Synthesis of the zoanthamine ABC ring system: Some surprises from intramolecular Diels-Alder reactions

Article abstract of DOI:10.1021/jo0520691

In connection with the total synthesis of the marine alkaloids zoanthamine and norzoanthamine, an elaborate model study was conducted starting from (-)-carvone. In nine steps alkenyl iodides corresponding to the C ₁₁-C₂₄ fragment of

Full text of DOI:10.1021/jo0520691

Synthesis of the Zoanthamine ABC Ring System: Some Surprises
from Intramolecular Diels-Alder Reactions
Martin Juhl, Thomas E. Nielsen, Sebastian Le Quement, and David Tanner*
Department of Chemistry, Technical UniVersity of Denmark, Building 201, KemitorVet,
DK-2800 Kgs. Lyngby, Denmark
dt@kemi.dtu.dk
ReceiVed October 3, 2005
In connection with the total synthesis of the marine alkaloids zoanthamine and norzoanthamine, an elaborate
model study was conducted starting from (-)-carvone. In nine steps alkenyl iodides corresponding to
the C11-C24 fragment of zoanthamine were obtained. The alkenyl iodides were coupled to various stannanes
(C6-C10 fragment) via the Corey modification of the Stille reaction, affording a variety of Diels-Alder
precursors. An interesting and highly unexpected cascade reaction sequence was observed during the
screening of an intramolecular Diels-Alder reaction, generating a novel tetracyclic framework. A slight
modification in the Diels-Alder precursor allowed the desired cycloaddition to take place, giving the
cycloadduct in 87% yield.
Introduction
The zoanthamine family is a structurally unique class of
densely functionalized heptacyclic alkaloids (Figure 1). The
parent member, zoanthamine (1), was isolated from the marine
organism Zoanthus sp. found off the coast of Visakhapatnam,
India and was characterized by means of X-ray crystallography
and NMR spectroscopy in 1984.1 Since that discovery, a whole
family of congeners has been found around the world.2 These
marine alkaloids have been tested for biological activity, and
zoanthamine itself has been found to show anti-inflammatory
effects against phorbol myristate acetate (PMA) induced inflam-
mation of the mouse ear,3 while norzoanthamine (2) has been
FIGURE 1. Zoanthamine alkaloids.
reported to be a promising drug candidate in the treatment of
osteoporosis, since significant suppression of bone weight
decrease and weakening in ovariectomized mice was observed
when treated with the natural product.4 Norzoanthamine has also
(1) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am. Chem.
Soc. 1984, 106, 7983.
(2) (a) Uramoto, M.; Hayashi, K.; Yamaguchi, K.; Yada, M.; Tsuji, T.;
Uemura, D. Bull. Chem. Soc. Jpn. 1998, 71, 771. (b) Atta-ur-Rahman; Alvi,
K. A.; Abbas, S. A.; Choudhary, M. I.; Clardy, J. Tetrahedron Lett. 1989,
30, 6825. (c) Daranas, A. H.; Ferna´ndez, J. J.; Gavin, J. A.; Norte, M.
Tetrahedron 1998, 54, 7891. (d) Daranas, A. H.; Ferna´ndez, J. J.; Gavin, J.
A.; Norte, M. Tetrahedron 1999, 55, 5539. (e) Nakamura, H.; Kawase, Y.;
Maruyama, K.; Murai, A. Bull. Chem. Pharm. Bull. 2000, 71, 781.
(3) (a) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M. Faulkner, D. J. J. Org. Chem. 1985, 50, 3757. (b) Rao,
C. B.; Rao, D. V.; Raju, V. S. N.; Sulliwan, B. W.; Faulkner, D. J.
Heterocycles 1989, 28, 103.
(4) Yamaguchi, K.; Yada, M.; Tsuji, T.; Kuramoto, M.; Uemura, D. Biol.
Pharm. Bull. 1999, 22, 920.
10.1021/jo0520691 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2005
J. Org. Chem. 2006, 71, 265-280
265

Juhl et al.
SCHEME 1
SCHEME 2
been reported to exhibit anticancer activity by inhibition of the
growth of murine leukemia cells.5
Results and Discussion
Previous studies in our group6a-d have secured a route to
advanced stage conjugated dienone 5 in 21 steps from (S)-
(-)-perillyl alcohol (Scheme 1). The key steps en route to 5
involve a Johnson-Claisen rearrangement, an iodolactonization-
elimination reaction, a regioselective hydrostannation, and a
Corey-modified (Cu-mediated) Stille coupling. An intramolecu-
lar Diels-Alder (IMDA) reaction was then envisaged for the
transformation of 5 to the ABC ring system of the zoanthamine
family.
Besides the impressively broad range of biological activities,
the intriguing topology of these alkaloids has stimulated several
research groups to attempt the daunting task of synthesizing
these natural products, i.e., zoanthamine (1),6,7 norzoanthamine
(2),7 zoanthenol (3),8 and zoanthamide (4).9 A benchmark for
synthetic efforts was established in 2004, when Miyashita and
co-workers reported the first total synthesis of a zoanthamine
alkaloid, norzoanthamine (2), after 41 steps and with an
impressive overall yield of 3.5%.10 For the past few years, our
own laboratory has been engaged in the development of a totally
synthetic route to the zoanthamine family.6a-d In the present
paper, we describe the development of a synthetic strategy for
the stereoselective construction of the zoanthamine ABC ring
system.
From our initial experiments with the IMDA reaction it
quickly became obvious that an optimization study would be
necessary. To save the precious synthetic intermediate 5, it was
decided to work with a model system that would provide more
rapid access to advanced stage intermediates. (-)-Carvone was
chosen as the starting material which allowed an expeditious
entry to an IMDA precursor differing mainly in the position of
the C27 methyl group (Figure 1, Scheme 2).
(5) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatu, A.; Yamada, K.;
Ijuin, Y. Heterocycl. Commun. 1995, 1, 207.
Aldehyde 7 was easily obtained from (-)-carvone (6 steps,
26% yield)11 and further transformed into the propargylic alcohol
8a by exposure to the lithium salt of the commercial available
tert-butyl(but-3-ynyloxy)dimethylsilane, in excellent yield (95%)
as a 1:1 mixture of diastereomers. Subjecting propargylic alcohol
8a to the regioselective Pd-catalyzed hydrostannation protocol
introduced by Greeves and further developed by our group6d,12
provided stannane 9a in 83% yield. Stannane 9a was oxidized
using Ley’s TPAP procedure13 to the enone (95% yield, one
diastereomer) and transformed into the iodide by reaction with
iodine.14 The Stille coupling between freshly prepared iodide
and stannane 1015 was performed using the Corey modification16
(6) (a) Tanner, D.; Andersson, P. G.; Tedenborg, L.; Somfai, P.
Tetrahedron 1994, 50, 9135. (b) Tanner, D.; Tedenborg, L.; Somfai, P.
Acta Chem. Scand. 1997, 51, 1217. (c) Nielsen, T. E.; Tanner, D. J. Org.
Chem. 2002, 67, 6366. (d) Nielsen, T. E.; Le Quement, S.; Juhl, M, Tanner,
D. Tetrahedron 2005, 61, 8013. (e) Ghosh, S.; Rivas, F.; Fischer, D.;
Gonza´lez, M. A.; Theodorakis, E. A. Org. Lett. 2004, 6, 941. (f) Rivas, F.;
Ghosh, S.; Theodorakis, E. A. Tetrahedron Lett. 2005, 46, 5281.
(7) (a) Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi, S. Tetrahedron
Lett. 1998, 39, 6237. (b) Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi,
S. Tetrahedron Lett. 1998, 39, 6241. (c) Hikage, N.; Furukawa, H.; Takao,
K.; Kobayashi, S. Chem. Pharm. Bull. 2000, 48, 1370. (d) Williams, D.
R.; Brugel, T. A. Org. Lett. 2000, 2, 1023.
(8) (a) Hirai, G.; Oguri, H.; Moharram, S. M.; Koyama, K.; Hirama, M.
Tetrahedron Lett. 2001, 42, 5783. (b) Hirai, G.; Koizumi, Y.; Moharram,
S. M.; Oguri, H.; Hirama, M. Org. Lett. 2002, 4, 1627. (c) Hirai, G.; Oguri,
H.; Hayashi, M.; Koyama, K.; Koizuma, Y.; Moharram, S. M.; Hirama,
M. Chem. Lett. 2004, 14, 2647.
(9) Williams, D. R.; Cortez, G. S. Tetrahedron Lett. 1998, 39, 2675.
(10) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science
2004, 305, 495.
(11) For the synthesis of aldehyde 7, see Supporting Information.
(12) Greeves, N.; Torode, J. S. Synlett 1994, 537.
(13) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 13.
266 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
SCHEME 3
SCHEME 4
to afford diene 11 in modest yield (24%) over the two-step
sequence. Unfortunately, after extensive experimentation, all
attempts17 to promote the IMDA reaction of diene 11 failed,
resulting only in recovered starting material or decomposition.
The complete failure of the normally reliable IMDA reaction
was surprising and prompted us to investigate whether the lack
of reactivity was due to steric effects, electronic effects, or a
combination of the two. Therefore, the system was simplified
by preparing diene 13 from stannane 9a in a two-step procedure
(Scheme 3). Performing the tin/iodide exchange on stannane
9a instead of the corresponding enone gave a faster and cleaner
reaction most likely due to the more electron rich double bond
in the former. Diene 13 was oxidized and subjected to elevated
temperatures in order to promote the IMDA reaction. Pleasingly,
tricyclic ketone 14 was isolated as a single diastereomer in 93%
yield, after heating the Diels-Alder precursor in toluene for 4
days.
the C10 position (zoanthamine numbering) instead of the
previously installed electron-donating oxygen of the dihydro-
pyran moiety in 11 (Scheme 2). Stannane 15 was chosen as the
new C6-C10 fragment,18 having the ester functionality as the
electron-withdrawing group and constitutes a suitable alternative
for the previously used dihydropyran ring system. This approach
would obviously entail a subsequent oxidative decarboxylation
reaction19 to access the correct oxidation state at C10.
Diene 17a was accessed through a three-step sequence from
stannane 9a (Scheme 4), in analogy to the previously used route.
To promote the thermal IMDA reaction, diene 17a was
dissolved in toluene and heated to 195 °C for 20 min in a sealed
Carius tube (Scheme 5). The desired Diels-Alder product was
indeed formed but to our surprise not as the main product of
the reaction, which proved to be the interesting 6-5-6-6
tetracyclic diene 19. Unfortunately, the two products were
inseparable using standard chromatographic techniques. A
possible mechanism for the formation of the rearrangement
product 19 is shown in Scheme 6.
This encouraging result indicated that steric effects alone were
perhaps not responsible for the failure of 11 to undergo the
IMDA reaction and led us to pursue a Diels-Alder precursor
having an additional electron-withdrawing group positioned at
We then hypothesized that changing the protecting group at
C
24 to either a TBDPS or Bn group should limit or prevent the
initial migration from taking place, thereby favoring the desired
IMDA products 18b-c. Dienes 17b and 17c were prepared
using an analogous route to that for 17a.20 Surprisingly,
subjecting either diene 17b or 17c to the previously used thermal
(14) The tin/iodide exchange was surprisingly sluggish. Furthermore the
iodo derivative proved to be unstable, which prompted us to find better-
suited reaction conditions for this exchange reaction (vide infra).
(15) For the synthesis of stannane 10, see ref 6d.
(16) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(17) Various reaction conditions, such as refluxing 11 in toluene or
xylene, as well as microwave heating the D-A precursor in NMP,
acetonitrile, and DMSO/H2O ((a) Toro´, A.; Deslongchamps, P. J. Org.
Chem. 2003, 68, 6847) were attempted without success. Lewis acid catalysis
using LiClO4 (5 M in Et2O) ((b) Braun, R.; Sauer, J. Chem. Ber. 1986,
119, 1269. (c) Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc.
1990, 112, 4595) and Yb(OTf)3 ((d) Han, G.; Laporte, M. G.; Folmer, J.
J.; Werner, K. M.; Weinreb, S. M. J. Org. Chem. 2000, 6293. Review on
rare-earth metal triflates in organic chemistry ((e) Kobayashi, S.; Sugiura,
M.; Kitagawa, H.; Lam. W.-L. Chem. ReV. 2002, 2227) did not yield any
product.
(18) For the synthesis of stannane 15, see Supporting Information.
(19) Examples of oxidative decarboxylation reactions used in total
synthesis: (a) Corey, E. J.; Imai, N.; Pikul, S. Tetrahedron Lett. 1991, 7517.
(b) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 8. (c) Hatanaka,
M.; Ueda, I. Chem. Lett. 1991, 1, 61. (d) Sebahar, P. R.; Williams, R. M.
J. Am. Chem. Soc. 2000, 122, 5666. (e) Kienzle, F.; Holland, G. W.; Jernow,
J. L.; Kwoh, S.; Rosen, P. J. Org. Chem. 1973, 38, 3440.
(20) Attempts to optimize the low yielding Cu-mediated Stille coupling
failed, mainly due to difficulties in removing undesired homocoupling
byproducts of the stannane. Reversing the stannane/iodide coupling partners
did not improve the overall yield either.
J. Org. Chem, Vol. 71, No. 1, 2006 267

Juhl et al.
SCHEME 5
SCHEME 6
SCHEME 7
conditions resulted in exclusive formation of the undesired
rearrangement product 19 in 60% starting from the TBDPS-
protected diene and 37% yield with Bn as the protecting group.
These findings made us modify the earlier proposed mechanism
to one that would accommodate the elimination of the protecting
group at C24, regardless of the nature of that protecting group
(Scheme 7). The R,â-unsaturated ketone moiety of 17a-c could
undergo a [1,5]-sigmatropic rearrangement, providing a highly
unstable conjugated allylic enol ether. Loss of the protecting
group at C24 would then afford a conjugated dienone, which
could undergo a 6π electrocyclic ringclosure affording a pyran,
which in turn is set up to participate in a hetero-IMDA,
providing the tetracyclic product 19.
To our delight, the IMDA reaction proved viable after
subjecting alcohol 16b-c to elevated temperatures for extended
periods of time, which provided the desired tricyclic Diels-
Alder product as a single diastereomer. That only one diaste-
reomer of the cycloaddition product was isolated presumably
stems from the difference in reaction rate for the pseudoequa-
torial (R)-C20 vs the pseudoaxial (S)-C20 configured alcohols
(Figure 2). As shown, the pseudoaxial oriented alcohol suffers
from an unfavorable 1,3-diaxial interaction with the C28 methyl
group. In the case where 16b was heated, the desired cycload-
duct product was isolated in 50% yield along with 10%
unreacted starting material, both as single diastereomers.
Subjecting the isolated slower reacting diastereomer 16b to 205
°C for 2 days gave an inseparable mixture of two diastereomers,
both different from 20b. Presumably these two products arise
from exo and endo TS respectively, in the IMDA reaction.
In an attempt to circumvent this rearrangement, the thermal
conditions were applied to the structurally related alcohols
16b-c (hydroxy functionality at C20, Scheme 8).
