Total synthesis of coraxeniolide-A

Article abstract of DOI:10.1021/jo005582h

The first total synthesis of optically active coraxeniolide-A (1a) and 4-epi-coraxeniolide-A (1b) is described. The approach is highly stereoselective and flexible in the preparation of a wide variety of members of the xeniolide family. The use of the Grob-fragmentation was pivotal for the stereospecific elaboration of the nine-membered ring. Coraxeniolide-A (1a) was synthesized in 28 steps by using the Hajos - Parrish diketone 2 as starting material which is available enantiomerically pure.

Full text of DOI:10.1021/jo005582h

J . Org. Chem. 2000, 65, 9069-9079
9069
Tota l Syn th esis of Cor a xen iolid e-A
Dorte Renneberg, Hanspeter Pfander, and Christian J . Leumann*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3,
CH-3012 Bern, Switzerland
leumann@ioc.unibe.ch
Received J uly 19, 2000
The first total synthesis of optically active coraxeniolide-A (1a ) and 4-epi-coraxeniolide-A (1b) is
described. The approach is highly stereoselective and flexible in the preparation of a wide variety
of members of the xeniolide family. The use of the Grob-fragmentation was pivotal for the
stereospecific elaboration of the nine-membered ring. Coraxeniolide-A (1a ) was synthesized in 28
steps by using the Hajos-Parrish diketone 2 as starting material which is available enantiomerically
pure.
In tr od u ction
The last couple of decades has seen a dramatic increase
in the number of highly bioactive natural products
isolated from marine organisms.1 Among these, a new
class of diterpenes, the xenicanes, was discovered which
exhibit interesting biological properties ranging from
cytotoxicity to antitumor activity.2 No biosynthetic stud-
ies have been performed on xenicanes but it is generally
believed that they derive from geranylgeraniol diphos-
phate via transannular carbocation cyclization in analogy
to the series of the caryophyllenes and related com-
pounds.3 They are also postulated to be the precursors
to a variety of other cyclic terpenoids.4
Coraxeniolide-A (1a ), a xenicane which belongs to the
xeniolide subclass, was isolated by Scheuer and co-
workers in 1981 from a pink coral, Corallium sp., as the
most abundant constituent in about 650 mg/kg animal.5
Structural key features include a nine-membered ring,
containing a E-double bond and an exocyclic methylene
function, reminicent to the structure of the caryophyl-
lenes, discovered in clove oil and other essential oils. They
also possess an R-substituted δ-lactone functionality
which is trans-fused to the nine-membered ring. The
present study reports the first total synthesis of cora-
xeniolide-A (1a ) and 4-epi-coraxeniolide-A (1b) (Figure
1). Synthetic efforts toward the total synthesis of xeni-
olides have already been reported by J ung and co-
workers.6
F igu r e 1.
Sch em e 1. Retr osyn th etic An a lysis
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. Our approach was based
on previous work of the total synthesis of caryophyllene
by Corey and co-workers7 (Scheme 1). We planned the
* To whom correspondence should be addressed. Tel. +41-31-631
43 55. Fax: +41-31-631 34 22.
(1) (a) Hanson, J . R. Nat. Prod. Rep. 1992, 9, 1. (b) Faulkner, D. J .
Nat. Prod. Rep. 1991, 8, 97; 1993, 10, 497; 1996, 13, 107; 2000, 17, 1.
(2) (a) Fusetani, N. Tetrahedron 1989, 45, 1647. (b) Hooper, G. J .;
Davies-Coleman, M. T.; Schleyer, M. J . Nat. Prod. 1997, 60, 889.
(3) Green, D.; Carmely, S.; Benayahu, Y.; Kashman, Y. Tetrahedron
Lett. 1988, 29, 1605.
introduction of the side chain at C(4) via ester enolate
chemistry as the final step in order to have easy access
to other xeniolides. We envisioned a Grob-fragmentation
to elaborate the nine-membered ring in a stereospecific
manner as a key step of the synthesis. Thus, tosylate 14
was regarded as a potential key intermediate. As starting
material we chose the Hajos-Parrish diketone 2, which
(4) Faulkner, D. J . Nat. Prod. Rep. 1984, 251.
(5) Schwartz, R. E.; Scheuer, P. J . Tetrahedron 1981, 37, 2725.
(6) Rayle, H. L. Diss. Abstr. Int. B 1994, 55(5), 1854, 1994.
(7) Corey, E. J .; Mitra, R. B.; Uda, H. J . Am. Chem. Soc. 1964, 86,
485.
10.1021/jo005582h CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/02/2000

9070 J . Org. Chem., Vol. 65, No. 26, 2000
Renneberg et al.
Sch em e 2. Syn th esis of Alcoh ol 12a
tramolecular aldol reaction afforded enantiomerically
pure diketone 2 in 61% yield over all three steps. Optical
purity was determined to be >95% by comparison of the
optical rotation. The single asymmetric center was
employed to control the remaining stereocenters. Chemose-
lective reduction of the isolated carbonyl function, which
was then protected as TBDMS ether followed by reduc-
tion of the conjugated carbonyl function with LiAlH4 gave
allyl alcohol 3 in 69% yield.10 Vinyl transetherification
of 3 with ethyl vinyl ether catalyzed by mercuric acetate
resulted in the allyl vinyl ether 4 in 80% yield. Due to
the hydrolytic instability of vinyl ethers,11 the crude
product was directly used for further transformations.
Indeed, attempts to purify 4 by column chromatography
gave only poor yields, and starting material 3 was
isolated as the main product.
12
After treatment of 4 with catalytic amounts of LiClO4
in nitromethane, the allylic ether underwent a [1,3]
sigmatropic rearrangement; however, aldehyde 5 was
only isolated in poor yield in this reaction. The yield of 5
could be greatly improved to 83% by replacement of
LiClO4 by Mg(ClO4)2. Aldehyde 5 showed to be thermally
instable which made careful evaporation of the solvent
necessary. The only side product in this reaction was the
diene, arising from elimination of the vinyl ether function
in 4, and could be isolated in 6% yield. No diastereoiso-
mer at the C(5)-position was detected. After protection
of the aldehyde function as the dimethylacetal with
montmorillonite clay K-1013 as catalyst (f 6), the double
bond was epoxidized with m-CPBA yielding epoxide 7 in
80% yield and in good stereoselectivity (R:â ∼ 11:1). The
mixture of both isomers was employed for the next step.
Regiospecific ring opening of epoxide 7 with LiCN14
afforded stereoselectively â-hydroxy nitrile 8 in 84% yield.
The â-isomer of 7 proved to be unreactive under these
conditions. The yield of the reaction could be drastically
improved by in situ preparation15 of LiCN (highly hy-
groscopic). Confirmation of the expected stereochemical
outcome of the epoxidation and the ring opening reaction
was obtained from X-ray crystallographic analysis of
nitrile 8 (see Figure 2) which corroborated the relative
configuration of the five stereocenters.16 As expected, the
nitrile and the hydroxy group are in a trans-diaxial
arrangement. The hydroxy group and the future tosylate
substituent are in the desired antiperiplanar orientation
which is necessary for the Grob-fragmentation reaction.
Nitrile 8 was then epimerized with ethanolic KOH to
the thermodynamically more stable nitrile 9. The con-
a
Reagents: (a) NaBH4, EtOH, -10-5 °C (94%); (b) TBDMSCl,
1
figuration of that center was proved by H NMR spec-
imidazole, DMAP, CH2Cl2 (82%); (c) LiAlH4, Et2O, -78 °C (90%);
(d) C2H5OC2H3, Hg(OAc)2, 40 °C (80%); (e) Mg(ClO4)2, CH3NO2
(83%); (f) CH(OCH3)3, montmorillonite clay K-10, Et2O (98%); (g)
m-CPBA, CH2Cl2, -5-0 °C (80%); (h) LiCN, THF, reflux (84%);
(i) KOH, EtOH (69%); (j) TMSCl, imidazole, DMAP, CH2Cl2 (99%);
(k) DIBALH, hexane (76%); (l) NaBH4, EtOH, -10 °C (89%).
troscopy. The signal of H-C(4) was shifted toward higher
field and a trans-diaxial coupling constant for H-C(4)
of J ) 12.1 Hz was observed. Since no reaction of 9 with
(10) (a) Hajos, Z. G. Tetrahedron 1968, 24, 2039. (b) Enev, V.
Tetrahedron 1997, 53, 13709.
is readily available in enantiomerically pure form. Pre-
liminary results have been disclosed previously as a short
communication.8
(11) Watanabe, W. H.; Conlon, L. E. J . Am. Chem. Soc. 1957, 79,
2828.
(12) Grieco, P. A.; Clark, J . D.; J agoe, C. T. J . Am. Chem. Soc. 1991,
113, 5488.
Syn th esis of Alcoh ol 12. The synthesis leading to the
required alcohol 12 is shown in Scheme 2. The Hajos-
Parrish diketone 2 was prepared in three steps using the
described procedure9 except for the substitution of (S)-
(-)-proline by (R)-(+)-proline. The proline-catalyzed in-
(13) Taylor, E. C.; Chiang, C. Synthesis 1977, 467.
(14) Ciaccio, J . A.; Stanescu, C.; Bontemps, J . Tetrahedron Lett.
1992, 33, 1431.
(15) Livinghouse, T. Org. Synth. Coll. Vol. VII 1990, 517.
(16) Crystallographic data (excluding structure factors) for the
structures 8, 17a , 18 reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as deposition No. CCDC
147327, CCDC 147328, CCDC 147329. Copies of the data can be
obtained, free of charge, on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ UK (fax: +44 (1223) 336 033; e-mail: deposit@
ccdc.cam.ac.uk).
(8) Liu, G.; Smith, T. C.; Pfander, H. Tetrahedron Lett. 1995, 36,
4979.
(9) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1984, 63, 26.

Total Synthesis of Coraxeniolide-A
J . Org. Chem., Vol. 65, No. 26, 2000 9071
Sch em e 4. Gr ob-F r a gm en ta tion a
F igu r e 2. X-ray crystal structure of â-hydroxy nitrile 8.
Sch em e 3. Syn th eses of Tosyla tes 14 a n d 16a
a
Reagents: (a) NaH, DMSO (89% for 17a /b, 71% for 18, 88%
for 20); (b) DIBALH, CH2Cl2, -65 °C (98%).
a
Reagents: (a) montmorillonite clay K-10, Et2O (95%); (b)
TBAF, THF (91%); (c) TsCl, pyridine, CHCl3 (90% for 14, 92% for
16); (d) HCl, THF; (e) Ag2CO3 on Celite, benzene, reflux (61% for
both steps).
F igu r e 3. X-ray crystal structure of cyclononenone 17a .
DIBALH, even in large excess, to form an aldehyde
occurred, it was assumed that the nonreactivity could be
due to the neighboring free alcohol function. We therefore
decided to protect the alcohol as the TMS ether (f 10)
which was realized in almost quantitative yield. Reduc-
tion of 10 with DIBALH was now successful, and alde-
hyde 11 was isolated in 70% yield. Further reduction with
NaBH4 furnished alcohol 12 in 89% yield.
refluxing for 6 h with Ag2CO3 on Celite17 in 61% yield.
