s, 1H), 3.61 (br s, 1H),
3.53-3.27 (m, 2H), 2.34-2.20 (m, 1H), 2.12-1.92 (m, 2H),
1.92-0.82 (m, 22H), 1.02 (s, 3H), 0.98 (s, 3H), 0.97 (d, 3H, J =
6.58 Hz), 0.78 (d, 3H, J = 6.03 Hz); 13C NMR (CDCl3, 75
MHz): δ 139.4, 139.1, 128.3, 128.1, 127.3, 126.9, 109.4, 80.7,
75.1, 73.2, 70.0, 69.6, 66.8, 62.7, 58.3, 58.2, 41.5, 40.8, 40.4, 39.9,
36.1, 32.7, 32.6, 31.6, 31.5, 31.3, 30.3, 28.8, 27.9, 25.4, 18.2, 17.1,
14.5; IR (NaCl): cm-1 2918.3, 2839.4, 1446.9, 1354.9, 1046.0;
HRMS (ESI) m/z calcd for C41H56O4 [M]þ 612.4178, found
612.4188 ( 0.0018.
Spiroketals 16 and 17: To a mixture of iodine (62 mg, 0.25
mmol) and iodobenzene diacetate (80 mg, 0.25 mmol) in hexanes
(4 mL) was added a solution of compound 15 (80 mg, 0.12 mmol)
in CH2Cl2 (4 mL) over 15 min via cannula. After 2 h, the reaction
solution was quenched by addition of a saturated aqueous
sodium thiosulfate solution (4 mL), and the resulting mixture
was stirred for 20 min. The aqueous layer was extracted with
ethyl acetate (3 ꢀ 5 mL), and the combined organic layers were
dried over Na2SO4. Solids were removed by filtration, and the
solvent was removed in vacuo. The crude material was purified
by flash chromatography (10% EtOAc/hexanes) to provide
clean spiroketals 16 (15 mg, 19%) and 17 (50 mg, 63%).
Spiroketal 16. Rf = 0.7 (50% EtOAc/hexanes); 1H NMR (300
MHz, CDCl3): δ 8.10-8.02 (m, 4H), 7.62-7.42 (m, 6H), 5.69-
5.63 (m, 1H), 5.28-5.20 (m, 1H), 4.14-4.04 (m, 1H), 2.28-0.80
(m, 39H); 13C NMR (75 MHz, CDCl3): δ 165.8, 165.5, 132.9,
132.7, 129.8, 129.5, 128.4, 128.3, 120.5, 81.6, 78.3, 70.3, 61.1,
57.3, 56.7, 44.8, 41.4, 39.9, 38.3, 36.9, 35.9, 33.1, 32.5, 32.4, 32.2,
31.8, 29.7, 29.3, 28.3, 27.7, 25.9, 19.4, 15.7, 14.7; IR (NaCl):
cm-1 2953, 2932, 1736, 1090, 1025; HRMS (ESI) m/z calcd for
C41H52O6 [M]þ 640.3764, found 640.3771 ( 0.0018.
Acetate 21: In a flame-dried, single-neck, round-bottom flask
was placed spiroketal 20 (500 mg, 0.815 mmol). The flask was
fitted with a reflux condenser, and Ac2O (5.0 mL) was added.
Pyridine hydrochloride (757 mg, 6.526 mmol) (Py HCl; must be
3
a white crystalline solid, otherwise, yields are low) was then
added, and the mixture was refluxed at 135 °C for 2 h. The
mixture was then cooled to 0 °C, some ice and water were added
to quench the reaction, and the mixture was diluted with CH2Cl2
and extracted with CH2Cl2. The organic layer was washed three
times with water, and aqueous NaHCO3 solution was added
cautiously at 0 °C. The mixture was stirred for 30 min. It was
then separated using a separating funnel, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. Purification
of the crude product by silica gel column chromatography (5%
EtOAc/hexanes) afforded the acetate 21 (405 mg, 76%) as a
colorless viscous liquid. Rf = 0.55 (SiO2, 10% EtOAc/hexanes);
1
Spiroketal 17. Rf = 0.75 (50% EtOAc/hexanes); H NMR
(300 MHz, CDCl3): δ 8.10-8.02 (m, 4H), 7.62-7.42 (m, 6H),
5.68-5.62 (m, 1H), 5.26-5.21 (m, 1H), 4.54-4.44 (m, 1H),
2.25-0.80 (m, 39H); 13C NMR (75 MHz, CDCl3): δ 165.9,
165.4, 132.8, 132.7, 129.7, 129.5, 128.4, 128.3, 120.0, 82.1, 80.2,
70.3, 70.2, 62.5, 57.4, 57.0, 44.4, 41.3, 39.6, 38.3, 37.0, 35.9, 33.7,
33.0, 32.3, 31.9, 31.6, 30.2, 28.4, 27.6, 25.9, 19.0, 19.0, 14.7, 14.5;
IR (NaCl): cm-1 2952, 2931, 1734, 1091, 1025; HRMS (ESI) m/z
calcd for C41H52O6 [M]þ 640.3764, found 640.3771 ( 0.0021.
3,11-Dihydroxy-spiroketal 18: LiAlH4 (5 mg, 0.12 mmol) was
added to a solution of 16 (20 mg, 0.031 mmol) at 0 °C, and the
[R]D þ39.4 (c = 1.2, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
20
7.41-7.21 (m, 10H), 4.77-4.68 (m, 1H), 4.67-4.19 (ABq, 2H,
J = 11.52 Hz), 4.49 (q, 2H, J = 12.62 Hz), 3.97-3.82 (m, 3H),
1278 J. Org. Chem. Vol. 76, No. 5, 2011

Ravindar et al.
JOCArticle
20
3.61 (br s, 1H), 2.47-2.38 (d, 1H, J = 10.42 Hz), 2.34 (dd, 1H,
J = 14.27, 2.19 Hz), 2.26-1.89 (m, 4H), 2.02 (s, 3H), 1.88-1.70
(m, 3H), 1.65-0.82 (m, 18H), 1.01 (s, 3H), 0.92 (d, 3H, J = 6.58
Hz), 0.87 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 171.3, 151.6,
139.4, 139.2, 128.3, 128.1, 127.4, 127.3, 126.9, 103.8, 84.2, 75.2,
73.2, 70.1, 69.6, 69.2, 64.8, 58.4, 56.7, 42.9, 40.7, 40.5, 36.2, 33.8,
32.9, 32.7, 32.6, 32.1, 31.4, 30.8, 27.9, 25.4, 23.2, 20.9, 16.7, 15.6,
14.6, 11.8; IR (NaCl): cm-1 2919.9, 2848.3, 1743.8, 1452.3,
1232.4, 1058.5; HRMS (ESI) m/z calcd for C43H58O5 [M]þ
654.4284, found 654.4292 ( 0.0019.
colorless viscous liquids. Analytical data for 24: [R]D -15.2
(c = 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.41-7.18 (m,
10H), 4.96-4.82 (m, 2H), 4.65 (Abq, 1H, J = 11.52 Hz),
4.60-4.38 (m, 4H), 4.21 (Abq, 1H, J = 11.52 Hz), 4.01-3.79
(m, 3H), 3.61 (s, 1H), 2.54-2.33 (m, 2H), 2.05 (s, 3H), 2.20-1.90
(m, 2H), 1.88-1.71 (m, 3H), 1.68-0.84 (m, 20), 0.99 (s, 3H), 0.93
(d, 3H, J= 6.58Hz);13CNMR(CDCl3, 75 MHz):δ171.3, 153.4,
139.4, 139.0, 128.3, 128.1, 127.5, 127.4, 127.3, 127.0, 104.8,
84.6, 82.8, 75.2, 73.2, 70.1, 69.6, 69.3, 62.1, 58.4, 58.1, 42.9, 40.5,
39.5, 36.2, 33.9, 33.6, 32.7, 32.6, 31.9, 29.7, 29.3, 27.9, 25.4, 21.0,
17.0, 15.7, 14.6; IR (NaCl): cm-1 2978.3, 1739.1; HRMS (ESI)
m/z calcd for C43H58O5 [M]þ 654.4284, found 654.4292 (
0.0019. The procedure described above for the preparation of
compound 24 was employed as such for the pre-
Tertiary Alcohols 23 and 23A: A stirred solution of olefin 21
(600 mg, 0.91 mmol) in dichloromethane/acetone (4 mL/2 mL,
2:1) was treated with a cold (0 °C) solution of dimethyldioxirane
(DMDO) (1.37 mmol in 5 mL of acetone) at -10 °C. The reac-
tion was continued for 4 h at 0 °C. After completion of the reac-
tion, solvents were removed under reduced pressure (at room
temperature). The resulting crude epoxide 22 was immediately
dissolved in glacial AcOH, treated with NaBH3CN (172.8 mg,
2.75 mmol) at room temperature, and stirred for 1.5 h. It was
then quenched with ice water and extracted with CH2Cl2 (3 ꢀ 15
mL), and the organic layer was washed with water and aqueous
NaHCO3 (25 mL) solution, dried over anhydrous Na2SO4, fil-
tered, and concentrated under vacuum. Purification of the crude
product using Al2O3 (neutral) column chromatography (30 f
40% EtOAc/hexanes) afforded the diastereomeric (C-22) mix-
ture of alcohols (diastereomer 23, 197 mg, 32%, Rf = 0.38
(SiO2, 40% EtOAc/hexanes); diastereomer 23A, 296 mg, 48%,
Rf = 0.36 (SiO2, 40% EtOAc/hexanes)) in a 4:6 ratio as color-
less viscous liquids. These two diastereomers are used individu-
ally in subsequent transformations. Analytical data of diastere-
20
paration of 24A from 23A. Analytical data of 24A: [R]D
þ15.8 (c = 0.45, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.42-7.17 (m, 10H), 4.93-4.79 (m, 2H), 4.66 (ABq, 1H, J =
10.97 Hz), 4.56-4.32 (m, 3H), 4.22 (ABq, 1H, J = 10.97 Hz),
4.22-4.14 (m, 1H), 4.01-3.80 (m, 3H), 3.60 (s, 1H), 2.57-2.33
(m, 2H), 2.04 (s, 3H), 2.22-1.92 (m, 2H), 1.88-1.71 (m, 3H),
1.69-0.81 (m, 17H), 0.96 (s, 3H), 0.99 (s, 3H), 0.93 (d, 3H, J =
6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 171.3, 152.9, 139.4,
139.1, 128.3, 128.1, 127.4, 127.3, 126.9, 104.2, 84.1, 82.7, 76.2, 73.2,
70.0, 69.6, 69.4, 61.8, 58.8, 58.3, 42.6, 40.5, 39.9, 36.2, 32.8, 32.7,
32.6, 32.6, 31.9, 30.4, 30.2, 27.9, 25.4, 21.0, 17.0, 16.7, 14.6; IR
(NaCl): cm-1 2919.9, 1753.5, 1452, 1242.6, 1063.6; HRMS (ESI)
m/z calcd for C43H58O5 [M]þ 654.4284, found 654.4279 ( 0.0019.
