Utilization of the Phenylthio Substituent as a Multipurpose Synthetic Tool. Direct Application to the Enantioselective Construction of (-)-Salsolene Oxide

Article abstract of DOI:10.1021/jo971244d

The architecturally unprecedented sesquiterpene (-)-salsolene oxide (1) has been synthesized in enantioselective fashion from (R)-(-)-carvone. Generation of the phenylthio-substituted vinyl ketene 4 is followed by intramolecular cyclization to the functio

Full text of DOI:10.1021/jo971244d

J . Org. Chem. 1997, 62, 8155-8161
8155
Utiliza tion of th e P h en ylth io Su bstitu en t a s a Mu ltip u r p ose
Syn th etic Tool. Dir ect Ap p lica tion to th e En a n tioselective
Con str u ction of (-)-Sa lsolen e Oxid e
Leo A. Paquette,* Li-Qiang Sun, Timothy J . N. Watson,† Dirk Friedrich,† and
Brett T. Freeman
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received J uly 9, 1997X
The architecturally unprecedented sesquiterpene (-)-salsolene oxide (1) has been synthesized in
enantioselective fashion from (R)-(-)-carvone. Generation of the phenylthio-substituted vinyl ketene
4 is followed by intramolecular cyclization to the functionalized cyclobutanone 9. Vinyllithium
addition to this intermediate proceeds in that stereocontrolled fashion which enables oxy-Cope
rearrangement to operate readily under conditions of kinetic control. After hydride reduction, the
desulfurization of 16 proceeds with inversion of bridgehead olefin geometry to deliver 17. This
access route to the thermodynamically more stable geometric arrangement permits direct entry to
1. Attention is called specifically to the critical 3-fold function played by a phenylthio group
introduced at the outset.
The isolation of diverse natural products featuring
bridgehead unsaturation in their framework has consti-
tuted an exciting branch of structural chemistry and
provided challenging targets for total synthesis.1 This
family of compounds includes, but is hardly limited to,
paclitaxel,2,3 taxusin,4,5 vulgarolide,6,7 eremantholide A,8-10
cerorubenic acid-III,11,12 O-methylshikoccin,13,14 and cle-
omeolide.15,16 Equally remarkable has been the discovery
essential oil of the Himalayan plant Artemisia salso-
loides.17 The disclosure of 1, known as salsolene oxide,
constitutes one of the few reports dealing with a more
highly oxidized array about the bridgehead site.14,18
by Weyerstahl et al. in 1991 of the architecturally
unusual bridgehead oxiranyl sesquiterpenoid 1 from the
† Present address: Hoechst Marion Roussel, Inc., 2110 East Gal-
braith Road, P.O. Box 156300, Cincinnati, OH 45215-6300.
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Paquette, L. A. Chem. Soc. Rev. 1995, 24, 9.
(2) Isolation: Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J . Am. Chem. Soc. 1971, 93, 2325.
The structure and relative stereochemistry of 1 were
deduced on the basis of extensive NMR spectroscopic
analysis. The very limited quantities of salsolene oxide
precluded proper establishment of its absolute configu-
ration and determination of whether 1 is dextro- or
levorotatory. We now report the complete details of an
enantioselective total synthesis of (-)-1 having well-
defined stereochemistry.19 The decision to prepare this
particular antipode of salsolene oxide was founded on its
likely biosynthesis from germacrene D.17,20
(3) Synthesis: (a) Nicolaou, K. C.; Yang, Z.; Liu, J . J .; Ueno, H.;
Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J .; Couladouros,
E. A.; Paulvannan, K.; Sorensen, E. J . Nature 1994, 367, 630. (b)
Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J .;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile,
L. N.; Liu, J . H. J . Am. Chem. Soc. 1994, 116, 1597. (c) Holton, R. A.;
Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J .; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.;
Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H. J .
Am. Chem. Soc. 1994, 116, 1599. (d) Masters, J . J .; Link, J . T.; Snyder,
L. B.; Young, W. B.; Danishefsky, S. J . Angew. Chem., Int. Ed. Engl.
1995, 34, 1723.
(4) Isolation: (a) Chan, W. R.; Halsall, T. G.; Hornby, G. M.; Oxford,
A. W.; Sabel, W.; Bjåmer, K.; Ferguson, G.; Robertson, J . M. J . Chem.
Soc., Chem. Commun. 1966, 923. (b) Miyazaki, M.; Shimizu, K.;
Mishima, H.; Kurabayashi, M. Chem. Pharm. Bull. 1968, 16, 546.
(5) Synthesis: Holton, R. A.; J uo, R. R.; Kim, H. B.; Williams, A.
D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J . Am. Chem. Soc. 1988,
110, 6558.
On this basis, the retrosynthesis of 1 leads back to 2,
which was expected to result from anionic oxy-Cope
21
22
rearrangement
of 3 via a chairlike transition state
followed by direct in situ methylation (Scheme 1). In-
troduction of the E-configured bridgehead double bond
under kinetic control in this fashion would subsequently
(6) Isolation: Appendino, G.; Gariboldi, P.; Valle, M. G. Gazz. Chim.
Ital. 1988, 118, 55.
(7) Synthesis: Paquette, L. A.; Sturino, C. F.; Wang, X.; Prodger,
J . C.; Koh, D. J . Am. Chem. Soc. 1996, 118, 5620.
(8) Isolation: Raffauf, R. F.; Huang, P.-K. C.; LeQuesne, P. W.;
Levery, S. B.; Brennan, T. F. J . Am. Chem. Soc. 1975, 97, 6884.
(9) Synthesis: Boeckman, R. K., J r.; Yoon, S. K.; Heckendorn, D.
K. J . Am. Chem. Soc. 1991, 113, 9682.
(10) Review: Brown, D. S.; Paquette, L. A. Heterocycles 1992, 34,
807.
(11) Isolation: Tempesta, M. S.; Iwashita, T.; Miyamoto, F.; Yoshi-
hara, K.; Naya, Y. J . Chem. Soc., Chem. Commun. 1983, 1182.
(12) Synthetic effort: Paquette, L. A.; Hormuth, S.; Lovely, C. J . J .
Org. Chem. 1995, 60, 4813 and earlier references therein.
(13) Isolation: (a) Node, M.; Ito, N.; Fuji, K.; Fujita, E. Chem.
Pharm. Bull. 1982, 30, 2639. (b) Node, M.; Ito, N.; Uchida, I.; Fujita,
E.; Fuji, K. Chem. Pharm. Bull. 1985, 33, 1029.
