Synthesis of the potent anticancer agents ottelione A and ottelione B in both racemic and natural optically pure forms

Article abstract of DOI:10.1021/jo702635t

(Chemical Equation Presented) The powerful antitumor agents ottelione A and B were synthesized in racemic form by a method that relies on selective ring closing metathesis. Optically pure natural (+)-ottelione A was then made from D-ribose, via an α-keto cyclopropane. A key feature of the route is that the cyclopropyl group controls the stereochemistry in the attachment of the ArCH₂ unit and is then converted by the action of SmI₂ into a vinyl group, so that the substituents on the resulting five-membered ring have the required trans relationship. Epimerization of an intermediate gave access by the same method to the trans ring fused isomer (-)-ottelione B.

Full text of DOI:10.1021/jo702635t

Synthesis of the Potent Anticancer Agents Ottelione A and Ottelione
B in Both Racemic and Natural Optically Pure Forms
Derrick L. J. Clive* and Dazhan Liu
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.cliVe@ualberta.ca
ReceiVed December 12, 2007
The powerful antitumor agents ottelione A and B were synthesized in racemic form by a method that
relies on selective ring closing metathesis. Optically pure natural (+)-ottelione A was then made from
D-ribose, via an R-keto cyclopropane. A key feature of the route is that the cyclopropyl group controls
the stereochemistry in the attachment of the ArCH2 unit and is then converted by the action of SmI2 into
a vinyl group, so that the substituents on the resulting five-membered ring have the required trans
relationship. Epimerization of an intermediate gave access by the same method to the trans ring fused
isomer (-)-ottelione B.
Introduction
The otteliones, designated as A (1)1,2 and B (2),1 are
exceedingly powerful anticancer agents,1 as judged by in vitro
tests against a large panel of tumor cell lines. Both compounds
were isolated from a freshwater plant, Ottelia alismoides,3
collected in Egypt,1 but the amount of each obtained represented
only 0.0009% of the dried weight of the sample. Structural
Ottelione A was found to be identical to a compound, also
isolated from O. alismoides, that had been described without
any stereochemistry assignment in a Rhone-Poulenc Rorer
patent.2 A later publication from the Rhone-Poulenc Rorer
laboratories4 assigned the relative stereochemistry shown in 1
to ottelione A, based on NOE measurements, and this conclusion
was subsequently confirmed by synthesis of the racemic
compound.5 Both the NMR structural work1 and the investiga-
tions at Rhone-Poulenc Rorer2,4 were combined with biological
evaluations that served to identify the extremely strong anti-
cancer activity. In the case of the evaluation1 at the National
Cancer Institute (U.S.) against a panel of ca. 60 tumor cell lines,
the impressive level of activity was quantified, and the
compounds were found to have GI50 values in the subnanomolar
studies were undertaken in the United States,1 and extensive
NMR investigations served to identify the structure and relative
stereochemistry of ottelione B as shown in 2. In the case of
ottelione A, however, these studies suggested the two possibili-
ties, 3 and 4.
(1) Ayyad, S.-E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R. J. Org. Chem.
1998, 63, 8102-8106.
(2) Leboul, J.; Provost, J. WO 96/00205.
(3) Cook, C. D. K.; Symoens, J.-J.; Urmi-Ko¨nig, K. Aquatic Botany 1984,
18, 263-274.
(4) Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.; Prod’homme,
F.; Herman, F.; Lavelle, F.; Leboul, J.; Vuilhorgne, M. Mol. Pharmacol.
2000, 57, 553-563. This publication identifies what is here called ottelione
A as substance PRP112378.
(5) Mehta, G.; Islam, K. Angew. Chem., Int. Ed. 2002, 41, 2396-2398.
10.1021/jo702635t CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/15/2008
3078
J. Org. Chem. 2008, 73, 3078-3087

Potent Anticancer Agents Ottelione A and B
to picomolar range. Ottelione B appears to be less potent than
ottelione A. Ottelione A has been shown to inhibit tubulin
polymerization and is able to disassemble preformed microtu-
bules.4 Some of the information available on the anticancer
activity of the otteliones appears to have been reported only in
a Ph.D. Thesis6 and in the Abstracts of ACS National Meetings.7
Ottelione B appears to be more selective toward cancer cell
lines than ottelione A.6 Extracts of O. alismoides also have been
reported to kill tubercular bacteria.8
isomer, ottelione B. During the course of these studies, the
racemic epi-ottelione derivatives 11 and 12 also were prepared.14
Examination of the structures of the otteliones raises the
possibility that they might be prone to tautomerization to the
aromatic compound 5, and in fact, 5 was isolated along with 12
Finally, Mehta and Islam described the synthesis of both
antipodes of otteliones A and B15 and established that the natural
compounds have the absolute configurations depicted by
structures 1 and 2. Again, the synthesis of ottelione B was by
way of a DBU-induced epimerization of the cis isomer (83%
yield). At the same time Katoh et al. independently synthesized
natural (+)-ottelione A and epimerized it to (-)-ottelione B.16
However, they reported that epimerization with DBU gave a
1:1 mixture of the two otteliones and found that the epimer-
ization was best performed with t-BuOK in t-BuOHsconditions
that led to a 1:3.3 mixture of the A/B isomers. Separation was
difficult but could be achieved by chiral HPLC to give ottelione
B (the major isomer of the mixture) in 23% yield. The same
group also prepared 3-epi-ottelione A in optically pure form.17
A very recent paper18 gives full details of the Japanese work
including growth inhibition data and inhibitory activity against
tubulin polymerization for (+)-ottelione A (1), (+)-3-epi-
ottelione A, and (+)-O-acetyl-3-epi-ottelione A; all are ex-
tremely potent in both respects but may not act by the same
mechanism.
and is also cytotoxic; its tubulin activity, however, is only a
fifth of that of ottelione A.4 A few extended dienone systems,
such as 69,10 and 7a,b,9c have been known for many years; they
were prepared under seemingly harsh conditions but do not
readily aromatize.
Discussion
The potent anticancer properties of the otteliones clearly make
them important synthetic objectives. As mentioned previously,
synthetic studies have played a role in establishing the structure
of ottelione A. The majority11 of the early synthetic work in
this area was reported from Mehta’s laboratory. Chemists in
his group first prepared the model compounds (()-8,12 (()-
9,12 and (-)-10.13 With the experience thus gained, structure 1
Preliminary Work. Our own work was begun before any
total synthesis had been completed and was initially aimed at
15, the core structure of ottelione B. This model was eventually
reached19 by way of an intramolecular Diels-Alder reaction
mediated by a chiral catalyst (Scheme 1). Just after that model
SCHEME 1. Model Study for Core Structure of
Ottelione B
was synthesized in a racemic form and was shown to correspond
to ottelione A.5 The remarkable key observation was also made5
that the treatment of (()-ottelione A with DBU in hot benzene
converted it smoothly (83% yield) into the trans ring fused
study was completed, the short synthesis of both racemic
otteliones was reported by Mehta and Islam,5 and it did not
seem appropriate to continue with our own much longer route.
However, about a year later when the syntheses of optically
pure otteliones was published from two laboratoriessboth using
(6) Lewis, H. J. Ph.D. Thesis, University of Minnesota, 2005 (Diss. Abstr.
Int. B 2005, 66, 2073).
(7) (a) Scully, S. L.; Ghose, S.; Marine, S.; Islam, K.; Hoye, T. R.; Mehta,
G.; Sreerama, L. Abstracts of Papers, 233rd ACS National Meeting,
Chicago, IL, March, 25-29, 2007. (b) Dechaine, J. L.; Lewis, H. J.; Ayyad,
S.-E. N.; Hoye, T. R.; Sreerama, L. Abstracts of Papers, 225th ACS National
Meeting, New Orleans, LA, March 23-27, 2003.
(8) Li, H.; Li, H.; Qu, X.; Zhao, D.; Shi, Y.; Guo, L.; Yuan, Z. Zhongguo
Zhongyao Zazhi 1995, 20, 115-116, 128.
(9) The dienone system of the otteliones is very rare. For examples,
see: (a) Birch, A. J. Proc. R. Soc. N. S. W. 1949, 83, 245-250. (b) Jung,
M. E.; Rayle, H. L. Synth. Commun. 1994, 24, 197-203. (c) Murray, D.
F.; Baum, M. W.; Jones, M., Jr. J. Org. Chem. 1986, 51, 1-7.
(10) Dienone 6 underwent both 1,4- and 1,6-addition with cuprates: Wild,
H. J. Org. Chem. 1994, 59, 2748-2761.
(11) For other synthetic work, see: (a) Hanson, G. H.; Hoye, T. R.;
Burke, S. D. Abstracts of Papers, 234th ACS National Meeting, Boston,
MA, August 19-23, 2007. (b) Kabrhel, J. E. Ph.D. Thesis, University of
Minnesota, 2006 (Diss. Abstr. Int. B 2007, 67, 4425). (c) Ref 7b. (d) Judd,
A. S. Ph.D. Thesis, University of Minnesota, 1999 (Diss. Abstr. Int. B 2000,
60, 5522). (e) Ref 6. (f) Trembleau, L.; Patiny, L.; Ghosez, L. Tetrahedron
Lett. 2000, 41, 6377-6381. (g) Hoye, T. R.; Lewis, H. J.; Ayyad, S.-E. N.;
Hans, J. J. Abstracts of Papers, 224th ACS National Meeting, Boston, MA
Aug 18-22, 2002.
(12) Mehta, G.; Srinivasa Reddy, D. Chem. Commun. (Cambridge, U.K.)
1999, 2193-2194.
J. Org. Chem, Vol. 73, No. 8, 2008 3079

Clive and Liu
SCHEME 3. Synthesis of Ottelione B Core Structure Based
on Ring Closing Metathesis
the base-induced isomerization of ottelione A to ottelione Bs
it became clear that routes involving the A f B isomerization
were not straightforward so that further synthetic work on the
otteliones was clearly justified, especially in view of their
exceptional anticancer potency. Therefore, we took up the
project again but with a new plan and, as before, adopted the
cautious approach of first making the core structure, although
this time we made both core structures,20 as described next.
