A novel route to the marasmane skeleton via a tandem rearrangement-cyclopropanation reaction. Total synthesis of (+)-isovelleral

Article abstract of DOI:10.1021/jo0015568

A general and efficient route to the marasmane skeleton is described. Total syntheses of two simple marasmanes (35 and 37) in racemic form were achieved using a MgI₂-catalyzed rearrangement-cyclopropanation reaction of trimethylsilyl enol ether 31 derived from naphthalenone 30. The reaction proceeds in high yield with complete diastereoselectivity and does not require the use of special cyclopropanation reagents. Application of this novel route to the marasmane framework was extended to the synthesis of naturally occurring (+)-isovelleral (41).

Full text of DOI:10.1021/jo0015568

2350
J . Org. Chem. 2001, 66, 2350-2357
A Novel Rou te to th e Ma r a sm a n e Sk eleton via a Ta n d em
Rea r r a n gem en t-Cyclop r op a n a tion Rea ction . Tota l Syn th esis of
(+)-Isoveller a l
Roel P. L. Bell, J oannes B. P. A. Wijnberg,* and Aede de Groot*
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,
6703 HB Wageningen, The Netherlands
aede.degroot@bio.oc.wag-ur.nl
Received November 2, 2000
A general and efficient route to the marasmane skeleton is described. Total syntheses of two simple
marasmanes (35 and 37) in racemic form were achieved using a MgI2-catalyzed rearrangement-
cyclopropanation reaction of trimethylsilyl enol ether 31 derived from naphthalenone 30. The
reaction proceeds in high yield with complete diastereoselectivity and does not require the use of
special cyclopropanation reagents. Application of this novel route to the marasmane framework
was extended to the synthesis of naturally occurring (+)-isovelleral (41).
In tr od u ction
that solvolytic rearrangement of the naturally occurring
brominated eudesmane 1 resulted in a ca. 70% yield of a
3:2 mixture of guaiane 4 and the ivaxillarane derivative
5, respectively, the latter with unknown orientation of
the cyclopropane ring (Scheme 1). The outcome of this
reaction suggests that it might be possible to convert an
appropriately functionalized bicyclic octahydronaphtha-
lene system to the tricyclic cyclopropa[e]indene system
present in marasmanes in a single step. Herein, we
report a novel synthetic approach to marasmanes using
a tandem rearrangement-cyclopropanation sequence as
key step.
The majority of marasmane sesquiterpenes found in
nature have been isolated from basidiomycete species
belonging to the genus Lactarius.1 Since a considerable
number of these secondary metabolites exhibit antifeed-
ant, antifungal, and antibacterial activities, these ses-
quiterpenes may take part in the chemical defense
system of the basidiomycete against predators.2 Despite
their interesting physiological activities and unusual
tricyclic cyclopropa[e]indene framework, relatively few
total syntheses of natural marasmanes have been
published.1b
Mesylate 6 possessing an allylic OH group at C6 is a
suitable substrate for studying this novel route to the
marasmane skeleton (Scheme 2). The C-6R orientation
of the OH group in 6 is essential because a â OH group
at that position would probably result in the formation
of a bridged ether.6 Previous studies on the chemical
consequences of through-bond interactions (TBI) in trans-
fused perhydronaphthalene-1,4-diol monosulfonate es-
ters7 suggested that deprotonation of the OH group in 6
in refluxing benzene or toluene would induce ionization
of the sulfonate ester bond and rearrangement to the
homoallylic cation 7. Successive rearrangement of 7 to
cyclopropylcarbinyl cation 88 followed by a stabilizing C6
f C7 1,2-H shift9 would give the marasmane ketone 9.
Because exploratory ab initio calculations indicated that
the cyclopropylcarbinyl cation 8 is more stable than the
stereoisomeric cation with opposite orientation of the
cyclopropane ring (∆E ) 31.3 kcal mol-1),10 it was further
The tricyclic core of marasmanes3 is also present in
sesquiterpenes belonging to the very small group of
ivaxillaranes.4 Although not aiming at synthesizing an
ivaxillarane sesquiterpene, Howard and Fenical5 found
* Corresponding authors. Phone: 31-317482370 or 31-317482375.
FAX: 31-317484914.
(1) Vidari, G.; Vita-Finzi, P. Studies in Natural Product Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1995; Vol. 17, pp 153-
206. (b) Daniewski, W. M.; Vidari, G. Progr. Chem. Org. Nat. Prod.
1999, 77, 69.
(2) Camazine, S. M.; Resch, J . F.; Eisner, T.; Meinwald, J . J . Chem.
Ecol. 1983, 9, 1439. (b) Sterner, O.; Bergman, R.; Kihlberg, J .;
Wickberg, B. J . Nat. Prod. 1985, 48, 279. (c) Sterner, O.; Bergman,
R.; Franzen, C.; Wickberg, B. Tetrahedron Lett. 1985, 26, 3163. (d)
Anke, H.; Sterner, O. Planta Medica 1991, 57, 344. (e) Daniewski, W.
M.; Gumulka, M.; Pankowska, E.; Ptaszynska, K.; Bloszyk, E.; J acob-
sson, U.; Norin, T. Phytochemistry 1993, 32, 1499. (f) Daniewski, W.
M.; Gumulka, M.; Przesmycka, D.; Ptaszynska, K.; Bloszyk, E.; Drozdz,
B. Phytochemistry 1995, 38, 1161.
(3) The numbering system used for the marasmane skeleton is based
on the system adopted for naphthalene (see structure 6) and will be
followed throughout the text of this paper.