Diols 26 and 26A: To a stirred solution of olefin 24 (250 mg,
0.381 mmol) in THF/water (3:1, 4.0 mL) wase added 4-methyl-
morpholine-N-oxide (105 mg, 0.894 mmol), followed by a solu-
tion of OsO4 in H2O (4% in H2O, 0.56 mL, 0.0025 mmol). The
resulting mixture was stirred for 12 h at rt. After the complete
conversion, THF was removed under reduced pressure. To this
crude diol was added EtOH/H2O (5:1, 5 mL), and the mixture
was cooled to -10 °C. NaIO4 (383 mg, 1.788 mmol) was then
added, and the mixture was stirred for 30 min at 0 °C and 15 min
at rt. EtOH was then removed under reduced pressure, and
water (2.5 mL) and brine solution (2.5 mL) were added. The
mixture was extracted with CH2Cl2, dried over anhydrous
Na2SO4, filtered, and concentrated. To this crude ketone 25 in
anhydrous THF (4.0 mL) was added methyl magnesium bro-
mide solution (3.0 M in THF, 0.761 mL, 2.28 mmol) dropwise at
-10 °C. The mixture was then slowly allowed to warm to 0 °C,
stirred for 30 min, quenched with aqueous NH4Cl solution (2
mL) at 0 °C, extracted with EtOAc (5 mL), washed with brine
solution, dried over anhydrous Na2SO4, and filtered, and
solvents were removed under reduced pressure. Purification of
the crude product by silica gel column chromatography (40 f
60% EtOAc/hexanes) afforded the diol 26 (132.5 mg, 55% for
omer 23: [R]D þ2.8 (c = 0.55, CHCl3); 1H NMR (CDCl3, 300
20
MHz): δ 7.43-7.13 (m, 10H), 4.75-4.55 (m, 2H), 4.54-4.39 (m,
2H), 4.33-4.17 (m, 1H), 4.02-3.77 (m, 3H), 3.77-3.51 (m, 2H),
2.53-2.33 (m, 1H), 2.04 (s, 3H), 2.20-1.94 (m, 2H), 1.93-0.73
(m, 21H), 1.38 (s, 3H), 1.19 (s, 3H), 1.01 (s, 3H), 0.95 (d, 3H, J =
6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 171.3, 139.4, 139.0,
128.3, 128.2, 127.4, 127.3, 127.1, 87.7, 81.7, 80.3, 75.2, 73.2, 70.3,
70.2, 69.6, 69.3, 58.2, 40.6, 40.5, 40.4, 36.2, 34.1, 32.9, 32.56,
30.9, 27.9, 26.9, 25.4, 21.0, 20.2, 16.9, 15.5, 14.6; IR (NaCl):
cm-1 3461.9, 2919.9, 2331.8, 1733.5, 1447.1, 1247.7; HRMS
(ESI) m/z calcd for C43H58O5 [M - H2O]þ 654.4284, found
20
654.4279 ( 0.0019. Analytical data of diastereomer 23A: [R]D
þ19.2 (c = 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.43-
7.15 (m, 10H), 4.73-4.58 (m, 1H), 4.54-4.38 (m, 3H), 4.34-
4.18 (m, 1H), 4.01-3.78 (m, 3H), 3.74-3.50 (m, 2H), 2.54-2.35
(m, 1H), 2.04 (s, 3H), 2.18-1.93 (m, 2H), 1.90-1.69 (m, 5H),
1.60-0.0.81 (m, 16H), 1.39 (s, 3H), 1.15 (s, 3H), 1.01 (s, 3H),
0.93 (d, 3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 171.3,
139.4, 139.11, 128.3, 128.1, 127.4, 127.3, 127.0, 92.3, 81.4, 81.3,
75.1, 73.2, 72.1, 70.2, 69.6, 69.3, 59.3, 58.2, 40.9, 40.4, 36.1, 32.7,
32.5, 32.4, 31.9, 31.3, 30.9, 27.9, 25.4, 21.2, 20.9, 18.0, 16.9, 14.5;
IR (NaCl): cm-1 3461.6, 2930.1, 1738.6, 1467.6, 1247.7; HRMS
(ESI) m/z calcd for C43H58O5 [M - H2O]þ 654.4284, found
654.4292 ( 0.0019.
20
three steps). Rf = 0.30 (SiO2, 50% EtOAc/hexanes); [R]D
þ14.2 (c = 0.4, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.40-7.18 (m, 10H), 4.67 (ABq, 1H, J = 11.52 Hz), 4.57-
4.40 (m, 3H), 4.22 (ABq, 1H, J = 11.52 Hz), 4.01-3.85 (m, 2H),
3.61 (s, 1H), 3.53-3.36 (m, 2H), 2.64-2.52 (m, 1H), 2.17-1.88
(m, 2H), 1.87-1.65 (m, 6H), 1.66-0.78 (m, 18H), 1.27 (s, 3H),
1.01 (s, 3H), 0.92 (d, 3H, J = 6.58 Hz); 13C NMR (CDCl3, 75
MHz): δ 139.4, 139.1, 128.3, 128.1, 127.5, 127.4, 127.3, 127.0,
85.8, 81.9, 80.5, 75.1, 73.2, 70.1, 69.6, 68.0, 67.3, 58.3, 57.7, 42.3,
40.8, 40.5, 36.2, 36.0, 34.9, 32.7, 32.2, 30.7, 30.4, 28.2, 27.9, 26.2,
25.4, 16.7, 16.2, 14.5; IR (NaCl): cm-1 3405.7, 2919.9, 2853.4,
1452.3, 1094.3, 1063.6; HRMS (ESI) m/z calcd for C40H55O5
[M - CH3]þ 615.4049, found 615.4061 ( 0.0018. The procedure
described above for the preparation of compound 26 was
employed as such for the preparation of 26A from 24A. Analy-
Exocyclic Olefins 24 and 24A: The alcohol 23 (350 mg, 0.52
mmol) was dissolved in anhydrous pyridine (4.5 mL) and cooled
to 0 °C. To this stirring solution was added SOCl2 (0.432 mL, 5.2
mmol) dropwise over 10 min. After stirring for 10 min, the ice
bath was removed, and the solution was stirred for 45 min. After
completion of the reaction, the contents were slowly and cau-
tiously poured into ice, and water (2.0 mL) and Et2O (5.0 mL)
were added. The solution was extracted with Et2O, washed with
water and brine solution, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Purification of the crude
product by Al2O3 (neutral) column chromatography (10%
EtOAc/hexanes) afforded the exocyclic olefin 24 (260 mg, Rf =
0.52 (SiO2, 15% EtOAc/hexanes)) and enolether 21 (28.9 mg,
Rf = 0.55 (SiO2, 15% EtOAc/hexanes) in a 9:1 ratio, 85%) as
20
1
tical data of 26A: [R]D þ18.8 (c = 0.45, CHCl3); H NMR
(CDCl3, 300 MHz): δ 7.48-7.12 (m, 10H), 4.76-4.56 (m, 1H),
4.56-4.33 (m, 2H), 4.31-4.02 (m, 2H), 3.98-3.76 (m, 1H),
3.69-3.25 (m, 4H), 2.69-2.41 (m, 1H), 2.23-1.94 (m, 4H),
J. Org. Chem. Vol. 76, No. 5, 2011 1279

Ravindar et al.
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20
1.92-0.68 (m, 19H), 1.34 (s, 3H), 1.27 (s, 3H), 1.01 (s, 3H), 0.91 (d,
3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 139.4, 139.1,
128.3, 128.1, 127.4, 127.7, 126.9, 90.1, 81.9, 80.4, 74.9, 73.1, 70.0, 69.,
68.9, 67.8, 59.1, 58.2, 42.2, 40.9, 40.4, 36.0, 35.6, 32.6, 32.4, 31.9, 31.1,
30.9, 30.0, 27.9, 26.2, 25.3, 18.5, 16.7, 14.5; IR (NaCl): cm-1 3400.6,
2919.9, 2858.5, 1452.3, 1094.3, 1068.8; HRMS (ESI) m/z calcd for
C40H55O5 [M - CH3]þ 615.4049, found 615.4061 ( 0.0018.