Second Generation Route to Core Structures. The readily
available unsaturated aldehyde 1621 (Scheme 2) was subjected
to conjugate addition, using the organocuprate 1722,23 in the
presence of Me3SiCl.24 The conjugate addition25 gave a mixture
of cis and trans isomers that was mainly (ca. 95%) the desired
cis compound 18.
SCHEME 2. Synthesis of Ottelione a Core Structure Based
on Ring Closing Metathesis
a Material contains ca. 15% of cis isomer.
The trans ring fused core was then made from 18 (Scheme
3). To this end, the aldehyde was exposed to the action of DBU
for 48 h at room temperature to produce material that was largely
(ca 85%) the trans isomer 22. Reaction with vinylmagnesium
bromide proceeded without incident, and it was possible to
isolate 23 (67% yield) as a mixture of C(4) epimers in both of
which the side arms on the five-membered ring were trans. Once
again, ring closing metathesis with the Grubbs I catalyst was
efficient (83%), and the resulting alcohols 24 were oxidized
with the Dess-Martin reagent so as to produce 25, the core of
ottelione B. Even though 24 has a trans ring fusion, the ring
closing metathesis still involves preferential cyclization via the
less substituted double bond of the 1,3-butadiene unit; this
preference would appear to be general.
a Material contains ca. 5% of the trans isomer.
Reaction with vinylmagnesium bromide afforded alcohol 19
as a single isomer whose stereochemistry at C(4) (ottelione
numbering) was not determined and is, in any case, inconse-
quential. In the presence of the Grubbs I catalyst (5 mol %),
ring closing metathesis occurred to give 20 in 78% yield. This
regiochemical outcome was expected, as preferential closure
involving the less substituted double bond of a 1,3-diene unit
has been observed previously.26 Finally, Dess-Martin oxidation
gave 21, the core of ottelione A.
With both the cis and the trans ring fused models in hand,
we were able to examine briefly the possibility of epimerizing
the cis isomer into the trans isomer, but treatment with DBU in
CH2Cl2 or in refluxing DME or refluxing PhMe did not effect
epimerization to any significant extent.
(13) Mehta, G; Islam, K. Synlett 2000, 1473-1475.
(14) Mehta, G.; Islam, K. Org. Lett. 2002, 4, 2881-2884.
(15) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733-6736.
(16) Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903-3906.
(17) Araki, H.; Inoue, M; Katoh, T. Synlett 2003, 2401-2403.
(18) Araki, H.; Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.; Watanabe,
K.; Abe, H.; Katoh, T. Chem.sEur. J. 2007, 13, 9866-9881.
(19) Clive, D. L. J.; Fletcher, S. P. J. Chem. Soc., Chem. Commun. 2002,
1940-1941.
Synthesis of Racemic Otteliones. At this stage of our studies,
the next obvious problem was to introduce substituents on the
five-membered ring. Suitable precursors to the aromatic subunit
appeared to be the readily available aldehyde 2627 and the
derived bromide 27.28 Attempts to use the bromide for alkylation
of 2-cyclopentenone or cyclopentanone were unpromising, but
aldol condensation of 2-cyclopentenone29 with aldehyde 26
worked well (28 f 29, 75%). Further experimentation quickly
showed that the C(1) vinyl group was best introduced by using
the O-silylated aldols 30 (Scheme 4). These were treated with
cuprate made from vinylmagnesium bromide and the CuBr‚
SMe2 complex. The conjugate addition gave 31 in 59% yield,
as well as the corresponding material with cis substituents on
the ring (24%). The desired product (31) was a 3:1 mixture of
epimers differing at the siloxy-bearing carbon. We note that
little work has been done on the relative thermodynamic stability
(20) Preliminary communication: Clive, D. L. J.; Liu, D. Tetrahedron
Lett. 2005, 46, 5305-5307.
(21) Kozikowski, A. P.; Tu¨ckmantel, W. J. Org. Chem. 1991, 56, 2826-
2837.
(22) Prepared from lithium 2-thienylcyanocuprate and 2-lithio-1,3-
butadiene, which was generated by the literature route: (a) Brown, P. A.;
Jenkins, P. R. J. Chem. Soc., Perkin Trans 1 1986, 1129-1131. (b) Brown,
P. A.; Jenkins, P. R. Tetrahedron Lett. 1982, 23, 3733-3734. (c)
Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978, 43,
147-154.
(23) 2-Lithio-1,3-butadiene is also available from 2-(tributylstannyl)-1,3-
butadiene: Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. Chem.
Soc. Jpn. 1985, 58, 1942-1945.
(24) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-
6022. (b) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27,
1047-1050.
(27) Pettit, G. R.; Singh, S. B.; Cragg, G. M. J. Org. Chem. 1985, 50,
3404-3406.
(28) Sing, S. B.; Pettit, G. R. J. Org. Chem. 1989, 54, 4105-4114.
(29) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani,
S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110-7123.
(25) Kende, A. S.; Jungheim, L. N. Tetrahedron Lett. 1980, 21, 3849-
3852.
(26) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-
7318.
3080 J. Org. Chem., Vol. 73, No. 8, 2008

Potent Anticancer Agents Ottelione A and B
the presence of Me3SiCl24 with enal 35. The crude product was
a mixture of 36 and the corresponding C(3a) epimer, with 36
being the major product (>7:1 to >10:1). The crude material
was treated with vinylmagnesium bromide, and a mixture of
the allylic alcohols 37 epimeric at C(4) was isolated. The minor
isomer (14% yield) and the major isomer (48% yield) were
individually subjected to the action of the Grubbs II36 catalyst
in CH2Cl2 at room temperature for 16 h. In both cases, ring
closing metathesis occurred in the desired fashion. The yield
was high (85-86%), and the presence of an additional double
bond in the starting material as compared to our model system
19 did not introduce any complications. On the basis of the
result of a single experiment with a mixture of epimeric alcohols,
the Grubbs I catalyst appeared to work just as well. Dess-
Martin oxidation of each alcohol to ketone 39 was likewise
uneventful (90%), but the final deprotection of the resulting
ketone 39 with Bu4NF had to be monitored closely, as too long
a reaction time caused decomposition of the product. When
performed in ice-cold CH2Cl2 for 15 min, the desilylation gave
racemic ottelione A in 81% yield. Our first experiments were
performed in THF, but in this solvent, neither the starting
material nor the desired product were obtained.
SCHEME 4. Route to r,â-Unsaturated Aldehyde Needed
for Synthesis of Racemic Otteliones
a Corrected for recovered 29. b Si* ) t-BuMe2Si.
Aldehyde 36 was then used to produce ottelione B (Scheme
6). Epimerization at C(3a) was again achieved by the action of
of the cis and trans isomers of 2,4-disubstituted cyclopentanones,
but the cis isomer appears to be more stable in those few cases
examined.30 At this point, the siloxy group was removed by
the action of Et3SiH31 in the presence of CF3CO2H (31 f 32).
Various sequences for the last few stepsshydroxyl protection,
conjugate addition, and deoxygenationswere examined; that
shown in Scheme 4 proved to be the most satisfactory.
Ketone 32 was converted regioselectively into the enol
triflate32 33, and this was carbonylated33 in the presence of
MeOH so as to afford ester 34. Overreduction with DIBAL-H
and Dess-Martin oxidation gave the key aldehyde 35. This
compound corresponds to aldehyde 16 used in our model studies
on the core skeleton but now carries the required peripheral
substituents, and the stage was set for construction of the six-
membered ring, which we hoped to accomplish by exactly the
same procedure used for the models.
SCHEME 6. Final Steps in Synthesis of Racemic Ottelione
B
DBU, and aldehyde 40 could be isolated in 62% yield. Reaction
with vinylmagnesium bromide gave 41 (83%) as an inseparable
mixture of C(4) epimers. Once again, the ring closing metathesis
worked well and without any sign of interference from the C(1)
vinyl group. Dess-Martin oxidation of alcohols 42 (as a mixture
of C(4) epimers) and controlled desilylation now presented no
difficulties, and we obtained pure racemic ottelione B. Its NMR
spectra are clearly distinguishable from those of ottelione A.
Synthesis of Optically Pure Otteliones.37 The previous
synthesis of the racemic otteliones established that the ring
SCHEME 5. Final Steps in Synthesis of Racemic Ottelione
A
(30) (a) Harispe, M.; Me´a, D.; Horeau, A.; Jacques, J. Bull. Soc. Chim.
Fr. 1963, 472-475. (b) Varech, D.; Jacques, J. Bull. Soc. Chim. Fr. 1969,
3505-3515. (c) Sprung, I.; Anhalt, K.; Wahren, U.; Schulze, K. Monatsh.
Chem. 1999, 130, 341-354.
(31) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993, 47,
10807-10816.
(32) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
a Two isomers obtained in 48 and 14% yields, respectively.
(33) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109-
1112.
Methyl vinyl ketone was converted into a hydrazone22a by
reaction with (2,4,6-tri-isopropylbenzene)sulfonylhydrazine34
and then, by reaction with MeLi, into 2-lithio-1,3-butadiene.22a
This was converted into the corresponding cuprate by reaction
with Bu3P‚CuI.35 The cuprate, in turn, was allowed to react in
(34) Cusak, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron
1976, 32, 2157-2162.
(35) Suzuki, M.; Suzuki, T.; Kawagishi, T.; Noyori, R. Tetrahedron Lett.
1980, 21, 1247-1250.
(36) Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihy-
droimidazol-2-ylidene][benzylidene]ruthenium(IV)-dichloride.