(4) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids; Chapman
& Hall: London, 1991; Vol. I, pp 553-554.
(5) Howard, B. M.; Fenical, W. J . Org. Chem. 1977, 42, 2518.
(6) See Scheme 1 and ref 7e.
(7) Wijnberg, J . B. P. A.; J enniskens, L. H. D.; Brunekreef, G. A.;
de Groot, A. J . Org. Chem. 1990, 55, 941. (b) J enniskens, L. H. D.;
Wijnberg, J . B. P. A.; de Groot, A. J . Org. Chem. 1991, 56, 6585. (c)
Orru, R. V. A.; Wijnberg, J . B. P. A.; Bouwman, C. T.; de Groot, A. J .
Org. Chem. 1994, 59, 374. (d) Piet, D. P.; Orru, R. V. A.; J enniskens,
L. H. D.; van de Haar, C.; van Beek, T. A.; Franssen, M. C. R.;
Wijnberg, J . B. P. A.; de Groot, A. Chem. Pharm. Bull. 1996, 44, 1400.
(e) Bell, R. P. L.; Sobolev, A.; Wijnberg, J . B. P. A.; de Groot, A. J .
Org. Chem. 1998, 63, 122.
(8) Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Suzuki, K. Bull. Chem.
Soc. J pn. 1996, 69, 31.
(9) Tobe, Y.; Sato, J .-i.; Sorori, T.; Kakiuchi, K.; Odaira, Y. Tetra-
hedron Lett. 1986, 27, 2905.
10.1021/jo0015568 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/08/2001

Total Synthesis of (+)-Isovelleral
J . Org. Chem., Vol. 66, No. 7, 2001 2351
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
expected that 9 would have the same stereochemistry as
found in naturally occurring marasmanes.
Resu lts a n d Discu ssion
To establish reaction conditions that would allow
selective formation of the tricyclic cyclopropa[e]indene
core, a model study was carried out with mesylate 12.
The synthesis of 12, structurally identical to 6 but lacking
the Me group at C8, started with the known ketone 107e
(Scheme 3). Following standard procedures, 10 was
converted to enone 11 in 65% overall yield.11 Reduction
12
of 11 with NaBH4 in the presence of CeCl3 produced a
separable mixture of 12 and its C6 epimer 13 in yields
of 34 and 49%, respectively.13 Improvement in the yield
of 12 via Mitsunobu inversion14 of 13 was unsuccessful.
With the limited amount of 12 obtained from the reduc-
tion of 11, we were able to demonstrate that the rear-
rangement-cyclopropanation reaction could be achieved
by treating 12 with 2.5 equiv of Li(Ot-Bu)3AlH15 in
refluxing benzene for 22 h. Although a complex mixture
was obtained, the tricyclic ketone 14 was isolated in
acceptable yield (36%). The formation of ketone 14 can
be explained by a mechanism analogous to that outlined
in Scheme 2. Reduction of 14 by the bulky Li(Ot-Bu)3AlH
did not occur because of steric hindrance. The identity
of 14 was unambiguously established using NMR. The
C-H coupling of ca. 160 Hz observed for both the C8 (d)
and C9 (t) signals at δ 27.21 and 15.24, respectively, in
1
the H-coupled 13C NMR spectrum is diagnostic for the
presence of the trisubstituted cyclopropane ring in 14.
Additional support was obtained from the HETCOR
spectrum in which C8 and C9 were correlated with the
upfield-shifted signals at δH 1.00 and 0.33 and 0.08,
respectively. A NOESY experiment, in which the ex-
pected key NOE correlations were observed, also con-
firmed the stereochemistry assigned to 14. As predicted
by ab initio calculations, this stereochemistry is the same
as in naturally occurring marasmanes. The reaction of
13 with Li(Ot-Bu)3AlH yielded 15 in 68% as expected.
We next investigated the rearrangement-cyclopropa-
nation reaction of mesylate 6. In light of the rather poor
yield of 12 via reduction of a carbonyl group (vide supra),
introduction of the C-6R OH group in 6 was planned via
osmylation (Scheme 4). A copper-catalyzed conjugate
addition of MeMgI to the known enone 16,7e trapping of
(10) The energy difference calculations were carried out with
B3LYP/6-31G(d,p) using the GAUSSIAN 98 program (Revision A.7),
Gaussian, Inc., Pittsburgh, PA, 1998.
(11) The experimental details are available as Supporting Informa-
tion.
(12) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(13) Other reducing agents were also tried, but their use did not
lead to improvement of the yield of 12.
(14) Mitsunobu, O. Synthesis 1981, 1.
(15) Li(Ot-Bu)3AlH was also employed successfully in the key step
of the total synthesis of furanether B. See ref 7e.

2352 J . Org. Chem., Vol. 66, No. 7, 2001
Bell et al.