The methylacetal 13 could be recycled. Tosylation of 15
then afforded 16 in 92% yield.
Gr ob-F r a gm en ta tion . Scheme 4 summarizes the
results on the fragmentation reaction. Compounds 14,
16, and 19 were treated at room temperature with the
methylsulfinyl carbanion which was prepared in the
usual way.18 The reaction was normally over within a few
minutes, and the cyclononenones were isolated in good
to excellent yields. So, the acetals 17a /17b could be
isolated in 89% yield in an epimeric ratio R:â ∼ 2.2:1.
Separation of the anomers was possible by column
chromatography. Crystals of 17a were obtained from
hexane, and its structure was solved by X-ray crystal-
lographic analysis (Figure 3).16 The crystal structure
clearly shows the E-configuration of the endocyclic double
bond. The six-membered ring is trans-fused and appears
in a chair conformation. Our attention was also focused
Syn th eses of Tosyla tes 14 a n d 16. In the following
part of the synthesis we investigated two different routes
(shown in Scheme 3). In the first route, alcohol 12 was
transacetalized by montmorillonite clay K-10 to give 13
(R:â 1.5:1) in 86% yield after standard removal of the
TMS and TBDMS groups. Since the separation of the
anomers was time consuming, it was decided to use the
mixture for the tosylation which yielded 14 in 90%. In
the second route, we were interested in tosylate 16, in
which the lactone function is already installed. Thus,
alcohol 12 was treated with 2 N HCl in THF to give the
desilylated hemiacetal in one step together with 32% of
13. After careful neutralization and drying of the crude
product, oxidation to the lactone 15 was performed by
(17) Fetizon, M.; Golfier, M.; Louis, J .-M. Tetrahedron 1975, 31,
171.
(18) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1345.

9072 J . Org. Chem., Vol. 65, No. 26, 2000
Renneberg et al.
Sch em e 6. Acid -Ca ta lyzed Cycliza tion of 21a a
F igu r e 4. X-ray crystal structure of cyclononenone 18.
Sch em e 5. Con ver sion of th e Cyclon on en on esa
a
Reagents: (a) 0.5 M HCl, THF, 60 °C; (b) Ag2CO3 on Celite,
benzene, reflux (61% for both steps).
the Tebbe-reagent19 was considered. Again, 21 was
isolated in only 37% yield. Both 17a and 17b were
employed separately in the olefination reaction and
showed no difference in reactivity. Despite the poor
yields, dienes 21a /b were tried to be converted to lactone
22. However, hydrolysis of the acetal function under
acidic conditions followed by oxidation with Ag2CO3 on
Celite did not result in the desired diene 22. Mass spectra
and extensive two-dimensional NMR experiments (HMBC
and ROESY) showed a 1:1 mixture of two compounds
that could be assigned as the structures 23a and 23b
(Scheme 6). To explain the formation of 23, an initial
protonation of the endocyclic double bond followed by
transannular ring closure seems plausible. Variations of
the acids (H2SO4, HCl, AcOH) and the concentrations did
not affect the reaction, and 23a /b were always isolated
as the main products (ca. 60%). Compounds 23a /b have
not been reported in the literature and were not described
as metabolites of the xenicanes so far. Similar carbocation
induced transannular cyclizations, however, are well-
known in the series of the caryophyllenes.20 Attempts to
convert the carbonyl group into the exocyclic double bond
in 18 were completely unsuccessful (Scheme 5). Neither
the Wittig-process nor the Tebbe-reaction (Lombardo-
variant)21 showed any signs of product, and only starting
material was recovered. Investigations with the “instant-
ylide” variant22 were also unsuccessful. Since enolization
of the ketone could be excluded by D2O quenching
experiments, we believe that the unreactivity is due to
the different sterical environment of the carbonyl func-
tion in 18 compared to 17a /b. Since the direct conversion
could not be realized, we planned an epoxidation/deoxy-
genation pathway to form the olefin 22 (Scheme 7).
Reaction of 18 with a large excess of dimethylsulfoxonium
methylide23,24 at 65 °C (to effect any reaction) led to a
product that was best characterized by two-dimensional
NMR-spectroscopy as the epoxide 25. Most probably, the
strong basic conditions provoked an opening of the
lactone ring via â-elimination to form the R,â-unsaturated
ketone 24 as an intermediate.
a
Reagents: (a) MePPh3Br, n-BuLi, THF; (b) TiCp2CH2ClAlMe3,
THF; (c) Zn, CH2Br2, THF, TiCl4; (d) HCl, THF; (e) Ag2CO3 on
Celite, benzene, reflux.
on the carbonyl group which appears in an almost
parallel orientation with respect to the methyl group.
Likewise, fragmentation of 16 furnished cyclononenone
18 in 71% yield. To prevent further decomposition the
reaction had to be quenched after 30 min by the addition
of phosphate buffer (pH 7.0). X-ray crystallographic
analysis (Figure 4) also confirmed the structure of 18.16
In contrast to 17a the six-membered ring appears now
in a boat conformation allowing the preferred planar
conformation of the ester function. Furthermore, both
rings are again trans-fused and the endocyclic double
bond had the desired E-configuration as expected. Com-
pared to structure 17a the carbonyl group is now in a
different steric environment as a result of the different
six-membered ring conformation. The Grob-fragmenta-
tion was also realized with lactol 19, which was obtained
by reduction of lactone 16 with DIBALH in 98% yield.
Cyclononenone 20 was isolated in 88% yield as a mixture
of both isomers (R:â ∼ 56:44). In none of the fragmenta-
tion reactions of 14, 16, and 19, products with Z-
configuration at the newly formed double bond could be
isolated.
Con ver sion of th e Cyclon on en on es. The introduc-
tion of the exocyclic double bond was planned by a
classical Wittig-olefination of 17a with methylene tri-
phenylphosphorane and proved to be difficult (Scheme
5). Transformation of 17 afforded diene 21 in only 23%
yield at the best, besides 20% of recovered starting
material. Systematic variation of the reaction conditions
did not raise the yield. Alternatively, methylenation with
(19) Pine, S. H. Org. React. 1993, 43, 1.
(20) Fitjer, L.; Malich, A.; Paschke, C.; Kluge, S.; Gerke, R.; Rissom,
B.; Weiser, J .; Noltemeyer, M. J . Am. Chem. Soc. 1995, 117, 9180.
(21) Lombardo, L. Org. Synth. 1987, 65, 81.
(22) Schlosser, M.; Schaub, B. Chimia 1982, 36, 396.
(23) Ng, J . S. Synth. Commun. 1990, 20, 193.
(24) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353.

Total Synthesis of Coraxeniolide-A
J . Org. Chem., Vol. 65, No. 26, 2000 9073
Sch em e 7. Ep oxid a tion /Deoxygen a tion P a th w a ya
Sch em e 9. Alk yla tion a n d Ep im er iza tion a
a
Reagents: (a) (CH3)3SOI, t-BuOK, DMSO, 65 °C.
Sch em e 8. Syn th esis of Dien e 22a
a
Reagents: (a) LDA, 1-bromo-4-methylpent-2ene, THF, DMPU,
-78 °C to -69 °C (50%); (b) TBD, toluene (80%).
F igu r e 5. NOEs of 1a and 1b.
a
Reagents: (a) TBDMSCl, imidazole, CH2Cl2 (98%); (b) TiCp2-
CH2ClAlMe3, THF, pyridine, -5 °C-rt (70%); (c) TBAF, THF
(85%); (d) Ag2CO3 on Celite, benzene, 60 °C (89%).
µmol-scale and afforded both isomers in 50% yield. The
1
full set of spectroscopic data (IR, MS, 13C and H NMR,
NOE) was in complete agreement with the data of
coraxeniolide-A from natural sources.5 In addition, a
crystal structure of 1a confirmed the assignments and
was within the limits identical to the one described. The
structure of 4-epi-coraxeniolide-A (1b) was also verified
by 1H NMR NOE experiments (Figure 5). 4-epi-Cora-
xeniolide-A (1b) could be equilibrated with 1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene (TBD) leading to a 1a :1b 3:1 ratio.
Rela tive Sta bilities of 1a a n d 1b. Accompanying the
experimental epimerization reaction we investigated in
the thermodynamically preferred configuration at C-4 by
molecular modeling (see Experimental Section). Simu-
lated annealing at 1000 K followed by full matrix
minimization with the CFF91 force field28 with the
program Insight II showed that the natural coraxeni-
olide-A (1a ) is about 0.6 kcal/mol more stable than the
unnatural 4-epi-coraxeniolide-A (1b) (Figure 6). This
corresponds extremely well with the experimental re-
sults.
As a consequence of the experiments with the olefina-
tion of 17 and 18, we decided to investigate the silylacetal
26. In 26 both, the elimination reaction as well as the
problems with acetal hydrolysis should be suppressed.
Syn th esis of Dien e 22. Silylacetal 26 was obtained
by silylation of lactol 20 with TBDMSCl in 98% yield as
a mixture of epimers (R:â ∼13:87) (Scheme 8). Unexpect-
edly, no reaction of 26 occurred by treatement with
methylene triphenylphosphorane. But diene 27 could be
isolated in 70% yield by reaction with the Tebbe-reagent.
A key requirement for the success of this reaction in good
yield was the addition of pyridine. Acting as a Lewis-
base, it is believed that it complexes with the aluminum
to generate the reactive methylidene titanium. Depro-
tection of 27 with TBAF (85%) followed by oxidation with
Ag2CO3 on Celite finally afforded diene 22 in 89% yield.
In tr od u ction of th e Sid e Ch a in . Deprotonation of
22 at -78 °C with LDA followed by treatement with
1-bromo-4-methylpent-2-ene (4:1 mixture with 3-bromo-
As known from the literature,29 xeniolides undergo
slow conformation ring flipping of the nine-membered
ring and appear as two separate conformers in solution
on the NMR time scale. By NOE experiments, the
prevailing conformer of coraxeniolide-A and some of its
4-methylpent-1-ene, prepared according to literature25,26,27
)
led to the mixture of coraxeniolide-A and its C-(4) epimer
in a ratio of 1a :1b 1:5.7, from which coraxeniolide-A (1a )
could be separated by column chromatography (Scheme
9). The alkylation was successfully realized even on the
(25) Seebach, D.; Widler, L. Helv. Chim. Acta 1982, 65, 1972.
(26) Kaga, H.; Goto, K.; Takahashi, M.; Hino, M.; Tokuhashi, T.;
Orito, K. Tetrahedron 1996, 52, 8451.
(28) Hwang, M. J .; Stockfisch, T. P.; Hagler, A. T. J . Am. Chem.
Soc. 1994, 116, 2515.
(29) Guella, G.; Chiasera, G.; N’Diaye, I.; Pietra, F. Helv. Chim. Acta
1994, 77, 1203.
(27) Bonis, M. M. Ann. Chim. 1928, 9, 402.

9074 J . Org. Chem., Vol. 65, No. 26, 2000
Renneberg et al.
bath temperatures were used to record all reaction tempera-
tures. Spectral data (NMR, IR, MS, optical rotation, melting
points) were measured with standard equipment and are
indicated in standard format.