268 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
SCHEME 8
SCHEME 9
This crucial piece of evidence regarding the configuration
of the alcohol at C20 in the IMDA reaction led us to improve
the strategy by selectively constructing the desired pseudoequa-
torial alcohol. The configuration at C20 was controlled by a
Carreira addition21 of acetylene 21 to aldehyde 7, with excellent
diastereoselectivity (19:1) and good isolated yield (74%),
Scheme 9. The triisopropylsilyl (TIPS) protecting group was
chosen to impose more stability toward the rather vigorous
thermal conditions of the IMDA reaction. The purpose of the
extra methylene group in the C22 side chain of 24 was to further
probe the mechanism of the formation of the rearrangement
product 19: on the basis of the mechanism proposed in Scheme
7, the loss of the protecting group should be prevented by the
introduction of the extra methylene unit. The propargylic alcohol
derived from the Carreira addition was first hydrostannylated
affording stannane 22 in 61% yield (Scheme 9). In initial studies,
an interesting observation was made when the subsequent tin/
iodide exchange reaction was performed using 2 equiv of iodine.
The product after the Stille coupling was lacking the MOM
protection group as well as the isopropenyl moiety and was
characterized as the 6-oxa-bicyclo[3,2,1]octane 23, stemming
from an 5-exo-trig iodoetherification. This observation provides
an explanation for the generally low to moderate yields of this
transformation in analogous cases (vide infra). After some
experimentation, improved yields of the desired mono-iodinated
product could be obtained by exposing the stannane 22 to 1
equiv of iodine for 1 min at -81 °C. After the subsequent Stille
coupling, diene 24 was produced in 48% yield for the two-step
sequence.
The stage was now set for the crucial IMDA reaction, and
gratifyingly, the cycloaddition went smoothly to afford cycload-
duct 25 in 87% yield as a single diastereomer. Oxidation of the
C
20 alcohol in 24 using the TPAP procedure gave ketone 26 in
81% yield. Heating the methylene-elongated ketone 26 to 240
°C for 2.5 h afforded the cycloadduct 27, with no rearrangement
(21) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806.
FIGURE 2. R1 ) (CH2)3OPMB, R2 ) (CH2)2OTBDPS/Bn.
J. Org. Chem, Vol. 71, No. 1, 2006 269

Juhl et al.
SCHEME 10
SCHEME 11
product similar to 19, thus supporting the proposed mechanism
(Scheme 7).
the free C20 hydroxyl group on to C17, with concomitant loss
of the MOM group. The IMDA product 31 was isolated as
the minor component in the reaction starting with diastereomer
29b.
The reason for the occurrence of this unexpected cyclization
pathway can be explained by the orientation of the MOM group
in 29a and 29b, in comparison to the previously prepared D-A
precursors 20a-c and 24. The allylic MOM groups in 29a-b
would be expected to be oriented in a pseudoaxial position
compared to the pseudoequatorial position of 20a-c and 24.
The axial orientation of the MOM groups in 29a-b positions
the MOM group perpendicular to the plane of the C15-C16
At this point, we decided that we had gathered enough
information about the IMDA process to allow us to turn from
the model systems to the substrate required for the synthesis of
zoanthamine itself. Previously prepared stannane 286c was
coupled with 15 to give a diastereomeric mixture of dienes
29a (39%) and 29b (17%), which was separated (Scheme 11).
As the stereochemical configuration at C20 of both the major
and minor diastereomer remained unknown, both were sub-
jected to the IMDA reaction conditions. Surprisingly, the main
product of both reactions turned out to be cyclization of
270 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
as well as 2.4 g (52%) of unreacted tert-butyl(but-3-ynyloxy)-
dimethylsilane. A portion of the more polar isomer was eluted
free of its epimer and characterized. In practice, the mixture
was used in the subsequent step without being separated. Rf 0.45
23
(Et2O:pentane, 1:4); [R]D +30.0 (c 2.9, CHCl3); IR (film) 3448,
1
2929, 1644, 1472, 1440, 1382, 1149, 1098, 1028, 838, 778; H
NMR (300 MHz, CDCl3) δ 5.66-5.62 (m, 1H), 4.79 (bs, 2H), 4.75
(d, J ) 6.6 Hz, 1H), 4.66-4.58 (m, 2H), 4.13 (d, J ) 8.2 Hz, 1H),
3.76 (d, J ) 7.5 Hz, 1H), 3.65 (t, J ) 7.4 Hz, 2H), 3.40 (s, 3H),
2.36 (td, J ) 1.9, 7.3 Hz, 2H), 2.20 (td, J ) 4.8, 10.2 Hz, 1H),
2.14-2.01 (m, 1H), 2.00-1.95 (m, 1H), 1.93-1.77 (m, 2H), 1.63
(s, 6H), 1.54 (ddd, J ) 3.3, 8.1, 14.6 Hz, 1H), 0.83 (s, 9H), 0.00
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 146.7, 133.2, 126.5, 113.1,
95.1, 83.1, 81.1, 62.0, 60.4, 56.4, 46.6, 40.7, 37.6, 30.3, 25.9, 23.2,
20.0, 18.2, -5.3; Fast-atom bombardment mass spectroscopy
(FAB-MS) calcd for [M + Na] 445.28; found 445.19; Anal.
Calcd for C24H42O4Si: C, 68.20; H, 10.02. Found: C, 67.94; H,
10.22.
FIGURE 3. SN1-type elimination of the MOM group in 29a-b.
(3E)-4-(Tributylstannyl)-6-(tert-butyldimethylsilyloxy)-1-
((1S,2R,6R)-2-(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)-
cyclohex-3-enyl)hex-3-en-2-ol (9a). To a 1:1 mixture of epimeric
alcohols 8a (1.95 g, 4.61 mmol) and dichlorobis(tris(o-toloyl)-
phosphine)palladium(II) (18 mg, 0.023 mmol) in THF (50 mL) was
added dropwise tributyltin hydride (4.03 g, 13.8 mmol) over a
period of 4.5 h. The reaction was stirred for an additional 1 h then
directly subjected to dry column vacuum chromatography (DCVC)
(AcOEt:heptane, 1:4-1:2) affording 9a (3.83 g, 83%) as a mixture
of diastereomers as well as recovered starting material 8a (137 mg,
7%). A portion of the less polar isomer was eluted free of its epimer
and characterized. In practice, the mixture was used in the
subsequent step without being separated. Mixture of diastereo-
mers: FAB-MS calcd for [M - C4H11]+ 781.37; found 781.4; Anal.
Calcd for C46H74O4SiSn: C, 65.94; H, 8.90. Found: C, 65.93; H,
FIGURE 4. Selected nuclear Overhauser effects correlations for
compounds 30a, 30b, and 31.
double bond, thus making the C-O bond more prone to SN1-
type substitution.
Extensive NMR analysis of 30a, 30b, and 31 confirmed the
assumption that the diene leading to the IMDA product 31 had
the C20 hydroxyl group in the more favorable pseudoequatorial
orientation in the IMDA TS (Figure 2 and Figure 4). The
obvious consequence of this result is that our original route6d
to key intermediates of the type 29 must be modified in order
to invert the stereochemistry at C17.
In conclusion, we have developed a route to the ABC ring
system of the zoanthamine alkaloid family based on an inverse
electron demand IMDA reaction. The IMDA process explored
in the present study provided some surprises as well as some
important lessons relevant to our ongoing work on the total
synthesis of the zoanthamine alkaloids.
23
8.98. Less polar diastereomer: Rf 0.61 (AcOEt:heptane, 1:4); [R]D
+ 5.9 (c 1.1, CHCl3); IR (film) 3466, 2924, 2854, 1644, 1459,
1
1376, 1254, 1148, 1096, 1031, 839; H NMR (300 MHz, CDCl3)
δ 5.67 (d, J ) 7.6, J(Sn-H) ) 68.8 Hz, 1H), 5.61 (bs, 1H), 4.79-
4.70 (m, 3H), 4.67 (d, J ) 6.5 Hz, 1H), 4.14 (d, J ) 7.0 Hz, 1H),
3.67-3.48 (m, 2H), 3.44 (s, 3H), 3.34 (d, J ) 3.9 Hz, 1H), 2.70
(dt, J ) 5.7, 14.6 Hz, 1H), 2.47-2.37 (m, 1H), 2.27 (td, J ) 4.9,
9.4 Hz, 1H), 2.20-1.90 (m, 3H), 2.79-1.72 (m, 3H), 1.70 (s, 3H),
1.69 (s, 3H), 1.54-1.37 (m, 6H), 1.30 (app. sextet, J ) 7.4 Hz,
6H), 0.91-0.84 (m, 24H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 147.1, 146.8, 141.2, 133.4, 125.8, 112.3, 95.7, 82.0, 64.3, 62.9,
56.1, 46.0, 39.5, 37.8, 37.1, 30.1, 29.8, 29.1, 27.4, 26.1, 20.4, 18.9,
18.5, 13.7, 9.7.
Experimental Section
(E)-(R)-6-(tert-Butyl-dimethyl-silanyloxy)-1-((1S,2R,6R)-2-
(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-
hex-3-yne-2-ol (8a). Aldehyde 7 (1.99 g, 8.35 mmol) was dissolved
in THF (20 mL), then added under argon to a mixture of tert-butyl-
(but-3-ynyloxy)dimethylsilane (4.62 g, 25.1 mmol) and n-BuLi
(15.6 mL, 24.2 mmol, 1.55 M in hexanes) in dry THF (20 mL) at
-78 °C which had been stirred for 1 h prior to the addition, stirred
for 2 h then the temperature was raised to -20 °C for 1 h, and
then warmed to room temperature. The reaction was quenched by
the addition of saturated aqueous NaHCO3 (60 mL) and diethyl
ether (200 mL). The aqueous phase was extracted with diethyl ether
(100 mL), and the combined organic phases were dried, filtered,
and evaporated to dryness in vacuo. The residue was purified
by flash column chromatography on silica gel (AcOEt:hexane,
1:2) affording 8a (3.34 g, 95%) as a 1:1 mixture of diastereomers
(3E)-4-(Tributylstannyl)-6-(tert-butyldimethylsilyloxy)-1-
((1S,2R,6R)-2-(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)-
cyclohex-3-enyl)hex-3-en-2-one (37). Alcohol 9a (241 mg, 0.338
mmol) was dissolved in CH2Cl2/CH3CN (2:3, 5 mL), then pulver-
ized 4-Å MS followed by 4-methylmorpholine N-oxide (64 mg,
0.071 mmol) was added under argon and stirred for 20 min, and
then tetrapropylammonium perruthenate (6.0 mg, 0.017 mmol) was
added. After 0.5 h, silica gel (1 g) was added and the reaction
mixture was filtered and washed with CH2Cl2 (2 × 5 mL) and
(AcOEt:hexanes, 1:4) (2 × 5 mL) and evaporated to dryness in
J. Org. Chem, Vol. 71, No. 1, 2006 271

Juhl et al.
vacuo. The residue was purified using flash column chromatography
1.84 (dddd, J ) 2.6, 6.2, 10.7, 13.4 Hz, 1H), 1.72 (s, 3H), 1.64 (s,
on silica gel (AcOEt:hexane, 1:10-1:5) affording 37 (209 mg, 87%)
3H), 1.26 (dd, J ) 2.7, 2.7 Hz, 1H), 0.88 (s, 9H), 0.03 (s, 6H); 13
C
23
as a slightly yellow oil. Rf 0.62 (AcOEt:heptane, 1:3); [R]D
+
NMR (300 MHz, CDCl3) δ 199.1, 152.8, 147.1, 137.4, 134.2, 128.4,
127.8, 125.0, 118.9, 115.1, 113.0, 97.0, 95.7, 82.5, 69.7, 63.8, 56.1,
46.1, 45.3, 39.2, 39.1, 31.5, 30.1, 25.9, 20.1, 18.7, 18.3, 17.5, -5.3,
-5.4; Anal. Calcd for C36H54O6Si: C, 70.78; H, 8.91. Found: C,
70.69; H, 8.88.
30.2 (c 1.1, CHCl3); IR (film) 2956, 2926, 2855, 1686, 1572, 1464,
1376, 1253, 1095, 1030, 838, 778, 760; 1H NMR (300 MHz, CDCl3)
δ 6.35 (s, 1H), 5.55 (bs, 1H), 4.73 (s, 1H), 4.71 (s, 1H), 4.70 (d, J
) 6.6 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H), 4.02 (d, J ) 7.4 Hz, 1H),
3.66 (t, J ) 7.1 Hz, 2H), 3.35 (s, 3H), 3.00 (app. t, J ) 7.0 Hz,
2H), 2.62 (dd, J ) 5.1, 17.3 Hz, 1H), 2.56 (dd, J ) 5.1, 17.3 Hz,
1H), 2.41 (ddd, J ) 4.9, 10.9, 10.9 Hz, 1H), 2.35-2.30 (m, 1H),
2.18-2.11 (m, 1H), 1.95-1.90 (m, 1H), 1.71 (s, 3H), 1.63 (s, 3H),
1.52-1.46 (m, 6H), 1.32 (app. quintet, J ) 7.3 Hz, 6H), 0.97-
0.89 (m, 24H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.9,
147.0, 138.4, 134.2, 125.0, 113.2, 97.0, 82.6, 63.0, 56.1, 54.4, 46.3,
44.5, 39.2, 39.1, 30.0, 29.0, 27.4, 26.1, 20.1, 18.6, 18.5, 13.7, 10.0,
-5.2; High-resolution mass spectrometry (electrospray ionization)
(HRMS (ESI)) calcd for C14H21O3 [M - H]: 237.1491; found
237.1483.
(3E)-4-(2-[tert-Butyldimethylsilyloxy]ethyl)-1-((1S,2R,6R)-2-
(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-
hexa-3,5-dien-2-ol (13). A solution of the â-stannylated allylic
alcohol 9a in CH2Cl2 (10 mL) was cooled to -78 °C, and a solution
of iodine was added at once and stirred under argon for 5 min.
The reaction mixture was washed with a saturated sodium thio-
sulfate solution (2 × 10 mL). The organic phase was dried (Na2-
SO4), and tetra-n-butylammonium diphenylphosphinate (Sn-
scavenger)23 was added and stirred for 5 min before the mixture
was filtered and evaporated to dryness in vacuo. The residue was
subjected to flash column chromatography on silica gel (AcOEt:
hexane, 1:19) affording the desired iodide (130 mg, 84%) as a
colorless oil. The iodide was used immediately in the next step. A
30-mL Schlenk tube was charged with LiCl (30.6 mg, 0.72 mmol)
and flame-dried under high vacuum. Upon cooling, tetrakis-
(triphenylphosphine)palladium(0) (12.5 mg, 0.010 mmol) and
copper(I) chloride (59 mg, 0.60 mmol) were added, and the mixture
was degassed (4×) under high vacuum with an argon purge. The
iodide (66 mg, 0.12 mmol) and vinyltributylstannane (45.7 mg,
0.144 mmol) were dissolved in dimethyl sulfoxide (2 mL) and added
to the salts. The resulting mixture was rigorously degassed (4×)
by the freeze-pump-thaw process (-78 °C-rt, Ar). The reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with diethyl ether (10 mL) and washed with a
mixture of brine and 5% ammonium hydroxide (10 mL, 1:1). The
aqueous layer was further extracted with diethyl ether (2 × 5 mL),
and the combined organic layers were washed with water (2 × 10
mL) and brine (10 mL), dried (Na2SO4), and evaporated to dryness
in vacuo. The residue was purified by flash column chromatography
on demetalated silica gel (AcOEt:hexane, 1:19-1:3) providing 13
(23 mg, 43%) as a colorless oil.