Sch em e 5
Sch em e 6
the resulting enolate by MeI, and subsequent epimer-
ization afforded dimethylated ketone 17 in excellent
yield. Treatment of 17 with LDA and trapping of the
resulting enolate with diethyl chlorophosphate gave
phosphate enol ester 1816 that was reduced with Li in
21
MeMgI or MgI2 also present in the reaction medium
via the Schlenk equilibrium may explain the ease by
which 6 and 12 reacted with MeMgI at room tempera-
ture. Support for this view came from two experiments
with tosylate 25 possessing a â MeO group at C6 through
which TBI-induced ionization of the sulfonate ester bond
can be ruled out.22 On exposure to MeMgI at room
temperature, 25 showed a fast rearrangement to bridged
ether 27 (Scheme 6). On the other hand, as expected, no
reaction took place when 25 was treated with Li(Ot-
Bu)3AlH in refluxing toluene. These experiments on 25
clearly demonstrate that MeMgI is capable of inducing
ionization of the sulfonate ester bond without involve-
ment of TBI. Another important conclusion from the
reaction of 25 with MeMgI is that rearrangement can
compete favorably with iodide formation when the posi-
tive charge of the homoallylic cation is effectively stabi-
lized. In case of 25 such an intramolecular stabilization
occurs via trapping of cation 26 by the proximate MeO
group (see Scheme 6). For a successful rearrangement-
cyclopropanation reaction, this means that the cyclopro-
pylcarbinyl cation must be much more stable than the
homoallylic cation. On the basis of these considerations,
we decided to investigate the reaction of silyl enol ether
31 with MeMgI (Scheme 7). Since the silyloxy group at
C7 would both increase the electron density of the double
bond in the homoallylic cation 32 and effectively stabilize
the cyclopropylcarbinyl cation 33, rearrangement of 31
to the normarasmane ketone 34 was expected to be the
preferred pathway. Addition of MeMgI to ketone 34
should then lead to the final product in this one-pot
operation, the marasmane alcohol 35. An additional
advantage of this approach is the relatively simple
synthesis of silyl enol ether 31.
17
NH3 to afford olefin 19 as the sole product in 51%
overall yield. Following standard procedures, 19 was
further converted to mesylate 20.11 Using a stoichiometric
amount of OsO4,18 dihydroxylation of 20 resulted in a 75%
yield of diol 21. The H-6 signal at δ 3.10 with a coupling
1
of 10.7 Hz in the H NMR spectrum of 21 confirmed the
R orientation of the secondary OH group. Completion of
the synthesis of 6 was accomplished in high yield by
selective protection of the secondary OH group as its
acetate, elimination of the tertiary OH group with SOCl2,
and reductive removal of the protecting acetyl group.
On exposure of 6 to Li(Ot-Bu)3AlH in toluene at 100
°C, a complex mixture was obtained with lactarane enone
22 (ca. 55%) as the major component and the desired
ketone 9 in only trace amounts (Scheme 5). Apparently,
a direct transannular C6 f C10 H shift (7 f 22) is
energetically more favorable than cyclopropane ring
formation (7 f 8, see Scheme 2). When MeMgI19 was
used instead of Li(Ot-Bu)3AlH, 6 reacted readily at room
temperature, but the outcome was again disappointing.
Although a small amount (6%) of ketone 920 could be
isolated, the major product (56%) was iodide 24. The H-1
1
signal at δ 4.37 with a coupling of 13.0 Hz in the H NMR
spectrum indicates that formation of 24 had proceeded
with retention of configuration suggesting involvement
of the bridged-ion intermediate 23. Iodide formation was
also observed on reaction of alcohol 12 with MeMgI, but
to a lesser extent (31%) than in the reaction of 6 (56%).
On the other hand, the yield of rearrangement-cyclo-
propanation product in this reaction of 12 was higher
(22% of 14 versus 6% of 9). These findings suggest that
steric repulsion between the Me groups at C8 and C10
in the transition state leading to intermediate 8 makes
the reaction pathway to 9 energetically less favorable
than the one to 14. Chelation of the sulfonate ester with
The synthesis of 31 started with allylic oxidation of the
known olefin 287e using CrO3-pyridine complex23 as
oxidant. The resulting enone 29 was converted via a five-
step reaction sequence to mesylate 30 in 68% overall
yield.11 Reaction of 30 with TMSI and HMDS24 completed
the synthesis of silyl enol ether 31. When 31 was treated
with 5 equiv of MeMgI at room temperature, a fast
reaction took place resulting in a ca. 3:2:5 mixture of
ketone 34, the expected alcohol 35, and the trimethylsilyl
(16) The C7 epimer of 17 refused to give 18.
(17) Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 2145.
(18) Dihydroxylation reactions on 20 with a catalytic amount of
highly toxic OsO4 and an amine oxide as the stoichiometric oxidant
were less successful.
(21) Place, P.; Roumestant, M.-L.; Gore, J . Bull. Soc. Chim. Fr. 1976,
169.
(19) Gerdes, H.; J averi, S.; Marschall, H. Chem. Ber. 1980, 113,
1907. (b) Kawana, M.; Koresawa, T.; Kuzuhara, H. Bull. Chem. Soc.
J pn. 1983, 56, 1095.
(22) Orru, R. V. A.; Wijnberg, J . B. P. A.; J enniskens, L. H. D.; de
Groot, A. J . Org. Chem. 1993, 58, 1199.
(23) Dauben, W. G.; Lorber, M.; Fullerton, D. S. J . Org. Chem. 1969,
34, 3587.
(20) The identity of 9 was tentatively assigned by 1H NMR spectral
comparison with 14.
(24) Miller, R. D.; McKean, D. R. Synthesis 1979, 730.

Total Synthesis of (+)-Isovelleral
J . Org. Chem., Vol. 66, No. 7, 2001 2353
Sch em e 7
Sch em e 8
methylated with Me2CuLi29 to provide another simple
marasmane derivative, olefin 37, in 40% overall yield.