Analytical data of 27A: [R]D þ16.8 (c = 0.4, CHCl3); 1H NMR
(CDCl3, 300 MHz): δ 7.45-7.19 (m, 10H), 4.79-4.63 (m, 3H),
4.58-4.41 (m, 2H), 4.31-4.12 (m, 2H), 3.91 (s, 1H), 3.61 (s, 1H),
3.51-3.35 (m, 1H), 2.68-2.51 (m, 1H), 2.28-1.95 (m, 4H),
1.89-1.67 (m, 3H), 1.72 (s, 3H), 1.66-0.74 (m, 18H), 1.34 (s,
3H), 1.01 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 145.8, 139.4,
139.0, 128.3, 128.1, 127.4, 127.3, 126.9, 109.7, 89.5, 81.9, 80.5,
74.9, 73.2, 70.0, 69.6, 68.9, 59.2, 58.2, 42.2, 40.9, 40.4, 36.1, 34.7,
32.7, 32.6, 32.5, 31.9, 30.9, 27.9, 27.2, 25.4, 22.7, 18.6, 14.5; IR
(NaCl): cm-1 3448.6, 2930, 2858.6, 1457.4, 1094, 1063; HRMS
(ESI) m/z calcd for C41H56O4 [M]þ 612.4178, found 612.4188 (
0.0018.
Iodide S5 and S5-A: To the diol 26 (110 mg, 0.17 mmol) in
anhydrous CH2Cl2 (2.5 mL) under an argon atmosphere was
added triphenylphosphine (228 mg, 0.87 mmol) and imidazole
(81 mg, 1.19 mmol), followed by iodine (129.5 mg, 0.51 mmol) at
0 °C. The reaction mixture was allowed to stir for 1.5 h at room
temperature, and then it was quenched with aqueous Na2S2O3
(5.0 mL) solution. It was then extracted with CH2Cl2 (5 mL) and
washed with water and brine solution. The organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the crude product by silica gel
column chromatography (12% EtOAc/hexanes) afforded iodide
S5 (98.15 mg, 76%). Rf = 0.50 (SiO2, 20% EtOAc/hexanes);
Diols 28 and 28A: The procedure used here is the same as that
described for the conversion of 14 to 15. Purification by flash
chromatography (35/45% EtOAc/hexanes) using silica gel gave
the alcohol 28 (31.5 mg, 68%) as a colorless viscous liquid. Rf =
20
0.35 (SiO2, 50% EtOAc/hexanes); [R]D þ18.6 (c = 0.6,
1
CHCl3); H NMR (CDCl3, 300 MHz): δ 7.43-7.17 (m, 10H),
4.67 (ABq, 1H, J = 11.52 Hz), 4.55-4.42 (m, 3H), 4.22 (ABq,
1H, J = 11.52 Hz), 4.02-3.86 (m, 2H), 3.61 (s, 1H), 3.47 (brs,
1H), 2.63-2.53 (m, 1H), 2.16-1.88 (m, 3H), 1.86-1.68 (m, 4H),
1.67-0.79 (m, 18H), 1.29 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 1.01(s,
3H); IR (NaCl): cm-1 3410.8, 2930.1, 2848.3, 1447.2, 1094.3,
1058.5; HRMS (ESI) m/z calcd for C40H55O5 [M - CH3]þ
615.4049, found 615.4061 ( 0.0018. The procedure described
above for the preparation of compound 28 was employed as such
for the preparation of 28A from 27A. Analytical data of 28A:
20
1
[R]D þ6.8 (c = 0.4, CHCl3); H NMR (CDCl3, 300 MHz): δ
7.43-7.18 (m, 10H), 4.67 (ABq, 1H, J = 11.52 Hz), 4.57-4.37
(m, 3H), 4.22 (ABq, 1H, J = 11.52 Hz), 3.98-3.83 (m, 2H), 3.61
(s, 1H), 3.31-3.19 (m, 1H), 3.18-3.04 (m, 1H), 2.65-2.47 (m,
1H), 2.17-1.88 (m, 2H), 1.87-1.64 (m, 3H), 1.63-0.75 (m, 21H),
1.27 (s, 3H), 1.01 (s, 3H), 0.99 (d, 3H, J = 6.58 Hz); 13C NMR
(CDCl3, 75 MHz): δ 139.4, 139.0, 128.3, 128.1, 127.5, 127.8,
127.3, 127.0, 85.5, 81.9, 80.6, 75.1, 73.2, 70.1, 69.6, 67.3, 58.3, 57.7,
42.3, 40.9, 40.5, 36.2, 35.2, 34.9, 33.8, 32.7, 32.5, 30.7, 28.2, 27.9,
26.3, 25.4, 20.5, 17.5, 16.3, 14.5; IR (NaCl): cm-1 3446.6, 2914.8,
2858.6, 1457.4, 1094.3, 1063.6; HRMS (ESI) m/z calcd for
C41H57IO4 [M]þ 740.3301, found 740.3289 ( 0.0022. The proce-
dure described above for the preparation of compound S5 was
employed as such for the preparation of S5-A from 26A. Analy-
20
[R]D þ21.6 (c = 0.8, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.42-7.18 (m, 10H), 4.69 (ABq, 1H, J = 11.52 Hz), 4.54-4.42
(m, 2H), 4.24 (ABq, 1H, J = 11.52 Hz), 4.23-4.16 (m, 1H), 3.90
(s, 1H), 3.60 (s, 1H), 3.46-3.38 (m, 1H), 2.64-2.54 (m, 1H),
2.13-1.99 (m, 3H), 1.84-0.79(m, 19H), 1.36 (s, 3H), 1.34(s, 3H),
1.21(s, 6H), 1.01 (s, 3H); IR (NaCl): cm-1 3410, 2930, 2844, 1446,
1094.1, 10582; HRMS (ESI) m/z calcd for C40H55O5 [M - CH3]þ
615.4049, found 615.4061 ( 0.0018. 13C NMR for compounds 28
and 28A was not analyzed; both of these C22 diastereomers were
used as such in subsequent transformations.
20
1
tical data of S5-A: [R]D þ12.2 (c = 0.45, CHCl3); H NMR
(CDCl3, 300 MHz): δ 7.42-7.19 (m, 10H), 4.70 (ABq, 1H, J =
12.07 Hz), 4.53-4.39 (m, 2H), 4.24 (ABq, 1H, J = 12.07 Hz),
4.22-4.12 (m, 1H), 3.91 (s, 1H), 3.61 (s, 1H), 3.46-3.32 (m, 1H),
3.31-3.11 (m, 2H), 2.66-2.51 (m, 1H), 2.19-1.96 (m, 2H),
1.87-1.64 (m, 4H), 1.63-0.84 (m, 20H), 1.34 (s, 3H), 1.01 (s,
3H), 0.98 (d, 3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ
139.4, 139.1, 128.29, 128.1, 127.3, 127.3, 126.9, 89.9, 82.0, 80.4,
74.9, 73.2, 70.0, 69.6, 68.8, 59.1, 58.2, 42.2, 40.9, 40.4, 36.1, 34.9,
33.7, 32.7, 32.6, 32.4,31.9, 31.1, 30.9, 27.9, 26.6, 25.4, 20.6, 18.6,
17.8, 14.5; IR (NaCl): cm-1 3477.3, 2930.1, 2853.4, 1452.3,
1089.2, 1063.6; HRMS (ESI) m/z calcd for C41H57IO4 [M]þ
740.3301, found 740.3289 ( 0.0022.
Ketone 29: To a well-stirred solution of compound 20 (500
mg, 0.81 mmol) in glacial acetic acid (8.5 mL) was added BF3
3
Et2O (0.640 mL, 4.86 mmol) slowly dropwise, and the mixture
was stirred for 5 min at room temperature. NaNO2 (619 mg, 8.91
mmol) was then added in small portions over an hour. The
stirring was maintained for 1 additional hour. The mixture was
poured into cool water and extracted with CH2C12 (2 ꢀ 30 mL).
The organic layer was washed with water (2 ꢀ 10 mL), 5%
NaOH (2 ꢀ 10 mL), and water (3 ꢀ 10 mL) and dried over an-
hydrous Na2S04, and the solvent was evaporated under vacuum.
The syrupy crude product was dissolved in benzene/hexanes
(10 mL, 3:2) and allowed to stand in a chromatographic column
packed with Brockmann activity-III (Al2O3 with 6.0 wt % of
H2O) before slow elution with 5-10% EtOAc/hexane. Eva-
poration of the solvent afforded the ketone 29 (51 mg, 10%) as a
viscous liquid. Rf = 0.50 (SiO2, 10% EtOAc/hexanes); 1H NMR
(CDCl3, 300 MHz): δ 7.44-7.20 (m, 10H), 4.62-4.57 (m, 1H),
4.55-4.50 (m, 2H), 4.27-4.15 (m, 1H), 3.90 (s, 1H), 3.85-3.72
(m, 1H), 3.62 (s, 1H), 3.59-3.52 (m, 1H), 2.97-2.83 (m, 1H),
2.49-2.51 (m, 2H), 2.38-2.19 (m, 2H), 2.13-1.94 (m, 2H),
1.88-1.66 (m, 4H), 1.64-0.72 (m, 14H), 0.94 (d, 3H, J = 6.58
Hz), 0.99 (s, 6H), 1.01 (s, 3H); IR (NaCl): cm-1 2918.3, 2839,
1732; HRMS (ESI) m/z calcd for C41H55O5 [M þ H]þ 627.4044,
found 627.4052 (Diff(ppm) = 1.28).