Molecu la r Mod elin g Ca lcu la tion s. All calculations were
performed using the CFF91 force field28 as implemented in
the Insight II v.98/Discover v.2.9.8 program package from
Molecular Simulations, Inc. on an Octane workstation from
SGI. The natural coraxeniolide-A (1a ) was built in the
conformation, determined by NOE experiments which is
similar to the one obtained from X-ray structure determina-
tion.5 This structure was fully minimized using the Steepest
Descent algorithm (down to a gradient of 10 kcal‚mol-1‚Å-1
)
followed by the Newton-Raphson algorithm (down to a
gradient of 0.001 kcal‚mol-1‚Å-1). The 4-epi-coraxeniolide-A
(1b) was constructed starting from the minimized conforma-
tion of 1a , inverting the configuration of the R-carbon and
constraining the lactone ring in the boat conformation with
the side chain in equatorial position. The structure was then
fully minimized as described for 1a . Both structures were then
submitted to a simulated annealing procedure in order to scan
the conformational space. The energy calculations of the two
ring-flipped conformers of 1a were performed in analogy.
Compounds 2 and 3 were prepared according to the proce-
dures reported previously, but in enantiomerically pure form.9,10
Yields and optical rotation data are given below.
F igu r e 6. Lowest energy conformers for 1a and 1b.
Sch em e 10. Low est En er gy Rep r esen ta tives of th e
Tw o Con for m a tion a l F a m ilies w ith In ver ted
Nin e-Mem ber ed Rin g Con for m a tion of 1a
(7a R)-7a -Meth yl-2,3,7,7a -tetr a h yd r o-6H-in d en e-1,5-d i-
on e (2). It was prepared in three steps in 61% yield. [R]24
D
-359 (c 4.8, benzene).9
(1R,5aR,7aR)-1-(ter t-Bu tyldim eth ylsilan yloxy)-7a-m eth -
yl-2,3,7,7a -tetr a h yd r o-1H,6H-in d en -5-on e (3). It was pre-
pared in three steps starting from 2 in 69% yield. [R]25 -28
D
(c 4.7, CHCl3).10b
(1R,5R,7a R)-ter t-Bu tyld im eth yl-(7a -m eth yl-5-vin yloxy-
2,3,5,6,7,7a -h exa h yd r o-1H-in d en -1-yloxy)sila n e (4). To a
solution of alcohol 3 (1.55 g, 5.49 mmol) in 40 mL of ethyl vinyl
ether were added Hg(OAc)2 (1.84 g, 5.76 mmol) and NaOAc‚
3H2O (52 mg, 0.39 mmol). The reaction mixture was heated
at 40 °C for 20 h. The solution was cooled (10 °C), and 15 mL
Et2O was added, followed by 5 mL of 15% NaOH solution
during which time a white precipitate developed. Then 0.87
mL of a 12% NaBH4 solution in 14 M NaOH was added. The
mixture was allowed to stirr for 1.5 h during which time the
mercury metal precipitates. The suspension was decanted and
the aqueous layer extracted with Et2O. The combined organic
layers were washed with brine, dried (Na2SO4), and filtered
through a pad of Celite. Evaporation of the solvent afforded
1.36 g (80%) of allyl vinyl ether 4 as a yellow oil which was of
sufficient purity for the next step. Data for 4: Rf 0.54 (3%
EtOAc/hexane); [R]25D +31.8 (c 4.96, CHCl3); IR 1632 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.89 (s, 9H), 1.00 (s,
3H), 1.27-1.39 (m, 1H), 1.64-1.88 (m, 4H), 2.00-2.13 (m, 2H),
2.42-2.48 (m, 1H), 3.55 (dd, J ) 8.1, 9.6 Hz, 1H), 4.01 (dd, J
) 1.5, 6.6 Hz, 1H), 4.32 (dd, J ) 1.5, 14.3 Hz, 1H), 4.42 (m,
1H), 5.40 (s, 1H), 6.38 (dd, J ) 6.6, 14.3 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ -4.91, -4.52, 16.50, 17.94, 25.71, 25.76, 29.56,
33.90, 34.04, 44.08, 68.54, 75.88, 81.22, 88.31, 118.86, 150.24;
MS (EI) m/z 265 (100).
(1R,5R,7a R)-[1-ter t-Bu tyld im eth ylsila n yloxy)-7a -m eth -
yl-2,3,5,6,7,7a -h exa h yd r o-1H-in d en -5-yl]a ceta ld eh yd e (5).
To a solution of allyl vinyl ether 4 (2.52 g, 8.16 mmol) in 50
mL freshly distilled CH3NO2 was added Mg(ClO4)2 aq (91 mg,
0.41 mmol). The mixture became cloudy after a few minutes
and was stirred for 3 h. Concentration and purification by flash
chromatography (SiO2, 3% EtOAc/hexane) provided 2.09 g
(83%) of aldehyde 5 as a colorless oil. Data for 5: Rf 0.41 (3%
EtOAc/hexane); [R]25D -109.3 (c 5.0, CHCl3); IR 1720 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.86 (s, 9H), 0.88 (s,
3H), 1.06 (td, J ) 2.9, 13.2 Hz, 1H), 1.23 (m, 1H), 1.39 (m,
1H), 1.53-1.62 (m, 2H), 1.77-1.89 (m, 2H), 1.98-2.11 (m, 1H),
2.32-2.38 (m, 2H), 2.66 (m, 1H), 3.50 (dd, J ) 8.1, 9.2 Hz,
1H), 5.20 (d, J ) 1.1 Hz, 1H), 9.72 (brt, J ) 2.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ -4.81, -4.43, 16.72, 18.01, 23.97,
25.79, 28.71, 29.74, 30.74, 43.59, 49.98, 81.74, 121.39, 146.56,
202.57; MS (EI) m/z 251 (100).
intermediates was assigned to have Me(7) trans to
H-C(4a), which is in agreement with published data on
members of the xeniolide family. Equilibrium ratios
varied from 1.8:1 in the case of 20 (â-isomer), where the
six-membered ring is in a chair conformation, to 19:1 in
the case of coraxeniolide-A (1a ) where the six-membered
ring is in a boat conformation. Molecular modeling for
both conformers of 1a confirmed our experimental ob-
servations and showed that the major conformer is by
about 1.6 kcal/mol more stable (Scheme 10).
Con clu sion . In conclusion, a highly stereocontrolled
total synthesis of optically active coraxeniolide-A (1a ) has
been achieved. The synthesis relies on a Grob-fragmenta-
tion as key step for the stereospecific construction of the
nine-membered ring. Given the late introduction of the
side chain in the lactone ring, this method may prove
useful in the preparation of a wide variety of members
of the xeniolide family.
Exp er im en ta l Section
Gen er a l. All experiments were carried out under Ar.
Solvents were distilled prior to use. All moisture sensitive
reactions were performed in oven-dried glassware. External

Total Synthesis of Coraxeniolide-A
J . Org. Chem., Vol. 65, No. 26, 2000 9075
(1R,5R,7aR)-ter t-Bu tyl-[5-(2,2-dim eth oxyeth yl)-7a-m eth -
yl-2,3,5,6,7,7a -h exa h yd r o-1H -in d en -1-yloxy]d im et h ylsi-
la n e (6). A suspension of montmorillonite clay K-10 (15 g) and
CH(OCH3)3 (22 mL) was stirred for 30 min. A solution of
aldehyde 5 (7.37 g, 23.88 mmol) in 66 mL of Et2O was added,
and stirring was continued for further 3.5 h. The mixture was
filtered through a pad of Celite and washed with Et2O. The
organic layer was washed with saturated aqueous NaHCO3
solution and brine, dried (Na2SO4) and evaporated to give 8.37
g (98%) of methylacetal 6 as a yellow oil. Data for 6: Rf 0.69
(10% EtOAc/toluene); [R]25D -90.4 (c 2.6, CHCl3); IR 1472, 2966
g (69%) of nitrile 9 as a white solid and 1.30 g (22%) of nitrile
8. Data for 9: mp 103 °C; Rf 0.35 (3:1 hexane/EtOAc); [R]27
D
-24.8 (c 2.94, CHCl3); IR 2240, 3471 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.02 (s, 6H), 0.88 (s, 9H), 0.93 (s, 3H), 1.13 (ddd, J )
4.0, 13.6, 17.7 Hz, 1H), 1.34 (td, J ) 4.4, 14.0 Hz, 1H), 1.43-
1.49 (m, 1H), 1.55 (m, 1H), 1.62-1.71 (m, 1H), 1.72-1.81 (m,
2H), 1.90-2.03 (m, 3H), 2.05-2.12 (m, 1H), 2.21 (br, D2O
exchange, 1H), 2.33 (d, J ) 12.1 Hz, 1H), 3.31 (s, 3H), 3.35 (s,
3H), 4.02 (brt, J ) 7.7 Hz, 1H), 4.55 (dd, J ) 4.8, 6.6 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ -4.99, -4.42, 16.77, 17.87, 25.67,
26.18, 28.52, 28.65, 31.94, 35.43, 37.04, 45.17, 46.62, 51.43,
53.37, 71.78, 78.10, 102.00, 120.03; MS (LSIMS) m/z 367 (25),
366 (100). Anal. Calcd for C21H39SiO4N: C, 63.43; H, 9.89; N,
3.52. Found: C, 63.36; H, 9.83; N, 3.52.
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.02, 0.03 (2s, 6H), 0.89
(s, 3H), 0.90 (s, 9H), 1.13 (td, J ) 2.9, 13.6 Hz, 1H), 1.44-1.64
(m, 5H), 1.73-1.91 (m, 2H), 2.00-2.10 (m, 1H), 2.19 (m, 1H),
2.44 (m, 1H), 3.32 (s, 3H), 3.32 (s, 3H), 3.53 (dd, J ) 8.1, 9.2
Hz, 1H), 4.47 (dd, J ) 5.5, 5.9 Hz, 1H), 5.28 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ -4.09, -3.74, 17.51, 18.75, 24.76, 26.51,
26.77, 30.58, 30.72, 31.66, 39.18, 44.49, 53.13, 53.20, 82.51,
103.94, 123.59, 145.67; MS (EI) m/z 322 (46), 265 (100).
(1R,2R,4a S,5R,7a R)-ter t-Bu tyl-[2-(2,2-d im eth oxyeth yl)-
4a -m eth ylocta h yd r o-1-oxa cyclop r op a [d ]in d en -5-yloxy]-
d im eth ylsila n e (7). A solution of methylacetal 6 (6.75 g, 19.03
mmol) in 100 mL of CH2Cl2 was cooled to -5 °C, and a solution
of m-CPBA (6.57 g, 26.64 mmol) in 200 mL of CH2Cl2 was
added over a period of 40 min. After stirring for 4 h at -5 °C
- 0 °C, the mixture was washed with saturated Na2SO3
solution, saturated aqueous NaHCO3 solution, dried (Na2SO4),
and evaporated. Purification by flash chromatography (SiO2,
20% EtOAc/hexane + 0.5% Et3N) yielded 5.64 g (80%) of
epoxide 7 and 0.49 g (7%) of the â-isomer both as a colorless
oil. Data for 7: Rf 0.48 (20% EtOAc/hexane); (Rf 0.44 (20%
EtOAc/hexane) â-isomer); [R]25D -70.5 (c 0.70, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.03 (s, 6H), 0.88 (s, 9H), 0.92 (s, 3H),
1.09-1.14 (m, 1H), 1.16-1.22 (m, 2H), 1.47-1.59 (m, 1H),
1.61-1.66 (m, 1H), 1.67-1.80 (m, 4H), 1.85-1.92 (m, 1H), 2.05
(m, 1H), 2.88 (d, J ) 1.1 Hz, 1H), 3.34 (s, 6H), 3.79 (m, 1H),
4.49 (t, J ) 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.90,
-4.38, 15.23, 17.01, 21.50, 25.72, 27.43, 29.54, 29.86, 30.80,
34.55, 40.76, 52.80, 52.94, 64.29, 66.25, 79.79, 103.42.