Application was next extended to the synthesis of the
naturally occurring marasmane (+)-isovelleral (41).30 To
date, two total syntheses of this strongly antifungal and
antibacterial dialdehyde with pungent taste were re-
ported. In Heathcock’s racemic approach,31 the Corey-
Chaykovsky reagent was employed to introduce the
cyclopropane ring, whereas Wickberg32 used methylcy-
clopropenyllithium in his asymmetric synthesis. In our
synthetic approach toward isovelleral, cyclopropane ring
formation proceeds intramolecularly (Scheme 8). As
starting material, we selected optically active mesylate
38 with an allyl group at C8. After conversion of 38 to
silyl enol ether 39, the key step in our approach, the
MgI2-induced rearrangement-cyclopropanation reaction
of 39, should then lead to ketone 40. It is noteworthy that
initial efforts to synthesize the corresponding silyl enol
ethers with an ester33 or a protected carbinol function at
C8, failed. With 40 in hand, completion of the synthesis
of (+)-isovelleral (41) was planned through conversion
of the allyl substituent to an aldehyde group34 and
introduction of the second aldehyde group at C7 via a
Pd-catalyzed one-carbon homologation.31
ether of 35, respectively, in 80% yield. A NOE difference
experiment on 34 in which selective irradiation of H-9R
at δ 1.11 resulted in positive enhancements of the H-5
(δ 1.91), H-1 (δ 2.09), and H-6R (δ 2.21) signals was in
agreement with the assigned stereochemistry. The isola-
tion of 34 in this reaction with MeMgI indicates that
enolization competes seriously with addition, probably
as a result of steric hindrance. The orientation of the Me
group at C7 in 35 could not be established by NMR
analysis, but was assumed to be R for steric reasons.25
Methylation of cation 33 or, alternatively, silylation of
35 by TMSI generated in this reaction might explain the
formation of the trimethylsilyl ether of 35. The formation
of only rearrangement-cyclopropanation products in this
reaction confirmed our hypothesis that the intermediacy
of the very stable oxonium ion in combination with an
enhanced electron density of the double bond is required
for a successful tandem reaction leading to the maras-
mane skeleton.
Mesylate 38 was prepared from optically pure (+)-2935
via a reaction sequence similar to that employed for the
synthesis of 30.11 Treatment of 38 with TMSI and HMDS
gave a high yield36 of crude 39 which was immediately
used in the next reaction with MgI2, providing the
tricyclic ketone 40 in ca. 50% overall yield from (+)-29.
All the NMR spectroscopic data collected for 40 are
consistent with the assigned structure.
Having accomplished the successful rearrangement to
40, its conversion to (+)-isovelleral was first tried as
outlined in Scheme 9. Isomerization of the double bond
37
in 40 with RhCl3 in the presence of K2CO3 furnished
42 as a 10:1 mixture of E and Z isomers, respectively, in
A selective formation of ketone 34 could be achieved
in 73% yield on exposure of 31 to MgI2 in the presence
(29) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1980, 21, 4313.
(30) Hansson, T.; Sterner, O.; Wickberg, B. J . Org. Chem. 1992, 57,
3822.
(31) Thompson, S. K.; Heathcock, C. H. J . Org. Chem. 1992, 57,
5979.
(32) Bergman, R.; Hansson, T.; Sterner, O.; Wickberg, B. J . Chem.
Soc., Chem. Commun. 1990, 865.
(33) A successful rearrangement-cyclopropanation of a silyl enol
ether with a Me ester at C8 would lead directly to a known intermedi-
ate in the synthesis of racemic isovelleral. See ref 31.
(34) Hanselmann, R.; Benn, M. Synth. Commun. 1996, 26, 945.
(35) The starting material for the synthesis of (+)-29, optically pure
(+)-(1S,8aS)-1,2,3,4,6,7,8,8a-octahydro-3,3,8a-trimethyl-1-naphthale-
nol, was prepared as previously described. See: Franssen, M. C. R.;
J ongejan, H.; Kooijman, H.; Spek, A. L.; Bell, R. P. L.; Wijnberg, J . B.
P. A.; de Groot, A. Tetrahedron: Asymm. 1999, 10, 2729.
(36) Purification by column chromatography resulted in a modest
yield (45%) of 39.
26
of HMDS.27 Subsequent reaction of 34 with MeMgCl then
yielded the desired marasmane alcohol 35 (61%) as a
single compound. Deprotonation of 34 with KHMDS28
followed by addition of N-phenyltrifluoromethanesulfo-
nimide (Tf2NPh) afforded enol triflate 36 which was
(25) Inspection of a molecular model of 34 indicated that the â
direction of approach is strongly shielded.
(26) MgI2 should be added quickly to avoid air contact as much as
possible. Prolonged air contact will lead to inactivity of the reagent.
(27) Without HMDS, the yield of 34 was much lower as a result of
cyclopropane ring opening.
(28) LDA, normally used in this reaction, gave only a poor yield of
36.

2354 J . Org. Chem., Vol. 66, No. 7, 2001
Bell et al.
Sch em e 9
Sch em e 11
Scheme 11. Ozonolysis of 45 and reduction with NaBH4
furnished, after purification, alcohol 49 in 39% yield.44
Due to lack of starting material 45, improvement of the
yield of alcohol 49 could not be investigated further, but
the results clearly showed that selective ozonolysis of an
alkyl-substituted double bond was possible in the pres-
ence of an enol triflate double bond.