(3E)-4-(6-(Benzyloxy)-5,6-dihydro-4H-pyran-3-yl)-6-tert-bu-
tyldimethylsilyloxy-1-((1S,2R,6R)-2-(methoxymethoxy)-3-meth-
yl-6-(prop-1-en-2-yl)cyclohex-3-enyl)hex-3-en-2-one (11). A so-
lution of stannane 37 (555 mg, 0.78 mmol) in CH2Cl2 (50 mL)
was cooled to 0 °C, and a solution of iodine (201 mg, 0.79 mmol)
in CH2Cl2 (20 mL) was added dropwise over a period of 2 min.
The ice bath was removed, and the mixture was stirred under argon
for 0.5 h. The reaction mixture was washed with a saturated sodium
thiosulfate solution (2 × 20 mL). The organic phase was dried (Na2-
SO4), filtered, and evaporated to dryness in vacuo. The residue was
subjected to flash column chromatography on silica gel (AcOEt:
hexane, 1:19) affording the desired iodide (179 mg, 42%) as a
colorless oil. The iodide was used immediately in the next step. A
30-mL Schlenk-tube was charged with LiCl (84 mg, 1.98 mmol)
and flame dried under high vacuum. Upon cooling, tetrakis-
(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) and copper-
(I) chloride (163 mg, 1.65 mmol) were added, and the mixture was
degassed (4×) under high vacuum with an argon purge. The iodide
(179 mg, 0.33 mmol) and stannane 10 (188 mg, 0.39 mmol) were
dissolved in dimethyl sulfoxide (4 mL) and added to the salts. The
resulting mixture was rigorously degassed (4×) by the freeze-
pump-thaw process (-78 °C to room temperature (rt), Ar). The
reaction mixture was stirred at rt for 8 h. The reaction mixture was
diluted with diethyl ether (50 mL) and washed with a mixture of
brine and 5% ammonium hydroxide (20 mL, 1:1). The aqueous
layer was further extracted with diethyl ether (2 × 10 mL), and
the combined organic layers were washed with water (2 × 20 mL)
and brine (20 mL), dried (Na2SO4), and evaporated to dryness in
vacuo. The residue was purified by flash column chromatography
on demetalated silica gel22 (AcOEt:hexane, 1:19-1:3) providing
11 (115 mg, 57%) as a colorless oil. Rf 0.45 (AcOEt:heptane, 1:3);
13: Rf 0.47 (AcOEt:heptane, 1:3); [R]D23 +19.0 (c 1.0, CHCl3);
IR (film) 3440, 2927, 1643, 1471, 1430, 1375, 1140, 1094, 1028,
1
778; H NMR (300 MHz, CDCl3) δ 6.23 (dd, J ) 10.8, 17.6 Hz,
1H), 6.00 (s, 1H), 5.59 (d, J ) 8.2 Hz, 1H), 5.56 (bs, 1H), 5.14 (d,
J ) 17.6 Hz, 1H), 4.98 (d, J ) 17.6 Hz, 1H), 4.76 (d, J ) 6.5 Hz,
1H), 4.74 (s, 2H), 4.68-4.59 (m, 2H), 4.09 (d, J ) 6.6 Hz, 1H),
3.71-3.58 (m, 2H), 3.49 (d, J ) 3.4 Hz, 1H), 4.41 (s, 3H), 2.63-
2.43 (m, 2H), 2.24 (td, J ) 5.1, 9.5 Hz, 1H), 2.16-2.04 (m, 1H),
1.99 (dd, J ) 4.0, 7.2 Hz, 1H) 1.95-1.85 (m, 1H), 1.80-1.69 (m,
2H), 1.66 (s, 3H), 1.63 (s, 3H), 1.39 (ddd, J ) 4.3, 7.1, 14.3 Hz,
1H), 0.84 (s, 9H), 0.01 (s, 6H); 13C NMR (300 MHz, CDCl3) δ
147.1, 139.8, 138.1, 135.8, 133.5, 128.5, 125.8, 112.5, 95.9, 82.3,
64.7, 61.8, 56.2, 46.2, 39.0, 37.8, 29.92 29.90, 26.0, 20.4, 18.7,
18.5, -5.4. HRMS (ESI) calcd for C26H46O4Si [M + H]+:
451.3238; found 451.3231.
23
[R]D +51.2 (c 0.7, CDCl3); IR (film) 2929, 2856, 1676, 1615,
1568, 1458, 1352, 1256, 1206, 1162, 1092, 1057, 1030, 918, 893,
840, 780; 1H NMR (500 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 7.10
(s, 1H), 6.03 (s, 1H), 5.55 (bs, 1H), 5.14 (app. t, J ) 2.7 Hz, 1H),
4.83 (d, J ) 12.1 Hz, 1H), 4.73-4.70 (m, 2H), 4.64-4.61 (s, 2H),
4.04 (d, J ) 9.0 Hz, 1H), 3.76 (app. t, J ) 6.6 Hz, 2H), 3.35 (s,
3H), 2.97 (app. t, J ) 6.6 Hz, 2H), 2.64 (ddd, J ) 3.5, 5.0, 17.1
Hz, 1H), 2.57 (ddd, J ) 2.9, 4.8, 17.1 Hz, 1H), 2.46-2.31 (m,
2H), 2.19-2.11 (m, 2H), 2.04-1.99 (m, 1H), 1.96-1.90 (m 1H),
(1R,4aR,4bS,8aR,10aS)-4,4a,5,6,10,10a-Hexahydro-8-(2-
[tert-butyldimethylsilyloxy]-ethyl)-1-(methoxymethoxy)-2,4b-di-
methylphenanthren-9(1H,4bH,8aH )-one (14). Diene 13 (23 mg,
(22) Hubbard, J. S.; Harris, T. M. J.Org. Chem. 1981, 46, 2566-2570.
272 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
0.051 mmol) was dissolved in CH2Cl2 (2 mL), then pulverized 4-Å
MS followed by 4-methylmorpholine N-oxide (10 mg, 0.071 mmol)
was added under argon and stirred for 20 min, and then tetrapro-
pylammonium perruthenate (1.0 mg, 0.026 mmol) was added. After
0.5 h, the reaction was complete based on analytical thin-layer
chromatography (TLC) analysis. Silica gel (1 g) was added, and
the reaction mixture was filtered and washed with CH2Cl2 (6 × 5
mL) and 20% AcOEt in hexanes (2 × 5 mL) affording the desired
enone (14 mg, 61%) as a slightly yellow oil, which was immediately
taken to the next step. The enone (14 mg, 0.031 mmol) was
dissolved in d8-toluene (0.7 mL) in a sealed NMR tube then warmed
to reflux by placing the tube in a preheated oilbath at 110 °C for
4 days. The mixture was cooled to rt and purified directly using
flash column chromatography on silica gel (AcOEt:hexane, 1:10)
affording cycloadduct 14 (13 mg, 93%) as a colorless oil. 14: Rf
0.40 (AcOEt:hexane, 1:3); [R]D23 -15.0 (c 1.2, CDCl3); IR (film)
J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H), 6.29 (s, 1H), 5.98 (s,
1H), 5.55 (bs, 1H), 4.70 (s, 2H), 4.68 (d, J ) 6.7 Hz, 1H), 4.62 (d,
J ) 6.7 Hz, 1H), 4.42 (s, 2H), 4.16 (q, J ) 7.1 Hz, 2H), 3.99 (d,
J ) 8.3 Hz, 1H), 3.79 (s, 3H), 3.67 (t, J ) 6.7 Hz, 2H), 3.47 (t, J
) 6.4 Hz, 2H), 3.33 (s, 3H), 2.92 (t, J ) 6.6 Hz, 2H), 2.89 (t, J )
7.9 Hz, 2H), 2.61 (dd, J ) 2.3, 17.7 Hz, 1H), 2.58 (dd, J ) 1.9,
17.7 Hz, 1H), 2.42-2.26 (m, 2H), 2.18-2.08 (m, 1H), 1.90 (app.
d, J ) 17.1 Hz, 1H), 1.70, (s, 3H), 1.69-1.65 (m, 2H), 1.60 (s,
3H), 1.28 (t, J ) 7.1 Hz, 3H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 199.9, 166.2, 160.9, 159.0, 154.3, 147.0, 134.2,
130.6, 129.2, 127.0, 125.1, 119.1, 113.6, 113.3, 97.0, 82.6, 72.5,
69.7, 62.6, 60.0, 56.0, 55.2, 46.4, 45.3, 39.3, 32.8, 30.0, 28.9, 26.0,
25.9, 20.0, 18.5, 18.2, 14.2, -5.5.
1
2942, 1680, 1512, 1465, 1380, 1375, 1299, 808, 732; H NMR
(500 MHz, CDCl3) δ 5.54 (bs, 1H), 4.70 (d, J ) 7.0 Hz, 1H), 4.68
(d, J ) 7.0 Hz, 1H), 3.91 (d, J ) 7.7 Hz, 1H), 3.65-4.55 (m, 2H),
3.44 (s, 3H), 3.26 (bs, 1H), 2.76 (dd, J ) 5.3, 12.3 Hz, 1H), 2.61
(dt, J ) 6.2, 12.7 Hz, 1H), 2.31-2.17 (m, 4H), 2.11 (dt, J ) 4.8,
17.4 Hz, 1H), 2.04-1.99 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.69
(m, 6H), 1.30 (td, J ) 7.0, 11.8 Hz, 1H), 0.88 (s, 9H), 0.70 (s,
3H), 0.03 (s, 3H) 0.02 (s, 3H); 13C NMR (500 MHz, CDCl3) δ
194.0, 134.6, 132.1, 124.8, 124,7, 97.6, 85.4, 63.1, 59.3, 56.4, 47.2,
46.9, 43.7, 41.1, 37.9, 33.2, 26.0, 25.7, 22.0, 19.5, 18.4, 12.8, -5.2;
HRMS (ESI) calcd for C26H45O4Si [M + H]+ 449.3082; found
449.3080.
(E)-(R)-6-(tert-Butyl-diphenyl-silyloxy)-1-((1S,2R,6R)-2-(meth-
oxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)hex-3-
yne-2-ol (8b). Aldehyde 7 (0.50 g, 2.1 mmol) was dissolved in
THF (5 mL) and added under argon to a mixture of 1-tert-
butyldiphenylsilanyloxy-but-3-yne (1.94 g, 6.3 mmol) and n-
butyllithium (3.93 mL, 6.09 mmol, 1.55 M in hexanes) in dry THF
(5 mL) at -78 °C, which had been stirred for 1 h prior to the
addition. The reaction mixture was stirred for 2 h, then the
temperature was raised to -20 °C for 1 h and then warmed to rt.
The reaction was quenched by the addition of saturated aqueous
NaHCO3 (20 mL) and diethyl ether (60 mL). The aqueous phase
was extracted with diethyl ether (25 mL), and the organic phases
were dried, filtered, and evaporated to dryness in vacuo. The residue
was purified by flash column chromatography on silica gel (AcOEt:
hexane, 1:4) affording 8b (1.10 g, 96%) as a 1:1 mixture of
diastereomers as well as 0.95 g (49%) of unreacted 1-tert-
butyldiphenylsilanyloxy-but-3-yne. A portion of the less polar
isomer was eluted free of its epimer and characterized. In practice,
the mixture was used in the subsequent step without being separated.
(2E,4E)-Ethyl 4-(2-[tert-butyldimethylsilyloxy]-ethyl)-3-(3-(4-
methoxy-benzyloxy)propyl)-7-(( 1S,2R,6R)-2-(methoxymethoxy)-
3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-6-oxohepta-2,4-di-
enoate (17a). A 30-mL Schlenk tube was charged with LiCl and
flame-dried under high vacuum. Upon cooling, tetrakis(triph-
enylphosphine)palladium(0) and copper(I) chloride were added, and
the mixture was degassed (4×) under high vacuum with an argon
purge. The freshly prepared iodide from 9a and the stannane 15
dissolved in dimethyl sulfoxide (6 mL) were added. The resulting
mixture was rigorously degassed (4×) by the freeze-pump-thaw
process (-78 °C-rt, Ar). The reaction mixture was stirred at rt
for 3 h. The reation mixture was diluted with diethyl ether (30 mL)
and washed with a mixture of brine and 5% ammonium hydroxide
(10 mL, 1:1). The aqueous layer was further extracted with diethyl
ether (2 × 20 mL) and the combined organic layers were washed
with water (2 × 20 mL) and brine (20 mL), dried (Na2SO4), and
evaporated to dryness in vacuo. The residue was purified by flash
column chromatography on demetalated silica gel (AcOEt:hexane,
1:4) providing diene 16a (95 mg, 58%) as an inseparable mixture
of diastereomers. Diene 16a (95 mg, 0.136 mmol) was dissolved
in CH2Cl2/CH3CN ((9:1), 4 mL), then pulverized 4-Å molecular
sieves (0.60 g) and 4-methylmorpholine N-oxide (27 mg, 0.20
mmol) was added under argon and stirred for 10 min, and then
tetrapropylammonium perruthenate (4 mg, 0.011 mmol) was added.
After 0.5 h, the reaction was complete according to TLC analysis.
Silica gel (1 g) was added, and the reaction mixture was filtered
and washed with CH2Cl2 (6 × 5 mL) and 20% AcOEt in hexanes
(2 × 5 mL) providing 17a (72 mg, 76%) as a colorless oil. 17a: Rf
0.52 (AcOEt:hexane, 2:3); 1H NMR (300 MHz, CDCl3) δ 7.26 (d,
23
8b: Rf 0.46 (Et2O:pentane, 1:4); [R]D + 46.5 (c 0.2, CDCl3); IR
(film) 3440, 3071, 2925, 1671, 1644, 1428, 1378, 1360, 1210, 1149,
1
1113, 1030, 917, 900, 822, 736, 702, 614; H NMR (300 MHz,
CDCl3) δ 7.67 (d, J ) 7.0 Hz, 4H), 7.46-7.34 (m, 6H), 5.63 (bs,
1H), 4.76 (bs, 2H), 4.72 (d, J ) 6.6 Hz, 1H), 4.69-4.60 (m, 2H),
4.15 (d, J ) 7.8 Hz, 1H), 3.75 (t, J ) 7.3 Hz, 2H), 3.73 (d, J ) 7.4
Hz, 1H), 3.42 (s, 3H), 2.48 (td, J ) 1.7, 7.2 Hz, 2H), 2.23 (td, J )
4.5, 10.0 Hz, 1H), 2.17-2.05 (m, 1H), 2.04-1.99 (m, 1H), 1.98-
1.85 (m, 2H), 1.76-1.89 (m, 1H), 1.67 (s, 3H), 1.64 (s, 3H), 1.05
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 146.6, 135.5, 133.6, 133.2,
129.7, 127.6, 126.5, 113.0, 95.1, 83.0, 81.1, 62.5, 60.4, 56.3, 46.6,
40.7, 37.6, 30.2, 29.7, 26.8, 22.9, 20.0, 19.2, 18.3; Anal. Calcd for
C34H46O4Si: C, 74.68; H, 8.48. Found: C, 74.59; H, 8.51.