Terminal Olefins 27 and 27A: To a solution of iodide S5 (75
mg, 0.10 mmol) in anhydrous DMF (1.5 mL) was added DBU
(76.6 μL, 0.30 mmol), and the mixture was heated at 85 °C for
4.5 h. After completion of the reaction, water and EtOAc were
added and the mixture was extracted with EtOAc, dried over
anhydrous Na2SO4, and concentrated under vacuum. Purifica-
tion of the crude product by flash chromatography (5% EtOAc/
hexanes) using silica gel afforded the olefin 27 (57 mg, 92%) as a
20
colorless liquid. Rf = 0.53 (SiO2, 20% EtOAc/hexanes); [R]D
þ12.5 (c = 0.42, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.42-7.17 (m, 10H), 4.76-4.61 (m, 3H), 4.57-4.40 (m, 3H),
4.30-4.18 (m, 1H), 4.01-3.86 (m, 2H), 3.61 (s, 1H), 2.65-2.53
(m, 1H), 2.27-1.91 (m, 4H), 1.86-1.68 (m, 3H), 1.72 (s, 3H),
1.66-0.80 (m, 18H), 1.28 (s, 3H), 1.01 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 145.9, 139.4, 139.1, 128.3, 128.1, 127.5,
127.4, 127.2, 127.0, 109.7, 85.2, 81.9, 80.6, 75.1, 73.2, 70.2, 69.6,
67.3, 58.3, 57.7, 42.3, 40.9, 40.5, 36.2, 35.1, 34.9, 32.7, 32.6, 32.5,
30.8, 29.1, 27.9, 26.3, 25.4, 22.6, 16.2, 14.5; IR (NaCl): cm-1
3446.6, 2925, 2858.6, 1457.4, 1089, 1058; HRMS (ESI) m/z calcd
for C41H56O4 [M]þ 612.4178, found 612.4188 ( 0.0018. The
procedure described above for the preparation of compound 27
was employed as such for the preparation of 27A from S5-A.
Ketone 29a: The procedure described above for the prepara-
tion of the ketone 29 was employed as such in this reaction. The
dibenzoate 12a (620 mg, 0.96 mmol) was treated with BF3 Et2O
3
(0.785 mL, 5.76 mmol), followed by NaNO2 (733 mg, 10.56
mmol), to afford the ketone 29a (410 mg) in 65% yield. Rf =
0.45 (SiO2, 15% EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz):
δ 8.13-7.95 (m, 4H), 7.62-7.38 (m, 6H), 5.66(brs, 1H), 5.23 (brs,
1280 J. Org. Chem. Vol. 76, No. 5, 2011

Ravindar et al.
JOCArticle
1H), 4.73-4.54 (m, 1H), 3.86-3.68 (m, 1H), 3.64-3.49 (m, 1H),
2.92-2.74 (m, 1H), 2.46-2.35 (m, 2H), 2.33-2.01 (m, 4H),
1.97-0.75 (m, 16H), 0.98 (s, 3H), 0.96 (s, 3H), 0.91 (d, 3H, J =
6.58 Hz), 0.88 (d, 3H, J = 7.13 Hz); 13C NMR (CDCl3, 75 MHz):
δ 201.6, 165.9, 165.4, 132.9, 132.8, 131.0, 130.5, 129.72, 129.5,
128.5, 128.3, 109.9, 83.1, 70.3, 70.0, 65.6, 62.4, 57.6, 57.0, 45.2,
44.1, 41.3, 40.1, 35.9, 35.6, 34.7, 33.0, 32.3, 31.9, 31.6, 27.6, 25.9,
18.9, 17.1, 14.7, 14.3; IR (NaCl): cm-1 2952, 2934, 1737, 1733,
1086, 1020; HRMS (ESI) m/z calcd for C41H51O7 [M þ H]þ
655.3635, found 655.3648 ( 0.0020.
4.54-4.43 (m, 1H), 3.52 (dd, 1H, J = 10.97, 4.94 Hz), 3.43 (t,
1H, J = 10.97 Hz), 2.12 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H),
2.16-1.94 (m, 4H), 1.89-0.71 (m, 18H), 0.97 (d, 3H, J = 7.13
Hz), 0.91 (s, 3H), 1.89 (s, 3H), 0.83 (d, 3H, J = 6.03 Hz), 0.77 (d,
3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 170.8, 170.6,
170.1, 109.4, 108.4, 81.2, 74.6, 69.7, 69.5, 66.4, 64.5, 57.6, 56.6,
52.3, 43.8, 40.9, 40.0, 39.9, 36.5, 35.7, 32.7, 32.2, 31.7, 31.0, 27.6,
26.5, 25.7, 21.9, 21.5, 20.9, 18.4, 15.9, 14.2, 14.1, 13.9; IR (NaCl):
cm-1 2956, 2931, 1738, 1241, 1091, 1051, 1025; HRMS (ESI) m/z
calcd for C34H52O8 [M]þ 588.3712, found 588.3712 ( 0.0012.
Acyloxy Ketone 39: The cyclic enol ether 21 (400 mg, 0.610
mmol) was dissolved in AcOH (2.5 mL) and cooled to 10 °C. To
this stirring solution was added CrO3 solution (1.4 M in 9:1
Ac2O/H2O, 0.760 mL, 1.067 mmol) dropwise over 10 min and
NaOAc (87.6 mg, 1.067 mmol). After stirring for 30 min, the ice
bath was removed, water (2.0 mL) and Et2O (5.0 mL) were
added, and the mixture was extracted with Et2O, washed with
water and brine solution, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Purification of the crude
product by silica gel column chromatography (20/30% EtOAc/
hexanes) afforded compound 39 (314 mg, 75%) as a colorless
Methylated Ketone 30: To a solution of Li-HMDS (1.0 M in
THF, 1.60 mL, 1.60 mmol) in THF at -78 °C was added a solu-
tion of ketone 29a (350 mg, 0.53 mmol) slowly over 15 min,
and the resulting mixture was stirred at -78 °C for 45 min. CH3I
(100 μL, 1.60 mmol) was added to the reaction mixture, and the
resulting solution was stirred at -78 °C for 20 min and at room
temperature for 2 h. The reaction mixture was quenched by
addition of saturated NH4Cl and extracted with Et2O. Combined
extracts were concentrated in vacuum. Purification of the crude
product by silica gel column chromatography (8% EtOAc/
hexanes) afforded the methylated compound 30 (equatorial/axial
isomers in a 2:1 ratio, 304 mg, 85%) as a viscous liquid. Rf = 0.55
20
viscous liquid. Rf = 0.71 (SiO2, 40% EtOAc/hexanes); [R]D
1
(SiO2, 10% EtOAc/hexanes); H NMR (CDCl3, 300 MHz): δ
þ40.6 (c = 2.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.48-7.09 (m, 10H), 5.59-5.37 (m, 1H), 4.78-4.62 (m, 1H),
4.48 (q, 2H, J = 12.07 Hz), 4.27-4.17 (m, 1H) 4.01-3.78 (m,
3H), 3.61 (br s, 1H), 2.72-2.57 (m, 1H), 2.56-2.13 (m, 4H), 2.07
(s, 3H), 2.04 (s, 3H), 2.12-0.74 (m, 19H), 1.25 (s, 3H), 0.99 (s,
3H), 0.92 (d, 3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ
205.5, 173.0, 171.2, 139.4, 138.9, 128.3, 128.1, 127.7, 127.4,
127.3, 127.0, 74.7, 74.2, 73.1, 70.2, 69.6, 68.8, 67.2, 58.5, 55.8,
42.1, 40.4, 39.0, 36.1, 34.9, 32.5, 32.3, 32.0, 31.9, 30.8, 30.6, 28.3,
27.8, 25.3, 20.9, 16.3, 15.1, 14.5; IR (NaCl): cm-1 2927.3, 2850.1,
1736.4, 1709.1, 1450, 1231.8, 1063.6; HRMS (ESI) m/z calcd for
C36H52O7 [M - C7H6]þ 596.3713, found 596.3716 ( 0.0018.
Diol 41: In a flame-dried, two-neck, round-bottom flask under
an argon atmosphere was placed keto-diester 39 (300 mg, 0.436
mmol) in anhydrous THF (2.0 mL). Vinylmagnesium bromide
solution (1.0 M in THF, 4.36 mL, 4.360 mmol) was added drop-
wise at ambient temperature. After 30 min, the reaction was
quenched with aqueous NH4Cl solution (2 mL) at 0 °C. The mix-
ture was extracted with EtOAc (5 mL), washed with brine solu-
tion, dried over anhydrous Na2SO4, and filtered. The solvents
were removed under reduced pressure. Purification of the crude
product by silica gel column chromatography (10/20% EtOAc/
hexanes) afforded a C20-diastereomeric mixture of allylalcohol
(major/minor (8:2), 224 mg, 92%). The major diastereomer 41
had a slightly higher Rf value (TLC) than that of the minor
diasteromer, and it was only separated partially from the minor
isomer. Major diastereomer: Rf = 0.70 (SiO2, 40% EtOAc/
8.11-8.01 (m, 4H), 7.63-7.39 (m, 6H), 5.69-5.63(m, 1H), 5.27-
5.21 (m, 1H), 4.69-4.54 (m, 1H), 3.90-3.73 (m, 1H), 3.65-3.49
(m, 1H), 2.87-2.36 (m, 2H), 2.28-2.01 (m, 3H), 1.96-0.76 (m,
32H). 13C NMR of this compound was not analyzed due to the
diastereomeric mixture (equatorial/axial isomers). IR (NaCl):
cm-1 2956, 2932, 1736, 1734, 1086; HRMS (ESI) m/z calcd for
C42H53O7 [M þ H]þ 669.3791, found 669.3798 ( 0.0020.