J. Org. Chem, Vol. 73, No. 8, 2008 3081

Clive and Liu
SCHEME 7. Planned Approach to Disubstituted
Cyclopentanone Needed for Synthesis of Optically Pure
Otteliones
SCHEME 9. Route to Optically Pure Cyclopropane from
Chiral Pool
closing metathesis procedure was a reliable method for the
tetraenes we had used, but our experiments also had shown that
setting up the trans stereochemistry of the C(1) and C(3)
substituents by conjugate addition gave an unsatisfactory ratio
of epimers. Our experiments also gave no guidance as to how
to make optically pure materials. Careful consideration of these
two problemsshow to improve the trans/cis selectivity and how
to obtain optically pure materialssuggested that starting materi-
als of type 44 (or synthetically equivalent substances) might
satisfy our requirements in all respects: we anticipated that
alkylation at C(3) would occur anti to the cyclopropyl group,
and if the ester was converted into a leaving group (cf. 45 f
46), then reduction with SmI2 might serve to open the cyclo-
propane and convert it into a vinyl group (cf. 46 f 47), the
overall result being that the cyclopropane would initially serve
as a steric shield and then as a vinyl precursor. A very
convenient aspect of this plan was that optically pure compounds
of type 44 and synthetically equivalent species were already
available by literature methods. In particular, the asymmetric
cyclopropanation method of Hanessian et al.38 (Scheme 8)
seemed well-suited to our needs, as did routes starting from a
carbohydrate. In the case of asymmetric cyclopropanation, we
expected that the intermediate 49 would be readily convertible
into ester 50, and in the event, this proved to be the case.39
Although we used this cyclopropanation in exploratory experi-
ments, most of our work was based on a route from D-ribose
because we then avoided the necessity of checking the optical
purity of each batch.
marized in Scheme 9.41 Methyl 2,3-O-ispropylidene-D-ribofura-
nosides (51)42 were converted into the corresponding iodides
52 using I2/Ph3P,43 and treatment with Zn then generated
aldehyde 53 that, without purification, was treated with vinyl-
magnesium bromide. The resulting epimeric alcohols 54 un-
derwent ring closing metathesis (54 f 55) in the presence of
the Grubbs I catalyst. PCC oxidation took the route as far as
enone 56, and this was cyclopropanated in near quantitative yield
by reaction with (carboethoxymethyl)dimethylsulfonium bro-
mide [Me2S+CH2CO2Et Br-] in the presence of DBU.44 Acidic
hydrolysis then liberated diol 58, which was converted into the
key compound 50 by dimesylation and reduction over Pd-C
in the presence of Hu¨nig’s base. This last step may involve both
hydrogenation and hydrogenolysis or merely two hydrogenation
steps.45
With the cyclopropane in hand, the next task was to attach
the aromatic subunit. Alkylation with bromide 27 gave a poor
yield (42%), but aldol condensation with aldehyde 26, followed
by deoxygenation46 (50 f 59 f 60), was satisfactory (79%
overall).
SCHEME 8. Route to Optically Pure Cyclopropane by
Asymmetric Synthesis
Reduction of both carbonyls (60 f 61), selective pivaloy-
lation of the primary hydroxyl in 61, and reoxidation of the
remaining secondary hydroxyl produced the cyclopropyl ketone
63sthe substrate for the crucial ring opening that would make
the cyclopropyl unit discharge its last function by serving as a
precursor to the C(1) vinyl group. On treatment below 0 °C
with freshly prepared SmI2,47 the desired change (63 f 47)
occurred in good yield (82%),48 bringing the work to a point
The individual steps of the carbohydrate route were selected
from a number of different publications, and we eventually
found an acceptable combination of procedures40 that is sum-
(41) See Supporting Information for a summary chart of the two other
routes we examined.
(37) Preliminary communication: Clive, D. L. J.; Liu, D. Angew. Chem.,
Int. Ed. 2007, 46, 3738-3740.
(42) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55, 3853-
3857.
(38) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am. Chem. Soc. 1995,
117, 10393-10394.
(43) (a) Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849-7856.
(b) Palmer, A. M.; Ja¨ger, V. Eur. J. Org. Chem. 2001, 1293-1308.
(44) (a) Dom´ınguez, C.; Ezquerra, J.; Prieto, L.; Espada, M.; Pedregal,
C. Tetrahedron: Asymmetry 1997, 8, 511-514. (b) Collado, I.; Dom´ınguez,
C.; Ezquerra, J.; Pedregal, C.; Monn, J. A. Tetrahedron Lett. 1997, 38,
2133-2136.
(45) Kalwinch, I.; Metten, K.-H.; Bru¨ckner, R. Heterocycles 1995, 40,
939-952.
(46) Orfanopoulos, M.; Smonou, I. Synth. Commun. 1988, 18, 833-
839.
(39) We prepared the required phosphorus reagent using a Z/E mixture
of 1,3-dichloro-1-propenes and obtained a C(6) epimeric mixture of
cyclopropanes that, upon ozonolysis, gave an epimeric mixture of acids.
The derived ethyl esters were separated to afford ester 50.
(40) Most of the sequence (51 f 56) turned out to be the same as that
used previously by others: (a) Smith, A. B., III; Han, Q.; Breslin, P. A. S.;
Beuchamp, G. K. Org. Lett. 2005, 7, 5075-5078. (b) Yang, M.; Ye, W.;
Schneller, S. W. J. Org. Chem. 2004, 69, 3993-3996.
3082 J. Org. Chem., Vol. 73, No. 8, 2008

Potent Anticancer Agents Ottelione A and B
SCHEME 10. Route to Optically Pure Aldehyde by Ring
Opening of Cyclopropane
SCHEME 12. Synthesis of Optically Pure Ottelione B
a Compound 72 is a 5:3 mixture of C(4) epimers.
cuprate,50 in the presence51 of both Me3SiCl and HMPA. The
conjugate addition occurred exclusively trans to the C(1) vinyl
group, and protonation gave mainly (7:1 to 10:1) the indicated
stereochemistry (see 67). The final product, (+)-ottelione A,
had a specific rotation very close to the values reported by Mehta
and Islam5 and Katoh et al.16,18
As implied previously, diversion of aldehyde 67 to (-)-
ottelione B was performed (Scheme 12) by the methods first
used with racemic compounds. Our sample of (-)-ottelione B
formed crystals suitable for X-ray analysis, but the structure
did not provide any obvious evidence that would account for
the absence of facile aromatization. The X-ray data (Figure 1)
showed that the six-membered ring is in a half-chair conforma-
tion with the vinyl group oriented in such a way that the
hydrogen atoms at C(1′) and C(7a) are syn and both of the C-H
bonds are parallel. The dihedral angle between the carbonyl
group and the C(3a)-H bond is about 114°. We were unable
to crystallize (+)-ottelione A.
SCHEME 11. Synthesis of Optically Pure Ottelione A
a Product 67 is mainly (7:1 to 10:1) the indicated stereoisomer. b Two
isomers obtained in 50 and 19% yields, respectively.
that overlaps structurally with our route to the racemic otteliones.
The choice of a pivaloate for the monoprotection of alcohols
61 was dictated by the greater selectivity in this protection as
compared to the use of a benzoate, but the benzoate also
underwent the samarium-induced reaction.
Ketone 47 was deprotonated with (Me3Si)2NK under kinetic
conditions, and the enolate was quenched with Comins’
reagent32 to afford enol triflate 64. This was carbonylated by a
standard method49 in the presence of MeOH so as to produce
ester 65. Reduction with DIBAL-H and reoxidation gave
aldehyde 66, from which point the procedure used to make
racemic otteliones was followed, with minor variations (Schemes
11 and 12), except for the conjugate addition step (Scheme 11,
66 f 67), which was performed with a magnesium-derived
FIGURE 1. ORTEP diagram of (-)-ottelione B.
The specific rotation of our material is close to that reported
by Katoh et al.,16,18 and the compound was easily shown
by NMR measurements to be free of contamination by (+)-
ottelione A.
Conclusion
(47) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693-2698. (b) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51,
1135-1138.
The synthetic method described here avoids difficulties
encountered in epimerizing ottelione A to ottelione B. Our X-ray
(48) For related opening of cyclopropyl ketones, see: (a) Beerli, R.;
Brunner, E. J.; Borschberg, H.-J. Tetrahedron Lett. 1992, 33, 6449-6452.
(b) Nivlet, A.; Le Guen, V.; Dechoux, L.; Le Gall, T.; Mioskowski, C.
Tetrahedron Lett. 1998, 39, 2115-2118.
(49) Cacchi, S.; Ciatinni, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 3931-3934.
(50) (a) Shea, K. J.; Kim, J.-S. J. Am. Chem. Soc. 1992, 114, 3044-
3051. (b) Shea, K. J.; Pham, P. Q. Tetrahedron Lett. 1983, 24, 1003-
1006.
(51) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetra-
hedron 1989, 45, 349-362.
J. Org. Chem, Vol. 73, No. 8, 2008 3083

Clive and Liu
oxobicyclo[3.1.0]hex-6-yl]methyl Ester (63). LiAlH4 (0.873 g, 23.0
mmol) was added to a stirred and cooled (0 °C) solution of 60
(3.20 g, 7.66 mmol) in THF (140 mL). The ice bath was removed,
and stirring was continued for 4 h. Na2SO4‚10H2O (24 g) was added,
and the solution was diluted with CH2Cl2 (50 mL). Stirring was
continued for 20 min, and then the mixture was filtered through a
pad of Celite (5 cm × 6 cm), using CH2Cl2 (30 mL) as a rinse.
The filtrate was dried (Na2SO4) and evaporated. The residue was
dissolved in THF (100 mL), and the solution was cooled to 0 °C.
Pyridine (3.72 mL, 46.0 mmol), followed by t-BuCOCl (1.89 mL,
15.3 mmol), was added dropwise with stirring. The ice bath was
left in place, but not recharged, and stirring was continued for 1.5
h, the mixture having reached room temperature after 1 h. Water
(10 mL) was added, and the aqueous phase was extracted with
EtOAc (3 × 25 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over silica gel (3 cm × 15 cm), using 1:3 hexane/
EtOAc, gave a colorless oil that was dissolved in CH2Cl2(60 mL).