(1R,3a R,4S,5R,7a S)-1-(ter t-Bu tyld im eth ylsila n yloxy)-
5-(2,2-d im eth oxyeth yl)-3a -h yd r oxy-7a -m eth ylocta h yd r o-
in d en e-4-ca r bon itr ile (8). A cooled (0 °C), vigorous stirred
suspension of LiH (550 mg, 69.33 mmol) in 170 mL of THF
was treated carefully with (CH3)2C(OH)CN (5.3 mL, 57.79
mmol). The ice bath was removed and the mixture stirred for
5 h at room temperature. Epoxide 7 (4.20 g, 13.0 mmol) in a
mixture with the â-isomer, dissolved in 25 mL of THF, was
then slowly added and the solution heated to reflux for 19 h.
H2O was added, THF evaporated, and the resulting oily
solution extracted with Et2O. The organic layer was washed
with saturated aqueous NaHCO3 solution and brine, dried
(Na2SO4), and evaporated. Purification by flash chromatogra-
phy (SiO2, 3:1 hexane/EtOAc) yielded 3.77 g (84%) of nitrile 8
as a white solid. Crystals of 8 suitable for X-ray structure
determination were obtained from hexane. Data for 8: mp 92-
93 °C; Rf 0.21 (3:1 hexane/EtOAc); [R]27D -21.5 (c 1.97, CHCl3);
IR 2240, 3487 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 6H),
0.88 (s, 9H), 0.95 (s, 3H), 1.15-1.30 (m, 1H), 1.42-1.48 (m,
1H), 1.50-1.58 (m, 3H), 1.61-1.78 (m, 2H), 2.01-2.11 (m, 4H),
2.67 (br, D2O exchange, 1H), 2.91 (d, J ) 5.1 Hz, 1H), 3.32 (s,
3H), 3.33 (s, 3H), 4.19 (brt, J ) 6.3 Hz, 1H), 4.42 (dd, J ) 4.8,
6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -5.07, -4.57, 16.02,
17.87, 23.76, 25.74, 28.86, 29.96, 31.10, 34.90, 36.06, 41.96,
48.09, 52.45, 53.29, 76.71, 80.16, 103.04, 119.81; MS (LSIMS)
m/z 396 (11), 366 (100). Anal. Calcd for C21H39SiO4N: C, 63.43;
H, 9.89; N, 3.52. Found: C, 63.30; H, 9.71; N, 3.55.
(1R,3a R,4S,5R,7a S)-1-(ter t-Bu tyld im eth ylsila n yloxy)-
5-(2,2-dim eth oxyeth yl)-7a-m eth yl-3a-tr im eth ylsilan yloxy-
oct a h yd r oin d en e-4-ca r bon it r ile (10). To a solution of
nitrile 9 (5.0 g, 12.57 mmol) in 100 mL of CH2Cl2 was added
in portions imidazole (2.57 g, 37.72 mmol). TMSCl (4.0 mL,
31.43 mmol) was added dropwise followed by DMAP (500 mg).
After stirring for 24 h, H2O was added and the aqueous layer
extracted with EtOAc. The combined organic layers were dried
(MgSO4) and evaporated. Purification by flash chromatography
(SiO2, 3:1 hexane/EtOAc) yielded 5.8 g (99%) of 10 as a viscous
colorless oil. Data for 10: Rf 0.68 (3:1 hexane/EtOAc); [R]27
D
-13.3 (c 0.62, CHCl3); IR 2240 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 0.00, 0.01 (2s, 6H), 0.22 (s, 9H), 0.83 (s, 3H), 0.88 (s,
9H), 1.10 (ddd, J ) 4.4, 13.6, 18.0 Hz, 1H), 1.27-1.32 (m, 1H),
1.35-1.50 (m, 2H), 1.57-1.68 (m, 2H), 1.68-1.73 (m, 1H),
1.88-2.01 (m, 2H), 2.03-2.14 (m, 2H), 2.24 (d, J ) 11.8 Hz,
1H), 3.30 (s, 3H), 3.35 (s, 3H), 3.98 (brt, J ) 7.0 Hz, 1H), 4.56
(dd, J ) 4.8, 7.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.99,
-4.43, 2.57, 17.86, 18.16, 25.67, 26.59, 28.49, 28.93, 31.54,
34.30, 36.83, 45.74, 47.63, 50.65, 53.61, 70.82, 82.07, 101.80,
120.66; MS (LSIMS) m/z 468 (9), 438 (100).
(1R,3a R,4R,5R,7a S)-1-(ter t-Bu tyld im eth ylsila n yloxy)-
5-(2,2-dim eth oxyeth yl)-7a-m eth yl-3a-tr im eth ylsilan yloxy-
octa h yd r oin d en e-4-ca r ba ld eh yd e (11). To a chilled (-60
°C) solution of silyl ether 10 (3.0 g, 6.38 mmol) in 75 mL of
hexane was added dropwise DIBALH (19.2 mL, 1 M in hexane,
19.2 mmol). The mixture was allowed to warm to room
temperature and was stirred for further 4 h. While cooling (0
°C), MeOH was added followed by H2O, and stirring was
continued for 1 h. The aqueous layer was separated and
extracted with Et2O, and the combined organic layers were
washed with brine, dried (MgSO4), and evaporated. Purifica-
tion by flash chromatography (SiO2, 5:1 hexane/EtOAc) af-
forded 2.3 g (76%) of aldehyde 11 as a colorless oil. Data for
11: Rf 0.48 (5:1 hexane/EtOAc); [R]27 +37.5 (c 1.20, CHCl3);
D
IR 1716 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.09
(s, 9H), 0.79 (s, 3H), 0.87 (s, 9H), 1.11 (ddd, J ) 4.8, 12.9, 17.6
Hz, 1H), 1.21-1.52 (m, 5H), 1.52-1.63 (m, 2H), 1.66 (dd, J )
4.8, 11.8 Hz, 1H), 1.75 (dd, J ) 3.3, 13.6 Hz, 1H), 1.83-2.02
(m, 4H), 2.18-2.32 (m, 1H), 3.29 (s, 3H), 4.01 (brdd, J ) 7.4,
8.5 Hz, 1H), 4.49 (dd, J ) 4.1, 7.4 Hz, 1H), 9.56 (d, J ) 4.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ -4.93, -4.38, 2.51, 17.72,
17.84, 25.75, 26.06, 28.86, 28.90, 32.37, 37.15, 48.07, 51.98,
52.91, 60.94, 70.99, 83.17, 102.25, 208.17; MS (LSIMS) m/z
441 (63), 133 (100).
(1R,3a R,4S,5R,7a S)-[1-ter t-Bu tyld im eth ylsila n yloxy)-
5-(2,2-dim eth oxyeth yl)-7a-m eth yl-3a-tr im eth ylsilan yloxy-
octa h yd r oin d en -4-yl]-m eth a n ol (12). A solution of aldehyde
11 (1.20 g, 2.53 mmol) in 16 mL of EtOH was cooled to -10
°C, and NaBH4 (47 mg, 1.26 mmol) was added in portions. The
mixture was stirred at this temperature and quenched after
1.5 h with 2 N HCl to adjust the pH to 5-7. The aqueous layer
was extracted with EtOAc, and the combined organic layers
were washed with saturated aqueous NaHCO3 solution and
brine, dried (MgSO4), and evaporated. Purification by flash
chromatography (SiO2, 3:1 hexane/EtOAc) afforded 1.07 g
(1R,3a R,4S,5R,7a S)-1-(ter t-Bu tyld im eth ylsila n yloxy)-
5-(2,2-d im eth oxyeth yl)-3a -h yd r oxy-7a -m eth ylocta h yd r o-
in d en e-4-ca r bon itr ile (9). To a solution of nitrile 8 (5.87 g,
14.76 mmol) in 70 mL of EtOH was added 58 mL of 2 N
aqueous KOH solution. The mixture was stirred overnight at
room temperature and then heated to 50 °C for 2 h. H2O was
added and the aqueous layer extracted with Et2O. The organic
layer was dried (Na2SO4) and evaporated. Purification by flash
chromatography (SiO2, 3:1 to 1:1 hexane/EtOAc) yielded 4.05
(89%) of alcohol 12 as a colorless oil. Data for 12: Rf 0.46 (3:1
1
hexane/EtOAc); [R]27 -6.4 (c 1.60, CHCl3); IR 3250 cm-1; H
D
NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.15 (s, 9H), 0.79 (s,
3H), 0.88 (s, 9H), 1.02 (dt, J ) 2.9, 11.8 Hz, 1H), 1.20-1.29
(m, 2H), 1.42-1.48 (m, 2H), 1.60-1.64 (m, 2H), 1.72-1.82 (m,

9076 J . Org. Chem., Vol. 65, No. 26, 2000
Renneberg et al.
1H), 1.83-1.91 (m, 1H), 1.92-1.99 (m, 2H), 2.00-2.09 (m, 1H),
2.31 (br, D2O exchange, 1H), 3.31 (s, 3H), 3.35 (s, 3H), 3.72
(dd, J ) 2.9, 11.8 Hz, 1H), 3.78 (dd, J ) 2.9, 11.8 Hz, 1H),
4.11 (m, 1H), 4.57 (dd, J ) 5.1, 7.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -4.88, -4.34, 2.93, 17.96, 18.73, 25.78, 26.74, 29.15,
29.40, 31.63, 32.81, 35.94, 48.09, 49.16, 51.19, 53.56, 62.49,
71.25, 85.58, 102.89; MS (LSIMS) m/z 411 (24), 133 (100).
(3R S ,4a R ,6a S ,7R ,9a R ,9b S )-3-Me t h o x y -6a -m e t h y l-
d eca h yd r ocyclop en ta [h ]isoch r om en e-7,9a -d iol (13). To a
solution of 12 (1.13 g, 2.37 mmol) in 30 mL of Et2O was added
montmorillonite clay K-10 (2 g), and the resulting suspension
was stirred for 2 h. It was filtered through a pad of Celite and
washed with Et2O. The organic layer was washed with brine,
dried (Na2SO4), and evaporated. Drying under high vacuum
afforded 1.05 g (95%) of the acetal as a slightly yellow oil. The
crude product was dissolved in 18 mL of THF, and TBAF‚3H2O
(1.4 g, 4.50 mmol) was added. After stirring for 24 h, more
TBAF (8.96 mL, 1 M in THF, 8.96 mmol) was added and
stirring continued for further 3 days. H2O was added, the
aqueous layer was extracted with EtOAc, and the combined
organic layers were washed with brine. Drying (Na2SO4),
evaporation of the solvent, and purification by flash chroma-
tography (SiO2, 1:5 hexane/EtOAc) afforded 0.50 g (91%) of
methylacetal 13 in an anomer mixture of R:â 1.5:1 as a white
with EtOAc in a Soxhlet apparatus overnight. Evaporation of
the solvent and drying overnight under high vacuum resulted
a white foam. This was dissolved in 20 mL of benzene, and
Ag2CO3 on Celite (2.7 g, 4.50 mmol) was added. The suspension
was heated to reflux for 6 h during which time the color turned
to black. It was filtered through a pad of Celite and washed
with EtOAc. Evaporation of the solvent and purification by
flash chromatography (SiO2, EtOAc) yielded 320 mg (61%) of
lactone 15 as a white solid and 177 mg (32%) of methylacetal
13 as a colorless oil. Crystals of 15 were obtained from EtOAc.