(15) Isolation: (a) Mahato, S. B.; Pal, B. C.; Kawasaki, T.; Miyahara,
K.; Tanaka, O.; Yamasaki, K. J . Am. Chem. Soc. 1979, 101, 4720. (b)
Burke, B. A.; Chan, W. R.; Honkan, V. A.; Blount, J . F.; Manchand, P.
S. Tetrahedron 1980, 36, 3489.
(16) Synthesis: Paquette, L. A.; Wang, T.-Z.; Philippo, C. M. G.;
Wang, S. J . Am. Chem. Soc. 1994, 116, 3367.
(17) Weyerstahl, P.; Marschall, H.; Wahlburg, H.-C.; Kaul, V. K.
Liebigs Ann. Chem. 1991, 1353. More recently, the isolation and
characterization of a salsolene ketone has been reported: Weyerstahl,
P.; Schneider, S.; Marschall, H.; Rustaiyan, A. Liebigs Ann. Chem.
1993, 111.
(18) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers,
R. D. J . Am. Chem. Soc. 1990, 112, 277.
(19) Preliminary communication: Paquette, L. A.; Sun, L.-Q.; Wat-
son, T. J . N.; Friedrich, D.; Freeman, B. T. J . Am. Chem. Soc. 1997,
119, 2767.
(20) (a) Fattorusso, E.; Magno, S.; Mayol, L.; Amico, V.; Oriente,
G.; Piattelli, M.; Tringali, C. Tetrahedron Lett. 1978, 4149. (b)
Bohlmann, F.; Singh, P.; J akupovic, J . Phytochemistry 1982, 21, 157.
(14) Synthesis: Paquette, L. A.; Backhaus, D.; Braun, R. J . Am.
Chem. Soc. 1996, 118, 11990.
S0022-3263(97)01244-9 CCC: $14.00 © 1997 American Chemical Society

8156 J . Org. Chem., Vol. 62, No. 23, 1997
Paquette et al.
Sch em e 1
Sch em e 2
require isomerization to the Z isomer prior to arrival at
1. The ketonic precursor to 3 requires assembly via “type
I” intramolecular [2 + 2] cycloaddition23 within R,â-
unsaturated ketene 4, a highly functionalized reactive
intermediate presumed to be accessible by suitable
chemical modification of (R)-(-)-carvone (5).
Specific attention is called to the particularly signifi-
cant role which the phenylthio substituent will play at
three stages of this reaction sequence. The efficiency of
“type I” ketene-olefin cycloadditions in a criss-cross mode
is appreciably heightened when the alkene component
is nucleophilic.23,24 Accordingly, the PhS group resident
in 4 was expected to significantly enhance its suitability
as a precursor to the cyclobutanone. In addition, the
steric contributions of the PhS substituent in this pivotal
ketone precursor should clearly direct the 1,2-addition
of vinyllithium to its exo surface as in 3. Finally, the
reductive removal of this substituent has proven to be a
protocol crucial to expedient arrival at salsolene oxide.
little consequence since subsequent saponification, con-
version to the acid chloride, and dehydrochlorination with
triethylamine converge to ketene 4 in all cases. The
involvement of 4 is, of course, inferred since this inter-
mediate was not isolated but transformed directly into 9
as formed. The overall yield for the conversion of 8 into
9 was 57%. This level of efficiency is notable for such
reactions.
With arrival at 9, the time had come to incorporate a
vinyl group stereoselectively as a prelude to the sigma-
tropic event. As expected, the strain inherent in 1,2-
divinylcyclobutanoxide 10 promoted rapid conversion to
enolate anion 11 under the reaction conditions (Scheme
3). This electronic reorganization can be relied upon to
proceed stereoselectively22 and to set the geometry of the
bridgehead double bond as shown. Direct methylation
of 11 with excess methyl iodide afforded ketone 2.
Resu lts a n d Discu ssion
At the outset, advantage was taken of the efficient
manner in which bromo ester 6 can be produced from
(R)-(-)-carvone (5).25 Dibal-H reduction of 6 at -78 °C
provided the aldehyde, condensation of which with
thiophenol in the presence of TiCl4 and Et3N afforded a
mixture of vinyl sulfides 7 rich in the E isomer (E:Z )
7:3) (Scheme 2). The predominance of the E form holds
considerable importance since trans-substituted olefins
undergo predominantly the requisite trans addition while
cis olefins react nonstereospecifically if at all.23 Submis-
sion of 7 to the Finkelstein reaction by heating with
sodium iodide in acetone and subsequent exposure of the
iodide to the enolate anion of methyl crotonate at -78
°C gave 8 (72%) as a mixture of R,â- and â,γ-unsaturated
isomers. The generation of a mixture at this point is of
The 1H NMR features of 2 are well resolved and readily
amenable to assignment on the basis of a DQF-COSY
analysis, which allowed to trace the entire atomic con-
nectivity. In particular, allylic coupling (J ) 3 Hz)
between H-5 and H-11R established the connection
between these two fragments. Similarly, homoallylic
coupling between H-4R and the downfield methine at δ
4.33 showed that C-7 was likewise attached to the double
bond. The relative stereochemistry and preferred con-
formation shown were deduced from the magnitudes of
the vicinal and long-range coupling constants and cor-
roborated by difference NOE experiments (see Support-
ing Information).
The response of 2 to Raney nickel desulfurization was
next examined. The intended reduction proceeded
smoothly in refluxing acetone. To reduce volatility and
facilitate characterization, the resulting ketone was
reduced with lithium aluminum hydride, and a single
alcohol was obtained in 55% overall yield. Quite unex-
pectedly, this compound was not the anticipated product
but an isomer in which the bridgehead double bond had
migrated to the alternative bridgehead site as in 12. Due
to slow conformational exchange, most of the resonances
in the 400 MHz 1H NMR spectrum of 12 appeared broad
and extensively overlapped under ordinary conditions in
(21) (a) Hill, R. K. In Asymmetric Synthesis, Vol. 3A; Morrison, J .
D., Ed.; Academic Press: London, 1984; p 503. (b) Hill, R. K. In
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1990; Chapter 7.1. (c) Wilson, S. R.
Org. React. 1993, 43, 93. (d) Paquette, L. A. Synlett 1990, 67. (e)
Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(22) (a) Snider, B. B.; Allentoff, A. J .; Walner, M. B. Tetrahedron
1990, 46, 8031. (b) Snider, B. B.; Allentoff, A. J . J . Org. Chem. 1991,
56, 321. (c) Zucker, P. A.; Lupia, J . A. Synlett 1990, 729.