Dess-Martin periodinane (3.25 g, 7.66 mmol) was added to the
previous solution, and the mixture was stirred for 1 h. Saturated
aqueous Na2S2O3 (15 mL) and saturated aqueous NaHCO3 (15 mL)
were added. The mixture was stirred for 5 min, diluted with water
(10 mL), and extracted with CH2Cl2 (3 × 25 mL). The combined
organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (3 cm × 20 cm),
using 1:6 EtOAc/hexane, gave 63 (2.72 g, 77%) as a yellow oil:
[R]D ) -27.7 (c 0.53, CHCl3); FTIR (CH2Cl2 cast) 2956, 2858,
structure of ottelione B appears to be the first such measurement
for the otteliones, and the route illustrates a very convenient
and apparently general level of discrimination between several
double bonds in ring closing metathesis. A special feature of
the synthesis is the use of a cyclopropane to shield one face of
an attached ring and at a later stage to act as a precursor to a
vinyl group. It is likely that our approach to the otteliones also
could be used to prepare analogues of these very powerful
anticancer agents.
Experimental Section
The symbols s, d, t, and q in 13C spectra refer to zero, one, two,
or three attached hydrogens, respectively.
(1S,3S,5R,6S)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]hydroxymethyl]-2-oxobicyclo[3.1.0]hexane-6-
carboxylic Acid Ethyl Ester (59). n-BuLi (1.6 M in hexane, 2.57
mL, 4.11 mmol) was added dropwise to a stirred and cooled (0
°C) solution of i-Pr2NH (0.576 mL, 4.11 mmol) in THF (10 mL).
Stirring was continued for 10 min, and the mixture was then cooled
to -78 °C. Keto ester 50 (0.574 g, 3.42 mmol) in THF (3 mL plus
0.5 mL as a rinse) was added dropwise, and stirring was continued
for 30 min. 3-[(t-Butyldimethylsilyl)oxy]-4-methoxybenzaldehyde
(2627) (1.09 g, 4.11 mmol) in THF (3 mL) was added dropwise,
and stirring was continued at -78 °C for 60 min. Saturated aqueous
NH4Cl (10 mL) was added, the organic layer was separated, and
the aqueous layer was extracted with Et2O (3 × 25 mL). The
combined organic extracts were washed with brine, dried (Na2-
SO4), and evaporated. Flash chromatography of the residue over
silica gel (2 cm × 20 cm), using 1:4 EtOAc/hexane, gave 59 (1.35
g, 91%) as a 1:1 mixture (1H NMR) of two isomers: [R]D ) 13.4
(c 3.40, CHCl3); FTIR (CH2Cl2 cast) 3496, 2954, 2930, 1727, 1511,
1
1728, 1152 cm-1; H NMR (400 MHz, CDCl3) δ 0.13 (s, 3 H),
0.14 (s, 3 H), 1.00 (s, 9 H), 1.19 (s, 9 H), 1.67-1.72 (m, 1 H),
1.80-1.86 (m, 2 H), 1.95 (dd, J ) 5.2, 9.2 Hz, 1 H), 2.09 (dd, J
) 7.2, 13.2 Hz, 1 H), 2.23-2.30 (m, 2 H), 3.01-3.08 (m, 1 H),
3.76 (s, 3 H), 3.89 (dd, J ) 6.4, 11.6 Hz, 1 H), 4.03 (dd, J ) 6.4,
11.6 Hz, 1 H), 6.61-6.66 (m, 2 H), 6.73 (d, J ) 8 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ -4.64 (q), -4.61 (q), 18.4 (s), 24.7
(d), 25.7 (q), 26.1 (d), 27.1 (q), 29.7 (t), 32.5 (d), 34.8 (t), 38.8 (s),
43.8 (d), 55.5 (q), 64.6 (t), 112.1 (d), 121.5 (d), 121.8 (d), 132.3
(s), 144.9 (s), 149.4 (s), 178.3 (s), 212.9 (s); exact mass m/z calcd
for C26H40O5Si 460.26450, found 460.26488.
1
1277, 849 cm-1; H NMR (500 MHz, CDCl3, signals for major
isomer) δ 0.14-0.15 (m, 6 H), 1.00 (s, 9 H), 1.23-1.27 (m, 3 H),
1.76-1.86 (m, 1.5 H), 1.98 (t, J ) 2.8 Hz, 0.5 H), 2.11 (t, J ) 3.0
Hz, 0.5 H), 2.25 (d, J ) 4.0 Hz, 0.5 H), 2.29-2.37 (m, 2 H), 2.42-
2.50 (m, 1.5 H), 3.71 (s, 3 H), 4.11-4.17 (m, 2 H), 4.52 (s, 0.5 H),
4.55 (s, 0.5 H), 5.21 (s, 0.5 H), 6.78-6.84 (m, 3 H); 13C NMR
(125 MHz, CDCl3, signals for major isomer) δ -4.61 (q), -4.58
(q), 14.1 (q), 18.5 (s), 25.7 (q), 26.8 (q), 27.5 (d), 28.1 (d), 36.0
(d), 48.0 (d), 55.5 (q), 61.3 (t), 75.0 (d), 111.9 (d), 118.2 (d), 119.4
(d), 133.3 (s), 145.0 (s), 150.9 (s), 169.9 (s), 214.74 (s); exact mass
m/z calcd for C23H34O6Si 434.21246, found 434.21153.
(2S,4R)-2-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-meth-
oxyphenyl]methyl]-4-ethenylcyclopentanone (47). A SmI2 solu-
tion (80.2 mL, 0.2 M in THF, concentration calculated on the basis
of the amount of 1,2-diiodoethane used, assuming 100% yield) was
added dropwise to a stirred and cooled (0 °C) solution of 63 (1.94
g, 4.22 mmol) in 10:1 THF-MeOH (5.5 mL). Stirring at 0 °C was
continued for 2 h, and another portion of the SmI2 solution (20
mL) was added. Stirring at 0 °C was continued for 3 h, and water
(15 mL) was added. A few drops of 10% HCl were added to
dissolve the white precipitate. The aqueous layer was extracted with
EtOAc (3 × 30 mL), and the combined organic extracts were
washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
and evaporated. Flash chromatography of the residue over silica
gel (3 cm × 20 cm), using 1:10 EtOAc/hexane, gave 47 (1.25 g,
82%) as a colorless oil: [R]D ) -97.0 (c 1.15, CHCl3); FTIR (CH2-
Cl2 cast) 2954, 2930, 1740, 1511, 841 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.15 (s, 3 H), 0.15 (s, 3 H), 1.00 (s, 9 H), 1.88 (dd, J )
7.0, 7.0 Hz, 2 H), 2.21 (dd, J ) 6.4, 18.4 Hz, 1 H), 2.34 (dd, J )
7.8, 18.4 Hz, 1 H), 2.46-2.53 (m, 2 H), 2.77-2.82 (m, 1 H), 2.93
(apparent q, J ) 9.0 Hz, 1 H), 3.78 (s, 3 H), 4.99 (d, J ) 1.5 Hz,
1 H), 5.02 (ddd, J ) 1.4, 1.4, 6.0 Hz, 1 H), 5.83 (ddd, J ) 6.3,
10.0, 17.5 Hz, 1 H), 6.65-6.70 (m, 2 H), 6.76 (d, J ) 8.0 Hz, 1
H); 13C NMR (100 MHz, CDCl3) δ -4.67 (q), -4.65 (q), 18.4 (s),
25.7 (q), 33.8 (t), 35.2 (t), 36.8 (d), 43.9 (t), 48.6 (d), 55.5 (q),
112.1 (d), 114.0 (t), 121.6 (d), 122.0 (d), 132.0 (s), 140.6 (d), 144.9
(s), 149.5 (s), 219.6 (s); exact mass m/z calcd for C21H32O3Si
360.21207, found 360.21273.
(1S,3S,5R,6S)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]methyl]-2-oxobicyclo[3.1.0]hexane-6-carboxyl-
ic Acid Ethyl Ester (60). Et3SiH (3.95 mL, 24.7 mmol), followed
by BF3‚Et2O (0.786 mL, 6.20 mmol) were added dropwise to a
stirred and cooled (0 °C) solution of 59 (1.35 g, 3.11 mmol) in
CH2Cl2 (25 mL). Stirring was continued for 1 h. Saturated aqueous
NaHCO3 (15 mL) was added, and the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash chro-
matography of the residue over silica gel (2 cm × 30 cm), using
1:6 EtOAc/hexane, gave 60 (1.12 g, 87%) as a colorless oil: [R]D
) 8.65 (c 1.65, CHCl3); FTIR (CH2Cl2 cast) 2931, 2857, 1730,
1
1512, 1269 cm-1; H NMR (400 MHz, CDCl3) δ 0.14 (s, 3 H),
0.15 (s, 3 H), 0.99 (s, 9 H), 1.26 (t, J ) 7.2 Hz, 3 H), 1.92 (ddd,
J ) 5.2, 8.8, 12.8 Hz, 1 H), 2.04 (t, J ) 2.8 Hz, 1 H), 2.13-2.29
(m, 2 H), 2.32-2.34 (m, 2 H), 2.39-2.42 (m, 1 H), 3.04 (dd, J )
3.8, 13.6 Hz, 1 H), 3.77 (s, 3 H), 4.13 (q, J ) 7.2 Hz, 2 H), 6.61-
6.66 (m, 2 H), 6.74 (d, J ) 8.4 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ -4.64 (q), -4.61 (q), 14.1 (q), 18.4 (s), 25.7 (q), 27.4
(d), 27.6 (d), 29.5 (t), 34.7 (t), 35.8 (d), 43.5 (d), 55.5 (q), 61.2 (t),
112.2 (d), 121.5 (d), 121.8 (d), 131.8 (s), 144.9 (s), 149.5 (s), 170.4
(s), 211.7 (s); exact mass m/z calcd for C23H34O5Si 418.21756, found
418.21677.