6-(Benzyloxy)-1-((1S,2R,6R)-2-(methoxymethoxy)-3-methyl-
6-(prop-1-en-2-yl)cyclohex-3-enyl)hex-3-yn-2-ol (8c). Aldehyde
7 (2 g, 8.39 mmol) was dissolved in THF (20 mL) and then added
under argon to a mixture of tert-butyldimethylsilanyloxy-but-3-yne
(4.03 g, 25.2 mmol) and n-butyllithium (15.8 mL, 25.2 mmol, 1.55
M in hexanes) in anhydrous THF (20 mL) at -78 °C, which had
been stirred for 1 h prior to the addition, stirred for 2 h, and then
the temperature was raised to -20 °C for 1 h and then warmed to
rt. The reaction was quenched by the addition of saturated aqueous
NaHCO3 (60 mL) and diethyl ether (200 mL). The aqueous phase
was extracted with diethyl ether (100 mL), and the organic phases
(23) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376.
J. Org. Chem, Vol. 71, No. 1, 2006 273

Juhl et al.
were dried, filtered, and evaporated to dryness in vacuo. The residue
was purified by flash column chromatography on silica gel (AcOEt:
hexane, 1:3) affording 8c (3.84 g, 85%) as a 1:1 mixture of
diastereomers as well as 1.97 g (49%) of unreacted tert-butyldi-
methylsilanyloxy-but-3-yne. A portion of both the less polar as well
as the more polar isomer was eluted free of its epimer and
characterized. In practice, the mixture was used in the subsequent
step without being separated. 8c: Mixture of diastereomers: FAB-
MS calcd for [M + Na] 421.24; found 421.18; Anal. Calcd for
C25H34O4: C, 75.34; H, 8.60. Found: C, 75.17; H, 8.65. More polar
(3E)-4-(Tributylstannyl)-6-(benzyloxy)-1-((1S,2R,6R)-2-(meth-
oxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)hex-3-
en-2-ol (9c). To a 1:1 mixture of epimeric alcohols 8c (2.7 g, 6.77
mmol) and dichlorobis(tris(o-toloyl)phosphine)palladium(II) (53 mg,
0.067 mmol) in THF (68 mL) was added dropwise tributyltin
hydride (6.4 mL, 23.7 mmol) over a period of 6 h, resulting in
80% conversion based on analytical TLC analysis. Additional
tributyltin hydride (1.3 mL, 4.83 mmol) was added over the next
2 h, which resulted in complete conversion. The reaction mixture
was evaporated to dryness and subsequently purified by flash
column chromatography (AcOEt:heptane, 1:9) affording 9c (2.98
g, 64%) as a colorless oil. A portion of both the less polar as well
as the more polar isomer was eluted free of its epimer and
characterized. In practice, the mixture was used in the subsequent
step without being separated. 9c: Less polar diastereomer: Rf 0.44
(AcOEt:heptane, 1:3); [R]D23 + 3.6 (c 3.4, CHCl3); IR (film) 3466,
2916, 1644, 1455, 1376, 1360, 1210, 1149, 1096, 1030, 909, 735,
698, 666; 1H NMR (300 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 5.68
(d, J ) 7.8 Hz, J(Sn-H) ) 34.3 Hz, 1H), 5.61 (bs, 1H), 4.78 (d,
J ) 6.7 Hz, 1H), 4.76 (s, 2H), 4.75-4.68 (m, 1H), 4.67 (d, J )
6.7 Hz, 1H) 4.49 (s, 2H), 4.11 (d, J ) 7.1 Hz, 1H), 3.43 (s, 3H),
3.41-3.35 (m, 2H), 2.80 (dt, J ) 7.0, 13.8 Hz, 1H), 2.47 (dt, J )
5.8, 13.8 Hz, 1H), 2.23 (td, J ) 4.9, 9.1 Hz, 1H), 2.19-1.89 (m,
3H), 1.78-1.72 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H), 1.50-1.39
(m, 6H), 1.28 (app. sextet, J ) 7.1 Hz, 6H), 0.90-0.81 (m, 15H);
13C NMR (75 MHz, CDCl3) δ 147.2, 146.6, 141.5, 137.9, 133.3,
128.4, 127.9, 127.7, 125.8, 112.2, 95.7, 82.0, 73.2, 69.4, 64.1, 56.2,
45.9, 39.3, 37.7, 33.9, 29.7, 29.1, 27.4, 20.5, 18.9, 13.7, 9.6; FAB-
MS calcd for [M]+ 689.37; found 689.25; Anal. Calcd for C37H62O4-
Sn: C, 64.44; H, 9.06. Found: C, 64.55; H, 9.21. More polar
23
diastereomer: Rf 0.21 (AcOEt:hexane, 1:3); [R]D + 40.7 (c 1.2,
CH2Cl2); IR (film) 3422, 2915, 2346, 1644, 1451, 1366, 1148, 1096,
1
1026, 899, 743, 700; H NMR (300 MHz, CDCl3) δ 7.36-7.26
(m, 5H), 5.60 (bs, 1H), 4.80 (bs, 2H), 4.76 (d, J ) 6.8 Hz, 1H),
4.65 (d, J ) 6.8 Hz, 1H), 4.54 (s, 2H), 4.52-4.44 (m, 1H), 3.96
(d, J ) 8.1 Hz, 1H), 3.58 (t, J ) 7.2 Hz, 2H), 3.45 (s, 3H), 3.18
(d, J ) 5.5 Hz, 1H), 2.53 (td, J ) 1.8, 7.2 Hz, 2H), 2.23 (td, J )
4.7, 10.0 Hz, 1H), 2.18-2.08 (m, 1H), 2.06-1.99 (m, 1H), 1.98-
1.88 (m, 1H), 1.87-1.80 (m, 2H), 1.69 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 146.7, 138.0, 133.2, 128.4, 127.7, 126.1, 113.1, 95.4,
83.1, 82.8, 80.0, 72.9, 68.4, 61.5, 56.5, 47.4, 40.6, 38.2, 30.1, 20.2,
20.1, 18.8; Less polar diastereomer: Rf 0.25 (AcOEt:hexane, 1:3);
23
[R]D + 44.8 (c 0.6, CH2Cl2); IR (film) 3447, 2922, 2238, 1643,
1438, 1359, 1148, 1094, 1030, 908, 743, 699; 1H NMR (300 MHz,
CDCl3) δ 7.36-7.26 (m, 5H), 5.64 (bs, 1H), 4.79 (bs, 2H), 4.75
(d, J ) 6.5 Hz, 1H), 4.72-4.68 (m, 1H) 4.67 (d, J ) 6.5 Hz, 1H),
4.54 (s, 2H), 4.17 (d, J ) 7.5 Hz, 1H), 3.88 (d, J ) 7.6 Hz, 1H),
3.58 (t, J ) 7.2 Hz, 2H), 3.45 (s, 3H), 2.53 (td, J ) 1.9, 7.1 Hz,
2H), 2.25 (td, J ) 4.8, 10.1 Hz, 1H), 2.13-2.02 (m, 1H),
1.96 (ddd, J ) 2.3, 9.0, 14.3 Hz, 1H), 1.77-1.72 (m, 2H), 1.68 (s,
6H, 1.59 (ddd, J ) 3.3, 8.1, 14.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 146.7, 138.0, 133.2, 128.4, 127.6, 126.5, 113.0, 94.9,
83.0, 81.8, 80.9, 72.9, 68.4, 60.4, 56.3, 46.6, 40.6, 37.5, 30.2, 20.1,
20.0, 18.2.
23
diastereomer: Rf 0.41 (AcOEt:hexane, 1:3); [R]D + 17.3 (c 3.5,
CHCl3); IR (film) 3474, 2925, 1644, 1376, 1359, 1210, 1149, 1092,
1
1029, 890, 735, 697; H NMR (300 MHz, CDCl3) δ 7.37-7.25
(m, 5H), 5.68 (d, J ) 7.9 Hz, J(Sn-H) ) 34.7 Hz, 1H), 5.61 (bs,
1H), 4.79 (s, 1H), 4.76 (s, 1H), 4.73 (d, J ) 6.8 Hz, 1H), 4.63 (d,
J ) 6.8 Hz, 1H), 4.59-4.52 (m, 1H), 4.49 (s, 2H), 3.87 (d, J )
6.1 Hz, 1H), 3.52-3.45 (m, 1H), 3.43 (s, 3H), 3.39-3.30 (m, 1H),
3.28 (d, J ) 3.0 Hz, 1H), 2.84 (dt, J ) 8.2, 13.6 Hz, 1H), 2.42 (dt,
J ) 5.0, 13.6 Hz, 1H), 2.21-2.11 (m, 2H), 2.05-1.93 (m, 2H),
1.72 (s, 3H), 1.71 (s, 3H), 1.67-1.54 (m, 2H), 1.50-1.39 (m, 6H),
1.29 (app. sextet, J ) 7.1 Hz, 6H), 0.90-0.81 (m, 15H); 13C NMR
(75 MHz, CDCl3) δ 147.2, 146.9, 142.2, 137.8, 133.1, 128.4, 127.9,
127.7, 125.7, 112.2, 95.2, 81.6, 73.2, 69.4, 65.1, 56.3, 46.8, 39.6,
37.8, 34.0, 29.3, 29.1, 27.4, 20.5, 19.5, 13.7, 9.6.
(3E)-4-(Tributylstannyl)-6-(tert-butyl-diphenyl-silyloxy)-1-
((1S,2R,6R)-2-(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)-
cyclohex-3-enyl)hex-3-en-2-ol (9b). To a 1:1 mixture of epimeric
alcohols 8b (4.0 g, 7.3 mmol) and dichlorobis(tris(o-toloyl)-
phosphine)palladium(II) in THF (73 mL) was added dropwise
tributyltin hydride (6.9 mL, 25.6 mmol) over a period of 6 h,
whereupon TLC showed complete conversion. The reaction mixture
was evaporated to dryness and directly purified by flash column
chromatography (AcOEt:hexane, 1:9) affording 9b (3.5 g, 57%).
A portion of the less polar isomer was eluted free of its epimer
and characterized. In practice, the mixture was used in the
subsequent step without being separated. 9b: Rf 0.62 (AcOEt:
heptane, 1:3); [R]D23 + 11.1 (c 1.0, CHCl3); IR (film) 3475, 3072,
2926, 2856, 1644, 1590, 1464, 1428, 1377, 1218, 1149, 1112, 1089,
1
1030, 936, 891, 823, 760, 702; H NMR (300 MHz, CDCl3) δ
7.69-7.65 (m, 4H), 7.45-7.34 (m, 6H), 5.63 (bs, 1H), 5.54 (d, J
) 7.6 Hz, J(Sn-H) ) 68.8 Hz, 1H), 4.85-4.78 (m, 1H), 4.769 (d,
J ) 6.5 Hz, 1H), 4.766 (s, 2H), 4.69 (d, J ) 6.5 Hz, 1H), 4.20 (d,
J ) 7.4 Hz, 1H), 3.57 (t, J ) 7.8 Hz, 2H), 3.44 (s, 3H), 3.25 (d,
J ) 4.7 Hz, 1H), 2.72 (dt, J ) 7.9, 13.6 Hz, 1H), 2.55 (dt, J ) 7.9,
13.6 Hz, 1H), 2.26 (td, J ) 5.0, 9.8 Hz, 1H), 2.19-2.08 (m, 1H),
2.06-1.90 (m, 2H), 1.79-1.71 (m, 2H) 1.70 (s, 3H), 1.67 (s, 3H),
1.43-1.31 (m, 6H), 1.23 (sextet, J ) 7.1 Hz, 6H), 1.05 (s, 9H),
0.83 (t, J ) 7.1 Hz, 9H) 0.78-0.72 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 147.0, 146.6, 140.2, 135.5, 133.7, 133.4, 129.6, 127.6,
126.0, 112.5, 95.6, 82.4, 66.2, 64.8, 63.9, 56.2, 47.3, 46.1, 39.5,
37.8, 37.1, 30.1, 29.0, 27.3, 26.9, 20.3, 19.2, 18.6, 13.7, 9.5; FAB-
MS calcd for [M - C4H11]+ 781.37; found 781.4; Anal. Calcd for
C46H74O4SiSn: C, 65.94; H, 8.90. Found: C, 65.93; H, 8.98.
(2E,4E)-Ethyl 4-(2-(tert-butyl-diphenyl-silyloxy)-ethyl)-6-hy-
droxy-3-(3-(4-methoxy-benzyloxy)propyl)-7-[(1S,2R,6R)-2-(meth-
oxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl]-hepta-
2,4-dienoate (16b). A solution of the â-stannylated allylic alcohol
9b (1.8 g, 2.15 mmol) in CH2Cl2 (100 mL) was cooled to -78 °C,
and a solution of iodine was added at once and stirred under argon
for 5 min. The reaction mixture was washed with a saturated sodium
thiosulfate solution (2 × 20 mL). The organic phase was dried (Na2-
SO4), and tetra-n-butylammonium diphenylphosphinate (Sn-
scavenger)23 was added and stirred for 5 min before the mixture
was filtered and evaporated to dryness in vacuo. The residue was
274 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
subjected to flash column chromatography on silica gel (AcOEt:
hexane, 1:20) affording the desired iodide (1.04 g, 71%) as a
transparent oil. The iodide was immediately taken to the next step.
A 100-mL Schlenk tube was charged with LiCl (391 mg, 9.21
mmol) and flame-dried under high vacuum. Upon cooling, tetrakis-
(triphenylphosphine)palladium(0) (178 mg, 0.154 mmol) and cop-
per(I) chloride (762 mg, 7.70 mmol) were added, and the mixture
was degassed (4×) under high vacuum with an argon purge. The
iodide (1.04 g, 1.54 mmol) and stannane 15 (961 mg, 1.69 mmol)
were dissolved in dimethyl sulfoxide (50 mL) and degassed then
added to the reaction mixture. The resulting mixture was rigorously
degassed (2×) by the freeze-pump-thaw process (-78 °C-rt,
Ar). The reaction mixture was stirred at room temperature for 20
h. The reaction mixture was diluted with diethyl ether (200 mL)
and washed with a mixture of brine and 5% aqueous ammonium
hydroxide (120 mL, 1:1). The aqueous layer was further extracted
with diethyl ether (2 × 150 mL), and the combined organic layers
were washed with water (2 × 100 mL) and brine (100 mL), dried
(Na2SO4), and evaporated to dryness in vacuo. The residue was
purified by flash column chromatography on demetalated silica gel
(AcOEt:hexane, 1:9) providing 16b (751 mg, 59%) as a colorless
oil. A portion of both the less polar as well as the more polar isomer
was eluted free of its epimer and characterized. In practice, the
(2E,4E)-Ethyl 4-(2-[benzyloxy]-ethyl)-6-hydroxy-3-(3-(4-meth-
oxy-benzyloxy)propyl)-7-((1S,2 R,6R)-2-(methoxymethoxy)-3-
methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-hepta-2,4-dienoate (16c).
A solution of the â-stannylated allylic alcohol 9c (2.98 g,
4.30 mmol) in CH2Cl2 (80 mL) was cooled to -78 °C, and a
solution of iodine (1.31 g, 5.16 mmol) in CH2Cl2 (80 mL) was
added in one portion and stirred under argon for 10 min. The
reaction mixture was washed with a saturated sodium thiosulfate
solution (2 × 20 mL). Tetrabutylammonium diphenylphos-
phinate (Sn-scavenger) was added and stirred for 5 min, then
n-hexane (150 mL) and Na2SO4 were added and cooled to 0 °C
then stirred for 10 min before the mixture was filtered and
evaporated to dryness in vacuo. The residue was subjected to flash
column chromatography on silica gel (AcOEt:heptane, 1:10-1:5)
affording the desired iodide (1.2 g, 53%) as a cloudy white oil.