(23) Snider, B. B. Chem. Rev. (Washington, D.C.) 1988, 88, 793.
(24) Snider, B. B.; Walner, M. Tetrahedron 1989, 45, 3171.
(25) Paquette, L. A.; Dahnke, K.; Doyon, J .; He, W.; Wyant, K.;
Friedrich, D. J . Org. Chem. 1991, 56, 6199.

PhS as a Multipurpose Synthetic Tool
J . Org. Chem., Vol. 62, No. 23, 1997 8157
Sch em e 3
Sch em e 4
are not identical. The close similarity of their 13C NMR
features indicated, however, that they were closely
related structurally. The connectivity in 13, identified
by careful examination of its COSY spectrum, is confir-
matory of its direct formation from 12 with steric ap-
proach control. The Z geometry of its double bond was
assigned on the basis of the strong NOE interaction
indicated in Scheme 3. Telltale vicinal coupling con-
stants such as those for H-7/H-8R, H-9/H-8R, H-9/H-10
(all close to zero), H-7/H-8â (3.5 Hz), and H-9/H-8â (7.5
Hz) indicate further that the six-membered ring adopts
a boatlike conformation. This conclusion is supported by
the observation of W-coupling involving H-9 and one of
the methylene bridge protons (see Supporting Informa-
tion).
As undesirable as the 2 f 12 structural change was,
it may well represent a unique example of an isomeriza-
tion involving the conversion of one bridgehead olefin into
another.
C6D6 solution. The situation improved to some degree
upon warming to 65 °C, but interpretation of the DQF-
COSY spectrum remained ambiguous. Severe exchange
broadening of many resonances surfaced as well in the
13C arena, thereby precluding the recording of a carbon-
detected 1H,13C one-bond correlation spectrum. However,
In 1980, Naruta demonstrated the feasibility of pre-
paring polyprenyl alcohols by reductive elimination of
allylic phenylthio groups with lithium metal in ethyl-
amine.27 Direct application of these conditions to 2
resulted in the formation of alcohol 15 in 74% yield
(Scheme 4). Although the exact stereochemistry of this
tricyclic alcohol was not determined, its formation was
clearly a result of the close proximity of the carbonyl
group and allylic anion in 14, which lends itself very
favorably to transannular bonding across the eight-
membered ring.
This problem was easily skirted by delaying desulfuri-
zation until after reduction of the carbonyl group (Scheme
5). That hydride delivery to 2 occurs from the equatorial
direction as anticipated on steric grounds was easily
deduced in several ways. The most convincing evidence
is the absence of a resolved vicinal coupling between the
protons on the carbinol carbon and the adjacent methyl-
substituted center. A 90° angular relationship is respon-
sible for the lack of spin-spin interaction.
1
these problems could be overcome by recording a H,13C-
HMQC spectrum in DMSO-d6 at ambient temperature.
Complete assignments of shifts and multiplicities now
became possible, because in this proton-detected tech-
nique the intensities of the cross peaks correlating 13C
1
with directly connected H nuclei depend chiefly on the
line width of the proton rather than the corresponding
carbon. Consequently, strong cross-peaks are observed
for 13C/1H pairs when the 1H resonance is sharp, even
when the corresponding 13C resonance is approaching
coalescence and can barely be localized in the 13C
spectrum. As a corollary, a weak cross-peak results for
a broad 1H resonance despite the existence of a sharp
correlated 13C resonance but can nevertheless be detected
due to the significantly higher sensitivity of the proton-
detected techinque. Through combination of the assign-
ments of methylene vs methine protons from the HMQC
1
spectrum with the H,1H coupling information from the
The reduction of 16 with lithium in ethylamine at -78
°C proceeded cleanly to deliver a single alcohol in 80%
yield. To simplify structural analysis, conversion to the
acetate preceded detailed NMR analysis. Remarkably,
this dissolving-metal protocol proceeds with inversion of
bridgehead olefin geometry precisely as mandated by the
DQF-COSY spectra, it was possible to trace the entire
connectivity of 12.
As a follow-up, 12 was epoxidized with dimethyldi-
oxirane and dehydrated with the Martin sulfurane
1
reagent.26 Comparison of the H NMR spectra of 13 and
salsolene oxide clearly showed that the two compounds
1
target terpenoid! The H NMR spectra of 18 in CDCl3 or
(26) Martin, J . C.; Arhart, R. J . J . Am. Chem. Soc. 1971, 93, 4327.
(27) Naruta, Y. J . Org. Chem. 1980, 45, 4097.

8158 J . Org. Chem., Vol. 62, No. 23, 1997
Paquette et al.
Sch em e 5
Ch a r t 1. Globa l Min im u m En er gy Con for m a tion s
of 21 a n d 22 As Deter m in ed by Molecu la r
Mech a n ics Ca lcu la tion s (Ch em 3-D Ou tp u t). All
En er gies Ar e in Un its of k ca l/m ol
DMSO-d6 at 25 °C exhibited considerable overlap, and
the broad appearance of several resonances suggested
that slow conformational exchange was operating. Vari-
tert-butylbiphenylide,29 lithium triethylborohydride,30 and
sodium borohydride in the presence of nickel chloride.31
For completion of the salsolene oxide synthesis, epoxi-
dation must be directed to take place on the exo surface
of the π-bond. This was not viewed as problematic.
Indeed, the reaction of 18 with m-chloroperbenzoic acid
gave rise to 19 in near-quantitative yield. Perhaps
because of an innate sensitivity to acidic conditions,
comparable treatment of alcohol 17 eventuated predomi-
nantly in decomposition.
1
able temperature H NMR studies conducted in DMSO-
d6 at 75, 100, and 125 °C were confirmatory of this
conclusion. For these reasons, the proton connectivities
observed in a DQF-COSY spectrum recorded at 25 °C
were ambiguous in part. Furthermore, 13C NMR spectra
obtained at 25 °C showed several exchange-broadened
resonances, and the complete set of 17 resonances
surfaced only upon heating to 125 °C in DMSO-d6.
However, all 13C resonances could be localized in proton-
detected HMQC (one-bond) and HMBC (multiple-bond)
1H,13C shift-correlation spectra obtained at 25 °C. The
information contained in these spectra, in conjunction
with the DQF-COSY spectrum, permitted derivation of
all 1H and 13C assignments and confirmation of the
constitution of the acetoxyalkene to be as shown in 18
(see Supporting Information). Assignment of olefin
geometry and relative stereochemistry is based on a
variety of NOE enhancements including those shown in
Scheme 5.