Data for 15: mp 165 °C; Rf 0.30 (EtOAc); [R]24 -51.9 (c 0.98,
D
CHCl3); IR 1727, 3448, 3619 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.91 (s, 3H), 1.19-1.27 (m, 1H), 1.34-1.39 (m, 1H), 1.45 (td,
J ) 4.4, 11.8 Hz, 1H), 1.48-1.53 (m, 1H), 1.64-1.72 (m, 3H),
1.92-1.99 (m, 2H), 2.07-2.16 (m, 2H), 2.75 (dd, J ) 5.5, 18.0
Hz, 1H), 4.29 (m, 1H), 4.38 (t, J ) 11.4 Hz, 1H), 4.47 (dd, J )
4.4, 11.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.66, 28.50,
29.03, 29.07, 31.98, 34.02, 37.56, 42.85, 47.91, 71.39, 72.24,
78.74, 171.47; MS (EI) m/z 220 (60), 54 (100). Anal. Calcd for
C13H20O4: C, 64.98; H, 8.39. Found: C, 64.99; H, 8.22.
(4a R,6a S,7R,9a R,9bS)-Tolu en e-4-su lfon ic Acid 9a -Hy-
d r oxy-6a -m e t h yl-3-oxod od e ca h yd r ocyclop e n t a [h ]iso-
ch r om en -7-yl Ester (16). To a solution of lactone 15 (303
mg, 1.26 mmol) in 2 mL of CHCl3 was added 0.21 mL of
pyridine followed by TsCl (601 mg, 3.15 mmol). The resulting
suspension was stirred for 22 h at room temperature when
another portion of TsCl (120 mg, 0.63 mmol) was added. After
45 h, the reaction was quenched by the addition of H2O. The
aqueous layer was extracted with EtOAc, and the combined
organic layers were washed with brine, dried (MgSO4), and
evaporated. Purification by flash chromatography (SiO2, EtOAc)
resulted 460 mg (92%) of tosylate 16 as a white foam. Data
solid. Data for R-isomer: mp 135-136 °C; Rf 0.31 (1:5 hexane/
1
EtOAc); [R]24 +70.7 (c 0.87, CHCl3); IR 3620 cm-1; H NMR
D
(300 MHz, CDCl3) δ 0.86 (s, 3H), 1.15 (dd, J ) 4.4, 12.5 Hz,
1H), 1.19-1.29 (m, 1H), 1.31-1.38 (m, 2H), 1.37-1.40 (m, 1H),
1.58-1.67 (m, 3H), 1.70-1.78 (m, 1H), 1.83-1.96 (m, 2H),
2.08-2.12 (m, 1H), 3.34 (s, 3H), 3.65 (dd, J ) 4.1, 11.0 Hz,
1H), 3.78 (t, J ) 11.0 Hz, 1H), 4.29 (brt, J ) 7.7 Hz, 1H), 4.67
(d, J ) 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.24, 27.91,
28.50, 28.96, 29.33, 32.29, 37.46, 45.01, 47.34, 54.51, 59.35,
72.18, 78.12, 98.00. Data for â-isomer: Rf 0.27 (1:5 hexane/
for 16: Rf 0.55 (EtOAc); [R]24 +0.2 (c 0.90, CHCl3); IR 1361,
D
1726, 3446, 3609 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.91 (m,
1H), 0.95 (s, 3H), 1.25-1.31 (m, 1H), 1.36 (td, J ) 4.1, 12.5
Hz, 1H), 1.42-1.53 (m, 2H), 1.69-1.82 (m, 2H), 1.83-1.88 (m,
1H), 1.89-2.00 (m, 2H), 2.08 (dd, J ) 11.8, 18.0 Hz, 1H), 2.46
(s, 3H), 2.72 (dd, J ) 5.9, 18.0 Hz, 1H), 4.33 (dd, J ) 10.3,
11.4 Hz, 1H), 4.41 (dd, J ) 4.4, 11.4 Hz, 1H), 4.85-4.90 (m,
1H), 7.35 (d, J ) 7.7 Hz, 2H), 7.79 (d, J ) 8.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 16.73, 21.63, 25.56, 27.50, 28.05,
31.14, 33.12, 36.69, 42.12, 47.12, 70.22, 80.50, 127.79, 129.87,
133.86, 144.97, 171.12; MS (LSIMS) m/ z 395 (54), 136 (100);
HRLSIMS m/z calcd for C20H27O6S 395.1528, found 395.1530.
(3S,4a R,11a S)-3-Meth oxy-7-m eth yl-3,4,4a ,5,6,9,10,11a -
octa h yd r o-1H-cyclon on a [c]p yr a n -11-on e (17a ). (3R,4a R,
11a S)-3-Meth oxy-7-m eth yl-3,4,4a ,5,6,9,10,11a -octa h yd r o-
1H-cyclon on a [c]p yr a n -11-on e (17b). NaH (76 mg, 3.14
mmol) was dissolved in 3.2 mL of DMSO, and the methyl-
sulfinyl carbanion was prepared in the usual way.18 At room
temperature, tosylate 14 (0.5 g, 1.21 mmol), dissolved in 3 mL
of DMSO, was added while the color turned to brown. The
reaction was quenched after 20 min by the addition of H2O.
The aqueous layer was extracted with EtOAc, and the com-
bined organic layers were washed with brine, dried (Na2SO4),
and evaporated. Purification by flash chromatography (SiO2,
3:2 hexane/EtOAc) afforded 175 mg (61%) of 17a as a white
solid and 82 mg (28%) of 17b as a colorless oil. Crystals of
17a suitable for X-ray structure determination were obtained
from hexane/EtOAc. Data for 17a : mp 77-79 °C; Rf 0.50 (3:2
EtOAc); [R]24 -56.9 (c 0.45, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 0.86 (s, 3H), 1.13-1.35 (m, 5H), 1.45-1.51 (m, 1H),
1.60-1.71 (m, 3H), 1.82 (ddd, J ) 2.2, 3.7, 12.8 Hz, 1H), 1.94-
1.99 (m, 1H), 2.02-2.10 (m, 1H), 3.46 (s, 3H), 3.52 (t, J ) 10.3
Hz, 1H), 4.08 (dd, J ) 3.7, 11.8 Hz, 1H), 4.30 (m, 2H).
(3RS,4a R,6a S,7R,9a R,9bS)-Tolu en e-4-su lfon ic Acid 9a -
Hyd r oxy-3-m eth oxy-6a -m eth yld od eca h yd r ocyclop en ta -
[h ]isoch r om en -7-yl Ester (14). To a solution of methylacetal
13 (0.64 g, 2.49 mmol) in 4.5 mL of CHCl3 and 0.39 mL of
pyridine was added TsCl (0.97 g, 4.98 mmol). After stirring
for 1.5 days, H2O was added and the aqueous layer extracted
with EtOAc. The combined organic layers were washed with
brine, dried (Na2SO4), and evaporated. Purification by flash
chromatography (SiO2, 1:5 hexane/EtOAc) yielded 0.90 g (90%)
of tosylate 14 (epimeric mixture R:â 1.45:1) as a colorless oil.
Data for R-isomer: Rf 0.59 (1:5 hexane/EtOAc); [R]22 +64.3
D
(c 1.40, CHCl3); IR 1360, 3620 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 0.83-0.94 (m, 1H), 0.91 (s, 3H), 1.10-1.16 (m, 1H),
1.24-1.32 (m, 4H), 1.42-1.47 (m, 1H), 1.68-1.90 (m, 5H), 2.46
(s, 3H), 3.32 (s, 3H), 3.59 (dd, J ) 3.7, 11.0 Hz, 1H), 3.73 (t, J
) 11.0 Hz, 1H), 4.65 (d, J ) 3.3 Hz, 1H), 4.89 (brt, J ) 7.0 Hz,
1H), 7.35 (d, J ) 8.1 Hz, 2H), 7.79 (d, J ) 8.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 17.00, 21.62, 25.60, 27.59, 28.55,
29.07, 32.14, 37.27, 44.93, 54.51, 59.04, 81.50, 97.90, 127.80,
129.78. Data for â-isomer: Rf 0.55 (1:5 hexane/EtOAc); 1H
NMR (300 MHz, CDCl3) δ 0.89-0.94 (m, 1H), 0.92 (s, 3H),
1.03-1.11 (m, 2H), 1.26-1.30 (m, 3H), 1.43-1.49 (m, 1H),
1.63-1.91 (m, 5H), 2.45 (s, 3H), 3.42 (t, J ) 11.0 Hz, 1H), 3.46
(s, 3H), 4.02 (dd, J ) 3.7, 11.8 Hz, 1H), 4.27 (dd, J ) 2.2, 9.6
Hz, 1H), 4.77-4.82 (m, 2H), 7.36 (d, J ) 7.7 Hz, 2H), 7.79 (d,
J ) 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 16.73, 25.49,
28.66, 32.69, 33.26, 38.35, 44.80, 47.17, 56.03, 65.75, 81.25,
102.76, 127.87, 129.80.
(4a R ,6a S ,7R ,9a R ,9b S )-7,9a -D ih y d r o x y -6a -m e t h y l-
d eca h yd r ocyclop en ta [h ]isoch r om en -3-on e (15). To a so-
lution of alcohol 12 (1.03 g, 2.17 mmol) in 10 mL of THF was
added 1.5 mL of 2 N aqueous HCl. After 3 days, further 2 N
HCl (1 mL) was added and the mixture stirred for 1 more day.