1,1,1-Trifluoromethanesulfonic Acid (3S,5S)-5-[[3-[[(1,1-Di-
methylethyl)dimethylsilyl]oxy]-4-methoxyphenyl]methyl]-3-ethe-
nyl-1-cyclopenten-1-yl Ester (64). A solution of 47 (0.986 g, 2.74
mmol) in THF (5 mL plus 1 mL as a rinse) was added dropwise to
2,2-Dimethylpropanoic Acid [(1S,3S,5S,6S)-3-[[3-[[(1,1-Di-
methylethyl)dimethylsilyl]oxy]-4-methoxyphenyl]methyl]-2-
3084 J. Org. Chem., Vol. 73, No. 8, 2008

Potent Anticancer Agents Ottelione A and B
a stirred and cooled (-78 °C) solution of (Me3Si)2NK (0.5 M in
PhMe, 7.12 mL, 3.56 mmol) in THF (10 mL). Stirring was
continued for 1 h, and 2-[N,N-bis(trifluoromethanesulfonyl)amino]-
pyridine32 (1.28 g, 3.57 mmol) in THF (5 mL plus 1 mL as a rinse)
was added dropwise. Stirring was continued for 2 h, and the cold
bath was then replaced by an ice bath. Saturated aqueous NH4Cl
(10 mL) was added, and the mixture was extracted with Et2O (3 ×
25 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (2 cm × 20 cm), using 1:20 EtOAc/hexane,
gave 64 (1.25 g, 92%) as a yellow oil: [R]D ) 59.9 (c 2.60, CHCl3);
Hz, 1 H), 2.99 (dd, J ) 4.0, 13.6 Hz, 1 H), 3.26-3.33 (m, 2 H),
3.77 (s, 3 H), 4.98-5.05 (m, 2 H), 5.70 (ddd, J ) 7.2, 10.0, 17.2
Hz, 1 H), 6.64-6.70 (m, 3 H), 6.74 (d, J ) 8.0 Hz, 1 H), 9.80 (s,
1 H); 13C NMR (100 MHz, CDCl3) δ -4.64 (q), -4.61 (q), 18.5
(s), 25.6 (q), 36.0 (t), 37.8 (t), 43.3 (d), 48.4 (d), 55.5 (q), 111.9
(d), 115.0 (t), 122.0 (d), 122.4 (d), 132.6 (s), 139.0 (d), 144.6 (s),
149.3 (s), 149.7 (s), 155.3 (d), 189.9 (s); exact mass m/z calcd for
C22H32O3Si 372.21207, found 372.21199.
(1R,2S,3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]methyl]-3-ethenyl-2-(1-methylene-2-propen-1-
yl)cyclopentanecarboxaldehyde (67). The chloroprene solution
was prepared by slight modification of a literature procedure.52 DBU
(7.15 mL, 47.8 mmol) was added to a stirred and cooled (0 °C)
solution of 3,4-dichloro-1-butene (5.0 g, 40.0 mmol) in PhMe (15
mL). The ice bath was removed, and stirring was continued for 2
h. THF (2 mL) and water (1 mL) were added to dissolve the
precipitate, and stirring was continued for 2 h. The organic phase
was washed with water, 5% hydrochloric acid, saturated aqueous
NaHCO3, and brine and then dried (MgSO4). The drying agent was
filtered off, using Et2O as a rinse, and a small amount of CaH2
was added to the filtrate. The mixture was kept (no stirring) at room
temperature for 30 min, THF (20 mL) and 1,2-dibromoethane (0.5
mL) were added, and, after a few minutes, most of the clear solution
(ca. 40 mL) was taken up into a syringe.
1,2-Dibromoethane (0.2 mL) was added to a stirred suspension
of Mg (1.65 g) in THF (5 mL). The solution was refluxed for 10
min and cooled to room temperature, and ZnCl2 (1.2 mL, 1 M in
THF), followed by the previous chloroprene solution (5 mL), was
added. The solution was stirred and heated until initiation occurred.
The remaining chloroprene solution was added dropwise at a rate
to maintain the reaction mixture at reflux, and refluxing was
continued for 1 h after the addition was complete. The concentration
of this Grignard solution was approximately 0.4 M as determined
(1H NMR) by reaction with an excess of PhCHO.
The previous chloroprene Grignard solution (0.4 M in THF-
PhMe, 1.23 mL, 0.492 mmol) was added to a stirred and cooled
(-78 °C) suspension of CuBr‚Me2S (27 mg, 0.131 mmol) in THF
(5 mL). The mixture was stirred for 20 min, and HMPA (0.11 mL,
0.632 mmol) was then added.
1
FTIR (CH2Cl2 cast) 2955, 2931, 1213, 850 cm-1; H NMR (500
MHz, CDCl3) δ 0.16 (s, 6 H), 1.01 (s, 9 H), 1.76-1.83 (m, 1 H),
1.99 (ddd, J ) 5.5, 7.5, 13.5 Hz, 1 H), 2.50 (dd, J ) 9.0, 13.5 Hz,
1 H), 2.89 (dd, J ) 4.1, 13.5 Hz, 1 H), 3.13 (d, J ) 6.5 Hz, 2 H),
3.79 (s, 3 H), 4.94-5.01 (m, 2 H), 5.58 (s, 1 H), 5.70 (ddd, J )
8.0, 9.5, 17.0 Hz, 1 H), 6.67-6.72 (m, 2 H), 6.78 (d, J ) 8.0 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ -4.68 (q), -4.66 (q), 18.4
(s), 25.7 (q), 33.9 (t), 37.0 (t), 43.0 (d), 44.3 (d), 55.5 (q), 112.0
(d), 114.4 (t), 118.6 (apparent q, J ) 320 Hz), 119.9 (d), 121.9
(d), 122.2 (d), 130.9 (s), 140.0 (d), 144.9 (s), 149.6 (s), 151.8 (s);
exact mass m/z calcd for C22H31F3O5SSi 492.16135, found 492.16030.
(3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-meth-
oxyphenyl]methyl]-3-ethenyl-1-cyclopentene-1-carboxylic Acid
Methyl Ester (65). Pd(OAc)2 (56.6 mg, 0.252 mmol), followed
by Ph3P (0.132 mg, 0.503 mmol), Et3N (0.50 mL), and MeOH (3.0
mL) were added to a stirred solution of 64 (1.24 g, 2.52 mmol) in
DMF (8 mL). The mixture was purged with CO for 10 min (via a
needle below the solvent surface) and stirred under CO (balloon
filled with CO) at room temperature for 24 h. Et2O (40 mL) was
added, and the mixture was washed with water (2 × 25 mL). The
aqueous phase was extracted with Et2O (3 × 20 mL), and the
combined organic extracts were washed with brine, dried (Na2-
SO4), and evaporated. Flash chromatography of the residue over
silica gel (2 cm × 25 cm), using 1:20 EtOAc/hexane, gave 65 (0.78
g, 77%) as a yellow oil: [R]D ) 52.2 (c 1.80, CHCl3); FTIR (CH2-
Cl2 cast) 2955, 2930, 1719, 1510 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.150 (s, 3 H), 0.154 (s, 3 H), 1.00 (s, 9 H), 1.73 (td, J ) 8.4,
13.2 Hz, 1 H), 2.00 (ddd, J ) 2.4, 7.6, 13.2 Hz, 1 H), 2.43 (dd, J
) 8.8, 13.6 Hz, 1 H), 2.96 (dd, J ) 4.0, 13.6 Hz, 1 H), 3.21-3.27
(m, 2 H), 3.76 (s, 3 H), 3.78 (s, 3 H), 4.97-5.01 (m, 2 H), 5.68
(ddd, J ) 7.2, 10.0, 17.2 Hz, 1 H), 6.62 (s, 1 H), 6.67 (d, J ) 2.0
Hz, 1 H), 6.70 (dd, J ) 2.0, 8.4 Hz, 1 H), 6.76 (d, J ) 8.4 Hz, 1
H); 13C NMR (125 MHz, CDCl3) δ -4.66 (q), -4.63 (q), 18.4 (s),
25.7 (q), 35.9 (t), 38.4 (t), 45.5 (d), 48.1 (d), 51.4 (q), 55.5 (q),
111.9 (d), 114.4 (t), 122.1 (d), 122.3 (d), 132.9 (s), 139.4 (s), 139.8
(d), 144.6 (s), 146.4 (d), 149.3 (s), 165.5 (s); exact mass m/z calcd
for C23H34O4Si 402.22263, found 402.22372.
(3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-meth-
oxyphenyl]methyl]-3-ethenyl-1-cyclopentene-1-carboxalde-
hyde (66). DIBAL-H (1.0 M in CH2Cl2, 1.20 mL, 1.20 mmol) was
added dropwise to a stirred and cooled (-78 °C) solution of 65
(0.220 g, 0.546 mmol) in CH2Cl2 (10 mL). Stirring was continued
for 1 h. Na2SO4‚10H2O (2.0 g) was added, the cold bath was
removed, and stirring was continued for 30 min. The mixture was
then filtered through a pad of Celite (3 cm × 5 cm), using CH2Cl2
(30 mL) as a rinse. The filtrate was evaporated, and the residue
was dissolved in CH2Cl2 (25 mL). Dess-Martin periodinane (0.278
g, 0.655 mmol) was added, and the mixture was stirred for 45 min.
Saturated aqueous Na2S2O3 (5 mL) and saturated aqueous NaHCO3
(4 mL) were added. The mixture was stirred for 5 min, diluted
with water (5 mL), and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4) and evaporated.