Following arrival at 19, it proved an easy matter to
cleave the acetate group by chemoselective reduction,
without opening of the oxirane ring. This is because
nucleophilic attack from the backside of either C-O bond
is very effectively deterred by the steric bulk of the
molecular framework. Dehydration of 20 with the Mar-
tin sulfurane reagent26 in benzene at 50 °C once again
resulted in the introduction of a Z double bond to deliver
salsolene oxide (1). This volatile substance proved to be
1
identical with the natural specimen by high-field H and
13C NMR spectroscopy. The synthetic sample exhibited
Molecular mechanics calculations28 were undertaken
to shed light on the thermodynamic relationship between
bridgehead olefin isomers of this type. The data com-
puted for enones 21 and 22, compiled in Chart 1,
indicated the Z isomer to be more stable by ca. 14 kcal/
mol. This stability ordering, which carries over to
derivatives such as 17 and 18, indicates that the original
anionic oxy-Cope rearrangement had necessarily to have
proceeded via a chairlike transition state under kinetic
control.
The ability to accomplish isomerization of the double
bond in 16 from E to Z during transient generation of
the allylic anion suggested itself on several fronts. In
particular, loss of stereocontrol has been reported for the
reduction of allyl phenyl sulfides with lithium p,p′-di-
an [R]22 of -24° (c 0.2, CHCl3). Since optical rotation
D
data on the material produced by nature is not available,
an open question remains as to whether the absolute
configuration defined by 1 is correct. Suffice it to say
that 1 is definitely levorotatory.
A concise synthesis of (-)-salsolene oxide has been
described. A phenylthio-substituted double bond in
unsaturated ketene 4 provides the proper electronic
balance to permit intramolecular cyclization and forma-
tion of 9. The phenylthio group in 9 directs entry of the
vinyl anion, setting the stage for an anionic oxy-Cope
(29) McCullough, D. W.; Bhupathy, M.; Piccolino, E.; Cohen, T.
Tetrahedron 1991, 47, 9727 and relevant references therein.
(30) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H.; Takagaki,
H.; Yamazaki, K. Chem. Lett. 1986, 1177.
(28) MODEL version 2.99 obtained from Prof. K. Steliou was used.
We thank Dr. Scott Edmondson for these data.
(31) Palmisano, G.; Danieli, B.; Lesma, G.; Mauro, M. J . Chem. Soc.,
Chem. Commun. 1986, 1564.

PhS as a Multipurpose Synthetic Tool
J . Org. Chem., Vol. 62, No. 23, 1997 8159
2.60 (dt, J ) 7.2, 9.1 Hz, 0.7 H), 2.46-2.40 (m, 0.3 H), 1.84-
1.74 (m, 1 H), 1.63-1.16 (series of m, 2.7 H), 0.80 (d, J ) 6.8
Hz, 0.9 H), 0.73 (d, J ) 6.8 Hz, 0.9 H), 0.68 (d, J ) 6.8 Hz, 2.1
H), 0.61 (d, J ) 6.8 Hz, 2.1 H); 13C NMR (75 MHz, CDCl3)
ppm 136.0, 135.8, 135.6, 133.1, 128.8, 128.7, 128.3, 126.0,
125.9, 125.7, 123.4, 50.4, 46.6, 37.0, 35.2, 31.8, 31.4, 20.5, 20.4,
19.0, 18.8, 5.8, 4.2; MS m/z (M+) calcd 346.0252, obsd 346.0268.
Anal. Calcd for C14H19IS: C, 48.56; H, 5.53. Found: C,
48.88; H, 5.72.
rearrangement that assembles the desired terpenoid
framework readily. The triple-threat role of the phen-
ylthio functionality surfaces finally during the dissolving-
metal reduction of 16, which is accompanied by necessary
inversion of the bridgehead double-bond geometry. These
tactical elements hold promise for application in other
synthetic undertakings.
Iod id e Alk yla tion w ith Meth yl Cr oton a te. A cold (0 °C),
magnetically stirred solution of LDA (37.2 mmol) in THF (125
mL) was treated with dry HMPA (6.48 mL, 37.2 mmol) and
stirred for 1.5 h prior to cooling to -78 °C. Methyl crotonate
(3.99 mL, 37.7 mmol) was introduced dropwise during 20 min
followed by a solution of the iodides (13.3 g, 38.4 mmol) in THF
(100 mL). Stirring was maintained at -78 °C for 2 h and at
0 °C for 30 min prior to quenching with water (200 mL) and
extraction with ether (300 mL). The organic phase was dried
and evaporated, and the residue was purified chromatographi-
cally on silica gel (elution with 5% ethyl acetate in hexanes).
There was isolated 8.95 g (72%) of 8 as a very pale yellow oil.
Exp er im en ta l Section
All reactions were performed in a flame-dried glass ap-
paratus equipped with rubber septa under a static nitrogen
or argon atmosphere. Thin-layer chromatography was per-
formed on EM Reagents precoated silica gel 60 F254 analytical
plates. Column chromatography was performed on Merck
silica gel HG254. The organic extracts were dried over anhy-
drous magnesium sulfate or sodium sulfate. Solvents were
reagent grade and in many cases dried before use. High-
resolution mass spectra were recorded at The Ohio State
University Chemical Instrumentation Center. Elemental
analyses were performed at the Scandinavian Microanalytical
Laboratory, Herlev, Denmark, and at Atlantic Microlab, Inc.,
Norcross, GA.