Sch em e 10
With 49 in hand, completion of the synthesis of (+)-
isovelleral (41) involved the Pd-catalyzed one-carbon
homologation of 49 to give lactone 50 in 85% yield.
Reduction of 50 with excess of DIBAL-H and subsequent
Swern oxidation completed the synthesis of (+)-isovelle-
ral. The [R]20 value of +234° measured for our sample
D
of isovelleral in CHCl3 matched very well with the value
of +251° reported for natural isovelleral isolated from
Lactarius vellereus.30
In summary, this novel tandem rearrangement-cy-
clopropanation approach presents an attractive route to
the marasmane framework. The stereocontrolled total
synthesis of (+)-isovelleral in 12 steps and ca. 10% overall
yield from optically active (+)-29 shows that this strategy
is a useful alternative for the synthesis of complex
marasmane sesquiterpenes.
77% yield. However, the following two steps proved to
be more problematic than expected. Ozonolysis of 4238
furnished aldehyde (+)-43 only in poor yield (26%),39
whereas conversion of 43 to enol triflate 44 as substrate
for the one-carbon homologation failed to give any
product, probably due to the internal chelation of the
enolate function with the aldehyde moiety.40 The reversed
sequence, one-carbon homologation prior to ozonolysis,
initially gave more promising results. Enol triflate for-
mation with 42 proceeded now without difficulties and
gave 45 in 94% yield (Scheme 10). Pd-catalyzed one-
carbon homologation of 45 resulted in a 86% yield of a
ca. 4:1 mixture of the R,â-unsaturated Me ester 46 and
the corresponding acid,41 respectively. Reduction of this
mixture with LAH afforded alcohol 47 as the sole product
in almost quantitative yield. Oxidation of 47 with PCC42
resulted in aldehyde 48, but subsequent ozonolysis of 48
failed. Ozonolysis of ester 46 gave a similar negative
result. In both cases, these failures were explained by
interference of the proximate carbonyl function at C7.43
Completion of the synthesis of isovelleral could be
achieved by following the reaction sequence shown in
Exp er im en ta l Section
Gen er a l Meth od s. Unless stated otherwise, all reactions
were carried out in oven-dried glassware under dry N2
atmosphere. Solvents were dried by appropriate methods
wherever needed. All organic extracts were dried over anhy-
drous MgSO4. Flash chromatography was performed on 230-
400 mesh silica gel. 1H and 13C NMR spectra were recorded
in CDCl3 or benzene-d6 at 200 and 50 MHz, respectively, unless
otherwise noted. Chemical shifts are reported in ppm (δ)
relative to CHCl3 (δ 7.24) or benzene (δ 7.15). Optical rotations
were taken at 20 °C. IR spectra were recorded as CHCl3
solutions. Mass spectra were determined at 70 eV in the elec-
tron impact mode.
Ma ter ia ls. Reagents were purchased from commercial
suppliers and used without further purification. The com-
pounds 10, 16, and 28 were prepared as previously described.7e
1
The H NMR assignments reported for the key compounds 14
and 34 are based on 2D NMR methods (HETCOR, COSY, and
NOESY) and NOE difference experiments. (+)-Isovelleral (41)
was characterized before.30,31
Tr ea tm en t of 12 w ith Li(Ot-Bu )3AlH. To a solution of
68.4 mg (0.23 mmol) of 12 in 10 mL of degassed benzene was
(37) Nakamura, H.; Arata, K.; Wakamatsu, T.; Ban, Y.; Shibasaki,
M. Chem. Pharm. Bull. 1990, 38, 2435.
(38) This and following reactions on 42 were carried out with the
pure E isomer.
(39) Opening of the cyclopropane ring during purification by column
chromatography was probably responsible for the modest yield of 43.
(40) In contrast to 43, enol triflate formation proceeded smoothly
with the compound possessing an ester group instead of an aldehyde
function at C8. See ref 31.
(41) The formation of carboxylic acid was explained by the use of
not completely dry DMF and/or MeOH in this reaction.
(42) The use of PCC resulted in a modest yield (25%) of 48. Swern
oxidation of 47 may give a better result. See ref 31.
(43) Wu, H.-J .; Lin, C.-C. J . Org. Chem. 1996, 61, 3820. (b) Wu, H.-
J .; Chern, J .-H.; Wu, C.-Y. Tetrahedron 1997, 53, 2401.
(44) This ozonolysis procedure applied on 45 also produced
a
diastereometric mixture (12%) of two cross ozonides as was deduced
from the 1H NMR spectrum showing two three-proton doublets at δ
1.26 and 1.31, a two-proton quartet at δ 5.11, and two one-proton
singlets at δ 5.06 and 5.19. For example, see: Griesbaum, K.;
Bandyopadhyay, A. R.; Meister, M. Can. J . Chem. 1986, 64, 1553.