Ketone S6: To a well-stirred solution of NaOMe (198 mg, 3.74
mmol) in MeOH was added a solution of the ketone 30 (250 mg,
0.37 mmol) in MeOH at room temperature, and the mixture was
allowed to stir for 45 min. After the completion of the reaction,
the solvent was removed under reduced pressure and the residue
was diluted with ether and water at 0 °C and extracted with Et2O.
The combined extracts were dried over anhydrous Na2SO4, fil-
tered, and concentrated under vacuum. Purification of the analy-
tical sample by silica gel column chromatography (30% EtOAc/
hexanes) afforded the isomerized product S6 (194 mg, 92%) as a
1
white solid. Rf = 0.45 (SiO2, 40% EtOAc/hexanes); H NMR
(CDCl3, 300 MHz): δ 8.09-7.99 (m, 2H), 7.62-7.38 (m, 3H),
5.69-5.60 (m, 1H), 4.71-4.56 (m, 1H), 4.01 (s, 1H), 3.85 (t, 1H,
J = 11.52 Hz), 3.53 (dd, 1H, J = 11.52, 4.90 Hz), 2.80 (qt, 1H, J =
6.58 Hz), 2.58-2.45 (m, 1H), 2.23-2.04 (m, 3H), 1.85-1.80 (m,
2H), 1.79-1.66 (m, 2H), 1.65-0.79 (m, 16H), 0.88 (s, 3H), 1.02 (d,
3H, J = 6.58 Hz), 0.97 (d, 3H, J = 6.58 Hz), 0.91 (s, 3H). Only the
analytical sample was purified due to the formation of byproducts
(due to 3 and 11-OBz groups deprotection), hence 13C NMR was
not analyzed. IR (NaCl): cm-1 3521, 2952, 2928, 1736, 1734;
HRMS (ESI) m/z calcd for C35H48O6[M]þ 564.3468, found
564.3468 ( 0.0018.
Triacetate 31: A mixture of ketone S6 (45 mg, 0.079 mmol)
and hydrazine hydrate (60 μL, 1.19 mmol) and powdered KOH
(100 mg, 1.99 mmol) in ethylene glycol (2 mL) was heated at
180 °C for 4 h. After cooling to room temperature, water was ad-
ded, and the mixture was extracted with CH2Cl2, washed with
brine solution, and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure. The crude product was
dissolved in anhydrous pyridine and treated with Ac2O, fol-
lowed by DMAP. The resulting reaction mixture was allowed to
stir at room temperature for 24 h. It was then diluted with water,
extracted with CH2Cl2, dried over anhydrous Na2SO4, and
concentrated under vacuum. Purification of the crude product
by Al2O3 (neutral) column chromatography (12% EtOAc/
hexanes) afforded the triacetate 31 (31.8 mg, 68% for two steps).
Rf = 0.45 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 300
MHz): δ 5.29 (s, 1H), 4.99 (s, 1H), 4.91 (d, 1H, J = 2.19 Hz),
20
hexanes); [R]D þ25.4 (c = 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz): δ 7.42-7.22 (m, 10H), 6.10 (dd, 1H, J = 17.01, 10.42
Hz), 5.33 (dd, 1H, J = 17.01, 1.64 Hz), 5.03 (dd, 1H, J = 10.42,
1.64 Hz), 4.76-4.19 (ABq, 2H, J = 10.97 Hz), 4.55-4.42 (m,
3H), 3.92 (br s, 1H), 3.62 (br s, 1H), 2.94 (br s, 1H), 2.75-2.65 (m,
1H), 2.28-2.15 (m, 1H), 2.05-1.89 (m, 1H), 1.88-1.71 (m, 2H),
1.61-0.72 (m, 17H), 1.38 (s, 3H), 0.99 (s, 3H); 13C NMR (CDCl3,
75 MHz): δ 148.1, 139.4, 139.0, 128.3, 128.1, 127.7, 127.4, 127.3,
127.1, 110.4, 76.5, 75.4, 74.5, 73.3, 70.4, 69.6, 61.6, 58.5, 55.9, 43.0,
41.5, 40.5, 36.2, 32.5, 32.4, 30.8, 28.4, 27.9, 25.3, 16.7, 14.5; IR
(NaCl): cm-1 3339.2, 2919.9, 2853.4, 1355.1, 1094.9, 1063.6,
910.23, 731.25; HRMS (ESI) m/z calcd for C37H48O3 [M -
H2O]þ 540.3603, found 540.3604 ( 0.0016.
Hydroxy Ketone 37: To a stirred solution of olefin 41 (250 mg,
0.447 mmol) in THF/water (3:1, 3.0 mL) was added 4-methyl-
morpholine-N-oxide (105 mg, 0.894 mmol), followed by a
solution of OsO4 in H2O (4% in H2O, 0.59 mL, 0.003 mmol).
The resulting mixture was stirred for 12 h at rt. After the com-
plete conversion, THF was removed under reduced pressure.
J. Org. Chem. Vol. 76, No. 5, 2011 1281

Ravindar et al.
JOCArticle
To this crude tetrol was added EtOH/H2O (5:1), and the mixture
was cooled to 0 °C. NaIO4 (383 mg, 1.788 mmol) was then
added, and the mixture was stirred for 30 min at 0 °C and 15 min
at rt. Water (2.5 mL) and brine solution (2.5 mL) were then
added, and the mixture was extracted with CH2Cl2, dried over
anhydrous Na2SO4, filtered, and concentrated. Purification
of the crude product by silica gel column chromatography
(20/30% EtOAc/hexanes) afforded the β-hydroxy ketone 37
(132 mg, 56%) as a white solid. Rf = 0.52 (SiO2, 40% EtOAc/
hexanes); mp 156-158 °C; [R]D þ52.5 (c = 0.5, CHCl3); H
NMR (CDCl3, 300 MHz): δ 7.40-7.25 (m, 10H), 4.68-4.28 (q,
2H, J = 11.3 Hz), 4.50 (q, 2H, J = 11.10 Hz), 4.62-4.50 (m,
1H), 3.99 (m, 1H), 3.62 (m, 1H), 2.56-2.51 (m, 1H), 2.40-0.79
(m, 18H), 2.21 (s, 3H), 1.12 (s, 3H), 1.02 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 213.3, 139.4, 138.8, 128.3, 128.2, 127.7,
127.4, 127.3, 127.2, 75.2, 73.2, 72.2, 70.6, 69.7, 66.5, 58.5, 55.5,
43.8, 40.5, 40.3, 36.9, 36.2, 32.7, 32.5, 32.4, 31.4, 27.9, 25.4, 16.5,
14.6; IR (NaCl): cm-1 3606.3, 3495.1, 2930.1, 2854.5, 1713.1,
1681.3, 1450, 1363.1; HRMS (ESI) m/z calcd for C35H46O4 [M]þ
530.3396, found 530.3408 ( 0.0016.
as a white solid. Rf = 0.35 (SiO2, 30% EtOAc/hexanes). Ana-
lytical data were in good agreement with the literature, and a
copy of the 1H NMR spectrum is provided in the Supporting In-
formation to demonstrate the purity.
24-Desmethylhippuristanol 3 and 24-desmethyl-22-epi-hippur-
istanol 4 via Suarez Cyclization: To a mixture of Iodine (23.9
mg, 0.095 mmol), and iodobenzene diacetate (30.6 mg, 0.095
mmol) in hexanes (1 mL) was added a solution of 28, 28A
(30 mg, 0.047 mmol) in CH2Cl2 (1 mL). After 2 h, the reaction
solution was quenched by addition of a saturated aqueous
sodium thiosulfate solution (2 mL), and the resulting mixture
was stirred until clear. The aqueous layer was extracted with
ethyl acetate (3 ꢀ 2 mL), and the combined organic layers were
dried over Na2SO4. Solids were removed by filtration, and the
solvent was removed under reduced pressure. To the crude
material was added to Li (metal) (5.64 mg, 0.94 mmol) in liquid
ammonia at -35 °C in anhydrous THF. After 30 min of stirring
at -35 °C, the mixture was quenched with solid NH4Cl, and
then excess NH3 was evaporated using a constant air flow. The
material was diluted with water, extracted with EtOAc, dried
over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. Purification by flash chromatography (15/20%
acetone/hexanes) using silica gel afforded 22-epi-24-desmethyl-
hippuristanol 4 (9.95 mg, Rf = 0.36 (SiO2, 30% acetone/hex-
anes)) and 24-desmethylhippuristanol 3 (8.15 mg, Rf = 0.38
(SiO2, 30% acetone/hexanes)) in 5.5:4.5 isolated (85% for two
steps) ratios as white solids. Analytical data of 24-desmethyl-22-
20
1
Enone 40: Compound 39 (300 mg, 0.43 mmol) was dissolved
in benzene (10 mL). To this mixture was added Al2O3 (basic,
1.0 g), and it was stirred at rt for 2.5 h. After completion of the
reaction, the contents were filtered using Celite and washed with
CH2Cl2. The solvents were removed under reduced pressure.
Purification by silica gel column chromatography (10% EtOAc/
hexanes) afforded the enone 40 (212 mg, 95%) as a colorless oil.