1
F or th e r,â isom er s: IR (neat, cm-1
) 1714; H NMR (300
MHz, C6D6) δ 7.45-7.41 (m, 1.4 H), 7.36-7.33 (m, 0.6 H),
7.11-6.86 (m, 4 H), 6.29 (d, J ) 9.4 Hz, 0.3 H), 6.16 (d, J )
15.0 Hz, 0.7 H), 5.86 (dd, J ) 15.0, 9.4 Hz, 0.7 H), 5.58 (dd, J
) 10.0, 9.6 Hz, 0.3 H), 3.50 (s, 0.9 H), 3.48 (s, 2.1 H), 2.73-
2.25 (series of m, 2 H), 1.87-1.29 (m, 4 H), 1.53 (d, J ) 7.1
Hz, 0.9 H), 1.49 (d, J ) 7.1 Hz, 2.1 H), 1.00 (d, J ) 6.8 Hz, 0.9
H), 0.94 (d, J ) 6.8 Hz, 0.9 H), 0.86 (d, J ) 6.8 Hz, 2.1 H),
(1E,3S)- a n d (1Z,3S)-5-Br om o-3-isop r op yl-1-p en t en yl
P h en yl Su lfid e (7). A solution of bromo ester 625 (31.86 g,
126.0 mmol, 98% ee) in CH2Cl2 (750 mL) was cooled to -78
°C, treated with Dibal-H in toluene (139 mL of 1.0 M in
toluene, 139 mmol) during 30 min, stirred at this temperature
for 2 h, and quenched with methanol (15 mL). The reaction
mixture was allowed to warm to 20 °C and treated with 10%
HCl solution. The separated organic layer was washed with
a saturated NaHCO3 solution (500 mL) and brine (500 mL),
dried, and evaporated to give the bromo aldehyde as a yellow
oil (26.0 g, 99%); IR (neat, cm-1) 1725; 1H NMR (200 MHz,
CDCl3) δ 9.78 (t, J ) 2.1 Hz, 1 H), 3.49-3.30 (m, 2 H), 2.45
(ddd, J ) 16.4, 5.6, 2.0 Hz, 1 H), 2.26 (ddd, J ) 16.4, 5.0, 2.1
Hz, 1 H), 2.18-1.67 (series of m, 4 H), 0.99 (d, J ) 5.8 Hz, 3
H), 0.86 (d, J ) 5.8 Hz, 3 H); 13C NMR (50 MHz, CDCl3) ppm
202.2, 44.8, 37.0, 34.7, 31.5, 29.7, 19.4, 18.3; MS m/z (M+) calcd
0.81 (d, J ) 6.8 Hz, 2.1 H);
13C NMR (75 MHz, CDCl3) ppm
168.2, 138.7, 137.3, 137.2, 135.8, 133.4, 133.3, 128.9, 128.7,
128.6, 126.0, 124.1, 122.0, 51.6, 51.5, 50.2, 45.9, 32.1, 31.8, 31.3,
24.8, 24.7, 20.8, 20.6, 19.0, 18.8, 14.2, 14.1; MS m/z (M+) calcd
318.479, obsd 318.165.
Anal. Calcd for C19H26O2S: C, 71.66; H, 8.23. Found: C,
71.87; H, 8.39.
(1R,4S,5R,7S)-4-Isopr opyl-7-(ph en ylth io)-1-vin ylbicyclo-
[3.1.1]h ep ta n -6-on e (9). A mixture of 8 (701 mg, 2.2 mmol)
and potassium hydroxide (850 mg, 13.2 mmol) in methanol
(10 mL) and water (10 mL) was refluxed for 2 days. The
methanol was removed under reduced pressure, and the
residue was carefully neutralized at 0 °C with 3 N HCl. The
acid was extracted into ether, washed with brine, dried, and
concentrated to leave 660 mg of material that was directly
dissolved in benzene (30 mL) and treated dropwise with oxalyl
chloride (1.06 mL, 13.2 mmol). This mixture was stirred for
1 h at 55 °C and for 15 h at 20 °C. The solvent was evaporated,
and the acid chloride was taken up in benzene (30 mL), treated
with triethylamine (4 mL, 31 mmol), and refluxed for 10 h
under N2. The solvents were removed, and the residue was
purified by MPLC on silica gel (elution with 2% ethyl acetate
in hexanes) to give 250 mg (57% based on original Z content)
206.0306, obsd 206.0263; [R]25 -19.1 (c 1.6, hexanes).
D
A solution of titanium tetrachloride (13.1 mL, 0.12 mol) in
dry 1,2-dimethoxyethane (250 mL) was added to a solution of
the above aldehyde (12.32 g, 59.5 mmol) in the same medium
(50 mL) over 10 min at 0 °C under N2. After 10 min, a solution
of thiophenol (6.76 g, 65.5 mmol) and triethylamine (9.12 mL,
65.5 mmol) in DME (50 mL) was added over 20 min. The
resulting mixture was stirred at room temperature for 3 days,
quenched with methanol (100 mL), concentrated in vacuo, and
taken up in ether (600 mL). The ethereal solution was washed
with brine, dried, and subjected to flash chromatography on
silica gel. Elution with 10% ethyl acetate in hexanes gave 12.0
g of sulfide 7 (E:Z ) 7:3) and returned 3.0 g of unreacted
aldehyde. The adjusted yield of 7 is 89%.
1
of 9 as a pale yellow oil; IR (neat, cm-1) 1783; H NMR (300
MHz, CDCl3) δ 7.37-7.20 (m, 5 H), 5.81 (dd, J ) 17.6, 11.9
Hz, 1 H), 5.43 (dd, J ) 17.6, 1.4 Hz, 1 H), 5.25 (dd, J ) 11.9,
1.4 Hz, 1 H), 3.92 (s, 1 H), 2.95 (s, 1 H), 2.43-2.36 (m, 1 H),
2.29-2.19 (m, 1 H), 2.07-2.02 (m, 1 H), 1.77-1.50 (m, 3 H),
0.81 (d, J ) 6.7 Hz, 3 H), 0.62 (d, J ) 6.7 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 211.4, 134.4, 132.6, 131.2, 128.9, 127.0,
118.4, 69.3, 64.9, 50.9, 42.0, 36.9, 32.6, 20.9, 20.0, 19.7; MS
1
F or 7: IR (neat, cm-1) 1590; H NMR (300 MHz, C6D6) δ
7.34-7.22 (m, 2 H), 7.05-6.89 (m, 3 H), 6.13 (d, J ) 9.3 Hz,
0.3 H), 6.06 (d, J ) 15.0 Hz, 0.7 H), 5.40 (dd, J ) 15.0, 9.9 Hz,
0.7 H), 5.05 (t, J ) 9.9 Hz, 0.3 H), 3.20-2.87 (series of m, 2
H), 2.55-2.49 (m, 0.3 H), 1.94-1.74 (m, 1 H), 1.64-1.18 (m,
2.7 H), 0.80 (d, J ) 6.8 Hz, 0.9 H), 0.73 (d, J ) 6.8 Hz, 0.9 H),
0.69 (d, J ) 6.8 Hz, 2.1 H), 0.62 (d, J ) 6.8 Hz, 2.1 H); 13C
NMR (75 MHz, CDCl3) ppm 136.2, 136.0, 135.9, 133.4, 128.9,
128.6, 126.3, 126.2, 125.8, 123.7, 48.4, 44.7, 36.1, 34.8, 32.4,
32.1, 31.8, 31.7, 20.6, 20.5, 19.1, 19.0; MS m/z (M+) calcd
298.0391, obsd 298.0388.
m/z (M+) calcd 286.1391, obsd 286.1388; [R]23 +29.7 (c 2.25,
D
CHCl3).