Total Synthesis of (+)-Isovelleral
J . Org. Chem., Vol. 66, No. 7, 2001 2355
added 0.144 g (0.57 mmol) of Li(Ot-Bu)3AlH. The reaction
mixture was refluxed for 22 h under Ar, cooled to room
temperature, and then quenched with 1 mL of saturated
aqueous Na2SO4. After 5 min of vigorous stirring, the reaction
mixture was diluted with ether, dried, and evaporated. The
remaining residue was flash chromatographed [5:1 petroleum
ether (bp 40-60 °C)/EtOAc] to give 16.8 mg (36%) of (1aS*,2R*,-
3aR*,6aS*,6bS*)-2,5,5,6b-tetramethyloctahydrocyclopropa[e]-
inden-3(1H)-one (14) as a colorless oil: 1H NMR (CDCl3, 400
MHz) δ 0.08 (dd, J ) 5.5, 4.8 Hz, H-9R), 0.33 (ddd, J ) 8.3,
5.5, 1.3 Hz, H-9â), 0.94 (s, 3H), 1.00 (dddd, J ) 8.3, 4.8, 3.0,
1.3 Hz, H-8), 1.05 (s, 3H), 1.06 (s, 3H), 1.06 (d, J ) 6.5 Hz,
3H), 1.36 (dd, J ) 13.1, 8.5 Hz, H-4â), 1.53 (dd, J ) 12.3, 12.3
Hz, H-2â), 1.75 (ddd, J ) 13.1, 9.4, 2.3 Hz, H-4R), 1.81 (ddd,
J ) 12.3, 6.8, 2.3 Hz, H-2R), 2.62 (ddd, J ) 9.8, 9.4, 8.5 Hz,
H-5), 2.78 (dddd, J ) 12.3, 9.8, 6.8, 1.3 Hz, H-1), 3.03 (qdd, J
) 6.5, 3.0, 1.3 Hz, H-7); 13C NMR (CDCl3, 100 MHz) δ 15.21,
15.24, 18.64, 24.28, 27.21, 27.32, 29.79, 38.76, 40.37, 45.43,
46.04, 48.33, 49.84, 216.23; HRMS calcd for C14H22O (M+)
206.1671, found 206.1670.
35.21, 37.82, 38.52, 44.93, 49.22, 49.40, 49.60, 75.66, 126.85,
128.20; HRMS calcd for C15H25IO (M+) 348.0950, found
348.0948.
Tr ea tm en t of 12 w ith MeMgI. Mesylate 12 (39.1 mg, 0.13
mmol) was treated with MeMgI (0.5 mL of 1 M in ether) for
35 min as described above for 6. Workup and flash chroma-
tography [10:1 to 5:1 petroleum ether (bp 40-60 °C)/EtOAc]
gave, in order of elution, 6.0 mg (22%) of 14 and 13.3 mg
(31%) of (1S*,4aS*,5S*,8aR*)-5-iodo-2,4a,7,7-tetramethyl-1,4,-
4a,5,6,7,8,8a-octahydro-1-naphthalenol as a colorless oil: 1H
NMR (CDCl3) δ 0.89 (s, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.20
(m, 1H), 1.42 (br s, OH), 1.62 (ddd, J ) 12.5, 9.0, 3.5 Hz, 1H),
1.73 (br s, 3H), 1.74-1.82 (m, 2H), 1.94 (m, 1H), 2.02 (dd, J )
4.4, 2.1 Hz, 1H), 2.15 (app t, J ) 13.1 Hz, 1H), 3.55 (br d, J )
9.0 Hz, 1H), 4.42 (dd, J ) 13.1, 4.3 Hz, 1H) 5.38 (br d, J ) 5.0
Hz, 1H); 13C NMR (CDCl3) δ 14.36, 19.08, 25.16, 32.53, 35.09,
37.64, 39.19, 43.04, 44.68, 49.14, 49.44, 74.27, 122.66, 134.80;
HRMS calcd for C14H23IO (M+) 334.0786, found 334.0770.
Tr ea tm en t of 25 w ith MeMgI. Tosylate 25 (11.7 mg, 28.8
µmol) was treated with MeMgI (0.2 mL of 0.8 M in ether) for
40 min as described above for 6. Workup gave (1R*,2S*,-
6R*,7R*)-1,4,4,8,9-pentamethyl-11-oxatricyclo[5.3.1.02,6]undec-
8-ene (27) as a light yellow oil in quantitative yield.45 Flash
chromatography [20:1 petroleum ether (bp 40-60 °C)/EtOAc]
provided a pure sample: 1H NMR (CDCl3) δ 0.85 (s, 3H), 1.02
(s, 3H), 1.15 (dd, J ) 11.5, 10.6 Hz, 1H), 1.25 (s, 3H), 1.29-
1.41 (m, 3H), 1.51 (br s, 3H), 1.60 (br s, 3H), 1.70 (br ABd, J )
17.5 Hz, 1H), 2.25 (br ABd, J ) 17.5 Hz, 1H), 2.38 (app q, J )
8.9 Hz, 1H), 2.66 (dt, J ) 10.2, 8.4 Hz, 1H), 3.74 (br s, 1H);
13C NMR (CDCl3) δ 15.06, 17.50, 23.00, 26.07, 28.34, 41.44,
43.00, 46.33, 46.43, 52.15, 54.44, 80.24, 81.91, 121.63, 131.66;
HRMS calcd for C15H24O (M+) 220.1827, found 220.1829.
Tr ea tm en t of 31 w ith MeMgI. A solution of 28.5 mg (76.2
µmol) of 31 in 5 mL of degassed toluene was treated with
MeMgI for 30 min as described above for 6. Workup and flash
chromatography [5:1 petroleum ether (bp 40-60 °C)/EtOAc]
gave 8.8 mg of an oil which, according to 1H NMR and GC
analysis, contained ca. 60% of the trimethylsilyl ether of 35:
1H NMR (main peaks, benzene-d6) δ -0.08 (d, J ) 4.6 Hz, 1H),
0.20 (s, 9H), 0.43 (d, J ) 4.6 Hz, 1H), 1.10 (s, 3H), 1.18 (s,
3H), 1.21 (s, 3H), 1.25 (s, 3 H), 1.37 (s, 3H), 2.48 (dt, J ) 6.8,
11.2 Hz, 1H); MS m/z 294 (M+). Further elution afforded 3.9
mg (25%) of 34 and 2.9 mg (17%) of 35. The spectroscopic data
of 34 and 35 are shown below.