20
20
Rf = 0.55 (SiO2, 20% EtOAc/hexanes); [R]D þ95.6 (c = 0.7,
epi-hippuristanol 4: [R]D -36.8 (c = 0.65, CHCl3/MeOH
1
CHCl3); H NMR (CDCl3, 300 MHz): δ 7.39-7.27 (m, 10H),
(1:1)); 1H NMR (CDCl3 þ 5% CD3OD, 300 MHz): δ 4.36
(dd, 1H, J = 12.62, 7.68 Hz), 4.22 (br s, 1H), 3.94 (br s, 1H),
2.20-2.04 (m, 2H), 2.04-0.76 (m, 20H), 1.26 (s, 3H), 1.24 (s,
3H), 1.23 (s, 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.71 (dd, 1H, J =
10.97, 2.74 Hz); 13C NMR (CDCl3 þ 5% CD3OD, 300 MHz): δ
120.9, 82.6, 82.2, 79.2, 67.74 66.2, 66.5, 58.3, 57.9, 48.3, 41.9,
39.8, 36.8, 36.1, 35.0, 32.3, 31.9, 31.6, 31.4, 30.2, 29.7, 28.3, 28.1,
27.4, 26.8, 19.2, 13.9; HRMS (ESI) m/z calcd for C27H45O5 [M þ
H]þ 449.3267, found 449.3273 ( 0.0013.Analytical data of 24-
6.69 (m, 1H), 4.81-4.22 (q, 2H, J = 11.4 Hz), 4.26 (q, 2H, J =
11.1 Hz), 3.98 (m, 1H), 3.63 (m, 1H), 3.01 (m, 1H), 2.26 (s, 3H),
2.3-0.8 (m, 17 H), 1.16 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3,
75 MHz): δ 196.8, 156.3, 144.4, 139.5, 139.2, 128.3, 128.1, 127.7,
127.4, 127.3, 126.9, 73.2, 70.2, 69.6, 59.4, 58.4, 45.8, 40.8, 36.4,
36.2, 32.7, 32.4, 32.3, 30.7, 27.9, 27.1, 25.3, 17.5, 14.7; IR (NaCl):
cm-1 2922, 2862.5, 1665.3, 1589.3, 1454, 1359, 1060; HRMS
(ESI) m/z calcd for C35H44O3 [M]þ 512.3290, found 512.3291 (
0.0015.
20
desmethylhippuristanol 3: [R]D þ60.4 (c = 0.45, CHCl3/
1
r-Bromo Ketone S7: The enone 40 (210 mg, 0.41 mmol) was
dissolved in acetone (5 mL), THF (1 mL), and H2O (0.5 mL),
and NBA (N-bromoacetamide, 169.78 mg, 1.23 mmol) was ad-
ded at room temperature. The mixture was stirred for 18 h in the
dark, and another portion of NBA (113.14 mg, 0.82 mmol) was
added. The stirring continued for an additional 10 h, and the
mixture was diluted with EtOAc (25 mL). The organic layer was
washed with saturated Na2SO3 and brine solution, dried over
anhydrous Na2SO4, and filtered, and then the solvent was re-
moved under vacuum. The crude product was purified by silica
gel column chromatography (10% EtOAc/hexanes) to afford
the R-bromo ketone S7 (141 mg, 56.5%) as a viscous liquid.
MeOH (1:1)); H NMR (CDCl3 þ 5% CD3OD, 300 MHz): δ
4.32-4.16 (m, 2H), 3.96 (br s, 1H), 2.19-2.06 (m, 1H),
2.07-1.94 (m, 1H), 1.94-0.86 (m, 20H), 1.32 (s, 6H), 1.26 (s,
3H), 1.11 (s, 3H), 0.97 (s, 3H), 0.86-0.70 (m, 1H); 13C NMR
(CDCl3 þ 5% CD3OD, 100 MHz): δ 116.4, 83.1, 80.6, 78.6,
68.12, 66.4, 66.3, 58.4, 57.4, 49.7, 42.3, 39.9, 37.2, 36.5, 35.4,
34.3, 33.8, 32.6, 31.8, 30.4, 30.3, 28.7, 28.4, 28.3, 27.9, 18.5, 14.1;
HRMS (ESI) m/z calcd for C27H45O5 [M þ H]þ 449.3267, found
449.3273 ( 0.0013.
Hydroxy Alkyne 44: To the terminal alkyne 43 (87.5 mg, 2.24
mL, 0.480 mmol) in anhydrous THF (1.5 mL) under argon
was added n-butyllithium solution (1.6 M solution in hexane,
0.292 mL, 0.480 mmol) at -78 °C. The resultant mixture was
stirred at -78 °C for 1 h, followed by the addition of ketone 37 (85
mg, 0.160 mmol) in anhydrous THF (1.2 mL). The resultant
mixture was stirred at -78 °C for 2 h, then quenched with satu-
rated aqueous NH4Cl solution at -78 °C, warmed to 0 °C, diluted
with water, extracted with EtOAc, dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. Purification by flash
column chromatography (silica gel, gradient elution with 10/20%
EtOAc/hexane) afforded the coupled product 44 (93.6 mg, 82%)
20
Rf = 0.60 (SiO2, 30% EtOAc/hexanes); [R]D þ17.4 (c = 0.35,
1
CHCl3); H NMR (CDCl3, 300 MHz): δ 7.36-7.25 (m, 10H),
4.95 (m, 1H), 4.68-4.30 (q, 2H, J = 11.4 Hz), 4.49 (q, 2H, J =
11.2 Hz), 4.04 (m, 1H), 3.62 (m, 1H), 2.40 (s, 3H), 2.39-1.0 (m,
19 H), 1.37 (s, 3H), 1.01 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ
204.1, 139.4, 138.7, 128.3, 128.2, 127.6, 127.4, 127.3, 85.5, 82.0,
75.5, 73.1, 70.7, 69.7, 57.8, 50.6, 45.7, 40.4, 37.9, 36.1, 34.3, 32.7,
32.5, 32.2, 31.8, 28.5, 27.8, 25.4, 15.8, 14.6; IR (NaCl): cm-1
36.05, 3517, 2940.9, 2859.1, 1702, 1693.2, 1454, 1359, 1270;
HRMS (ESI) m/z calcd for C35H45O4Br [M - OBr]þ 513.3368,
found 513.3365 ( 0.0015.
1
as a viscous liquid. Rf = 0.65 (SiO2, 40% EtOAc/hexanes); H
NMR (CDCl3, 300 MHz) mixture of (OTHP) diastereomers: δ
7.43-7.20 (m, 10H), 4.94-4.75 (m, 1H), 4.74-4.60 (m, 2H),
4.60-4.41 (m, 2H), 4.25-4.17 (m, 1H), 4.03-3.85 (m, 2H), 3.61
(s, 1H), 3.52-3.39 (m, 1H), 2.73-2.57 (m, 1H), 2.52-0.75 (m,
29H), 1.31 (s, 6H), 1.27 (s, 3H), 0.98 (s, 3H). 13C NMR was not
analyzed; the diastereomeric (OTHP ether) mixture was used as
such in the next step. IR (NaCl): cm-1 3390, 2919.6, 2852.2, 1446,
1348, 1156.31, 1060. We could not obtain HRMS data for this
Compound 37: To a solution of bromide S7 (125 mg, 0.20
mmol) in anhydrous CH2Cl2 (2.5 mL) was added Bu3SnH (0.543
mL, 2.05 mmol), followed by Et3B (1 M in hexane, 0.2 mL,
0.4 mmol) and air with an empty syringe (1 mL). The reaction
was allowed to stir for 35 min at rt and then concentrated. The
resulting residue was purified by silica gel column chromatog-
raphy (25/30% EtOAc/hexanes) to afford the 37 (100 mg, 92%)
1282 J. Org. Chem. Vol. 76, No. 5, 2011

Ravindar et al.
JOCArticle
compound after several attempts. This may be due to the insta-
bility of the OTHP group; hence, the LRMS (low-resolution mass
spectrum) is provided. LRMS (ESI-MS) m/z: [M - H2O]þ = 696.
24-Desmethylhippuristanol 3 and 24-desmethyl-22-epi-hippur-
istanol 4 via Hg(OTf)2-Catalyzed Spiroketalization: To a stirred
mixture of hydroxy alkyne 44 (60 mg, 0.084 mmol) and H2O
(4.54 mg, 0.252 mmol) in CH3CN (1.5 mL) was added Hg(OTf)2
(8.38 mg, 0.0168 mmol) at room temperature, and the mixture
was stirred for 20 min at the same temperature. The reaction was
quenched by the addition of Et3N (40 μL). The resulting mixture
was diluted with Et2O (2 mL) and extracted with Et2O, and the
combined extracts were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude product 45
was subjected to Birch reduction. A flame-dried, two-neck,
round-bottom flask was topped with a dry ice condenser, and
the system was flushed with argon. The condenser was filled
with a dry ice/acetone mixture. Ammonia was condensed, and
the lithium metal (10.08 mg, 1.68 mmol) (washed with hexane)
was added cautiously through the side neck of the round-bottom
flask. The contents were stirred at -33 °C until no further lithium
was seen, and when bronze globules (golden liquid) started to
appear, the system was allowed to equilibrate to the refluxing
temperature (-33 °C). THF (1.5 mL) was added to disperse the
newly formed reagent, and then a solution of crude dibenzylether
was added slowly. A cautious addition is needed to ensure a re-
gular andsmoothammoniareflux. The reaction mixture was then
stirred at -33 °C for 1.5 h and NH4Cl powder was carefully and
slowly added at -33 °C to quench the excess of lithium. Ammo-
nia was allowed to evaporate under a stream of air. To the residue
was added H2O (5 mL), and it was extracted with EtOAc (5 mL).