Anal. Calcd for C18H22OS: C, 75.48; H, 7.74. Found: C,
75.38; H, 7.87.
(1R,3S,6E,10S,11S)-10-Isop r op yl-3-m eth yl-11-(p h en yl-
th io)bicyclo[5.3.1]u n d ec-6-en -2-on e (2). To tributylvinyltin
(190 mg, 0.60 mmol) dissolved in dry THF (3 mL) at -78 °C
was added a solution of 2.5 M n-butyllithium in hexanes (0.22
mL, 0.55 mmol). The mixture was stirred for 15 min, and a
solution of 9 (143 mg, 0.50 mmol) in THF (0.3 mL) was added.
The reaction mixture was stirred at -78 °C for 2 h, warmed
to room temperature, and quenched with methyl iodide (1 mL).
The mixture was extracted with ethyl acetate (15 mL) and
washed with water (2 × 15 mL). The ethereal layer was dried,
filtered, and concentrated to leave a residue which was
chromatographed on silica gel (elution with 5% ethyl acetate/
(1E,3S)- a n d (1Z,3S)-5-Iod o-3-isop r op yl-1-p en t en yl
P h en yl Su lfid e. A mixture of 7 (10.25 g, 34.3 mmol), sodium
iodide (7.80 g, 52.0 mmol), and acetone (220 mL) was refluxed
for 15 h, freed of solvent under reduced pressure, taken up in
ether (300 mL), and washed with water (2 × 300 mL). The
ethereal solution was dried and evaporated to furnish 11.28 g
(95%) of iodides (E:Z ) 7:3) as a yellow oil: IR (neat, cm-1
)
1
1475; H NMR (300 MHz, C6D6) δ 7.41-7.18 (m, 2 H), 7.11-
6.88 (m, 3 H), 6.13 (d, J ) 9.2 Hz, 0.3 H), 6.09 (d, J ) 15.0 Hz,
0.7 H), 5.37 (dd, J ) 15.0, 9.9 Hz, 0.7 H), 5.03 (t, J ) 9.9 Hz,
0.3 H), 2.95 (dt, J ) 4.9, 9.5 Hz, 0.3 H), 2.86-2.75 (m, 1 H),

8160 J . Org. Chem., Vol. 62, No. 23, 1997
Paquette et al.
hexanes) to furnish 131 mg (80%) of 2 as a colorless oil: IR
mmol) in THF (1 mL) was introduced. After 10 min, the
reaction mixture was quenched by the addition of solid NH4-
Cl and the ethylamine was allowed to evaporate overnight.
The residue was taken up in ether (20 mL) and washed with
water (20 mL), the separated aqueous layer was extracted with
ether (2 × 20 mL), and the ethereal layers were combined,
dried, filtered, and evaporated. Chromatography of the prod-
uct on Florisil delivered 3.5 mg (74%) of 15 as a white
crystalline solid: IR (neat, cm-1) 3600; 1H NMR (300 MHz,
C6D6) δ 2.30-2.22 (m, 1 H), 2.12-1.96 (m, 3 H), 1.93-1.84
(m, 1 H), 1.74-1.20 (series of m, 12 H), 0.90 (d, J ) 6.6 Hz, 3
H), 0.89 (d, J ) 6.5 Hz, 3 H), 0.86 (d, J ) 6.6 Hz, 3 H); 13C
NMR (75 MHz, C6D6) ppm 92.5, 59.2, 46.9, 42.2, 37.9, 36.2,
35.7, 34.9, 29.6, 25.0, 24.2, 22.6, 21.3, 21.0, 13.8; MS m/z (M+)
1
(neat, cm-1) 1689; H NMR (400 MHz, C6D6) δ 7.46 (m, 2 H),
7.02 (m, 2 H), 6.91 (m, 1 H), 6.21 (br ddd, J ) 12, 4, 3 Hz, 1
H), 4.33 (br s, 1 H), 2.86 (br s, 1 H), 2.73 (dddd, J ) 17, 12,
7.5, 1 Hz, 1 H), 2.59 (br ddq, J ) 11.5, 1.5, 7 Hz, 1 H), 2.20
(dddd, J ) 12.5, 12.5, 12, 4.5 Hz, 1 H), 2.04 (br m, 1 H), 2.02
(dddd, J ) 13, 12, 11.5, 4.5 Hz, 1 H), 1.82 (br ddd, J ) 12.5,
4.5, 4 Hz, 1 H), 1.76 (br ddd, J ) 11.5, 7.5, 6.5 Hz, 1 H), 1.51-
1.32 (m, 3 H), 1.18 (dqq, J ) 6.5, 6.5, 6.5 Hz, 1 H), 0.81 (d, J
) 7 Hz, 3 H), 0.60 (d, J ) 6.5 Hz, 3 H), 0.59 (d, J ) 6.5 Hz, 3
H); 13C NMR (75 MHz, CDCl3) ppm 216.3, 137.9, 136.4, 129.8,
128.8, 126.0, 123.9, 62.2, 54.4, 41.7, 40.9, 40.2, 33.3, 27.5, 27.2,
23.1, 19.6, 19.1, 18.6; MS m/z (M+) calcd 328.8661, obsd
328.1866; [R]23 -16.5 (c 0.75, CHCl3).
D
calcd 222.1977, obsd 222.1982; [R]25 -20.7 (c 0.01, CHCl3).
Anal. Calcd for C21H28OS: C, 76.78; H, 8.59. Found: C,
76.40; H, 8.56.
D
(1R,2S,3S,6E,10S,11S)-10-Isop r op yl-3-m eth yl-11-(p h en -
ylth io)bicyclo[5.3.1]u n d ec-6-en -2-ol (16). To a solution of
2 (32 mg, 0.098 mmol) in dry THF (20 mL) at -78 °C was
added lithium aluminum hydride (35 mg, 0.92 mmol). The
reaction mixture was stirred for 10 min, quenched with water
(15 mL), and filtered. The aluminum salts were washed with
ethyl acetate (3 × 20 mL), and the filtrate was washed with
water (50 mL). The separated organic layer was dried and
evaporated to yield 31 mg (96%) of 16 as a colorless oil: IR
(1R,2S,3S,7Z,10S)-10-Isop r op yl-3-m eth ylbicyclo[5.3.1]-
u n d ec-7-en -2-ol (12). Raney nickel (200 mg, previously
stored in ethanol) was refluxed in acetone (15 mL) for 15 min,
treated with 2 (50 mg, 0.15 mmol), and heated until TLC
analysis indicated that no starting material remained. The
reaction mixture was cooled, filtered through Celite (ethyl
acetate rinse), washed with water (2 × 40 mL), dried, and
concentrated to leave a ketone that was directly reduced.