Tr ea t m en t of 31 w it h MgI2 a n d HMDS. To a stirring
solution of 63.6 mg (0.17 mmol) of 31 and 180 µL (0.85 mmol)
of HMDS in 5 mL of degassed toluene at room temperature
was added 70.0 mg (0.25 mmol) of MgI2. After 2 h, the reaction
mixture was quenched with saturated aqueous Na2S2O3 and
diluted with ether. The organic phase was washed with 1 M
aqueous HCl and brine, dried, and evaporated. The remaining
residue was flash chromatographed [20:1 petroleum ether (bp
40-60 °C)/EtOAc] to give 25.6 mg (73%) of (1aR*,3aS*,6aS*,-
6bR*)-1a,5,5,6b-tetramethyloctahydrocyclopropa[e]inden-2(1H)-
one (34) as a colorless oil: 1H NMR (400 MHz, benzene-d6) δ
0.30 (d, J ) 4.9 Hz, H-9â), 0.82 (s, 3H), 0.91 (s, 6H), 1.00 (dd,
J ) 13.3, 3.4 Hz, 1H), 1.02 (app t, J ) 12.6 Hz, 1H), 1.11 (d,
J ) 4.9 Hz, H-9R), 1.32 (s, 3H), 1.39 (dd, J ) 13.3, 6.9 Hz,
1H), 1.44 (dd, J ) 12.6, 6.6 Hz, 1H), 1.88 (dd, J ) 19.1, 6.4
Hz, H-6â), 1.91 (m, H-5), 2.09 (ddd, J ) 12.6, 6.9, 6.6 Hz, H-1),
2.21 (dd, J ) 19.1, 11.5 Hz, H-6R); 13C NMR (100 MHz,
benzene-d6) δ 14.49, 20.63, 28.40, 30.81, 31.40, 32.77, 34.87,
36.09, 37.44, 40.75, 43.71, 45.84, 49.57, 208.50; HRMS calcd
for C14H22O (M+) 206.1671, found 206.1673.
Tr ea tm en t of 13 w ith Li(Ot-Bu )3AlH. Alcohol 13 (0.113
g, 0.37 mmol) was treated with Li(Ot-Bu)3AlH (0.237 g, 0.93
mmol) for 1.75 h as described above for 12. Workup and flash
chromatography [5:1 petroleum ether (bp 40-60 °C)/EtOAc]
gave 51.9 mg (67%) of (1R*,2S*,6R*,7R*)-1,4,4,8-tetramethyl-
11-oxatricyclo[5.3.1.02,6]undec-8-ene (15) as a colorless oil: 1H
NMR (CDCl3) δ 0.85 (s, 3H), 1.01 (s, 3H), 1.16 (m, 1H), 1.23
(s, 3H), 1.30-1.39 (m, 2H), 1.54 (ddd, J ) 11.7, 7.8, 2.0 Hz,
1H), 1.63 (br s, 3H), 1.81 (dm, J ) 17.6 Hz, 1H), 2.29 (dm, J
) 17.6 Hz, 1H), 2.41 (app q, J ) 8.8 Hz, 1H), 2.71 (dt, J )
10.2, 8.3 Hz, 1H), 3.74 (s, 1H), 5.13 (br s, 1H); 13C NMR (CDCl3)
δ 19.32, 22.97, 26.00, 28.30, 40.77, 41.36, 42.94, 46.25, 52.16,
54.83, 79.42, 81.12, 116.27, 139.79; HRMS calcd for C14H22
O
(M+) 206.1671, found 206.1673.
Tr ea tm en t of 6 w ith Li(Ot-Bu )3AlH. A solution of 6 (35.8
mg, 0.11 mmol) in 5 mL of degassed toluene was treated with
Li(Ot-Bu)3AlH (46.0 mg, 0.18 mmol) at 100 °C for 6 h as
described above for 12. Workup afforded 23.4 mg (97%) of a
light yellow oil which, according to GCMS analysis, consisted
of 22 (55%), 9 (11%), and at least four other compounds.
Careful flash chromatography [10:1 petroleum ether (bp 40-
60 °C)/EtOAc] provided 3.8 mg (15%) of almost pure (3aR*,8S*,-
8aR*)-2,2,5,6,8-pentamethyl-2,3,3a,7,8,8a-hexahydro-4(1H)-
azulenone (22): 1H NMR (benzene-d6) δ 0.72 (d, J ) 6.5 Hz,
3H), 0.93 (s, 3H), 1.07 (app t, J ) 12.5 Hz, 1H), 1.21-1.43 (m,
3H), 1.26 (s, 3H), 1.46 (br s, 3H), 1.72-2.06 (m, 3H), 1.84 (br
s, 3H), 2.56 (dd, J ) 13.4, 4.6 Hz, 1H), 2.99 (ddd, J ) 9.9, 8.3,
4.6 Hz, 1H); 13C NMR (100 MHz, benzene-d6) δ 16.27, 22.36
(2C), 30.00, 30.32, 37.70, 38.34, 41.07, 46.85, 47.03, 50.86,
55.64, 133.92, 144.32, 205.21; HRMS calcd for C15H24O (M+)
220.1827, found 220.1824.