Flash chromatography of the residue over silica gel (2 cm × 15
cm), using 1:10 EtOAc/hexane, gave 66 (0.189 g, 93%) as a
colorless oil: [R]D ) 72.4 (c 1.25, CHCl3); FTIR (CH2Cl2 cast)
2954, 2857, 1682, 1270 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.15
(s, 3 H), 0.15 (s, 3 H), 1.00 (s, 9 H), 1.77 (td, J ) 8.4, 13.2 Hz, 1
H), 2.04 (ddd, J ) 3.2, 8.0, 13.6 Hz, 1 H), 2.40 (dd, J ) 9.2, 13.6
Me3SiCl (84 µL, 0.642 mmol) was added to 66 (0.120 g, 0.333
mmol) in THF (4 mL), and the resulting solution was added
dropwise to the previous organocopper solution over 10 min by
syringe. Stirring at -78 °C was continued for 1 h. Saturated aqueous
NH4Cl (5 mL) was added, and the aqueous layer was extracted
with Et2O (2 × 20 mL). The combined organic extracts were stirred
at 0 °C, and CF3CO2H (0.4 mL) was added. Stirring was continued
for 1 h, and saturated aqueous NaHCO3 (10 mL) was added. The
mixture was extracted with Et2O (2 × 15 mL), and the combined
organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 cm × 15 cm),
using 1:10 Et2O/hexane, gave 67 [87.1 mg, 61%, containing <10%
of the C(3a)/C(7a) trans isomer (1H NMR)]) as a colorless oil: [R]D
) -47.4 (c 0.51, CHCl3); FTIR (CH2Cl2 cast) 2953, 2856, 1720,
1
1511, 851 cm-1; H NMR (500 MHz, CDCl3, signals for C(3a)/
C(7a) cis isomer 67 only) δ 0.15 (s, 6 H), 1.00 (s, 9 H), 1.81 (ddd,
J ) 6.5, 9.0, 13.5 Hz, 1 H), 2.04 (ddd, J ) 9.5, 9.5, 13.5 Hz, 1 H),
2.50-2.59 (m, 2 H), 2.68 (dd, J ) 6.0, 12.5 Hz, 1 H), 2.88 (dd, J
) 6.5, 11.0 Hz, 1 H), 3.06 (dd, J ) 6.0, 11.0 Hz, 1 H), 3.22 (ddd,
J ) 7.0, 10.5, 17.5 Hz, 1 H), 3.78 (s, 3 H), 4.95-5.01 (m, 2 H),
5.08-5.12 (m, 2 H), 5.23 (d, J ) 18.0 Hz, 2 H), 5.71 (ddd, J )
7.4, 10.5, 16.6 Hz, 1 H), 6.35 (dd, J ) 11.0, 17.5 Hz, 1 H), 6.65-
6.76 (m, 3 H), 9.62 (d, J ) 4.0 Hz, 1 H); 13C NMR (100 MHz,
CDCl3, signals for C(3a)/C(7a) cis isomer 67 only) δ -4.60 (q),
18.5 (s), 25.8 (q), 36.1 (t), 36.8 (t), 43.2 (d), 44.3 (d), 49.0 (d),
55.6 (q), 56.8 (d), 112.2 (d), 113.7 (t), 114.4 (t), 116.4 (t), 121.2
(d), 121.6 (d), 133.6 (s), 139.4 (d), 140.9 (d), 142.3 (s), 144.9 (s),
(52) Cottrell, L.; Golding, B. T.; Munter, T.; Watson, W. P. Chem. Res.
Toxicol. 2001, 14, 1552-1562.
J. Org. Chem, Vol. 73, No. 8, 2008 3085

Clive and Liu
149.2 (s), 204.9 (d); exact mass m/z calcd for C26H38O3Si
426.25903, found 426.29821.
(d), 121.5 (d), 128.7 (d), 131.5 (d), 134.5 (s), 141.6 (s), 142.0 (d),
144.8 (s), 149.1 (s); exact mass m/z calcd for C26H38O3Si 426.25903,
found 426.25793.
(1R,2S,3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]methyl]-r,3-diethenyl-2-(1-methylene-2-propen-
1-yl)cyclopentanemethanol (68). Vinylmagnesium bromide (1 M
in THF, 0.36 mL, 0.36 mmol) was added dropwise to a stirred and
cooled (0 °C) solution of 67 (77.0 mg, 0.181 mmol, C(3a)/C(7a)
cis isomer/trans isomer ) 7:1) in THF (5 mL), and the mixture
was stirred for 45 min. Saturated aqueous NH4Cl (4 mL) and water
(3 mL) were added, and the mixture was extracted with Et2O (3 ×
15 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel (2 cm × 15 cm), using 1:5 EtOAc/hexane,
gave 68 as a mixture of two isomers epimeric at the hydroxyl-
bearing carbon (major isomer, 40.9 mg, 50% and minor isomer,
15.2 mg, 19%). The major isomer had [R]D ) -70.8 (c 0.40,
CHCl3); FTIR (CH2Cl2 cast) 3566, 2953, 1512, 881 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.16 (s, 3 H), 0.16 (s, 3 H), 1.00 (s, 9 H),
1.44-1.52 (m, 2 H), 1.90 (ddd, J ) 8.5, 10.0, 13.0 Hz, 1 H), 2.46-
2.60 (m, 3 H), 2.80 (dd, J ) 7.0, 11.0 Hz, 1 H), 2.96 (dd, J ) 2.8,
12.5 Hz, 1 H), 3.12 (ddd, J ) 7.5, 10.5, 17.5 Hz, 1 H), 3.77 (s, 3
H), 4.30 (s, 1 H), 4.85 (d, J ) 10.0 Hz, 1 H), 4.91 (d, J ) 17.5 Hz,
1 H), 5.09 (t, J ) 11.5 Hz, 2 H), 5.20 (d, J ) 19.5 Hz, 2 H),
5.28-5.32 (m, 2 H), 5.66 (ddd, J ) 7.5, 10.0, 17.5 Hz, 1 H), 6.04
(ddd, J ) 5.0, 10.5, 17.0 Hz, 1 H), 6.43 (dd, J ) 11.0, 17.5 Hz, 1
H), 6.69-6.76 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ -4.61
(q), -4.58 (q), 18.5 (s), 25.8 (q), 36.8 (t), 37.7 (t), 44.36 (d), 44.37
(d), 50.1 (d), 50.3 (d), 55.6 (q), 72.8 (d), 112.1 (d), 113.2 (t), 113.5
(t), 113.6 (t), 117.0 (t), 121.4 (d), 121.6 (d), 135.0 (s), 140.2 (d),
142.1 (d), 142.8 (d), 144.7 (s), 145.1 (s), 148.9 (s); exact mass m/z
calcd for C28H42O3Si 454.29031, found 454.29092.
Ar was bubbled for ca. 5 min through a stirred solution of alcohol
68 (minor isomer, 7.0 mg, 0.0154 mmol) in CH2Cl2 (2.0 mL), and
the Grubbs catalyst (first generation, 0.64 mg, 0.00078 mmol) was
then added. The mixture was stirred for 24 h and then evaporated.
Flash chromatography of the residue over silica gel (1.5 cm × 10
cm), using 1:10 EtOAc/hexane, gave 69 (6.1 mg, 91%) as a
colorless oil: [R]D ) 37.0 (c 0.20, CHCl3); FTIR (CH2Cl2 cast)
3490, 2954, 1511, 882 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.15
(s, 6 H), 0.99 (s, 9 H), 1.03 (d, J ) 6.5 Hz, 1 H), 1.65 (ddd, J )
6.0, 10.0, 13.0 Hz, 1 H), 1.98-2.08 (m, 2 H), 2.42-2.51 (m, 2 H),
2.58 (ddd, J ) 6.5, 10.5, 19.5 Hz, 1 H), 2.85 (dd, J ) 8.5, 13.5
Hz, 1 H), 2.95 (dd, J ) 8.5, 13.5 Hz, 1 H), 3.78 (s, 3 H), 4.36 (dd,
J ) 5.5, 11.0 Hz, 1 H), 4.84-4.91 (m, 3 H), 5.01 (s, 1 H), 5.70
(ddd, J ) 9.5, 9.5, 17.0 Hz, 1 H), 5.93 (dd, J ) 6.0, 9.5 Hz, 1 H),
6.19 (d, J ) 9.5 Hz, 1 H), 6.74-6.79 (m, 3 H); 13C NMR (125
MHz, CDCl3) δ -4.60 (q), 18.5 (s), 25.8 (q), 36.2 (t), 37.9 (t),
44.6 (d), 45.0 (d), 48.6 (d), 49.9 (d), 55.6 (q), 64.4 (d), 112.1 (d),
113.8 (t), 115.8 (t), 121.4 (d), 121.5 (d), 128.2 (d), 131.5 (d), 135.2
(s), 142.2 (s), 143.7 (d), 144.8 (s), 148.9 (s); exact mass m/z calcd
for C26H38O3Si 426.25903, found 426.25904.
(1S,3S,3aR,7aS)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
4-methoxyphenyl]methyl]-1-ethenyl-1,2,3,3a,7,7a-hexahydro-7-
methylene-4H-inden-4-one (70). Dess-Martin periodinane (12.0
mg, 0.0283 mmol) was added to a stirred solution of alcohols 69
(10.0 mg, 0.0235 mmol) in CH2Cl2 (2 mL). Stirring was continued
for 1 h, and then saturated aqueous Na2S2O3(1 mL), followed by
saturated aqueous NaHCO3(1 mL), was added. The mixture was
stirred for 5 min, diluted with water (3 mL), and extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue over
silica gel (1.5 cm × 10 cm), using 1:10 EtOAc/hexane, gave 70
(9.1 mg, 91%) as an oil: [R]D ) 14.6 (c 0.35, CHCl3); FTIR (CH2-
Cl2 cast) 2953, 1666, 1510, 853 cm-1; 1H NMR (500 MHz, CDCl3)
δ 0.14 (s, 6 H), 0.99 (s, 9 H), 1.51-1.56 (m, 1 H), 1.71 (ddd, J )
7.1, 9.1, 13.1 Hz, 1 H), 2.43-2.52 (m, 2 H), 2.62 (td, J ) 8.2,
16.4 Hz, 1 H), 2.79 (t, J ) 8.2 Hz, 1 H), 2.86 (dd, J ) 6.1, 8.2 Hz,
1 H), 3.02 (dd, J ) 4.7, 12.3 Hz, 1 H), 3.77 (s, 3 H), 4.92-4.98
(m, 2 H), 5.33 (s, 2 H), 5.76 (ddd, J ) 8.1, 10.1, 17.1 Hz, 1 H),
5.94 (d, J ) 10.1 Hz, 1 H), 6.70-6.75 (m, 3 H), 6.98 (d, J ) 9.9
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.61 (q), 18.5 (s), 25.8
(q), 35.6 (t), 35.6 (t), 46.4 (d), 48.4 (d), 49.1 (d), 51.4 (d), 55.6 (q),
112.1 (d), 114.4 (t), 119.9 (t), 121.6 (d), 121.8 (d), 128.3 (d), 134.4
(s), 141.9 (d), 143.1 (s), 144.7 (s), 146.0 (d), 149.1 (s), 200.3 (s);
exact mass m/z calcd for C26H36O3Si 424.24338, found 424.24383.