The iodide was immediately taken on to the next step. A 100-mL
Schlenk tube was charged with LiCl (580 mg, 13.7 mmol) and
flame-dried under high vacuum. Upon cooling, tetrakis-
(triphenylphosphine)palladium(0) (264 mg, 0.23 mmol) and
copper(I) chloride (1.13 g, 11.4 mmol) were added, and the mixture
was degassed (4×) under high vacuum with an argon purge. The
iodide (1.20 g, 2.28 mmol) and stannane 15 (1.30 g, 2.28 mmol)
were dissolved in dimethyl sulfoxide (50 mL) and degassed and
then added to the reaction mixture. The resulting mixture was
rigorously degassed (3×) by the freeze-pump-thaw process (-78
°C-rt, Ar). The reaction mixture was stirred at room temperature
for 14 h before being diluted with diethyl ether (200 mL) and
washed with a mixture of brine and 5% aqueous ammonium
hydroxide (120 mL, 1:1). The aqueous layer was further extracted
with diethyl ether (2 × 150 mL), and the combined organic layers
were washed with water (2 × 100 mL) and brine (100 mL), dried
(Na2SO4), and evaporated to dryness in vacuo. The residue was
purified by flash column chromatography on demetalated silica gel
(AcOEt:heptane, 2:3) affording 16c (788 mg, 51%) as a colorless
oil and a mixture of diastereomers. A portion of the less polar
isomer was eluted free of its epimer and characterized. In practice,
mixture was used in the subsequent step without being separated.
23
Less polar diastereomer: Rf 0.46 (AcOEt:heptane, 2:3); [R]D
+
9.5 (c 1.1, CDCl3); IR (film) 3448, 2933, 1714, 1609, 1512, 1466,
1430, 1376, 1298, 1245, 1174, 1112, 1032, 882, 822, 743, 708; 1H
NMR (300 MHz, CDCl3) δ 7.63 (td, J ) 1.6, 7.6 Hz, 4H), 7.41-
7.32 (m, 6H), 7.24 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H),
5.80 (s, 1H), 5.79 (d, J ) 7.5 Hz, 1H), 5.63 (bs, 1H), 4.80-4.72
(m, 4H), 4.67 (d, J ) 6.5 Hz, 1H), 4.40 (s, 2H), 4.19 (d, J ) 8.5
Hz, 1H), 4.13 (q, J ) 7.1 Hz, 2H), 3.79 (s, 3H), 3.61 (td, J ) 2.3,
6.5 Hz, 2H), 3.44 (t, J ) 6.7 Hz, 2H), 3.41 (s, 3H), 2.77 (td, J )
4.0, 7.8 Hz, 2H), 2.68-2.51 (m, 2H), 2.24 (td, J ) 4.6, 10.1 Hz,
1H), 2.17-2.09 (m, 1H), 2.06-1.99 (m, 1H), 1.92 (dt, J ) 3.4,
17.5 Hz, 1H), 1.79 (ddd, J ) 3.0, 10.4, 14.3, 1H), 1.68 (s, 3H),
1.65 (s, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 1.03 (s, 9H), 0.94-0.86 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 166.6, 161.1, 159.0, 146.9,
138.0, 136.6, 135.5, 133.4, 130.8, 129.6, 129.2, 127.7, 126.2, 116.5,
113.7, 112.8, 95.6, 82.9, 72.4, 69.9, 68.1, 65.4, 62.7, 59.6, 56.2,
55.2, 46.5, 39.5, 37.7, 31.5, 30.4, 29.2, 26.8, 25.7, 20.2, 19.1, 18.3,
14.3; HRMS (ESI) calcd for C50H68O8SiNa [M + Na]+ 847.4581;
found 847.4569. More polar diastereomer: Rf 0.43 (AcOEt:heptane,
the mixture was used in the subsequent step without being separated.
23
Less polar diastereomer: Rf 0.29 (AcOEt:heptane, 2:3); [R]D
+
2.0 (c 0.5, CH2Cl2); IR (film) 3448, 2924, 1714, 1614, 1609, 1512,
1456, 1376, 1367, 1298, 1245, 1174, 1093, 1031, 882, 821, 743,
1
699; H NMR (300 MHz, CDCl3) δ 7.35-7.23 (m, 7H), 6.86 (d,
J ) 8.6 Hz, 2H), 5.83 (d, J ) 8.4 Hz, 1H), 5.81 (s, 1H), 5.61 (bs,
1H), 4.77 (d, J ) 6.5 Hz, 1H), 4.76 (s, 2H), 4.75-4.69 (m, 1H),
4.66 (d, J ) 6.5 Hz, 1H), 4.46 (s, 2H), 4.41 (s, 2H), 4.15 (q, J )
7.1 Hz, 2H), 3.79 (s, 3H), 3.54 (d, J ) 3.6 Hz, 1H), 3.47 (t, J )
6.5 Hz, 1H), 3.42 (s, 3H), 2.99-2.89 (m, 1H), 2.80-2.69 (m, 2H),
2.53 (dt, J ) 5.5, 14.2 Hz, 1H), 2.23 (td, J ) 4.7, 9.6 Hz, 1H),
2.13-1.99 (m, 2H), 1.97-1.87 (m, 1H), 1.82-1.73 (m, 1H), 1.69
(s, 3H), 1.66 (s, 3H), 1.37 (ddd, J ) 3.5, 7.9, 14.4 Hz, 1H), 1.28
(t, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.6, 160.7,
159.0, 147.0, 138.0, 137.7, 136.8, 133.4, 130.7, 129.2, 128.4, 127.8,
127.7, 126.0, 116.5, 113.6, 112.5, 95.6, 82.3, 72.4, 69.9, 68.1, 65.0,
59.7, 56.2, 55.2, 46.3, 39.2, 37.6, 29.9, 29.2, 28.8, 25.7, 20.3, 18.6,
14.3; HRMS (ESI) calcd for C41H56O8Na [M + Na] 699.3873;
found 699.3888.
23
2:3); [R]D + 11.0 (c 0.7, CDCl3); IR (film) 3449, 2934, 2855,
1715, 1610, 1513, 1466, 1430, 1368, 1298, 1246, 1175, 1096, 1033,
1
918, 822, 744, 702; H NMR (300 MHz, CDCl3) δ 7.64 (td, J )
1.7, 7.6 Hz, 4H), 7.41-7.32 (m, 6H), 7.25 (d, J ) 7.8 Hz, 2H),
6.85 (d, J ) 7.8 Hz, 2H), 5.77 (d, J ) 8.1 Hz, 1H) 5.76 (s, 1H),
5.61 (bs, 1H), 4.78 (s, 1H), 4.76 (s, 1H), 4.74 (d, J ) 6.8 Hz, 1H),
4.63 (d, J ) 6.8 Hz, 1H), 4.50-4.42 (m, 1H), 4.40 (s, 2H), 4.13
(q, J ) 7.1 Hz, 2H), 3.86 (d, J ) 7.1 Hz, 1H), 3.79 (s, 3H), 3.61-
3.55 (m, 2H), 3.43 (t, J ) 7.0 Hz, 2H), 3.42 (s, 3H), 3.31 (d, J )
3.9 Hz, 1H), 2.75 (t, J ) 6.7 Hz, 2H), 2.68-2.59 (m, 1H), 2.54-
2.45 (m, 1H), 2.18 (d, J ) 8.7 Hz, 1H), 2.05-1.85 (m, 2H), 1.71
(s, 3H), 1.70 (s, 3H), 1.67-1.58 (m, 1H), 1.36 (dd, J ) 7.2, 14.9
Hz, 1H), 1.26 (t, J ) 7.1 Hz, 3H), 1.03 (s, 9H), 0.92 (t, J ) 7.3
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.6, 160.9, 159.0, 146.9,
137.8, 137.1, 135.5, 133.3, 130.8, 129.7, 129.2, 127.7, 126.0, 116.4,
113.7, 113.0, 95.3, 82.8, 72.4, 69.9, 67.2, 62.8, 59.7, 56.4, 55.2,
47.7, 39.5, 38.0, 31.5, 30.0, 29.2, 26.8, 25.6, 20.2, 19.1, 19.0, 14.3.
(2E,4E)-Ethyl 4-(2-(tert-butyl-diphenyl-silyloxy)-ethyl)-3-(3-
(4-methoxy-benzyloxy)propyl)-7-[(1S,2R,6R)-2-(methoxymethoxy)-
3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl]-6-oxo-hepta-2,4-
dienoate (17b). 16b (95 mg, 0.12 mmol) was dissolved in CH2Cl2/
CH3CN ((9:1), 4 mL), then pulverized 4-Å MS (0.6 g) followed
J. Org. Chem, Vol. 71, No. 1, 2006 275

Juhl et al.
by 4-methylmorpholine N-oxide (23 mg, 0.17 mmol) were added
under argon. The reaction mixture was stirred for 10 min, then
tetrapropylammoniumperruthenate (4 mg, 0.011 mmol) was added.
After 0.5 h, the reaction was complete according to TLC analysis.
Silica gel (1 g) was added, and the reaction mixture was filtered
and washed with CH2Cl2 (6 × 5 mL) and 20% AcOEt in n-hexane
(2 × 5 mL) affording 17b (73 mg, 77%) as a colorless oil. 17b: Rf
0.48 (AcOEt:heptane, 1:4); [R]D23 +25.0 (c 2.1, CHCl3); IR (film)
3074, 2936, 2364, 1713, 1686, 1616, 1590, 1512, 1467, 1428, 1366,
1304, 1252, 1174, 1121, 925, 821, 743, 708; 1H NMR (500 MHz,
CDCl3) δ 7.64 (d, J ) 7.4 Hz, 4H), 7.41-7.33 (m, 6H) 7.25 (d, J
) 8.5 Hz, 2H) 6.87 (d, J ) 8.5 Hz, 2H), 6.28 (s, 1H), 5.95 (s, 1H),
5.56 (bs, 1H), 4.66 (app. d, J ) 6.6 Hz, 3H) 4.59 (d, J ) 6.6 Hz,
1H), 4.40, (s, 2H), 4.16 (q, J ) 7.1 Hz, 2H), 3.99 (d, J ) 8.5 Hz,
1H), 3.80 (s, 3H), 3.71 (t, J ) 6.6 Hz, 2H), 3.45 (t, J ) 6.4 Hz,
2H), 3.29 (s, 3H), 3.01 (t, J ) 6.6 Hz, 2H), 2.84 (t, J ) 7.8 Hz,
2H), 2.61 (dd, J ) 4.8, 17.5 Hz, 1H), 2.56 (dd, J ) 4.8, 17.5 Hz,
1H), 2.36 (dt, J ) 4.6, 10.7 Hz, 1H), 2.33-2.26 (m, 1H), 2.17-
2.09 (m, 1H), 1.90 (app. d, J ) 17.4 Hz, 1H), 1.71, (s, 3H), 1.70-
1.64 (m, 2H), 1.57 (s, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 1.01 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 200.0, 166.2, 161.1, 159.2, 154.3,
147.6, 135.8, 134.5, 133.6, 130.6, 129.5, 129.2, 129.0, 128.2, 127.6,
127.2, 125.3, 125.1, 119.4, 114.3, 113.6, 96.9, 82.7, 72.6, 69.7,
63.4, 60.1, 56.0, 55.2, 46.3, 45.2, 39.3, 32.4, 30.1, 28.9, 26.8, 25.9,
20.0, 19.1, 18.4, 14.4; HRMS (ESI) calcd for C50H67O8Si [M +
H] 823.4605; found 823.4633.
degassed by bubbling argon through for 1 min. The Carius tube
was then lowered into a preheated saltbath at 195 °C, and the
reaction mixture was stirred for 30 min before cooling to rt. The
reaction mixture was evaporated to dryness and purified by flash
column chromatography (Et2O:hexane, 2:5) providing 12 mg (60%)
23
of 19 as a colorless oil. 19: Rf 0.41 (AcOEt:heptane, 1:4); [R]D
+7.5 (c 1.1, CHCl3); IR (film) 2934, 2856, 1715, 1610, 1514, 1456,
1
1298, 1246, 1175, 1096, 1032, 918, 822; H NMR (500 MHz,
CDCl3) δ 7.27 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 6.79
(s, 1H), 5.91 (s, 1H), 5.61 (bs, 1H), 4.76 (d, J ) 6.8 Hz, 1H) 4.71
(d, J ) 6.8 Hz, 1H), 4.44 (s, 2H), 4.18 (q, J ) 7.1 Hz, 2H), 4.06
(d, J ) 6.5 Hz, 1H), 3.80 (s, 3H), 3.69 (dd, J ) 1.8, 6.9 Hz, 1H),
3.53 (t, J ) 6.4 Hz, 2H), 3.40 (s, 3H), 3.15 (d, J ) 7.0 Hz, 1H),
3.03-2.96 (m, 2H), 2.89 (ddd, J ) 6.0, 9.9, 12.3 Hz, 1H),2.22
(dd, J ) 9.7, 14.2 Hz, 1H), 2.11-2.05 (m, 2H), 1.98 (dd, J ) 4.9,
14.3 Hz, 1H), 1.95-1.90 (m, 2H), 1.86-1.77 (m, 2H), 1.73 (s,
3H), 1.48 (d, J ) 12.6 Hz, 1H), 1.29 (t, J ) 7.1 Hz, 3H), 1.26 (s,
1H), 1.07 (ddd, J ) 3.1, 3.6, 12.4 Hz, 1H), 0.56 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.7, 155.2, 142.7, 136.7, 135.0, 130.7, 129.1,
126.3, 114.7, 113.7, 96.5, 84.9, 84.0, 72.5, 70.0, 68.1, 59.9, 55.6,
55.3, 50.1, 46.9, 45.7, 35.0, 33.9, 33.6, 30.1, 26.7, 25.2, 20.8, 19.6,
14.3; HRMS (ESI) calcd for C34H47O7 [M + H] 567.3322; found
567.3308.
(2E,4E)-Ethyl-4-(2-(benzyloxy)-ethyl)-3-(3-(4-methoxy-benzy-
loxy)propyl)-7-[(1S,2R,6R)-2-(methoxymethoxy)-3-methyl-6-
(prop-1-en-2-yl)cyclohex-3-enyl]-6-oxo-hepta-2,4-dienoate (17c).