The combined extracts were dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification by
silica gel column chromatography (15% acetone/hexanes) af-
forded 22-epi-24-desmethylhippuristanol 4 (25.04 mg) and 24-
desmethylhippuristanol 3 (6.26 mg) (22S/22R in an 8:2 ratio,
respectively, 83% for two steps) as white solids. Analytical data
wereingood agreementwiththe literatureandwithdataobtained
under reduced pressure. Purification of the crude product by
silica gel column chromatography (5% EtOAc/hexanes) afforded
the THP ether 48 (1.390 g, 90%, mixture of diastereomers
obtained due to OTHP group) as a yellow oil. Rf = 0.82 (SiO2,
20% EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) mixture of
diastereomers: δ 7.71-7.64 (m, 4H), 7.47-7.32 (m, 6H), 4.75-
4.69 (m, 1H), 3.92-3.78 (m, 1H), 3.56-3.45 (m, 1H), 3.45-3.32
(m, 1H), 1.92-1.79 (m, 1H), 1.79-1.65 (m, 1H), 1.94-0.98 (m,
24H); 13C NMR (CDCl3, 75 MHz) mixture of diastereomers: δ
135.7, 129.5, 127.6, 93.2, 93.0, 65.5, 65.4, 62.8, 62.71, 45.7, 45.4,
32.3, 26.9, 26.8, 25.5, 25.2, 24.1, 22.9, 20.4, 20.3, 19.4, 19.3, 12.8,
12.6; IR (NaCl): cm-1 2940.3, 2858.5, 1427.7, 1421.6, 1358.8,
1114.8, 1079.0, 981.8, 823.3, 700.5; HRMS (ESI) m/z calcd for
C23H31O3Si [M - C4H9]þ 383.2042, found 383.2044 ( 0.0011.
Alcohol 49: TBDPS ether 48 (1.3 g, 2.949 mmol) was placed in
a flame-dried, round-bottom flask under an argon atmosphere.
To this was added anhydrous THF (10 mL), followed by TBAF
(1.0 M in THF, 5.89 mL, 5.899 mmol) at 0 °C. The cooling bath
was removed, and the system was allowed to stir at room tem-
perature for 3 h. After complete conversion, the reaction mix-
ture was as such concentrated and flashed through silica gel
column chromatography (30% EtOAc/hexanes) to afford the
alcohol 49 (506 mg, 86%) as a colorless oil. Rf = 0.12 (SiO2,
20% EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) mixture of
diastereomers: δ 4.95-4.82 (m, 1H), 4.05-3.86 (m, 1H), 3.80-
3.39 (m, 4H), 2.01-0.81 (m, 16H); 13C NMR (CDCl3, 75 MHz)
mixture of diastereomers: δ 93.4, 93.1, 81.0, 65.8, 62.9, 62.9,
44.5, 44.4, 32.2, 26.4, 25.2, 25.1, 22.0, 20.8, 20.3, 20.2, 13.0; IR
(NaCl): cm-1 3431.3, 2976.1, 2950.6, 1442.2, 1467.6, 1365.3,
1130.1, 1022.7, 986.9.
Aldehyde 50: Anhydrous powdered molecular sieves (4 A, 200
mg) were placed in a flame-dried, round-bottom flask under an
argon atmosphere. It was then cooled to 0 °C, and anhydrous
CH2Cl2 (5 mL) was added. Alcohol 49 (300 mg, 1.478 mmol)
in anhydrous CH2Cl2 (3 mL) was added, and the content was
stirred for 10 min. 4-Methylmorpholine-N-oxide (347 mg, 2.966
mmol) was then added, followed by tetrapropylammonium-
perruthenate (TPAP) at 0 °C, and it was allowed to stir at room
temperature for 1 h. After the completion of the reaction, some
silica gel was added to the reaction mixture and it was directly
subjected to column chromatography (12% EtOAc/hexanes) to
afford the aldehyde 50 (245 mg, 82%) as an oily liquid. Rf = 0.4
(SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz)
mixture of diastereomers: δ 9.93-6.87 (m, 1H), 4.93-4.83 (m,
1H), 3.99-3.87 (m, 1H), 3.53-3.42 (m, 1H), 2.62-2.41 (m, 1H),
1.91-1.01 (m, 15H); 13C NMR (CDCl3, 75 MHz) mixture of
diastereomers: δ 205.8, 205.5, 93.6, 93.1, 63.0, 62.8, 55.7, 55.4,
32.05, 25.9, 25.3, 24.6, 24.2, 22.9, 20.2, 20.0, 9.4; IR (NaCl):
cm-1 2981.3, 2945.5, 2868.8, 1723.3, 1452.1, 1390.9, 1380.7,
1130.1, 1073.9, 1027.8, 981.8, 869.3; HRMS (ESI) m/z calcd for
C11H20O3 [M]þ 200.1412, found 200.1412 ( 0.0006.
ꢀ
˚
1
via Suarez cyclization, and a copy of the H NMR spectrum is
provided in the Supporting Information.
TBDPS Ether S8: To an ice-cold solution of diol 46 (500 mg,
4.231 mmol) and imidazole (576 mg, 8.462 mmol) in anhydrous
CH2Cl2 (4.0 mL) was added TBDPS-Cl (1.30 mL, 5.077 mmol)
in CH2Cl2 (1.0 mL). After stirring for 15 min at 0 °C, the reaction
mixture was brought to room temperature, and the stirring was
continued for 1 h. It was then quenched with saturated aqueous
NH4Cl solution and extracted with CH2Cl2. The combined ex-
tracts were washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuum. The residue was purified
by silica gel column chromatography (100% hexanes to 10%
EtOAc/hexanes) to afford the pure primary monosilylether S8
(1.417 g, 94%) as a viscous liquid. Rf = 0.8 (SiO2, 40% EtOAc/
20
hexanes); [R]D þ5.8 (c = 1.5, CHCl3); 1H NMR (CDCl3, 300
Alkyne 36: To trimethylsilyldiazomethane (2.0 M solution in
Et2O, 2.24 mL, 4.488 mmol) in anhydrous THF (1.5 mL) under
argon was added n-butyllithium solution (1.6 M solution in hex-
ane, 2.33 mL, 3.744 mmol) at -78 °C. The resultant mixture was
stirred at -78 °C for 45 min, and aldehyde 50 (150 mg, 0.748
mmol) in anhydrous THF (1.2 mL) was added. The resultant
mixture was stirred at -78 °C for 30 min and warmed to 0 °C
over 40 min. The reaction mixture was recooled to -78 °C,
quenched with saturated aqueous NH4Cl solution, warmed to
0 °C, diluted with water, extracted with Et2O, dried over anhy-
drous Na2SO4, filtered, and concentrated under vacuum. Puri-
fication of the crude product by flash column chromatography
(silica gel, 4% EtOAc/hexane) afforded terminal alkyne 36 (125
mg, 85%) as a pale yellow oil. Rf = 0.75 (SiO2, 20% EtOAc/
MHz): δ 7.77-7.60 (m, 4H), 7.50-7.32 (m, 6H), 3.78-3.61 (m,
2H), 1.97-1.79 (m, 1H), 1.23 (s, 3H), 1.19 (s, 3H), 1.06 (s, 9H),
0.80 (d, 3H, J = 6.58 Hz); 13C NMR (CDCl3, 75 MHz): δ 135.7,
129.9, 127.8, 67.9, 43.9, 29.1, 26.8, 24.6, 12.9; IR (NaCl): cm-1
3456.8, 3083.5, 2965.9, 2930.1, 2858.5, 1472.7, 1426.7, 1114.8,
1058.5, 823.3; HRMS (ESI) m/z calcd for C18H23O2Si [M -
C4H9]þ 299.1467, found 299.1468 ( 0.0009.
TBDPS-THP Ether 48: To the alcohol S8 (1.25 g, 3.505
mmol) in anhydrous CH2Cl2 (8.0 mL) under an argon atmo-
sphere was added 3,4-dihydro-2H-pyran (DHP, 0.639 mL,
7.011 mmol), followed by pyridine-p-toluenesulfonate (PPTS,
176 mg, 0.701 mmol). The reaction mixture was allowed to stir
for 2.5 h at room temperature and then quenched with aqueous
NaHCO3 (5.0 mL) solution. It was then extracted with CH2Cl2
and washed with water and brine solution. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated
1
hexanes); H NMR (CDCl3, 300 MHz) mixture of diastereo-
mers: δ 4.87-4.74 (m, 1H), 4.03-3.88 (m, 1H), 3.55-3.36 (m,
1H), 2.73-2.54 (m, 1H), 2.05-2.04 (m, 1H), 1.97-1.93 (m, 1H),
J. Org. Chem. Vol. 76, No. 5, 2011 1283

Ravindar et al.