(1S,3S,3aR,7aS)-1-Ethenyl-1,2,3,3a,7,7a-hexahydro-3-[(3-hy-
droxy-4-methoxyphenyl)methyl]-7-methylene-4H-inden-4-one
[(+)-1]. Bu4NF (1.0 M in THF, 21.5 µL, 0.0215 mmol) was added
dropwise to a stirred and cooled (0 °C) solution of 70 (9.1 mg,
0.0215 mmol) in CH2Cl2 (2 mL). Stirring was continued for 5 min,
and another portion of Bu4NF (1.0 M in THF, 1.5 µL, 0.0015 mmol)
was added. The mixture was stirred at 0 °C for a further 5 min.
Water (3 mL) was added, and the mixture was extracted with CH2-
Cl2 (3 × 5 mL). The combined organic extracts were dried (Na2-
SO4) and evaporated. Flash chromatography of the residue over
silica gel (1.5 cm × 7 cm), using 1:20 EtOAc-CH2Cl2, gave (+)-1
(5.6 mg, 84%) as a colorless oil: [R]D ) 19.7 (c 0.28, CHCl3)
[lit.16,18 [R]D ) 17.3 (c 0.55, CHCl3); lit.15 [R]D ) 19.2 (c 0.52,
CHCl3)]; FTIR (CH2Cl2 cast) 3417, 2917, 1658, 1510, 1273, 1130,
The minor isomer had [R]D ) -59.5 (c 0.30, CHCl3); FTIR
1
(CH2Cl2 cast) 3487, 2953, 1511, 840 cm-1; H NMR (500 MHz,
CDCl3) δ 0.15 (s, 3 H), 0.16 (s, 3 H), 1.00 (s, 9 H), 1.44-1.55 (m,
1 H), 1.67 (d, J ) 4.0 Hz, 1 H), 1.86 (ddd, J ) 7.0, 8.5, 13.0 Hz,
1 H), 2.35-2.40 (m, 1 H), 2.47-2.53 (m, 2 H), 2.83-2.89 (m, 2
H), 3.01 (td, J ) 8.5, 18.0 Hz, 1 H), 3.78 (s, 3 H), 4.27 (dd, J )
5.5, 11.0 Hz, 1 H), 4.87 (d, J ) 10.5, 1 H), 4.91 (d, J ) 17.0 Hz,
1 H), 5.13 (dd, J ) 9.5, 10.5 Hz, 2 H), 5.24 (d, J ) 16.5 Hz, 2 H),
5.34-5.40 (m, 2 H), 5.69 (ddd, J ) 7.5, 10.5, 17.5 Hz, 1 H), 6.01
(ddd, J ) 6.5, 10.5, 17.5 Hz, 1 H), 6.47 (dd, J ) 11.0, 17.5 Hz, 1
H), 6.68-6.77 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ -4.61
(q), -4.58 (q), 18.5 (s), 25.8 (q), 35.7 (t), 36.4 (t), 44.3 (d), 46.3
(d), 48.3 (d), 51.0 (d), 55.6 (q), 72.9 (d), 112.1 (d), 113.3 (t), 113.8
(t), 115.5 (t), 117.1 (t), 121.4 (d), 121.7 (d), 134.3 (s), 140.1 (d),
140.5 (d), 142.2 (d), 144.8 (s), 145.8 (s), 149.1 (s); exact mass m/z
calcd for C28H42O3Si 454.29031, found 454.29129.
(1S,3S,3aR,7aS)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
4-methoxyphenyl]methyl]-1-ethenyl-2,3,3a,4,7,7a-hexahydro-7-
methylene-1H-inden-4-ol (69). Ar was bubbled for ca. 5 min
through a stirred solution of 68 (major isomer, 30.0 mg, 0.0665
mmol) in CH2Cl2 (4 mL), and the Grubbs catalyst (first generation,
2.7 mg, 0.0033 mmol) was then added. The mixture was stirred
for 24 h and then evaporated. Flash chromatography of the residue
over silica gel (1.5 cm × 12 cm), using 1:5 EtOAc/hexane, gave
69 (26.2 mg, 93%) as a colorless oil: [R]D ) -32.7 (c 0.63,
CHCl3); FTIR (CH2Cl2 cast) 3403, 2929, 1512, 881 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.16 (s, 6 H), 1.00 (s, 9 H), 1.37 (d, J ) 7.0
Hz, 1 H), 1.64 (ddd, J ) 5.5, 9.0, 14.5 Hz, 1 H), 1.77 (td, J )
10.5, 14.0 Hz, 1 H), 2.05 (td, J ) 5.5, 8.5 Hz, 1 H), 2.24 (ddd, J
) 6.0, 10.5, 19.0 Hz, 1 H), 2.39 (dd, J ) 5.5, 10.5 Hz, 1 H), 2.46
(ddd, J ) 5.5, 10.0, 19.0 Hz, 1 H), 2.61 (dd, J ) 9.5, 13.5 Hz, 1
H), 3.03 (dd, J ) 6.0, 14.0 Hz, 1 H), 3.78 (s, 3 H), 4.32 (broad s,
1 H), 4.72 (s, 1 H), 4.79 (d, J ) 17.0 Hz, 1 H), 4.89 (dd, J ) 1.5,
10.0 Hz, 1 H), 4.92 (s, 1 H), 5.62 (ddd, J ) 8.5, 10.5, 17.0 Hz, 1
H), 5.68 (d, J ) 10.0 Hz, 1 H), 6.10 (dd, J ) 2.0, 10.0 Hz, 1 H),
6.74-6.76 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ -4.59 (q),
18.5 (s), 25.8 (q), 35.6 (t), 37.3 (t), 44.6 (d), 47.2 (d), 50.4 (d),
50.9 (d), 55.6 (q), 65.4 (d), 112.2 (d), 113.6 (t), 114.1 (t), 121.4
1
757 cm-1; H NMR (500 MHz, CDCl3) δ 1.54-1.59 (m, 1 H),
1.73 (ddd, J ) 7.1, 9.2, 13.5 Hz, 1 H), 2.48-2.53 (m, 2 H), 2.62
(td, J ) 8.1, 16.4 Hz, 1 H), 2.79 (t, J ) 8.2 Hz, 1 H), 2.86 (dd, J
) 5.8, 8.1 Hz, 1 H), 3.03-3.09 (m, 1 H), 3.86 (s, 3 H), 4.92-4.98
(m, 2 H), 5.32 (d, J ) 4.1 Hz, 2 H), 5.52 (s, 1 H), 5.76 (ddd, J )
8.2, 10.0, 16.8 Hz, 1 H), 5.93 (d, J ) 9.9 Hz, 1 H), 6.68 (dd, J )
1.7, 8.2 Hz, 1 H), 6.75 (d, J ) 8.2 Hz, 1 H), 6.78 (d, J ) 1.7 Hz,
1 H), 6.98 (d, J ) 9.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
3086 J. Org. Chem., Vol. 73, No. 8, 2008

Potent Anticancer Agents Ottelione A and B
35.7 (t), 35.9 (t), 46.3 (d), 48.6 (d), 49.0 (d), 51.4 (d), 56.0 (q),
110.5 (d), 114.4 (t), 115.0 (d), 119.9 (t), 120.3 (d), 128.3 (d), 135.1
(s), 141.8 (d), 143.0 (s), 144.7 (s), 145.3 (s), 145.9 (d), 200.3 (s);
exact mass m/z calcd for C20H22O3310.15689, found 310.15721.
The compound is acid sensitive, and so the solvents for NMR and
optical rotation measurements were stored over anhydrous K2CO3.
1S,2S,3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]methyl]-3-ethenyl-2-(1-methylene-2-propen-1-
yl)cyclopentanecarboxaldehyde (71). DBU (1 drop) was added
to a stirred solution of 66 (42.0 mg, 0.099 mmol) in CH2Cl2 (7
mL). Stirring was continued for 36 h, and then the solvent was
evaporated. Flash chromatography of the residue over silica gel (2
cm × 10 cm), using 1:10 EtOAc/hexane, gave 71 (38.2 mg, 91%)
as a yellow oil: [R]D ) -15.3 (c 0.30, CHCl3); FTIR (CH2Cl2
signals) δ -4.64 (q), -4.61 (q), 18.5 (s), 25.8 (q), 38.7 (t), 41.4
(t), 43.9 (d), 44.3 (d), 49.5 (d), 55.5 (q), 56.7 (d), 74.6 (d), 110.1
(t), 112.1 (d), 113.8 (t), 121.6 (d), 121.9 (d), 131.4 (d), 133.8 (d),
133.9 (s), 142.9 (d), 144.9 (s), 145.7 (s), 149.3 (s); exact mass m/z
calcd for C26H38O3Si 426.25903, found 426.25945.
(1S,3S,3aS,7aS)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
4-methoxyphenyl]methyl]-1-ethenyl-1,2,3,3a,7,7a-hexahydro-7-
methylene-4H-inden-4-one (74). Dess-Martin periodinane (28.7
mg, 0.0676 mmol) was added to a stirred solution of 72 (mixture
of two isomers, 24.0 mg, 0.0563 mmol) in CH2Cl2 (4 mL). Stirring
was continued for 1 h, and then saturated aqueous Na2S2O3 (3 mL),
followed by saturated aqueous NaHCO3 (2 mL), was added. The
mixture was stirred for 5 min, diluted with water (5 mL), and
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried (Na2SO4) and evaporated. Flash chromatography of the
residue over silica gel (2 cm × 7 cm), using 1:10 EtOAc/hexane,
gave 74 (22.1 mg, 93%) as an oil: [R]D ) -248.8 (c 0.27, CHCl3);
1
cast) 2930, 2857, 1722, 1511, 1272 cm-1; H NMR (500 MHz,
CDCl3) δ 0.15 (s, 6 H), 1.00 (s, 9 H), 1.69-1.82 (m, 2 H), 2.57-
2.64 (m, 4 H), 2.69 (td, J ) 8.5, 17.0 Hz, 1 H), 2.84 (t, J ) 9.5
Hz, 1 H), 3.77 (s, 3 H), 4.93-4.98 (m, 2 H), 5.06 (d, J ) 13.5 Hz,
2 H), 5.18 (s, 1 H), 5.30 (d, J ) 17.5 Hz, 1 H), 5.68 (ddd, J ) 7.5,
10.0, 17.0 Hz, 1 H), 6.31 (dd, J ) 11.0, 18.0 Hz, 1 H), 6.67-6.77
(m, 3 H), 9.39 (d, J ) 2.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ -4.65 (q), 18.5 (s), 25.7 (q), 36.9 (t), 40.7 (t), 40.8 (d), 48.3 (d),
49.0 (d), 55.5 (q), 63.4 (d), 112.1 (d), 114.5 (t), 114.5 (t), 115.0
(t), 121.7 (d), 122.1 (d), 132.5 (s), 137.7 (d), 139.9 (d), 144.9 (s),
146.3 (s), 149.5 (s), 202.1 (d); exact mass m/z calcd for C26H38O3-
Si 426.25903, found 426.25882.