16b (389 mg, 0.575 mmol) was dissolved in CH2Cl2/CH3CN ((9:
1), 15 mL), then pulverized 4-Å MS (3 g) and 4-methylmorpholine-
N-oxide (109 mg, 0.805 mmol) were added under argon and stirred
for 10 min, and then tetrapropylammonium perruthenate (20 mg,
0.058 mmol) was added. After 0.5, h the reaction was complete
according to TLC analysis. Silica gel (30 g) was added, and the
reaction mixture was filtered and washed with CH2Cl2 (2 × 20
mL) and AcOEt (6 × 20 mL) and then evaporated to dryness. The
residue was purified by flash column chromatography (AcOEt:
heptane, 1:4) affording 17c (304 mg, 78% and 20 mg contaminated
with small amount of unidentified byproduct) as a colorless oil. Rf
0.35 (AcOEt:heptane, 1:3) [R]D23 + 16.6 (c 2.0, CHCl3); IR (film)
3406, 2935, 1716, 1688, 1610, 1513, 1451, 1368, 1298, 1246, 1175,
(3R,4aS,4bR,8R,8aS,10aS)-Ethyl 1-(2-(tert-butyl-diphenyl-si-
lyloxy)-ethyl)-2-(3-(4-methoxybenzyloxy)propyl)-3,4,4a,4b,5,8,-
8a,9,10,10a-decahydro-10-hydroxy-8-(methoxymethoxy)-4a,7-
dimethylphenanthrene-3-carboxylate (20b). A diastereomeric
mixture (ratio not determined) of 16b (18 mg, 0.022 mmol) was
dissolved in anhydrous toluene in a Carius tube and degassed by
bubbling argon through for 2 min. The mixture of diastereomers
was then heated to 195 °C for 24 h. The mixture was evaporated
to dryness and purified by flash column chromatography (AcOEt:
heptane, 2:3) affording 20b (9 mg, 50%) as one diastereomer. 20b:
Rf 0.26 (AcOEt:heptane, 2:3); [R]D23 -23.9 (c 0.8, CDCl3); IR (film)
3440, 3049, 2934, 1724, 1611, 1513, 1465, 1428, 1368, 1299, 1246,
1
1096, 1033, 918, 883, 822, 744; H NMR (300 MHz, CDCl3) δ
1
1175, 1094, 1032, 918, 822, 736, 703, 613; H NMR (500 MHz,
7.28-7.25 (m, 5H), 7.21 (d, J ) 8.3 Hz, 2H), 6.82 (d, J ) 8.3 Hz,
2H), 6.26 (s, 1H), 5.90 (s, 1H), 5.51 (bs, 1H), 4.66-4.63 (m, 3H),
4.57 (d, J ) 6.7 Hz, 1H), 4.44 (s, 2H), 4.37 (s, 2H), 4.13 (q, J )
7.2 Hz, 2H), 3.96 (d, J ) 7.8 Hz, 1H), 3.75 (s, 3H), 3.50 (t, J )
7.0 Hz, 2H), 3.42 (t, J ) 6.4 Hz, 2H), 3.27 (s, 3H), 3.01 (t, J ) 6.9
Hz, 2H), 2.88-2.82 (m, 2H), 2.59 (dd, J ) 2.7, 17.3 Hz, 1H),
2.54 (dd, J ) 2.3, 17.5 Hz, 1H), 2.39-2.22 (m, 2H), 2.15-2.02
(m, 1H), 1.86 (dt, J ) 4.6, 17.3 Hz, 1H), 1.74-1.61 (m, 5H), 1.55
(s, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
200.0, 166.1, 160.7, 159.1, 153.5, 147.0, 138.4, 134.2, 130.6, 129.3,
128.3, 127.5, 127.4, 127.3, 125.1, 118.9, 113.7, 113.4, 97.1, 82.7,
72.7, 72.5, 69.7, 69.1, 60.1, 56.0, 55.2, 46.4, 45.3, 39.3, 30.1, 29.8,
28.9, 26.0, 20.0, 18.5, 14.2; HRMS (ESI) calcd for C41H54O8
[M+H] 675.3897; found 675.3861.
CDCl3) δ 7.68 (dd, J ) 6.4, 14.0 Hz, 4H), 7.43-737 (m, 6H),
7.17 (d, J ) 8.4 Hz, 2H), 6.81 (d, J ) 8.4 Hz, 2H), 5.53 (bs, 1H),
4.75 (d, J ) 6.8 Hz, 1H), 4.72 (d, J ) 6.8 Hz, 1H), 4.32 (s, 2H),
4.18-4.08 (m, 2H), 3.94 (app. td, J ) 4.7, 10.5 Hz, 1H), 3.79 (s,
3H), 3.81-3.78 (m, 5H), 3.67 (d, J ) 7.7 Hz, 1H), 3.46 (s, 3H),
3.41 (app. td, J ) 3.4, 13.4 Hz, 1H), 3.32 (d, J ) 3.6 Hz, 1H),
3.26 (td, J ) 2.9, 6.3 Hz, 2H), 3.12 (t, J ) 7.4 Hz, 1H), 2.80-2.68
(m, 2H), 2.51 (dt, J ) 4.4, 12.8 Hz, 1H), 2.19-2.08 (m, 2H), 1.98
(dt, J ) 5.0, 17.0 Hz, 1H), 1.85-1.64 (m, 6H), 1.59-1.45 (m,
2H), 1.24 (t, J ) 7.2 Hz, 3H), 1.05 (s, 9H), 0.67 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 174.8, 158.9, 147.2, 135.7, 133.8, 133.0, 132.6,
130.6, 129.8, 129.1, 127.7, 125.1, 113.6, 97.8, 85.3, 72.3, 69.8,
67.0, 65.2, 60.5, 56.3, 55.2, 55.0, 46.6, 43.4, 41.6, 39.5, 38.9, 38.7,
31.4, 28.6, 27.2, 26.8, 25.4, 19.9, 19.0, 17.1, 14.7, 14.2; HRMS
calcd for C50H69O8 [M + H] 825.4762; found 825.4720.
Compound 19. Ketone 17b (20 mg, 0.024 mmol) was dissolved
in anhydrous toluene (5 mL) in an oven-dried Carius tube and
276 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
7.2 Hz, 2H), 2.21 (dd, J ) 4.4, 10.3 Hz, 1H), 2.16-1.99 (m, 2H),
1.98-1.88 (m, 1H), 1.86-1.79 (m, 2H), 1.73-1.68 (m, 9H), 1.05
(s, 18H), 1.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.8, 133.4,
126.0, 113.0, 95.5, 84.3, 82.7, 82.0, 61.9, 61.5, 56.5, 47.4, 40.8,
38.2, 31.9, 30.1, 20.2, 18.0, 15.2, 11.9; FAB-MS calcd for [M +
Na] 501.34; found 501.33; Anal. Calcd for C27H48O4Si: C, 70.20;
H, 10.53. Found: C, 69.96; H, 10.61.
(3R,4aS,4bR,8R,8aS,10aS)-Ethyl 1-(2-benzyloxy-ethyl)-2-(3-
(4-methoxybenzyloxy)propyl)-3,4,4a,4b,5,8,8a,9,10, 10a-decahy-
dro-10-hydroxy-8-(methoxymethoxy)-4a,7-dimethylphenanthrene-
3-carboxylate (20c). A diastereomeric mixture of 16c (10 mg,
0.0148 mmol) was dissolved in toluene (5 mL) in a Carius tube
and degassed by bubbling argon through for 2 min. The mixture
of diastereomers was then heated to 195 °C for 24 h. The mixture
was evaporated to dryness and purified by flash column chroma-
tography (AcOEt:heptane, 2:3) providing a single diastereomer 20c
(3.8 mg, 38%) as a colorless film. 20c: Rf 0.28 (AcOEt:heptane,
(R,4E)-4-(Tributylstannyl)-1-(tri-isopropyl-silyloxy)-7-((1S,-
2R,6R)-2-(methoxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclo-
hex-3-enyl)hept-4-ene-6-ol (22). To alcohol 38 (9.89 g, 20.7 mmol)
and dichlorobis(tris(o-toloyl)phosphine)palladium(II) (168 mg, 63.9
mg, 0.21 mmol) in THF (200 mL) was added dropwise tributyltin
hydride (18.6 g, 63.9 mmol) during 6 h. Full conversion was
achieved after additional tributyltinhydride was added (24.8 g, 85.2
mmol) as indicated by TLC analysis. The reaction mixture was
evaporated to a volume of 50 mL and purified by directly subjecting
the reaction mixture to flash column chromatography (AcOEt:
heptane, 1:9) and (AcOEt:heptane, 1:10) affording 22 (9.64 g, 61%)
as a colorless oil. 22: Rf 0.68 (AcOEt:heptane, 1:3); [R]D23 + 23.8
(c 1.5, CHCl3); IR (film) 3465, 2925, 1643, 1464, 1377, 1149, 1096,
1016, 882, 683; 1H NMR (300 MHz, CDCl3) δ 5.60 (bs, 1H), 5.54
(d, J ) 7.9 Hz, 1H), 4.78 (bs, 2H), 4.76 (d, J ) 6.9 Hz, 1H), 4.65
(d, J ) 6.9 Hz, 1H), 4.58-4.49 (m, 1H), 3.89 (d, J ) 7.6 Hz, 1H),
3.68 (t, J ) 6.3 Hz, 2H), 3.46 (s, 3H), 3.17 (d, J ) 3.9 Hz, 1H),
2.49-2.37 (m, 2H), 2.30-2.11 (m, 3H), 2.08-1.90 (m, 2H), 1.76-
1.68 (m, 10H), 1.64-1.41 (m, 12H), 1.30 (sextet, J ) 7.0 Hz, 6H),
1.07 (s, 18H), 1.05 (s, 3H), 0.88 (t, J ) 7.0 Hz, 9H); 13C NMR (75
MHz, CDCl3) δ 147.2, 145.1, 144.7, 133.4, 125.9, 112.5, 95.3, 82.6,
66.1, 63.1, 56.4, 47.3, 40.0, 38.2, 33.9, 30.1, 29.8, 29.1, 27.4, 20.4,
19.2, 18.0, 13.7, 12.0, 9.7; MS (FAB) calcd for [M + Na] 793.46;
found 793.46; Anal. Calcd for C39H76O4SiSn: C, 62.41; H, 10.21.
Found: C, 62.09; H, 10.36.
1
1:1); H NMR (500 MHz, CDCl3) δ 7.33-7.31 (m, 3H), 7.26 (s,
2H), 7.23 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 5.51 (bs,
1H), 4.70 (d, J ) 6.8 Hz, 1H), 4.66 (d, J ) 6.8 Hz, 1H), 4.51 (d,
J ) 12.0 Hz, 1H), 4.48 (d, J ) 12.0 Hz, 1H), 4.40 (s, 2H), 4.30-
4.27 (m, 1H), 4.12-4.00 (m, 2H), 3.79 (s, 3H), 3.65 (d, J ) 8.4
Hz, 1H), 3.56 (dd, J ) 5.5, 8.9 Hz, 1H), 3.47 (dd, J ) 8.1, 9.8 Hz,
1H), 3.43 (s, 3H), 3.38 (t, J ) 6.4 Hz, 1H), 3.05-3.02 (m, 1H),
(ddd, J ) 7.1, 8.5, 14.5 Hz, 1H), 2.48-2.36 (m, 2H), 2.08 (dt, J )
4.7, 13.8 Hz, 1H), 2.02 (d, J ) 4.5 Hz, 1H), 1.99-1.91 (m, 4H),
1.88-1.83 (m, 2H), 1.67-1.61 (m, 5H), 1.55-1.52 (m, 2H), 1.47
(td, J ) 5.4, 11.9 Hz, 1H), (ddd, J ) 3.9, 11.0, 14.5 Hz, 1H), 1.24
(t, J ) 7.1 Hz, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
174.9, 137.6, 134.0, 133.8, 132.7, 130.6, 129.2, 129.1, 128.4, 127.8,
127.7, 125.1, 113.7, 97.9, 85.3, 73.2, 72.4, 71.0, 69.9, 66.7, 60.5,
56.3, 55.2, 55.0, 54.4, 46.5, 43.4, 41.3, 39.6, 39.0, 38.8, 29.4, 28.8,
27.3, 25.4, 19.9, 17.2, 14.2; HRMS calcd for C41H56O8Na [M +
Na] 699.3873; found 699.3871.
(R)-1-(Triisopropyl-silyloxy)-7-[(1S,2R,6R)-2-(methoxymethoxy)-
3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl]hept-4-yne-6-ol (38).
A 100-mL Schlenk flask was charged with Zn(OTf)2 (26.5 g, 72.9
mmol) and heated to 120 °C under vacuum for 24 h. After cooling
to rt (+)-N-methylephedrine ((+)-NME) (13.3 g, 74.1 mmol) was
added under Ar, purging with Ar (2×) and kept under vacuum for
15 min. Anhydrous toluene (16.5 mL) followed by Et3N (10.3 mL)
was added, and after 2 h triisopropyl(pent-4-ynyloxy)silane (21)
(16.8 g, 69.82 mmol) was added in one portion. After 1 h, aldehyde
7 (5.89 g, 24.7 mmol) was added in one portion at rt and stirred
under argon. The reaction mixture was stirred for 25 h upon which
the reaction mixture had turned yellow. The mixture was diluted
with AcOEt (180 mL), washed with saturated aqueous NH4Cl (2
× 50 mL). The combined aqueous phases were back extracted with
AcOEt (3 × 15 mL) and the combined organic phases were dried
(Na2SO4) filtered and evaporated to dryness in vacuo. The residue
was purified by flash column chromatography (Et2O:n-hexane, 1:2)
(3×) providing the alcohol 38 (8.49 g, 74%) as a colorless oil and
as a single diastereomer. TIPS-butanol (8.6 g, 51%) was recovered
from the column chromatography procedure and (+)-NME (12.0
g, 90%) was recovered from the combined aqueous phases by the
addition of concentrated NaOH and subsequent collection of the
(R,2E,4E)-Ethyl 3-(3-(4-methoxybenzyloxy)propyl)-6-hydroxy-
4-(3-(tri-isopropylsilyloxy)propy l)-7-(7-(iodomethyl)-4,7-dimethyl-
6-oxa-bicyclo[3.2.1]oct-3-en-8-yl)hepta-2,4-dienoate (23). A so-
lution of the â-stannylated allylic alcohol 22 (100 mg, 0.13 mmol)
in CH2Cl2 (5 mL) was cooled to -78 °C and a solution of I2 in
CH2Cl2 (73 mg, 0.29 mmol, 5 mL, 1.1 equiv) was added in one
portion and stirred under argon for 10 min. This was followed by
the addition of another solution of I2 in CH2Cl2 (73 mg, 0.29 mmol,
5 mL, 1.1 equiv), and the reaction mixture was stirred for 10 min.
The reaction mixture was washed with a saturated sodium thio-
sulfate solution (10 mL), the aqueous phase was back extracted
with CH2Cl2 (10 mL), and the combined organic phases were
evaporated to dryness and subjected to flash column chromatog-
raphy on silica gel (AcOEt:heptane, 1:10) affording the di-iodinated
product (59 mg, 66%) as a transparent oil. The reaction was also
tried with ICl providing the di-iodinated product in 60% yield (53
mg). The products from both reactions were immediately taken on
to the next step. A 100-mL Schlenk tube was charged with LiCl
and flame-dried under high vacuum. Upon cooling, tetrakis-
(triphenylphosphine)palladium(0) and copper(I) chloride were
added, and the mixture was degassed (4×) under high vacuum with
an argon purge. The iodide (99 mg, 0.144 mmol) and the stannane
23
precipitate. 38: Rf 0.18 (Et2O:hexane, 1:3); [R]D +34.2 (c 2.3,
CHCl3); IR (film) 3441, 2944, 2866, 1644, 1472, 1463, 1381, 1149,
1
1105, 1028, 883, 682; H NMR (300 MHz, CDCl3) δ 5.60 (bs,
1H), 4.80 (bs, 2H), 4.77 (d, J ) 7.3 Hz, 1H), 4.66 (d, J ) 7.3 Hz,
1H), 4.51-4.43 (m, 1H), 3.96 (d, J ) 7.7 Hz, 1H), 3.74 (t, J ) 6.1
Hz, 2H), 3.46 (s, 3H), 3.08 (d, J ) 5.5 Hz, 1H), 2.32 (td, J ) 1.9,
J. Org. Chem, Vol. 71, No. 1, 2006 277

Juhl et al.