1
A cold (-78 °C), magnetically stirred slurry of lithium
aluminum hydride (50 mg, 1.35 mmol) in dry THF (30 mL)
was treated with a solution of the above ketone in THF (5 mL),
allowed to warm to room temperature, quenched with water,
and filtered. The aluminum salts were triturated with ethyl
acetate (3 × 50 mL), and the filtrate was washed with water
(100 mL). The organic layer was dried and evaporated. The
residue was purified by MPLC on silica gel (elution with 7%
ethyl acetate in hexanes) to give 12 (18 mg, 55%) as a clear
oil that decomposed on prolonged standing at room tempera-
(neat, cm-1) 3462; H NMR (300 MHz, C6D6) δ 7.46 (dd, J )
8.2, 1.0 Hz, 2 H), 7.06-7.03 (m, 2 H), 6.95-6.89 (m, 1 H), 6.28
(d, J ) 12 Hz, 1 H), 4.08 (s, 1 H), 3.40 (dd, J ) 9.4, 5.5 Hz, 1
H), 2.79-2.61 (m, 2 H), 2.49 (d, J ) 9.5 Hz, 1 H), 2.39 (dq, J
) 4.0, 12.3 Hz, 1 H), 2.12-1.76 (m, 4 H), 1.45-1.27 (m, 3 H),
1.16-1.02 (m, 2 H), 0.97 (d, J ) 7.2 Hz, 3 H), 0.62 (d, J ) 6.4
Hz, 3 H), 0.61 (d, J ) 6.7 Hz, 3 H); 13C NMR (75 MHz, C6D6)
ppm 137.8, 137.1, 130.7, 129.1, 126.5, 123.9, 82.2, 53.8, 52.3,
42.4, 38.0, 33.6, 33.2, 29.0, 27.7, 27.3, 23.1, 19.5, 19.0; MS m/z
(M+) calcd 330.2010, obsd 330.2014.
1
ture: IR (neat, cm-1) 3382; H NMR (400 MHz, C6D6, 65 °C)
(1R,2S,3S,6Z,10S)-10-Isop r op yl-3-m eth ylbicyclo[5.3.1]-
u n d ec-6-en -2-ol (17) a n d Aceta te (18). To ethylamine (1.5
mL) at -78 °C was added lithium metal (10 mg, 1.44 mmol).
The mixture was warmed to 0 °C until a blue color persisted
and then recooled to -78 °C. A solution of 16 (7 mg, 0.021
mmol) in THF (1 mL) was added. After 10 min, the reaction
mixture was quenched with solid NH4Cl and the ethylamine
was allowed to evaporate overnight. The resulting mixture
was taken up in ether (20 mL) and washed with water (20
mL). The separated aqueous layer was extracted with ether
(2 × 20 mL), and the combined ethereal layers were dried and
evaporated. Chromatography of the residue on Florisil (elution
with 2% ethyl acetate in hexanes) afforded 4 mg (80%) of 17
as a crystalline solid: IR (neat, cm-1) 3513; 1H NMR (300 MHz,
C6D6) δ 5.33 (t, J ) 7.5 Hz, 1 H), 3.65 (d, J ) 7.2 Hz, 1 H),
2.64 (d, J ) 12.4 Hz, 1 H), 2.42-2.27 (m, 1 H), 2.20-2.05 (m,
1 H), 2.00-1.83 (m, 3 H), 1.80-1.15 (m, 9 H), 1.07 (d, J ) 7.5
Hz, 3 H), 0.89 (d, J ) 6.7 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H);
the 13C NMR spectrum (75 MHz, C6D6) exhibited broadened
peaks; those peaks that were discernible under ordinary
conditions appear at 141.2, 121.0, 75.7, 46.0, 42.9, 35.9, 32.6,
30.2, 28.1, 26.4, 23.4, 21.5 ppm; MS m/z (M+) calcd 222.1977,
δ 5.57 (m, 1 H), 3.22 (br s, 1 H), 2.44 (br d, J ) 12.5 Hz, 1 H),
2.24 (ddd, J ) 12.5, 5.0, 4.5 Hz, 1 H), 1.99 (ddd, J ) 14, 7.5,
6 Hz, 1 H), 1.98-1.58 (series of m, 7 H), 1.49 (dqq, J ) 6.5,
6.5, 6.5 Hz, 1H), 1.39 (m, 1 H), 1.11 (br m, 1 H), 0.92 (m, 1 H),
0.90 (d, J ) 7 Hz, 3 H), 0.87 (d, J ) 6.5 Hz, 3 H), 0.84 (d, J )
6.5 Hz, 3 H), 0.81 (br s, 1 H); 13C NMR (100 MHz, DMSO-d6,
25 °C) ppm 142.4, 121.4, 78.0,* 44.1,* 43.1, 35.6, 33.4,* 32.5,
30.8,* 28.4, 27.9, 26.0, 25.6,* 20.4, 19.7 (asterisked carbons
are near coalescence, chemical shifts extracted from HMQC
spectrum); MS m/z (M+) calcd 222.1984, obsd 222.1985.
(1R,2Z,7R,8S,10S)-7,8-Ep oxy-10-isop r op yl-3-m eth ylbi-
cyclo[5.3.1]u n d ec-2-en e (13). Alcohol 12 (8.0 mg, 0.036
mmol) was dissolved in acetone (1 mL), cooled to -78 °C,
treated with 10 equiv of a dimethyldioxirane solution in
acetone,32 and allowed to warm to room temperature. The
reaction mixture was concentrated under reduced pressure,
the residue was dissolved in benzene (1 mL), and this solution
was added to Martin’s sulfurane (50 mg) dissolved in benzene.