(1S,2S,3S,5S)-5-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-
methoxyphenyl]methyl]-r,3-diethenyl-2-(1-methylene-2-propen-
1-yl)cyclopentanemethanol (72). Vinylmagnesium bromide (1 M
in THF, 0.20 mL, 0.20 mmol) was added dropwise to a stirred and
cooled (0 °C) solution of 71 (36.3 mg, 0.0852 mmol) in THF (4
mL). Stirring at 0 °C was continued for 1 h, and saturated aqueous
NH4Cl (4 mL), followed by water (1 mL), was added. The mixture
was extracted with Et2O (3 × 10 mL), and the combined organic
extracts were washed with brine, dried (Na2SO4), and evaporated.
Flash chromatography of the residue over silica gel (2 cm × 15
cm), using 1:10 EtOAc/hexane, gave 72 (34.1 mg, 88%) as a 5:3
mixture (1H NMR) of two isomers epimeric at the hydroxyl-bearing
carbon: [R]D ) -116.3 (c 0.25, CHCl3); FTIR (CH2Cl2 cast) 3531,
2930, 2857, 1511, 840 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.16
(s, 6 H), 1.01 (s, 9 H), 1.46 (broad s, 1 H), 1.53-1.59 (m, 1 H),
1.66-1.67 (m, 1 H), 1.88-1.92 (m, 1 H), 2.16-2.26 (m, 1 H),
2.49-2.56 (m, 3 H), 2.68-2.75 (m, 1 H), 3.78 (s, 3 H), 4.02 (s,
0.5 H), 4.10 (s, 0.5 H), 5.02-5.43 (m, 8 H), 5.61-5.68 (m, 1 H),
5.78-5.86 (m, 1 H), 6.33-6.40 (m, 1 H), 6.68-6.78 (m, 3 H);
13C NMR (125 MHz, CDCl3, signals for major isomer) δ -4.61
(q), 18.5 (s), 25.7 (q), 37.0 (t), 39.3 (d), 42.3 (t), 48.9 (d), 51.3 (d),
55.6 (q), 56.5 (d), 73.5 (d), 112.1 (d), 113.9 (t), 114.1 (t), 114.4
(t), 114.8 (t), 121.9 (d), 122.0 (d), 133.9 (s), 138.2 (d), 139.8 (d),
140.5 (d), 144.8 (s), 148.4 (s), 149.2 (s); exact mass m/z calcd for
C28H42O3Si 454.29031, found 454.28975.
1
FTIR (CH2Cl2 cast) 2952, 2929, 1682, 1511, 841 cm-1; H NMR
(500 MHz, CDCl3) δ 0.15 (s, 6 H), 0.99 (s, 9 H), 1.52-1.62 (m,
1 H), 1.78 (ddd, J ) 6.8, 9.8, 13.9 Hz, 1 H), 2.27 (dd, J ) 9.8,
13.9 Hz, 1 H), 2.36 (dd, J ) 9.8, 13.4 Hz, 1 H), 2.45-2.56 (m, 2
H), 2.70 (td, J ) 9.0, 18.8 Hz, 1 H), 3.11 (dd, J ) 3.6, 13.4 Hz, 1
H), 3.78 (s, 3 H), 5.00 (d, J ) 10.3 Hz, 1 H), 5.08 (d, J ) 17.5 Hz,
1 H), 5.30 (s, 1 H), 5.44 (s, 1 H), 5.74 (ddd, J ) 8.1, 10.2, 17.3
Hz, 1 H), 5.94 (d, J ) 9.7 Hz, 1 H), 6.71-6.75 (m, 3 H), 7.00 (d,
J ) 9.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.61 (q), -4.59
(q), 18.5 (s), 25.8 (q), 36.9 (t), 37.9 (d), 40.3 (t), 44.5 (d), 50.5 (d),
55.6 (q), 58.2 (d), 112.0 (d), 114.6 (t), 117.1 (t), 122.0 (d), 122.2
(d), 128.7 (d), 133.3 (s), 141.6 (d), 144.7 (s), 144.8 (s), 147.5 (d),
149.2 (s), 200.6 (s); exact mass m/z calcd for C26H36O3Si 424.24338,
found 424.24366.
(1S,3S,3aS,7aS)-1-Ethenyl-1,2,3,3a,7,7a-hexahydro-3-[(3-hy-
droxy-4-methoxyphenyl)methyl]-7-methylene-4H-inden-4-one
[(-)-2]. Bu4NF (1.0 M in THF, 34.0 µL, 0.034 mmol) was added
dropwise to a stirred and cooled (0 °C) solution of 74 (12.0 mg,
0.0283 mmol) in CH2Cl2 (2 mL). Stirring was continued for 10
min, water (3 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 5 mL). The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue over
silica gel (1.5 cm × 7 cm), using 1:4 EtOAc/hexane, gave (-)-2
(7.6 mg, 87%) as a colorless solid: mp 141-142 °C [lit.16,18 142.2-
143.0 °C]; [R]D ) -331.4 (c 0.18, CHCl3) [lit.16,18 -333.0 (c 0.18,
CHCl3)]; FTIR (CH2Cl2 cast) 3431, 2927, 1676, 1511, 1273 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.59 (ddd, J ) 8.1, 10.1, 13.5 Hz,
1 H), 1.79 (ddd, J ) 6.8, 9.9, 13.8 Hz, 1 H), 2.27 (dd, J ) 9.9,
13.9 Hz, 1 H), 2.35 (dd, J ) 10.1, 13.5 Hz, 1 H), 2.48-2.55 (m,
2 H), 2.70-2.77 (m, 1 H), 3.15 (dd, J ) 3.7, 13.5 Hz, 1 H), 3.86
(s, 3 H), 5.00 (dd, J ) 1.2, 10.2 Hz, 1 H), 5.09 (d, J ) 17.1 Hz,
1 H), 5.30 (s, 1 H), 5.45 (s, 1 H), 5.53 (s, 1 H), 5.74 (ddd, J ) 8.1,
10.2, 17.1 Hz, 1 H), 5.95 (d, J ) 9.7 Hz, 1 H), 6.69 (dd, J ) 2.0,
8.2 Hz, 1 H), 6.76 (d, J ) 8.2 Hz, 1 H), 6.81 (d, J ) 2.0 Hz, 1 H),
7.00 (d, J ) 9.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 37.0 (t),
37.9 (d), 40.6 (t), 44.5 (d), 50.5 (d), 56.0 (q), 58.3 (d), 110.5 (d),
114.6 (t), 115.4 (d), 117.1 (t), 120.5 (d), 128.7 (d), 134.2 (s), 141.6
(d), 144.8 (s), 144.8 (s), 145.3 (s), 147.6 (d), 200.6 (s); exact mass
m/z calcd for C20H22O3310.15689, found 310.15659.
(1S,3S,3aS,7aS)-3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
4-methoxyphenyl]methyl]-1-ethenyl-2,3,3a,4,7,7a-hexahydro-7-
methylene-1H-inden-4-ol (73). Ar was bubbled for ca. 10 min
through a stirred solution of alcohols 72 (25.0 mg, 0.055 mmol) in
CH2Cl2 (5 mL), and the Grubbs catalyst (first generation, 4.5 mg,
0.0055 mmol) was added. The mixture was stirred for 20 h and
then evaporated. Flash chromatography of the residue over silica
gel (2 cm × 10 cm), using 1:6 EtOAc/hexane, gave 73 (20.3 mg,
86%) as a mixture of two epimeric isomers at the hydroxyl-bearing
carbon: [R]D ) -132.3 (c 0.16, CHCl3); FTIR (CH2Cl2 cast) 3397,
Acknowledgment. The NSERC is thanked for financial
support. D.L. held a Province of Alberta Graduate Fellowship.
X-ray data have been deposited in the Cambridge Crystal-
lographic Data Centre and assigned the registry number CCDC
635712.
Supporting Information Available: Experimental procedures
for 18-25, 29-43, (()-1, (()-2, benzoate corresponding to 63,
47, 50, 57-58. NMR spectra of (+)-1, (-)-2, (()-1, (()-2, 19-
21, 23-25, 29-35, 37-39, 41-43, 47, 50, 57-60, 63-74, and
benzoate corresponding to 63. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
2929, 1511, 1270, 840 cm-1; H NMR (500 MHz, CDCl3, major
isomer signals) δ 0.15 (s, 6 H), 1.00 (s, 9 H), 1.31 (broad s, 1 H),
1.42-1.51 (m, 1 H), 1.63-1.76 (m, 2 H), 2.09-2.21 (m, 2 H),
2.49 (dd, J ) 8.8, 13.8 Hz, 1 H), 2.63-2.70 (m, 1 H), 3.01 (dd, J
) 5.8, 13.8 Hz, 1 H), 3.78 (s, 3 H), 4.28 (s, 1 H), 4.87 (s, 1 H),
4.97 (d, J ) 10.2 Hz, 1 H), 5.04-5.08 (m, 2 H), 5.64 (d, J ) 9.7
Hz, 1 H), 5.74-5.83 (m, 1 H), 6.10 (dd, J ) 1.5, 9.7 Hz, 1 H),
6.71-6.76 (m, 3 H); 13C NMR (125 MHz, CDCl3, major isomer
JO702635T
J. Org. Chem, Vol. 73, No. 8, 2008 3087