15 (108 mg, 0.19 mmol) were dissolved in dimethyl sulfoxide (2
mL) and were degassed and added to the Schlenk flask containing
the salts. The flask was washed with DMSO (1 mL) and the
washings were added to the reaction mixture. The resulting mixture
was rigorously degassed (4×) by the freeze-pump-thaw process
(-78 °C-rt, Ar). The reaction mixture was stirred at room
temperature for 20 h. The reaction mixture was diluted with diethyl
ether (20 mL) and washed with a mixture of brine and 5%
ammonium hydroxide (12 mL, 1:1). The aqueous layer was further
extracted with diethyl ether (2 × 15 mL), and the combined organic
layers were washed with water (2 × 10 mL) and brine (10 mL),
dried (Na2SO4), and evaporated to dryness in vacuo. The residue
was purified by flash column chromatography on demetalated silica
gel (AcOEt:heptane, 2:5) affording 23 (84 mg, 70%) as a colorless
flash column chromatography on demetalated silica gel (AcOEt:
heptane, 1:3) and subsequently further purified on regular silica
gel twice with (MeOH:CH2Cl2, 1:49) and once with (AcOEt:CH2-
Cl2, 1:9) affording 24 (202 mg, 63%) as a colorless oil. 24: Rf 0.36
(MeOH:CH2Cl2, 3:97); [R]D23 +6.0 (c 3.4, CHCl3); IR (film) 3450,
2944, 2965, 1714, 1609, 1512, 1459, 1368, 1245, 1174, 1096, 1034,
882, 821, 683; 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J ) 8.7 Hz,
2H), 6.85 (d, J ) 8.7 Hz, 2H), 5.85 (s, 1H), 5.68 (d, J ) 8.3 Hz,
1H), 5.60 (bs, 1H), 4.78 (s, 2H), 4.74 (d, J ) 6.8 Hz, 1H), 4.63 (d,
J ) 6.8 Hz, 1H), 4.49-4.42 (m, 1H), 4.41 (s, 2H), 4.13 (q, J )
7.1 Hz, 2H), 3.87 (d, J ) 7.5 Hz, 1H), 3.78 (s, 3H), 3.65 (td, J )
1.6, 5.9 Hz, 2H), 3.46 (t, J ) 6.7 Hz, 2H), 3.45-3.43 (m, 1H),
3.43 (s, 3H), 2.93-2.76 (m, 2H), 2.44-2.26 (m, 2H), 2.25-1.88
(m, 4H), 1.72 (s, 3H), 1.76-1.64 (m, 8H), 1.59-1.50 (m, 3H),
1.27 (t, J ) 7.1 Hz, 3H), 1.05 (s, 18H), 1.04 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 166.7, 161.0, 159.0, 147.0, 140.6, 135.3, 133.3,
130.7, 129.1, 126.0, 116.3, 113.6, 112.8, 95.3, 82.9, 72.4, 69.9,
67.1, 62.7, 59.6, 56.4, 55.2, 47.7, 39.6, 38.1, 32.1, 30.1, 29.2, 25.5,
24.5, 20.2, 19.0, 18.0, 14.2, 11.9; HRMS calcd for [M - C3H7]
713.4451; found 713.4356.
23
oil. 23: Rf 0.21 (AcOEt:heptane, 1:2); [R]D +1.4 (c 0.9, CH2-
Cl2); IR (film) 3442, 2933, 2864, 1713, 1612, 1514, 1464, 1368,
1302, 1248, 1178, 1099, 1037, 882, 819, 689; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 5.85
(s, 1H), 5.76 (d, J ) 8.6 Hz, 1H), 5.32 (bs, 1H), 4.49-4.43 (m,
1H), 4.42 (s, 2H), 4.14 (q, J ) 7.1 Hz, 2H), 4.03 (d, J ) 4.5 Hz,
1H), 3.80 (s, 3H), 3.72-3.60 (m, 2H), 3.47 (t, J ) 6.5 Hz, 2H),
3.34-3.27 (m, 2H), 3.02 (ddd, J ) 6.4, 9.7, 13.0 Hz, 1H), 2.72-
2.61 (m, 4H), 2.47-2.29 (m, 2H), 2.21-2.13 (m, 2H), 1.74-1.61
(m, 9H), 1.47 (m, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 1.07 (s, 18H),
1.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 160.8, 159.0,
141.7, 136.8, 134.6, 130.6, 129.2, 121.0, 116.9, 113.7, 83.7, 79.9,
72.5, 69.8, 67.1, 61.4, 59.8, 55.2, 42.8, 39.8, 34.2, 31.1, 29.2, 28.0,
25.5, 25.3, 23.5, 21.8, 18.01, 17.98, 14.3, 11.9.
(3R,4aS,4bR,8R,8aS,10R,10aS)-Ethyl 2-(3-(4-methoxybenzy-
loxy)propyl)-3,4,4a,4b,5,8,8a,9,10,10a-decahydro-10-hydroxy-1-
(3-(tri-isopropylsilyloxy)-propyl)-8-(methoxymethoxy)-4a,7-dim-
ethylphenanthrene-3-carboxylate (25). The diastereomerically
pure alcohol 24 (117 mg, 0.155 mmol) was dissolved in anhydrous
toluene (10 mL) and transferred to a Carius tube and warmed to
205-210 °C in a saltbath and stirred overnight. At this point, NMR
analysis (CDCl3) indicated that no starting material was left. The
reaction mixture was evaporated to dryness in vacuo and purified
by flash column chromatography (AcOEt:CH2Cl2, 1:9-1:8) provid-
ing (101 mg, 87%) 25 as a colorless oil. 25: Rf 0.36 (AcOEt:CH2-
Cl2, 1:4); [R]D23 -32.01 (c 1.8, CHCl3); IR (film) 3482, 2942, 1740,
1732, 1715, 1609, 1514, 1464, 1385, 1359, 1298, 1253, 1174, 1148,
(R,2E,4E)-Ethyl 3-(3-(4-methoxybenzyloxy)propyl)-6-hydroxy-
4-(3-(tri-isopropylsilyloxy)-propyl)-7-((1S,2R,6R)-2-(meth-
oxymethoxy)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)hepta-
2,4-dienoate (24). A solution of the â-stannylated allylic alcohol
22 (490 mg, 0.64 mmol) in CH2Cl2 (30 mL) was cooled to -81
°C (Et2O/CO2) and a solution of I2 in CH2Cl2 (178 mg, 0.70 mmol,
1.1 equiv, 20 mL) precooled to -81 °C was transferred using
cannula to the reaction flask in one portion. The reaction mixture
was stirred under argon for 1 min, then poured into a saturated
sodium thiosulfate solution (10 mL), the aqueous phase was back
extracted with CH2Cl2 (10 mL), and the combined organic phases
were evaporated to dryness and subjected to flash column chro-
matography on demetalated silica gel (AcOEt:heptane, 1:10)
affording the desired iodide (270 mg, 70%) as a slightly yellow oil
and was immediately taken on to the Stille coupling. A 100-mL
Schlenk tube was charged with LiCl (110 mg, 2.59 mmol) and
flame-dried under high vacuum. Upon cooling, tetrakis(triph-
enylphosphine)palladium(0) (50 mg, 0.046 mmol) and copper(I)
chloride (214 mg, 2.16 mmol) were added, and the mixture was
degassed (4×) under high vacuum with an argon purge. The iodide
(256 mg, 0.432 mmol) and stannane 15 (294 mg, 0.52 mmol) were
dissolved in DMSO (1 mL) and were degassed and added to the
Schlenk flask containing the salts. The flask that contained the
iodide and the stannane 15 was washed with DMSO (1 mL) and
the washings were added to the reaction mixture. The resulting
mixture was rigorously degassed (3×) by the freeze-pump-thaw
process (-78 °C-rt, Ar). The reaction mixture was stirred at rt
overnight, then diluted with diethyl ether (30 mL) and washed with
a mixture of brine and 5% aqueous ammonium hydroxide (30 mL,
1:1). The aqueous layer was further extracted with diethyl ether (2
× 30 mL), and the combined organic layers were dried (Na2SO4)
and evaporated to dryness in vacuo. The residue was purified by
1
1096, 1030, 917, 882, 821, 804, 735, 683; H NMR (500 MHz,
CDCl3) δ 7.23 (d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 5.53
(bs, 1H), 4.74 (d, J ) 6.9 Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 4.40
(s, 2H), 4.19-4.03 (m, 2H), 3.94 (td, J ) 4.7, 10.5 Hz), 3.79 (s,
3H) 3.73-3.67 (m, 2H), 3.62 (td, J ) 3.7, 9.1 Hz), 3.44 (s, 3H),
3.39 (t, J ) 6.4 Hz, 2H), 3.21 (bs, 1H), 3.09 (t, J ) 7.6 Hz, 1H),
2.57 (td, J ) 6.0, 12.9 Hz, 1H), 2.51 (dt, J ) 4.4, 17.2 Hz, 1H),
2.36-2.25 (m, 2H), 2.13 (td, J ) 5.5, 10.6 Hz, 1H), 1.97 (dt, J )
4.3, 17.3 Hz, 1H), 1.87-1.77 (m, 3H, H-5), 1.73-1.56 (m, 9H),
1.28-1.21 (app. t, J ) 7.1 Hz, 4H), 1.11 (td, J ) 7.2, 14.7 Hz,
1H), 1.08-1.05 (m, 21H), 0.69 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 175.2, 159.0, 136.6, 133.6, 130.7, 130.5, 129.1, 125.3, 113.6,
97.6, 85.3, 72.4, 70.0, 66.8, 63.2, 60.4, 56.2, 55.2, 54.8, 46.5, 43.2,
41.3, 39.9, 39.1, 38.6, 32.2, 29.7, 29.4, 26.9, 25.4, 19.8, 18.0, 17.3,
14.2, 11.9; HRMS (ESI) calcd for C44H72O8SiNa [M + Na]
779.4894; found 779.4919.
(2E,4E)-Ethyl 3-(3-(4-methoxybenzyloxy)propyl)-4-(3-(tri-iso-
propylsilyloxy)-propyl)-7-((1S,2 R,6R)-2-(methoxymethoxy)-3-
methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-6-oxohepta-2,4-di-
278 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of the Zoanthamine ABC Ring System
enoate (26). Alcohol 24 (30 mg, 0.040 mmol) was dissolved in
CH2Cl2/CH3CN ((9:1), 2 mL), then pulverized 4-Å MS (0.5 g) and
4-methylmorpholine-N-oxide (7.6 mg, 0.056 mmol) was added
under argon. The mixture was stirred for 10 min, then tetrapropyl-
ammonium perruthenate (1.4 mg, 0.004 mmol) was added. After 1
h, the reaction was complete according to TLC analysis. The
reaction mixture was filtered through a plug of Celite and washed
with 0.25% MeOH in CH2Cl2 (6 × 5 mL) and evaporated to
dryness. The residue was purified by flash column chromatography
(AcOEt:heptane, 1:4) affording 26 (24.5 mg, 81%) as a colorless
(2E,4E,6R,7R)-Ethyl 3-(3-(4-methoxybenzyloxy)propyl)-6-hy-
droxy-4-(2-(tert-butyldimethylsilyloxy)-ethyl)-7-((1R,2S,6R)-2-
(methoxymethoxy)-4-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)-
octa-2,4-dienoate (29a) and (2E,4E,6S,7R)-Ethyl 3-(3-(4-methoxy-
benzyloxy)propyl)-6-hydroxy-4-(2-(tert-butyldimethylsilyloxy)-
ethyl)-7-((1R,2S,6R)-2-(methoxymethoxy)-4-methyl-6-(prop-1-
en-2-yl)cyclohex-3-enyl)octa-2,4-dienoate (29b). A 30-mL Schlenk
tube was charged with LiCl (37 mg, 1.07 mmol) and flame-dried
under high vacuum. Upon cooling, tetrakis(triphenylphosphine)-
palladium(0) (21 mg, 0.018 mmol) and copper(I) chloride (89 mg,
0.90 mmol) were added, and the mixture was degassed (4×) under
high vacuum with an argon purge. The iodide (prepared from
stannane 28) (101 mg, 0.179 mmol) and stannane 15 (122 mg, 0.21
mmol) was dissolved in dimethyl sulfoxide (6 mL), degassed by
bubbling argon through for 2 min, and then added to the solids
under vacuum at -78 °C. The resulting mixture was rigorously
degassed (3×) by the freeze-pump-thaw process (-78 °C-rt,
Ar). The reaction mixture was stirred at room temperature for 18
h. The reaction mixture was diluted with diethyl ether (10 mL)
and washed with a mixture of brine and 5% aqueous ammonium
hydroxide (10 mL, 1:1). The aqueous layer was further extracted
with diethyl ether (10 mL), and the combined organic layers were
washed with water (10 mL), dried (Na2SO4), and evaporated to
dryness in vacuo. The residue was purified by flash column
chromatography on demetalated silica gel (AcOEt:pentane, 1:20-
1:5) followed by flash column chromatography on silica gel (Et2O:
CH2Cl2, 1:20-1:10) providing the two separated diastereomers of
the title compound (major diastereomer 29a, 50 mg, 39%; minor
diastereomer 29b, 22 mg, 17%, total yield 56%) each as colorless
23
oil. 26: Rf: 0.48 (AcOEt:heptane, 1:3); [R]D + 35.9 (c 1.1,
CHCl3); IR (film) 2942, 2865, 1716, 1688, 1609, 1513, 1460, 1367,
1246, 1175, 1096, 1034, 883, 822, 735, 683; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.3 Hz, 2H), 6.86 (d, J ) 8.3 Hz, 2H), 6.24
(s, 1H), 5.94 (s, 1H), 5.54 (bs, 1H), 4.70 (s, 2H), 4.68 (d, J ) 6.8
Hz, 1H), 4.61 (d, J ) 6.8 Hz, 1H), 4.41 (s, 2H), 4.16 (q, J ) 7.07
Hz, 2H), 3.99 (d, J ) 7.7 Hz, 1H), 3.79 (s, 3H), 3.70 (t, J ) 6.1
Hz, 2H), 3.47 (t, J ) 6.4 Hz, 2H), 3.32 (s, 3H), 2.90-2.85 (m,
2H), 2.79-2.74 (m, 2H), 2.61 (dd, J ) 4.1, 17.5 Hz, 1H), 2.57
(dd, J ) 3.3, 17.5 Hz, 1H), 2.42-2.25 (m, 2H), 2.19-2.07 (m,
1H), 1.90 (dt, J ) 4.4, 17.5 Hz, 1H), 1.75-1.65 (m, 5H), 1.62-
1.54 (m, 6H), 1.28 (t, J ) 7.1 Hz, 3H), 1.07-1.00 (m, 21H); 13C
NMR (75 MHz, CDCl3) δ 200.1, 166.2, 160.4, 159.1, 156.7, 147.0,
134.2, 130.6, 129.2, 126.1, 125.1, 118.7, 113.7, 113.3, 97.1, 82.7,
72.5, 72.5, 69.7, 63.1, 60.0, 56.0, 55.2, 46.4, 45.2, 39.3, 32.2, 30.1,
29.0, 25.68, 25, 59, 20.0, 18.4, 18.0, 14.2; HRMS (ESI) calcd for
C44H70O8SiNa [M + Na] 777.4738; found 777.4767.