Saturated aqueous NaHCO3 solution was then added to adjust
the pH to 7, the THF was evaporated, and the mixture was
lyophilized. The resulting white powder was then extracted
hexane/EtOAc); [R]24 +64.5 (c 1.40, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 1.28 (dt, J ) 3.8, 14.5 Hz, 1H), 1.43 (m, 1H),
1.48 (m, 1H), 1.52 (s, 3H), 1.77 (ddd, J ) 2.3, 4.6, 13.8 Hz,
1H), 1.95 (m, 2H), 2.02 (m, 1H), 2.06 (m, 1H), 2.20 (m, 1H),
2.31 (td, J ) 4.4, 11.5 Hz, 1H), 2.59 (td, J ) 4.9, 11.2 Hz, 1H),
2.69 (m, 1H), 3.36 (s, 3H), 3.40 (dd, J ) 4.4, 11.1 Hz, 1H), 3.86
(t, J ) 11.3 Hz, 1H), 4.63 (dd, J ) 2.6, 3.2 Hz, 1H), 5.42 (dd,
J ) 3.6, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.22,
24.64, 31.67, 35.05, 37.29, 38.91, 39.22, 54.69, 59.10, 97.88,
124.15, 136.47, 213.01. Data for 17b: Rf 0.37 (3:2 hexane/
EtOAc); [R]23 -66.3 (c 2.40, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.37 (td, J ) 9.2, 12.9 Hz, 1H), 1.46-1.50 (m, 1H),
1.60 (s, 3H), 1.86 (ddd, J ) 3.3, 4.4, 13.6 Hz, 1H), 1.99-2.03
(m, 3H), 2.12 (m, 1H), 2.23-2.33 (m, 3H), 2.48-2.57 (m, 1H),
2.64-2.79 (m, 1H), 3.45 (s, 3H), 3.53 (dd, J ) 8.1, 12.1 Hz,

Total Synthesis of Coraxeniolide-A
J . Org. Chem., Vol. 65, No. 26, 2000 9077
1H), 3.86 (dd, J ) 4.8, 12.1 Hz, 1H), 4.48 (dd, J ) 3.3, 9.2 Hz,
1H), 5.37 (dd, J ) 1.1, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 16.97, 23.73, 34.67, 37.20, 38.75, 41.47, 55.95, 60.33, 62.66,
101.52, 123.96, 136.50, 212.89.
and evaporation of the solvent, the crude product was purified
by flash chromatography (SiO2, EtOAc + 0.5% Et3N) to yield
10 mg (88%) of enone 20 (R:â 56:44) as a white solid. Data for
20: mp 102 °C; Rf 0.57 (EtOAc); IR 1692, 3620 cm-1; NMR
signals for R-isomer indicated: 1H NMR (300 MHz, CDCl3) δ
1.40-1.42 (m, 2H), 1.64 (s, 3H), 1.67-1.69 (m, 1H), 1.85 (ddd,
J ) 2.9, 4.8, 14.0 Hz, 1H), 2.00-2.05 (m, 2H), 2.15-2.17 (m,
1H), 2.15-2.19 (m, 1H), 2.35-2.40 (m, 1H), 2.38-2.43 (m, 1H),
2.50-2.54 (m, 1H), 2.61-2.66 (m, 1H), 3.56 (dd, J ) 4.8, 11.8
Hz, 1H), 3.98 (dd, J ) 8.5, 11.8 Hz, 1H), 5.24 (q, J ) 2.9 Hz,
1H), 5.39 (brdd, J ) 4.8, 11.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 16.97, 23.38, 30.56, 34.93, 36.33, 38.92, 39.37, 58.80,
60.12, 91.56, 123.37, 137.23, 214.85; NMR signals for â-isomer
indicated: 1H NMR (300 MHz, CDCl3) δ 1.25-1.33 (m, 1H),
1.35-1.38 (m, 2H), 1.59 (s, 3H), 1.95-1.98 (m, 1H), 1.99-2.03
(m, 2H), 2.10-2.15 (m, 1H), 2.15-2.20 (m, 1H), 2.25-2.30 (m,
1H), 2.38-2.44 (m, 1H), 2.45-2.55 (m, 1H), 2.62-2.70 (m, 1H),
3.55-3.60 (m, 1H), 3.83 (dd, J ) 4.4, 11.8 Hz, 1H), 4.85 (m,
1H), 5.39 (brdd, J ) 4.8, 11.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 17.23, 24.12, 29.56, 34.85, 38.79, 38.89, 39.50, 60.70,
64.02, 95.28, 124.11, 136.70, 213.03; MS (EI) m/z 224 (3), 67
(100); HREIMS m/z calcd for C13H20O3 224.1412, found 224.1412.
(3S,4aR,11aR)-3-Meth oxy-7-m eth yl-11-m eth ylen e-1,3,4,-
4a ,5,6,9,10,11,11a -d eca h yd r ocyclon on a [c]p yr a n (21a ). A
solution of MePPh3Br (135 mg, 0.38 mmol) in 0.4 mL of THF
was cooled to -30 °C, and n-BuLi (0.23 mL, 1.6 M in hexane,
0.38 mmol) was slowly added to give an orange/yellow suspen-
sion. After stirring for 1 h at this temperature, a solution of
methylacetal 17a (45 mg, 0.19 mmol) in 0.2 mL of THF was
added dropwise, and the suspension was allowed to warm to
room temperature. After the suspension was stirred overnight
(white suspension), H2O was added and the aqueous layer
extracted with Et2O. The combined organic layers were dried
(Na2SO4) and evaporated. Purification by flash chromatogra-
phy (SiO2, 5:1 hexane/EtOAc) yielded 10 mg (23%) of diene
21a as a colorless oil and 33 mg (73%) of starting material.
Data for 21a : Rf 0.52 (5:1 hexane/EtOAc); 1H NMR (300 MHz,
CDCl3) δ 1.22-1.30 (m, 1H), 1.35-1.42 (m, 1H), 1.58 (s, 3H),
1.78-1.88 (m, 3H), 1.96-2.00 (m, 5H), 2.12-2.21 (m, 1H), 2.37
(dd, J ) 5.1, 11.4 Hz, 1H), 3.30 (dd, J ) 4.1, 11.4 Hz, 1H),
3.37 (s, 3H), 3.65 (t, J ) 11.4 Hz, 1H), 4.64 (dd, J ) 2.2, 3.3
Hz, 1H), 4.85 (s, 1H), 4.95 (s, 1H), 5.34 (dd, J ) 4.0, 11.7 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 16.10, 26.25, 29.54, 29.92,
33.14, 35.99, 36.95, 52.22, 60.55, 62.85, 95.93, 113.84, 122.17,
133.65, 146.99; MS (EI) m/z 236 (10), 28 (100).
(3R ,4a R ,11a R )-3-Me t h oxy-7-m e t h yl-11-m e t h yle n e -
1,3,4,4a,5,6,9,10,11,11a-decah ydr ocyclon on a[c]pyr an (21b).
To a cooled solution (-40 °C) of methylacetal 17b (60 mg, 0.25
mmol) in 1.5 mL of THF was added dropwise the Tebbe
reagent (0.5 mL, 0.5 M in toluol, 0.25 mmol). The reaction
mixture was allowed to warm to room temperature and stirred
for another 4 h. The suspension was again cooled to -20 °C,
and 0.3 mL of a 15% aqueous NaOH solution was added
dropwise. THF (2 mL) was added, and stirring was continued
for 10 h. The suspension was filtered through a pad of Celite
and washed with EtOAc. The solvent was removed and
purification by flash chromatography (SiO2, 3:1 to 5:1 hexane/
EtOAc) afforded 22 mg (37%) of diene 21b as a colorless oil.
Data for 21b: Rf 0.42 (5:1 hexane/EtOAc); 1H NMR (300 MHz,
CDCl3) δ 1.31-1.39 (m, 2H), 1.58 (s, 3H), 1.76-1.78 (m, 1H),
1.82-1.85 (m, 1H), 1.86-1.91 (m, 1H), 1.93-2.08 (m, 5H),
2.12-2.23 (m, 1H), 2.37 (dd, J ) 4.8, 11.8 Hz, 1H), 3.38 (t, J
) 11.8 Hz, 1H), 3.47 (s, 3H), 3.71 (dd, J ) 4.4, 11.8 Hz, 1H),
4.27 (dd, J ) 2.2, 9.6 Hz, 1H), 4.87 (s, 1H), 4.96 (s, 1H), 5.27
(dd, J ) 5.5, 11.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 18.46,
31.58, 35.20, 35.90, 39.71, 54.76, 55.99, 102.78, 116.91, 124.36,
136.04, 148.04.
(4a R,11a S)-7-Met h yl-1,4,4a ,5,6,9,10,11a -oct a h yd r ocy-
clon on a [c]p yr a n -3,11-d ion e (18). NaH (8 mg, 0.33 mmol)
was dissolved in 0.53 mL of DMSO, and the methylsulfinyl
carbanion was prepared in the usual way. At room tempera-
ture, tosylate 16 (50 mg, 0.13 mmol) in 2 mL of DMSO was
added. The reaction was quenched after 30 min by the addition
of phosphate buffer (pH 7.0, c (KH2PO4) ) 0.026 mol/L, c (Na2-
HPO4) ) 0.041 mol/L). The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4), and evaporated. Purification by flash chro-
matography (SiO2, 1:3 hexane/EtOAc) afforded 20 mg (71%)
of enone 18 as a white solid. Crystals of 18 suitable for X-ray
structure determination were obtained from MeOH. Data for
18: mp 163 °C; Rf 0.56 (1:3 hexane/EtOAc); [R]23D +111 (c 0.25,
CHCl3); IR 1706, 1753 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.57-1.63 (m, 2H), 1.82 (s, 3H), 2.03-2.13 (m, 1H), 2.21 (dt, J
) 3.7, 12.1 Hz, 1H), 2.25-2.28 (m, 1H), 2.30-2.37 (m, 3H),
2.56-2.66 (m, 1H), 2.73 (ddd, J ) 4.0, 5.5, 9.9 Hz, 1H), 2.84
(dd, J ) 7.4, 14.7 Hz, 1H), 2.92 (dd, J ) 1.8, 9.9 Hz, 1H), 3.98
(dd, J ) 9.9, 11.4 Hz, 1H), 4.22 (dd, J ) 5.5, 11.4 Hz, 1H),
5.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 16.52, 21.08, 36.13,
36.34, 36.37, 39.50, 40.18, 55.38, 66.50, 122.69, 138.29, 172.40,
213.67; MS (EI) m/z 222 (68), 55 (100).
(3RS,4aR,6aS,7R,9aR,9bS)-Tolu en e-4-su lfon ic Acid 3,9a-
Dih yd r oxy-6a -m e t h yl-d od e ca h yd r ocyclop e n t a [h ]iso-
ch r om en -7-yl Ester (19). To a cooled (-65 °C) solution of
tosylate 16 (60 mg, 0.15 mmol) in 12 mL of CH2Cl2 was added
dropwise DIBALH (0.19 mL, 1 M in THF, 0.19 mmol). After
stirring for 30 min at this temperature, the reaction was
quenched by the addition of 6 mL of MeOH followed by 6 mL
of phosphate buffer (pH 7.0). The reaction mixture was stirred
for 1 h at room temperature and then extracted with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO4), and evaporated to a volume of 20 mL. The residue
was filtered through a 10 cm thick pad of SiO2 with EtOAc.