This reaction mixture was stirred at 20 °C for 6 h, quenched
with saturated NaHCO3 solution, extracted with ether (3 ×
20 mL), and concentrated. The residue was subjected to MPLC
on silica gel (elution with 2% ethyl acetate in hexanes) and
gave 8.0 mg (95%) of 13 as a stable colorless oil: 1H NMR (300
MHz, CDCl3) δ 4.96 (br s, 1 H), 2.72 (br d, J ) 3.5 Hz, 1 H),
2.66 (br dd, J ) 12.5, 12 Hz, 1 H), 2.41 (br s, 1 H), 2.36 (br dd,
J ) 15.5, 3 Hz, 1 H), 2.05 (m, 1 H), 2.00 (br d, J ) 16 Hz, 1 H),
1.89 (m, 1 H), 1.86 (br dd, J ) 15.5, 3 Hz, 1 H), 1.82 (ddd, J )
16, 7.5, 3.5 Hz, 1 H), 1.75 (dd, J ) 2, 1 Hz, 3 H), 1.68 (dqq, J
) 10.5, 6.5, 6.5 Hz, 1 H), 1.42-1.25 (m, 2 H), 1.20 (br dd, J )
12.5, 5 Hz, 1 H), 0.99 (m, 1 H), 0.91 (d, J ) 6.5 Hz, 3 H), 0.80
(d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 134.8,
129.2, 59.2, 56.9, 44.3, 37.0, 34.0, 29.8, 29.4, 28.4 (2 C), 24.5,
22.7, 21.9, 21.0; MS m/z (M+) calcd 220.1827, obsd 220.1816.
obsd 222.1985; [R]25 +12.5 (c 0.8, CHCl3).
D
A solution of 17 (44 mg, 0.20 mmol) in pyridine (0.3 mL)
and acetic anhydride (0.2 mL) was stirred overnight and
evaporated. The residue was dissolved in ethyl acetate,
washed with brine, dried, concentrated, and purified by flash
chromatography on silica gel. Elution with 10% ethyl acetate
in hexanes gave 52 mg (98%) of 18: IR (neat, cm-1) 1731, 1368,
1245; 1H NMR (400 MHz, CDCl3) δ 5.40 (br dd, J ) 8, 7 Hz, 1
H), 5.14 (br d, J ) 9 Hz, 1 H), 2.64 (br d, J ) 12.5 Hz, 1 H),
2.32 (dddd, J ) 14, 13, 8, 2.5 Hz, 1 H), 2.14 (m, 1 H), 2.10 (m,
1 H), 2.07 (m, 1 H), 2.00 (s, 3 H), 1.99 (dddd, J ) 12, 4.5, 4, 2
Hz, 1 H), 1.86 (dqq, J ) 9.5, 6.5, 6.5 Hz, 1 H), 1.82 (dd, J )
12.5, 4 Hz, 1 H), 1.82 (m, 1 H), 1.78 (ABm, 2 H), 1.74 (br m, 1
H), 1.67 (br m, 1 H), 1.13 (br d, J ) 7.5 Hz, 3 H), 0.94 (m, 1
H), 0.94 (d, J ) 6.5 Hz, 3 H), 0.91 (d, J ) 6.5 Hz, 3 H); 13C
NMR (100 MHz, DMSO-d6, 125 °C) ppm 169.3, 139.6, 120.3,
77.5, 41.7, 41.6, 36.1 (br), 34.3, 31.2, 27.1, 25.7, 25.0, 22.0, 20.5,
20.4, 20.2, 13.7 (br); (MS m/z (M+) calcd 264.2089, obsd
(3S,4R,5S,8R)-Octah ydr o-5-isopr opyl-3-m eth yl-4,8-m eth -
a n oa zu len -3a (1H)-ol (15). Lithium metal (10 mg, 1.44
mmol) was added to ethylamine (1.5 mL) at -78 °C, the
mixture was warmed to 0 °C until a blue color persisted, and
following recooling to -78 °C, a solution of 2 (7 mg, 0.021
(32) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91.
264.2101; [R]22 112.7 (c 0.66, ethyl acetate).
D

PhS as a Multipurpose Synthetic Tool
J . Org. Chem., Vol. 62, No. 23, 1997 8161
(1R,2S,3S,6R,7S,10S)-6,7-Ep oxy-10-isop r op yl-3-m eth yl-
bicyclo[5.3.1]u n d eca n -2-ol Aceta te (19). A suspension of
18 (61 mg, 0.23 mmol) and sodium carbonate (97 mg, 1.15
mmol) in CH2Cl2 (5 mL) was treated with m-chloroperbenzoic
acid (176 mg, 0.92 mmol), stirred for 5 h, and quenched with
water. The separated aqueous phase was extracted with ether,
and the combined organic layers were washed with brine,
dried, and concentrated. Purification of the residue by chro-
matography on silica gel (elution with 10% ethyl acetate in
hexanes) furnished 63 mg (97%) of 19 as a colorless oil: IR
(neat, cm-1) 1732, 1475, 1240; 1H NMR (300 MHz, C6D6) δ 5.23
(br d, J ) 9.2 Hz, 1 H), 2.45 (dd, J ) 9.2, 4.8 Hz, 1 H), 2.14-
2.06 (m, 1 H), 2.04-1.98 (m, 1 H), 1.92-1.26 (series of m, 10
H), 1.66 (s, 3 H), 1.02-0.98 (m, 2 H), 0.85 (d, J ) 7.4 Hz, 3 H),
0.80 (d, J ) 6.6 Hz, 3 H), 0.79 (d, J ) 6.6 Hz, 3 H); MS m/z
(M+) calcd 280.2038, obsd 280.2039; [R]22D +11.1 (c 0.85, ethyl
acetate).
(-)-Sa lsolen e Oxid e (1). To a solution of 19 (28 mg, 0.10
mmol) in ether (5 mL) was added lithium aluminum hydride
(8 mg, 0.2 mmol). The reaction mixture was stirred for 5 h,
quenched with ethyl acetate (1 mL) and water (2 drops), and
filtered through a plug of basic alumina (ethyl acetate rinse).
The filtrate was concentrated, and the resultant alcohol (20)
was stirred with the Martin sulfurane (135 mg, 0.2 mmol) in
benzene (5 mL) at 50 °C under N2 for 2 h. After being cooled,
the reaction mixture was quenched with saturated NaHCO3
solution and extracted with ether. The combined ethereal
solutions were washed with brine, dried, and concentrated to
leave a residue, which was purified by MPLC on silica gel
(elution with 2% ether in pentane) to give 18 mg (80%) of
salsolene oxide, spectroscopically identical with the natural
product:17 [R]25 -24 (c 0.2, CHCl3).
D
Ack n ow led gm en t. Financial support from the Eli
Lilly Company and Hoechst Marion Roussel is acknowl-
edged. We thank Professor P. Weyerstahl for providing
us with copies of the NMR spectra of the title compound.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for intermediates 15-19 together with detailed analy-
ses of the structure and stereochemistry of 2, 12, 13, and 18
(26 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O971244D