23
oils. Major diastereomer 29a: Rf 0.42 (Et2O:CH2Cl2, 1:4); [R]D
- 23.7 (c 2.4, CDCl3); IR (film) 3406, 2935, 1715, 1610, 1513,
1466, 1368, 1246, 1166, 1096, 1032, 831, 778; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 7.2 Hz, 2H), 6.86 (d, J ) 7.2 Hz, 2H), 5.83
(s, 1H), 5.82 (d, J ) 7.2 Hz, 1H), 5.68 (bs, 1H), 4.90-4.86 (m,
3H), 4.76 (s, 1H), 4.68 (d, J ) 7.3 Hz, 1H), 4.61 (d, J ) 6.7 Hz,
1H), 4.41 (s, 2H), 4.25 (bs, 1H), 4.14 (q, J ) 7.2 Hz, 2H), 3.80 (s,
3H), 3.54 (t, J ) 6.8 Hz, 2H), 3.47 (t, J ) 6.7 Hz, 2H), 3.42 (s,
3H), 2.88-2.78 (m, 3H), 2.63-2.54 (m, 1H), 2.53-2.43 (m, 1H),
2.12 (dd, J ) 6.2, 12.3 Hz, 1H), 2.03-1.87 (m, 1H), 1.82-1.75
(m, 1H), 1.72 (s, 3H), 1.71-1.67 (m, 5H), 1.26 (t, J ) 7.2 Hz,
3H), 1.05 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 166.7, 161.8, 157.2, 146.8, 139.9, 136.1, 130.8,
129.2, 119.9, 116.0, 113.9, 113.6, 93.9, 72.4, 69.9, 68.6, 66.4, 62.1,
59.6, 56.3, 55.2, 52.2, 44.8, 40.1, 39.6, 37.3, 31.8, 29.1, 25.9, 23.0,
18.9, 18.3, 14.3, 11.9, -5.4; HRMS (ESI) calcd for C41H66O8SiNa
[M+Na]: 737.4420; found 737.4416. Minor diastereomer 29b:
Rf: 0.34 (Et2O:CH2Cl2, 1:4); [R]D23 -11.0 (c 1.0, CDCl3); IR (film)
3442, 2934, 1715, 1610, 1513, 1468, 1368, 1298, 1246, 1174, 1096,
(3R,4aS,4bR,8R,8aS,10aS)-Ethyl 2-(3-(4-methoxybenzyloxy)-
propyl)-3,4,4a,4b,5,8,8a,9,10,10a-decahydro-1-(3-(tri-isopropyl-
silyloxy)-propyl)-8-(methoxymethoxy)-4a,7-dimethyl-10-oxophe-
nanthrene-3-carboxylate (27). The keto-ester 26 (50 mg, 0.066
mmol) was dissolved in anhydrous toluene (5 mL) and transferred
to a Carius tube. The solution was degassed by bubbling argon
through and lowered into a preheated 240 °C saltbath and stirred
for 2.5 h. The reaction mixture was evaporated to dryness in vacuo
and purified by flash column chromatography (AcOEt:pentane,
1:5-1:3) providing 26 (33 mg, 66%) as a colorless oil. 26: Rf 0.34
(AcOEt:pentane, 1:2); [R]D23 +42.0 (c 0.7, CDCl3); IR (film) 2943,
2864, 1716, 1610, 1512, 1467, 1386, 1368, 1351, 1298, 1246, 1175,
1148, 1096, 1033, 918, 882, 822, 683; 1H NMR (300 MHz, CDCl3)
δ 7.23 (d, J ) 8.4 Hz, 2H), 6.86 (d, J ) 8.4 Hz, 2H), 5.54 (bs,
1H), 4.69 (d, J ) 7.0 Hz, 1H), 4.66 (d, J ) 7.0 Hz, 1H), 4.39 (s,
2H), 4.20-4.01 (m, 2H), 3.90 (d, J ) 8.8 Hz, 1H), 3.80 (s, 3H)
3.62 (td, J ) 1.5, 6.4 Hz, 2H), 3.42 (s, 3H), 3.39 (td, J ) 1.3, 6.4
Hz, 2H), 3.20 (bs, 1H), 3.06 (d, J ) 6.8 Hz, 1H), 2.73 (dd, J )
5.5, 12.1 Hz, 1H), 2.55-2.25 (m, 5H), 2.22-2.07 (m, 3H), 2.00
(dd, J ) 7.5, 14.7 Hz, 2H), 1.83 (app. d, J ) 14.3 Hz, 1H), 1.74-
1.64 (m, 6H), 1.55-1.40 (m, 3H) 1.22 (t, J ) 7.2 Hz, 3H), 1.05 (s,
18H), 1.04 (s, 3H), 0.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
209.3, 174.5, 159.0, 134.6, 130.9, 130.6, 129.5, 129.2, 124.6, 113.7,
97.6, 85.2, 72.5, 70.0, 63.6, 60.7, 59.4, 56.5, 55.2, 54.4, 47.3, 46.8,
43.6, 42.6, 40.7, 32.2, 29.2, 28.9, 25.9, 25.6, 19.5, 18.0, 14.1, 13.4,
11.9; HRMS (ESI) calcd for C44H70O8Si [M + H] 755.4918; found
755.4921.
1
1035, 830, 778; H NMR (300 MHz, CDCl3) δ 7.25 (d, J ) 8.7
Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H), 5.81 (s, 1H), 5.75 (d, J ) 8.6
Hz, 1H), 5.63 (bs, 1H), 4.86 (bs, 2H), 4.76 (d, J ) 6.6 Hz, 1H),
4.64 (d, J ) 6.6 Hz, 1H), 4.41 (s, 2H), 4.28 (t, J ) 9.4 Hz, 1H),
4.15 (q, J ) 7.1 Hz, 2H), 4.08 (d, J ) 4.3 Hz, 1H) 3.80 (s, 3H),
3.68-3.61 (m, 1H), 3.56-3.49 (m, 1H), 3.47 (t, J ) 6.4 Hz, 2H),
3.38 (s, 3H), 3.16 (d, J ) 2.3 Hz, 1H), 2.98 (ddd, J ) 6.5, 9.8,
12.7 Hz, 1H), 2.84-2.67 (m, 2H), 2.61 (app. q, J ) 7.2 Hz, 1H),
2.43 (dt, J ) 5.6, 14.1 Hz, 1H), 2.14 (dt, J ) 2.8, 11.0 Hz, 1H),
2.01 (app. d, J ) 7.6 Hz, 2H), 1.87 (t, J ) 7.2 Hz, 1H), 1.77 (s,
3H), 1.74-1.66 (m, 5H), 1.27 (t, J ) 7.1 Hz, 3H), 0.95 (d, J ) 6.9
Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
166.6, 161.1, 159.0, 148.3, 139.7, 138.2, 136.4, 130.7, 129.2, 121.5,
116.6, 113.7, 113.0, 95.4, 74.2, 72.4, 69.9, 69.8, 61.5, 59.8, 55.7,
55.2, 52.2, 40.8, 40.7, 40.4, 36.9, 30.2, 29.1, 26.0, 23.2, 19.5, 18.4,
14.5, 14.3, -5.4; HRMS (ESI) calcd for C41H66O8SiNa [M + Na]
737.4420; found 737.4389.
J. Org. Chem, Vol. 71, No. 1, 2006 279

Juhl et al.
hex-2-enoate (30b) and (3R,4aS,4bR,8S,8aR,9R,10R,10aS)-Ethyl
2-(3-(4-methoxybenzyloxy)propyl)-3,4,4a,4b,5,8,8a,9,10,10a-
decahydro-10-hydroxy-1-(2-(tert-butyldimethyl-silyloxy)-ethyl)-
8-(methoxymethoxy)-4a,6,9-trimethylphenanthrene-3-carboxy-
late (31). The diastereomerically pure alcohol 29b (7 mg, 0.0098
mmol) was dissolved in anhydrous toluene (5 mL) and transferred
to a Carius tube and warmed to 185 °C in a saltbath with stirring
for 15 h. The reaction mixture was evaporated to dryness in vacuo
and purified by flash column chromatography (AcOEt:CH2Cl2,
1:10-1:6) providing 30b (2 mg, 31%), cycloadduct 31 (1 mg, 14%),
and starting material 29b (1 mg) all as colorless films. 30b: Rf
0.73 (AcOEt:CH2Cl2, 1:4); 1H NMR (500 MHz, CDCl3) δ 7.25 (d,
J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 5.84 (s, 1H), 5.73 (d,
J ) 8.7 Hz, 1H), 5.62 (bs, 1H), 4.81 (s, 1H), 4.78 (s, 1H), 4.41 (s,
2H), 4.21 (bs, 1H), 4.16-4.11 (m, 3H), 3.80 (s, 3H), 3.62-3.53
(m, 2H), 3.46 (t, J ) 6.6 Hz, 2H), 2.92-2.86 (m, 1H), 2.83-2.77
(m, 1H), 2.57 (app. q, J ) 7.4 Hz, 2H), 2.15 (td, J ) 4.3, 11.1 Hz,
1H), 1.97 (app. q, J ) 11.6 Hz, 1H), 1.87 (dd, J ) 4.3, 16.6 Hz,
1H), 1.74 (s, 3H), 1.73-1.69 (m, 5H), 1.27 (t, J ) 7.1 Hz, 3H),
1.04(d, J ) 6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); HRMS (ESI)
calcd for C39H61O6Si [M + H] 653.4206; found 653.4207. 31: Rf
0.23 (AcOEt:CH2Cl2, 1:4); [R]D23 -74.0 (c 0.1, CDCl3); IR (film)
3450, 2930, 1731, 1625, 1512, 1459, 1253, 1241, 1174, 1087, 1034,
821; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.86
(d, J ) 8.6 Hz, 2H), 5.70 (d, J ) 4.1 Hz, 1H), 4.78 (d, J ) 6.7 Hz,
1H), 4.63 (d, J ) 6.7 Hz, 1H), 4.41 (s, 2H), 4.26 (d, J ) 7.0 Hz,
1H), 4.12 (q, J ) 7.1 Hz, 2H), 4.03 (dd, J ) 2.9, 4.8 Hz, 1H), 3.93
(ddd, J ) 4.7, 5.9, 7.0 Hz, 1H), 3.80 (s, 3H), 3.74 (dt, J ) 7.3, 9.7
Hz, 1H), 3.64 (dt, J ) 6.1, 9.7 Hz, 1H), 3.40 (t, J ) 6.2 Hz, 2H),
3.15 (dd, J ) 3.9, 8.3 Hz, 1H), 2.64-2.54 (m, 2H), 2.40-2.27 (m,
2H), 2.18 (d, J ) 5.9 Hz, 1H), 2.11 (td, J ) 5.6, 11.0 Hz, 1H),
2.07 (dd, J ) 3.9, 16.1 Hz, 1H), 1.88-1.82 (m, 2H), 1.80-1.73
(m, 2H), 1.71 (s, 3H), 1.69-1.65 (m, 2H), 1.24 (t, J ) 7.1 Hz,
3H), 1.14 (d, J ) 7.1 Hz, 3H), 0.89 (s, 9H), 0.76 (s, 3H), 0.06 (s,
6H); 13C NMR (50 MHz, CDCl3) δ 175.3, 161.0, 139.9, 132.9,
130.6, 129.1, 121.5, 113.6, 112.9, 95.0, 72.4, 71.8, 70.3, 69.8, 63.3,
60.4, 55.9, 55.2, 54.7, 42.7, 40.9, 40.1, 38.4, 36.2, 35.6, 31.8, 28.7,
27.7, 25.9, 23.6, 16.2, 14.1, 11.9, -5.4; HRMS (ESI) calcd for
C41H66O8SiNa [M + Na] 737.4419; found 737.4399.
(2E,4E)-Ethyl 6-(tert-butyldimethyl-silyloxy)-hex-3-(3-(4-
methoxybenzyloxy)propyl)-4-(((2S, 3R,3aR,4R,7aR)-2,3,3a,4,5,-
7a-hexahydro-3,6-dimethyl-4-(prop-1-en-2-yl)benzofuran-2-yl)-
methylene)-2-enoate (30a). The diastereomerically pure alcohol
29a (18 mg, 0.025 mmol) was dissolved in anhydrous toluene (10
mL) and transferred to a Carius tube and warmed to 185 °C in a
saltbath with stirring for 10 h. The reaction mixture was evaporated
to dryness in vacuo and purified by flash column chromatography
(AcOEt:CH2Cl2, 1:10-1:6) providing 30a (7 mg, 43%) as a
colorless oil. 30a: Rf 0.73 (AcOEt:CH2Cl2, 1:4); IR (film) 2929,
1712, 1611, 1514, 1464, 1378, 1249, 1171, 1096, 1036, 836, 776;
1H NMR (500 MHz, CDCl3) δ 7.25 (d, J ) 8.5 Hz, 2H), 6.86 (d,
J ) 8.5 Hz, 2H), 5.85 (d, J ) 6.1 Hz, 1H), 5.84 (s, 1H), 5.59 (bs,
1H), 4.86 (dd, J ) 6.3, 7.9 Hz, 1H), 4.84 (s, 1H), 4.81 (s, 1H),
4.48 (bs, 1H), 4.41 (s, 2H), 4.14 (q, J ) 7.1 Hz, 2H), 3.80 (s, 3H),
3.58-3.49 (m, 2H), 3.47 (t, J ) 6.5 Hz, 2H), 2.94-2.88 (m, 1H),
2.85-2.79 (m, 1H), 2.52-2.40 (m, 2H), 2.31-2.22 (m, 2H), 1.94-
1.92 (m, 2H), 1.87 (dd, J ) 5.9, 11.8 Hz, 1H), 1.74 (s, 3H), 1.73-
1.69 (m, 5H), 1.27 (t, J ) 7.1 Hz, 3H), 0.94 (d, J ) 7.3 Hz, 3H),
0.86 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.6,
160.9, 158.9, 146.9, 138.60, 138.59, 132.1, 130.8, 129.1, 120.0,
116.1, 113.6, 112.3, 76.2, 73.6, 72.4, 69.9, 62.0, 59.7, 55.2, 47.7,
43.3, 41.3, 35.0, 32.1, 29.2, 25.9, 25.7, 23.6, 19.2, 18.2, 15.8, 14.2,
-5.4; HRMS (ESI) calcd for C39H61O6Si [M + H] 653.4232; found
653.4239.
Acknowledgment. We thank the Technical University of
Denmark and the Augustinus Foundation for financial support.
Supporting Information Available: Experimental details for
1
the synthesis of stannane 15 and aldehyde 7. Copies of H NMR
and 13C NMR spectra of 7, 37, 13, 14, 17a, 16b-R, 16b-â, 17b,
19, 16c-R, 17c, 20c, 20b, 23, 24, 25, 26, 27, 29b, 29a, 30a, 30b,
31. This material is available free of charge via the Internet at
http://pubs.acs.org.
(2E,4E)-Ethyl 6-(tert-butyldimethyl-silyloxy)-3-(3-(4-methoxy-
benzyloxy)propyl)-4-(((2R,3R,3aR,4R,7aR)-2,3,3a,4,5,7a-hexahy-
dro-3,6-dimethyl-4-(prop-1-en-2-yl)benzofuran-2-yl)methylene)-
JO0520691
280 J. Org. Chem., Vol. 71, No. 1, 2006