The solvent was evaporated and the crude product purified
by flash chromatography (SiO2, EtOAc) to afford 59 mg (98%)
of lactol 19 (R:â 1:1) as a white foam. Data for 19: Rf 0.36
(EtOAc); IR 1358, 3446, 3609 cm-1; NMR signals for R-isomer
indicated: 1H NMR (300 MHz, CDCl3) δ 0.80-0.90 (m, 1H),
0.91 (s, 3H), 1.04-1.06 (m, 1H), 1.17-1.18 (m, 1H), 1.20-1.35
(m, 1H), 1.25 (m, 1H), 1.45 (m, 1H), 1.58-1.63 (m, 1H), 1.65-
1.68 (m, 1H), 1.80-1.84 (m, 2H), 1.80-1.90 (m, 1H), 2.45 (s,
3H), 3.39 (brs, 1H), 3.61 (dd, J ) 3.7, 11.4 Hz, 1H), 3.96 (m,
1H), 4.68 (dd, J ) 2.2, 9.9 Hz, 1H), 4.89 (m, 1H), 7.35 (d, J )
7.7, 2H), 7.79 (d, J ) 8.1, 2H); 13C NMR (75 MHz, CDCl3) δ
16.77, 21.57, 28.49, 32.59, 33.26, 39.86, 44.96, 47.24, 59.09,
77.26, 81.51, 96.07, 127.73, 129.74, 133.96, 144.72; NMR
signals for â-isomer indicated: 1H NMR (300 MHz, CDCl3) δ
0.80-0.90 (m, 1H), 0.91 (s, 3H), 1.08-1.12 (m, 1H), 1.20-1.35
(m, 1H), 1.25-1.35 (m, 1H), 1.28-1.45 (m, 2H), 1.68-1.75 (m,
1H), 1.77-1.80 (m, 2H), 1.88-1.92 (m, 1H), 1.90-1.95 (m, 1H),
2.45 (s, 3H), 2.95 (brs, 1H), 3.52 (dd, J ) 10.3, 11.4 Hz, 1H),
4.01 (m, 1H), 4.83 (t, J ) 7.7 Hz, 1H), 5.23 (d, J ) 2.9 Hz,
1H), 7.35 (d, J ) 7.7, 2H), 7.79 (d, J ) 8.1, 2H); 13C NMR (75
MHz, CDCl3) δ 17.02, 21.57, 25.52, 27.50, 28.18, 28.65, 31.95,
37.38, 44.49, 66.01, 81.28, 91.30, 127.73, 129.74, 133.78,
144.75; MS (LSIMS) m/z 397 (11), 379 (100); HRLSIMS m/z
calcd for C20H29O6S 397.1684, found 397.1685.
(3RS,4a R,11a S)-3-Hyd r oxy-7-m eth yl-3,4,4a ,5,6,9,10,11a -
octa h yd r o-1H-cyclon on a [c]p yr a n -11-on e (20). To a solu-
tion of lactol 19 (20 mg, 50.4 µmol) in 0.3 mL of DMSO was
added a solution of methylsulfinyl carbanion (0.22 mL, 0.17
mmol), prepared from 33 mg of NaH and 1 mL of DMSO in
the usual manner, at room temperature under vigorous
stirring. The mixture turned immediately to yellow and was
stirred for 10 min while more methylsulfinyl carbanion (60
µL, 45.4 µmol) was added. The reaction was quenched with
10 mL of phosphate buffer (pH 7.0, c (KH2PO4) ) 0.026 mol/
L, c (Na2HPO4) ) 0.041 mol/L). H2O was added and the
aqueous layer extracted with EtOAC. After drying (MgSO4)
(4a R,11a R)-7-Meth yl-11-m eth ylen e-4,4a ,5,6,9,10,11,11a -
octa h yd r o-1H-cyclon on a [c]p yr a n -3-on e (22). To a solution
of lactol 28 (60 mg, 0.27 mmol) in 2.5 mL of benzene was added
Ag2CO3 on Celite (324 mg, 0.54 mmol). The suspension was
heated for 30 min at 60 °C while the color turned to black.
The mixture was filtered through a pad of Celite and washed
with EtOAc. Evaporation of the solvent and purification by
flash chromatography (SiO2, 2:1 hexane/EtOAc + 0.5% Et3N)

9078 J . Org. Chem., Vol. 65, No. 26, 2000
Renneberg et al.
afforded 53 mg (89%) of lactone 22 as a white solid. Crystals
were obtained from hexane. Data for 22: mp 44-45 °C; Rf 0.58
(2:1 hexane/EtOAc); [R]27D +159 (c 0.70, CHCl3); IR 1744, 3013,
1.48 (m, 2H), 1.57 (s, 3H), 1.81-1.85 (m, 1H), 1.98-2.01 (m,
2H), 2.00-2.05 (m, 1H), 2.07-2.09 (m, 1H), 2.18-2.22 (m, 1H),
2.28 (td, J ) 4.4, 9.9 Hz, 1H), 2.54 (td, J ) 5.5, 11.4 Hz, 1H),
2.70-2.75 (m, 1H), 3.53 (dd, J ) 9.9, 11.8 Hz, 1H), 3.84 (dd, J
) 4.4, 11.8 Hz, 1H), 4.78 (dd, J ) 2.6, 9.2 Hz, 1H), 5.39 (brdd,
J ) 3.3, 11.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -5.19,
-4.28, 17.36, 18.00, 24.32, 25.72, 34.83, 35.79, 38.75, 38.92,
41.12, 61.05, 64.40, 96.08, 124.18, 136.71, 213.12; MS (LSIMS)
m/z 337 (45), 133 (100).
1
3028 cm-1; H NMR (500 MHz, CDCl3) δ 1.53-1.58 (m, 2H),
1.66 (d, J ) 1.2 Hz, 3H), 1.87-1.92 (m, J ) 1.0, 5.9, 10.0 Hz,
1H), 2.01-2.03 (m, 1H), 2.08-2.19 (m, 4H), 2.31-2.32 (m, 1H),
2.30-2.35 (dd, J ) 4.1, 14.5 Hz, 1H), 2.41-2.47 (m, 1H), 2.79
(dd, J ) 7.0, 14.5 Hz, 1H), 3.85 (ddd, J ) 0.4, 10.0, 11.7 Hz,
1H), 4.11 (dd, J ) 5.9, 11.7 Hz, 1H), 4.87 (s, 1H), 4.93 (s, 1H),
5.31 (brt, J ) 7.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 16.34,
24.76, 35.26, 36.96, 37.27, 39.75, 40.78, 48.30, 70.72, 112.64,
124.32, 135.45, 152.70, 173.47; MS (EI) m/z 220 (34), 81 (100);
HREIMS m/z calcd for C14H20O2 220.1463, found 220.1463;
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.33;
H, 9.01.
(3R S ,4a R ,11a R )-t er t -B u t y ld im e t h y l-(7-m e t h y l-11-
m eth ylen e-1,3,4,4a ,5,6,9,10,11,11a -d eca h yd r ocyclon on a -
[c]p yr a n -3-yloxy)sila n e (27). A solution of silylacetal 26 (82
mg, 0.24 mmol) in 2 mL of THF and 0.14 mL of pyridine at
-5 °C was treated with Tebbe reagent (0.67 mL, 0.5 M in
toluene, 0.336 mmol). The solution was allowed to warm to
room temperature over a period of 30 min. After 1.5 h, the
solution was cooled (0 °C) and stirred vigorously, and 5 mL of
THF was added, followed by careful addition of 2 mL of 15%
aqueous NaOH solution. The deep red suspension was stirred
for 1 h, MgSO4 was added, and stirring was continued for
further 30 min. It was filtered through a pad of Celite and
washed with EtOAc. Evaporation of the solvent yielded a red/
brown oil which was filtered through a column (Al2O3 neutral
II, 30:1 hexane/EtOAc) to give a yellow oil. Purification by flash
chromatography (SiO2, 30:1 hexane/EtOAc + 0.5% Et3N)
afforded 57 mg (70%) of diene 27 (R:â 5:95) as a slightly yellow
oil. Data for 27: Rf 0.54 (30:1 hexane/EtOAc); IR 3015, 3028
cm-1; NMR signals for â-isomer indicated: 1H NMR (500 MHz,
CDCl3) δ 0.14 (s, 6H), 0.93 (s, 9H), 1.36-1.38 (m, 1H), 1.42-
1.44 (m, 1H), 1.60 (s, 3H), 1.75-1.79 (m, 1H), 1.81-1.82 (m,
1H), 1.83 (ddd, J ) 2.1, 4.4, 12.8 Hz, 1H), 1.96-1.99 (m, 2H),
1.97-1.99 (m, 2H), 2.03-2.06 (m, 1H), 2.20 (dbrt, J ) 13.3
Hz, 1H), 2.38 (dd, J ) 4.9, 12.0 Hz, 1H), 3.38 (t, J ) 11.5 Hz,
1H), 3.68 (dd, J ) 4.4, 11.7 Hz, 1H), 4.65 (dd, J ) 2.1, 9.3 Hz,
1H), 4.88 (d, J ) 1.5 Hz, 1H), 4.97 (d, J ) 1.7 Hz, 1H), 5.31
(dd, J ) 5.4, 11.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ -5.16,
-4.18, 18.04, 18.47, 25.77, 28.66, 31.52, 35.20, 36.22, 39.13,
42.86, 54.68, 69.27, 96.64, 116.87, 124.33, 136.06, 147.79; MS
(LSIMS) m/z 337 (9), 161 (100); HRLSIMS m/z calcd for
1-H yd r oxy-10-m e t h yl-4-oxa t r icyclo[8.3.1.02,7]t e t r a -
d eca n -5-on e (23a /23b). Diene 21a (30 mg, 0.13 mmol) was
dissolved in 0.6 mL of THF, and 0.6 mL 0.5 M aqueous HCl
was added. The mixture was heated to 60 °C and stirred for
24 h. EtOAc was added and the organic layer washed with
saturated aqueous NaHCO3 solution and brine, dried (Na2SO4),
and evaporated. The crude product was dried under high
vacuum overnight and directly dissolved in 1.5 mL of benzene.
Ag2CO3 on Celite (0.7 g, 1.22 mmol) was added and the
suspension heated to reflux for 3 h. Filtration through a pad
of Celite, washing with EtOAc, evaporation, and purification
by flash chromatography (SiO2, 1:2 hexane/EtOAc) afforded
18 mg (61%) of 23a /b (unseparable 1:1 mixture) as a colorless
oil. Data for 23a /b: Rf 0.58 (1:2 hexane/EtOAc); 1H NMR (300
MHz, CDCl3) δ 0.90 (s, 3H), 0.99 (s, 3H), 1.02-1.06 (m, 1H),
1.11-1.26 (m, 8H), 1.37-1.47 (m, 6H), 1.60-1.75 (m, 7H),
1.81-1.96 (m, 5H), 1.98-2.06 (m, 2H), 2.09-2.12 (m, 1H),
2.16-2.20 (m, 1H), 2.22-2.32 (m, 1H), 2.67 (dd, J ) 5.2, 18.0
Hz, 1H), 2.75 (dd, J ) 6.3, 15.8 Hz, 1H), 4.17 (t, J ) 11.0 Hz,
1H), 4.23 (dd, J ) 9.6, 11.8 Hz, 1H), 4.36 (dd, J ) 4.4, 11.8
Hz, 1H), 4.67 (dd, J ) 3.7, 10.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 19.40, 19.67, 29.40, 29.50, 31.18, 31.24, 32.16, 32.32,
32.87, 33.41, 34.05, 35.90, 36.62, 37.26, 37.79, 38.05, 38.24,
39.96, 41.16, 48.30, 50.25, 50.48, 68.33, 70.46, 71.49, 72.07,
170.03, 171.66; MS (LSIMS) m/z 239 (21), 133 (100).