JOCArticle
1.74-1.60 (m, 1H), 1.59-1.14 (m, 13H); 13C NMR (CDCl3, 75
MHz) mixture of diastereomers: δ 94.1, 93.5, 69.4, 63.2, 62.9, 36.9,
32.2, 29.7, 25.9, 25.5, 24.4, 22.3, 21.6, 20.6, 20.2, 15.6; IR (NaCl):
cm-1 2931, 2860.5, 1448.9, 1360.8, 1243.7, 1149.3, 1125.7, 1020,
984.7. We could not obtain HRMS data for this compound after
several attempts; this may be due to the instability of the OTHP
group. LRMS (ESI-MS) m/z [M - C5H9O]þ: 113.
and when bronze globules (golden liquid) started to appear, the
system was allowed to equilibrate to the refluxing temperature
(-33 °C). THF (1.5 mL) was added to disperse the newly formed
reagent, and then a solution of dibenzylether 51 (70 mg, 0.109
mmol) was added slowly. A cautious addition is needed to en-
sure a regular and smooth ammonia reflux. The reaction mix-
ture was then stirred at -33 °C for 1.5 h, and NH4Cl powder was
carefully and slowly added at -33 °C to quench the excess of
lithium. Ammonia was allowed to evaporate under a stream of
air. To the residue was added H2O (5 mL), and the mixture was
extracted with EtOAc (5 mL). The combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. Purification bysilica gelcolumn chromatography
(15% acetone/hexanes) afforded 22-epi-hippuristanol 2 (45.95
mg, 92%) as a white solid. Rf = 0.38 (SiO2, 30% acetone/
Dihydroxy Alkyne 34: To the terminal alkyne 36 (99.8 mg,
2.24 mL, 0.508 mmol) in anhydrous THF (1.5 mL) under argon
was added n-butyllithium solution (1.6 M solution in hexane,
0.321 mL, 0.508 mmol) at -78 °C. The resultant mixture was
stirred at -78 °C for 1 h, followed by the addition of ketone 37
(90 mg, 0.169 mmol) in anhydrous THF (1.2 mL). The resultant
mixture was stirred at -78 °C for 2 h and then quenched with
saturated aqueous NH4Cl solution at -78 °C, warmed to 0 °C,
diluted with water, extracted with EtOAc, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. Purification
by flash column chromatography (silica gel, gradient elution
with 4-20% EtOAc/hexane) afforded the coupled product 34
(98.5 mg, 80%) as a viscous liquid. Rf = 0.73 (SiO2, 40%
EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) mixture of
diastereomers: δ 7.45-7.20 (m, 10H), 4.95-4.61 (m, 3H),
4.59-4.39 (m, 2H), 4.31-4.13 (m, 1H), 4.01-3.83 (m, 2H),
3.73-3.57 (m, 1H), 3.54-3.35 (m, 1H), 2.76-2.56 (m, 1H),
hexanes); [R]D -45.8 (c = 0.5, CHCl3/CH3OH (1:1)); 1H
20
NMR (CDCl3 þ 2% CD3OD, 300 MHz): δ 4.46-4.34 (m,
1H), 4.24 (br s, 1H), 3.98 (br s, 1H), 2.29-2.16 (m, 1H),
2.16-2.07 (m, 1H), 2.06-0.79 (m, 19H), 1.27 (s, 3H), 1.25 (s,
3H), 1.23 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H), 0.89 (d, 3H, J = 6.58
Hz), 0.79-0.69 (dd, 1H, J = 10.97, 3.29 Hz); 13C NMR (CDCl3 þ
2% CD3OD, 75 MHz): δ 118.7, 84.3, 82.33, 79.1, 67.7, 66.3, 66.1,
58.3, 57.9, 48.3, 41.9, 40.9, 39.7, 36.1, 35.0, 32.3, 31.6, 31.4, 30.2,
28.9, 28.3, 27.8, 26.9, 22.8, 19.1, 13.9, 13.8; HRMS (ESI) m/z
calcd for C28H46O5 [M]þ 462.3345, found 462.3348 ( 0.0014.
Hippuristanol 1: 22-epi-Hippuristanol 2 (45 mg, 0.097 mmol)
was dissolved in CHCl3 (1.0 mL) in a single-neck, round-bottom
flask, and to this solution was added pyridine-p-toluenesulfo-
nate (PPTS, 3.74 mg, 0.015 mmol) at rt. After stirring for 8.5 h at
room temperature, the solvent was removed under the reduced
pressure. Chromatography of the residue (without further
workup) on silica gel (15% acetone/hexanes) afforded hippur-
istanol 1 (18.9 mg, 87% brsm (based on recovered starting
material of 42%) as a white solid. Rf = 0.4 (SiO2, 30%
2.29-2.11 (m, 1H), 2.08-1.73 (m, 4H), 1.72-0.73 (m, 38H); 13
C
NMR (CDCl3, 75 MHz) mixture of diastereomers: δ 139.4,
138.8, 128.9, 128.1, 127.5, 127.4, 127.3, 127.1, 94.1, 93.4, 86.5,
83.6, 77.7, 77.6, 75.4, 73.2, 72.8, 70.4, 69.6, 67.7, 63.2, 62.7, 59.7,
58.5, 56.9, 42.5, 40.6, 36.7, 36.1, 35.3, 32.5, 32.4, 32.2, 31.0, 29.7,
27.9, 27.9, 25.9, 25.5, 25.4, 25.4, 24.4, 22.9, 21.8, 20.6, 20.2, 15.8,
15.6, 15.6, 15.4, 14.6, 7.7, 7.6, 7.5; IR (NaCl): cm-1 3389.3,
2919.2, 2848.2, 1448.9, 1349.1, 1155.1, 1061.1, 1020.2, 762.2. We
could not obtain HRMS data for this compound after several
attempts; this may be due to the instability of the OTHP group.
LRMS (ESI-MS) m/z [M - C5H6O]þ: 644.
20
acetone/hexanes); [R]D þ31.7 (c = 0.45, CCl4); 1H NMR
Spiroketal 51: To a stirred mixture of dihydroxy-alkyne 34 (90
mg, 0.123 mmol) and H2O (11.13 mg, 0.615 mmol) in CH3CN
(1.5 mL) was added Hg(OTf)2 (12.3 mg, 0.0246 mmol) at room
temperature, and the mixture was stirred for 10 min at the same
temperature. The reaction was quenched by the addition of
Et3N (50 μL). The resulting mixture was diluted with Et2O
(2 mL) and extracted with Et2O, and the combined extracts were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was subjected to silica gel
column chromatography (elution with 12% EtOAc/hexanes) to
afford the spiroketal 51 (71.5 mg, 90%) as a white solid. Rf =
0.48 (SiO2, 20% EtOAc/hexanes); 1H NMR (CDCl3 þ 5%
CD3OD, 300 MHz): δ 7.38-7.18 (m, 10H), 4.66-4.13 (ABq,
2H, J = 10.97 Hz), 4.50-4.39 (m, 2H), 4.39-4.30 (m, 1H),
3.88-3.81 (m, 1H), 3.61-3.54 (m, 1H), 2.48 (dd, 1H, J = 13.72,
1.64 Hz), 2.11-1.92 (m, 2H), 1.81-1.68 (m, 3H), 1.55-0.83 (m,
21H), 1.28 (s, 3H), 1.11 (s, 3H), 1.10 (d, 3H, J = 6.03 Hz), 0.92
(s, 3H), 0.82-0.74 (m, 1H); 13C NMR (CDCl3 þ 5% CD3OD,
75 MHz): δ 139.3, 138.9, 128.2, 128.1, 127.6, 127.4, 127.3, 127.0,
122.5, 83.7, 82.1, 79.0, 74.7, 73.20, 70.2, 69.6, 67.3, 58.8,
58.0, 49.0, 42.8, 40.4, 36.1, 32.6, 32.4, 31.2, 30.7, 307, 29.7,
29.6, 27.8, 25.3, 22.4, 19.7, 18.9, 14.3; IR (NaCl): cm-1 3612.6,
3001.5, 2954.5, 2919.2, 1448.9, 1378.4, 1357.9, 1243.3, 1161.0,
1084.6, 1061.4, 1046.4, 1025.9, 964.2, 917.1, 879.1; HRMS
(ESI) m/z calcd for C42H58O5 [M]þ 642.4284, found 642.4284 (
0.0019.
(300 MHz, 9:1 CCl4/C6D6): δ 4.15-4.03 (m, 2H), 3.80 (br s,
1H), 2.71 (s, 1H), 2.25-2.13 (m, 1H), 2.07-1.96 (m, 1H),
1.94-0.65 (m, 19H), 1.24 (s, 3H), 1.18 (s, 3H), 1.14 (s, 3H),
1.10 (s, 3H), 0.90 (s, 3H), 0.86 (d, 3H, J = 7.13 Hz), 0.62-0.54
(m, 1H); 13C NMR (75 MHz, 9:1 CCl4/C6D6): δ 115.6, 84.4,
80.5, 79.4, 68.1, 66.6, 66.2, 58.7, 57.6, 50.6, 42.6, 42.1, 41.2, 40.2,
36.8, 36.0, 34.5, 33.1, 31.8, 30.6, 29.6, 29.1, 28.5, 23.6, 18.9, 15.5,
14.3; HRMS (ESI) m/z calcd for C27H43O5 [M - CH3]þ 447.3110,
found 447.3113 ( 0.0013.
Assessment of Biological Activity. The biological activity of
the compounds was tested in in vitro translation reactions using
rabbit reticulocyte lysates as per the manufacturer’s instructions
(Promega Corp.) (Bordeleau et al. 2006).1a The compound was
added to translation reactions to a final concentration of 5 μM.
Translation reactions were programmed with FF/HCV/Ren
mRNA (8 μg/mL) and contained a final concentration of 135
mM KCl. After 1 h at 30 °C, aliquots were removed and moni-
tored with a Berthold Lumat LB 9507 luminometer following
addition of the Firefly or Renilla luciferase substrate. Data for
Firefly luciferase were normalized to Renilla luciferase readings
(since translation of the latter is resistant to hippuristanol) and
compared to vehicle controls. Experiments were always per-
formed alongside reactions containing 5 μM hippuristanol pur-
ified from natural sources as a positive control.1a
Acknowledgment. We thank the NSERC for funding. We
also thank Atul Mahajan and Gopalpeta Venkata Ramana for
valuable model studies and for providing starting materials.
22-epi-hippuristanol 2: A flame-dried, two-neck, round-bottom
flask was topped with a dry ice condenser, and the system was
flushed with argon. The condenser was filled with a dry ice/
acetone mixture. Ammonia was condensed, and the lithium
metal (13 mg, 2.176 mmol) (washed with hexane) was added
cautiously through the side neck of the round-bottom flak. The
contents were stirred at -33 °C until no further lithium was seen,
1
Supporting Information Available: H and 13C spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1284 J. Org. Chem. Vol. 76, No. 5, 2011