C
20H36O2Si 337.2562, found 337.2560.
(10-Meth oxy-1-oxadispir o[2.0.2.7]tr idec-10-en -7-yl)-ace-
tic Acid Meth yl Ester (25). To a solution of trimethylsul-
foxonium iodide (67 mg, 0.30 mmol) in 0.6 mL of DMSO was
added a solution of t-BuOK (30 mg, 0.27 mmol) in 0.4 mL of
DMSO. After stirring for 20 min, enone 18 (15 mg, 0.07 mmol)
in 0.5 mL of DMSO was added. After heating at 60 °C for 24
h, a further portion of trimethylsulfoxonium iodide (67 mg,
0.30 mmol) in 0.6 mL of DMSO and t-BuOK (30 mg, 0.27
mmol) in 0.4 mL of DMSO (prepared as above) was added.
Stirring and heating at 60 °C for further 24 h was continued.
The reaction was quenched by the addition of phosphate buffer
(pH 7.0). The aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and evaporated.
Purification by flash chromatography (SiO2, 3:2 hexane/EtOAc)
afforded 5.5 mg (35%) of 25 as a colorless oil. Data for 25: Rf
0.40 (3:1 hexane/EtOAc); 1H NMR (300 MHz, CDCl3) δ 0.47-
0.54 (m, 1H), 0.60-0.67 (m, 1H), 0.74-0.81 (m, 1H), 1.25-
1.30 (m, 1H), 1.40 (ddd, J ) 4.8, 6.3, 10.7 Hz, 1H), 1.51 (s,
3H), 1.52-1.63 (m, 4H), 2.05-2.17 (m, 3H), 2.18-2.23 (m, 1H),
2.24-2.27 (m, 1H), 2.71 (td, J ) 4.4, 11.8 Hz, 1H), 2.81-2.88
(m, 2H), 3.70 (s, 3H), 5.70 (dd, J ) 3.3, 11.0 Hz, 1H); MS (EI)
m/z 264 (1), 40 (100).
(3RS,4a R,11a R)-7-Met h yl-11-m et h ylen e-1,3,4,4a ,5,6,9,
10,11,11a -d eca h yd r ocyclon on a [c]p yr a n -3-ol (28). To a
solution of diene 27 (106 mg, 0.31 mmol) in 3.5 mL of THF
was added TBAF (0.47 mL, 1 M in THF, 0.47 mmol). After
stirring for 4 h, H2O was added. The aqueous layer was
extracted with EtOAc, and the combined organic layers were
washed with brine, dried (MgSO4), and evaporated. Purifica-
tion by flash chromatography (SiO2, 1:1 hexane/EtOAc + 0.5%
Et3N) afforded 60 mg (85%) of lactol 28 (R:â 47:53) as a
colorless oil. Data for 28: Rf 0.46 (1:1 hexane/EtOAc); IR 2929,
3007, 3595 cm-1; NMR signals for â-isomer indicated: 1H NMR
(300 MHz, CDCl3) δ 1.59 (s, 3H), 1.22-2.55 (m, 13H), 3.33 (dd,
J ) 4.4, 11.4 Hz, 1H), 3.89 (t, J ) 11.4 Hz, 1H), 4.68 (dd, J )
1.8, 2.2 Hz, 1H), 4.88 (s, 1H), 4.97 (d, J ) 1.1 Hz, 1H), 5.34
(m, 1H); MS (EI) m/z 222 (2), 41 (100); HREIMS m/z calcd for
C
14H22O2 222.1619, found 222.1622.
(4S,4a S,11aR)-7-Meth yl-11-m eth ylen e-4-(4-m eth ylp en t-
2-en yl)-4,4a ,5,6,9,10,11,11a -oct a h yd r o-1H -cyclon on a [c]-
p yr a n -3-on e (1a ). (4R,4a S,11a R)-7-Meth yl-11-m eth ylen e-
4-(4-m et h ylp en t -2-en yl)-4,4a ,5,6,9,10,11,11a -oct a h yd r o-
1H-cyclon on a [c]p yr a n -3-on e (1b). A solution of diisopropyl-
amine (DIPA) (59.7 µL, 0.42 mmol) in 0.63 mL of 2:1 THF/
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)
was cooled to -35 °C, and n-BuLi (255 µL, 1.6 M in hexane,
0.41 mmol) was added dropwise. After the mixture was stirred
for 5 min, the dry ice-2-propanol bath was replaced by an ice
bath, and the mixture was stirred for 30 min. From this
solution was taken 315 µL and recooled to -78 °C. Lactone
22 (10 mg, 45.4 µmol), dissolved in 0.15 mL of THF, was added
dropwise, and the reaction mixture was stirred for 1 h.
1-Bromo-4-methylpent-2ene (7.3 µL, 54.5 µmol) (in a 4:1
mixture with 3-bromo-4-methylpent-1-ene) was added. The
reaction mixture was stirred for 10 min and then left for 17 h
at -68 °C. Quenching with 5 mL of saturated aqueous
NaHCO3 solution at -68 °C followed by extraction with Et2O
(3R S ,4a R ,11a S )-3-(t er t -Bu t yld im e t h ylsila n yloxy)-7-
m eth yl-3,4,4a ,5,6,9,10,11a -octa h yd r o-1H-cyclon on a [c]p y-
r a n -11-on e (26). To a solution of lactol 20 (71 mg, 0.32 mmol)
in 4.5 mL of CH2Cl2 was added imidazole (65 mg, 0.95 mmol)
followed by TBDMSCl (96 mg, 0.63 mmol). After stirring for
29 h, H2O was added. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with
brine, dried (Na2SO4), and evaporated. Purification by flash
chromatography (SiO2, 10:1 hexane/EtOAc + 0.5% Et3N)
afforded 105 mg (98%) of silylacetal 26 (R:â 13:87) as a colorless
oil. Data for 26: Rf 0.39 (10:1 hexane/EtOAc); IR 1694 cm-1
;
NMR signals for â-isomer indicated: 1H NMR (300 MHz,
CDCl3) δ 0.11 (s, 6H), 0.90 (s, 9H), 1.35-1.42 (m, 1H), 1.40-

Total Synthesis of Coraxeniolide-A
J . Org. Chem., Vol. 65, No. 26, 2000 9079
afforded after drying (MgSO4) and purification by flash chro-
matography (SiO2, 2:1 hexane/EtOAc + 0.5% Et3N) 5.8 mg
(42%) of 4-epi-coraxeniolide-A (1b) and 1.0 mg (7%) of corax-
eniolide-A (1a ) as colorless oils, together with 3.0 mg (30%) of
unreacted starting material 22. Crystals of 1a suitable for
X-ray structure determination were obtained from CH2Cl2 at
5 °C. Data for coraxeniolide-A (1a ): Rf 0.63 (2:1 hexane/
1H), 4.68 (s, 1H), 4.86 (s, 1H), 5.30 (brt, J ) 7.4 Hz, 1H), 5.43
(dd, J ) 5.4, 15.4 Hz, 1H), 5.47-5.52 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 16.46, 22.64, 22.67, 25.07, 31.09, 31.53, 34.68,
35.17, 39.64, 43.81, 44.90, 48.84, 66.97, 113.37, 123.76, 124.49,
135.43, 141.04, 152.70, 175.00; MS (EI) m/z 302 (16), 41 (100);
HREIMS m/z calcd for C20H30O2 302.2245, found 302.2244.
Ep im er iza tion of 4-epi-Cor a xen iolid e-A (1b). A solution
of 1b (5 mg, 16.5 µmol) in 0.1 mL of toluene was treated with
a solution of TBD (5 mg, 35.9 µmol) in 0.04 mL of toluene at
room temperature. The reaction was stirred for 5 min and left
for 18 h. A small amount of saturated aqueous NaHCO3
solution was added to the mixture, followed by dilution of
EtOAc and direct drying over MgSO4. Filtration, evaporation,
and purification by flash chromatography (SiO2, 3:1 hexane/
EtOAc + 0.5% Et3N) provided 3 mg (60%) of 1a and 1 mg (20%)
of 1b.
EtOAc); [R]22D +72.0 (c 0.47, CHCl3); IR 1740, 3011, 3028 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.97 (dd, J ) 1.6, 6.8 Hz, 6H),
1.03 (ddd, J ) 2.7, 3.2, 13.1 Hz, 1H), 1.66 (d, J ) 1.2, 3H),
1.71 (ddd, J ) 3.5, 3.6, 14.0, 1H), 1.92 (td, J ) 4.4, 12.6, 1H),
1.97-2.02 (m, 1H), 2.03-2.05 (m, 1H), 2.05-2.07 (m, 1H),
2.07-2.11 (m, 1H), 2.14-2.16 (m, 1H), 2.18-2.20 (m, 1H), 2.24
(dd, J ) 6.8, 13.5 Hz, 1H), 2.30-2.34 (m, 1H), 2.43-2.47 (m,
1H), 2.52-2.59 (m, 1H), 2.77-2.83 (m, J ) 6.1, 14.2 Hz, 1H),
3.90 (t, J ) 11.7 Hz, 1H), 4.15 (dd, J ) 6.9, 11.7 Hz, 1H), 4.94
(s, 1H), 4.95 (s, 1H), 5.28-5.32 (m, 2H), 5.47 (dd, J ) 6.8, 15.3
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.38, 22.58, 24.92,
29.59, 29.89, 31.06, 35.54, 39.55, 42.67, 44.06, 49.61, 70.56,
112.04, 123.26, 123.79, 135.90, 140.61, 152.98, 175.15; MS (EI)
m/z 302 (10), 41 (100); HREIMS m/z calcd for C20H30O2
302.2245, found 302.2247. Data for 4-epi-coraxeniolide-A
(1b): Rf 0.59 (2:1 hexane/EtOAc); [R]22D -25.6 (c 0.22, CHCl3);
Ack n ow led gm en t. The X-ray data sets were mea-
sured by the BENEFRI Small Molecule Crystallography
Service directed by Prof. Helen Stoeckli-Evans. We
gratefully acknowledge Prof. Dr. P. Bigler, Dr. P. Mu¨ller,
and Dr. Ch. Schorn for NMR assistance, and the Swiss
National Science Foundation for financial support.
1
IR 1735, 3011, 3028 cm-1; H NMR (400 MHz, CDCl3) δ 0.96
(dd, J ) 1.6, 6.8 Hz, 6H), 1.39-1.49 (m, 1H), 1.66 (d, J ) 1.3
Hz, 3H), 1.71-1.73 (m, 1H), 1.75-1.78 (m, 1H), 1.82 (td, J )
7.4, 10.0 Hz, 1H), 1.99-2.05 (m, 3H), 2.17 (dt, J ) 3.6, 12.4
Hz, 1H), 2.21-2.24 (m, 1H), 2.25-2.30 (m, 2H), 2.32 (dd, J )
7.1, 13.5 Hz, 1H), 2.40-2.48 (m, 1H), 2.50-2.53 (m, 1H), 3.98
(ddd, J ) 0.5, 2.6, 11.3 Hz, 1H), 4.14 (dd, J ) 3.5, 11.3 Hz,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
1a , 1b, 4-28 and crystallographic data for 8, 17a , 18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O005582H