Tr ea tm en t of 6 w ith MeMgI. To a stirring solution of 20.6
mg (65 µmol) of 6 in 5 mL of degassed toluene at room
temperature was added MeMgI (0.2 mL of 0.8 M in ether).
After 1.25 h, the reaction mixture was quenched with brine
and diluted with ether. The organic phase was washed with
brine, dried, and evaporated. The remaining residue was flash
chromatographed [5:1 petroleum ether (bp 40-60 °C)/EtOAc]
to afford, in order of elution, 0.8 mg (6%) of 9 (GC purity ≈
90%) and 12.7 mg (56%) of 24, both as colorless oils. (1aS*,2R*,-
3aR*,6aS*,6bS*)-1a,2,5,5,6b-Pentamethyloctahydrocyclopro-
pa[e]inden-3(1H)-one (9): IR (CHCl3) 1725 cm-1 1H NMR
;
(CDCl3) δ 0.01 (dd, J ) 5.6, 1.8 Hz, 1H), 0.28 (d, J ) 5.6 Hz,
1H), 0.83-1.45 (m, 3H), 0.93 (s, 3H), 1.05 (s, 3H), 1.08 (d, J )
6.6 Hz, 3H), 1.11 (s, 3H), 1.13 (s, 3H), 1.60-1.90 (m, 2H), 2.60-
2.85 (m, 2H); MS m/z 220 (M+). (1S*,4aS*,5S*,8aR*)-5-Iodo-
2,3,4a,7,7-pentamethyl-1,4,4a,5,6,7,8,8a-octahydro-1-naphtha-
lenol (24): 1H NMR (CDCl3) δ 0.86 (s, 3H), 0.94 (s, 3H), 0.95
(s, 3H), 1.12-1.26 (m, 2H), 1.25 (br s, OH), 1.51-1.79 (m, 3H),
1.62 (br s, 3H), 1.68 (br s, 3H), 1.98 (ddd, J ) 13.4, 4.3, 2.1
Hz, 1H), 2.14 (app t, J ) 13.2 Hz, 1H), 3.51 (br s, 1H; becomes
br d, J ) 8.6 Hz, with D2O added), 4.41 (dd, J ) 13.0, 4.3 Hz,
1H); 13C NMR (CDCl3) δ 14.34, 14.40, 19.59, 25.22, 32.60,
(1a R*,2R*,3a S*,6a S*,6b R*)-1a ,2,5,5,6b -P en t a m et h yl-
d eca h yd r ocyclop r op a [e]in d en -2-ol (35). To a stirring solu-
tion of 24.3 mg (0.12 mmol) of 34 in 5 mL of THF at room
temperature was added MeMgCl (0.1 mL of 3 M in THF). After
1.25 and 4.25 h, two other 0.1 mL-portions of MeMgCl were
added. The reaction mixture was stirred at room temperature
for an additional 4 h, quenched with saturated aqueous NH4-
(45) GC analysis revealed the presence (ca. 15%) of another,
unknown product.

2356 J . Org. Chem., Vol. 66, No. 7, 2001
Bell et al.
Cl, and diluted with ether. The organic phase was washed with
brine, dried, and evaporated to give an oily residue which was
flash chromatographed on basic alumina [10:1 petroleum ether
(bp 40-60 °C)/EtOAc] to afford 16.1 mg (61%) of 35 as a
colorless oil:1H NMR (benzene-d6) δ -0.10 (d, J ) 4.6 Hz, 1H),
0.47 (d, J ) 4.6 Hz, 1H), 0.75 (br s, OH), 0.90 (m, 1H), 0.92 (s,
3H), 1.05 (s, 3H), 1.11 (s, 6H), 1.12 (s, 3H), 1.19 (dd, J ) 14.8,
2.2 Hz, 1H), 1.40 (dd, J ) 14.8, 8.3 Hz, 1H), 1.55-1.62 (m,
2H), 1.73 (dd, J ) 12.2, 9.8 Hz, 1H), 2.05 (m, 1H), 2.44 (dt, J
) 8.3, 10.9, 1H); 13C NMR (100 MHz, benzene-d6) δ 14.88,
22.21, 23.82, 25.21, 27.22, 29.26, 29.46, 29.90, 32.01, 37.96,
39.50, 42.00, 48.39, 50.95, 73.54; HRMS calcd for C15H26O (M+)
222.1984, found 222.1982.
(1a R *,3a R *,6a S *,6b R *)-1a ,5,5,6b -Te t r a m e t h yl-1,1a ,-
3a ,4,5,6,6a ,6b-octa h yd r ocyclop r op a [e]in d en -2-yl Tr iflu o-
r om eth a n esu lfon a te (36). To a solution of 10.0 mg (48.5
µmol) of 34 and 87.0 mg (0.24 mmol) of Tf2NPh in 1.5 mL of
2:1 THF/toluene, cooled to -78 °C, was added KHMDS (0.5
mL of 0.5 M in toluene). After being stirred at -78 °C for 2 h,
the reaction mixture was quenched with brine and diluted with
ether. The organic phase was washed with brine, dried, and
evaporated. The remaining residue was flash chromatographed
[7:1 petroleum ether (bp 40-60 °C)/EtOAc] to give 11.0 mg
(67%) of 36 as a colorless oil: 1H NMR (benzene-d6) δ 0.22 (d,
J ) 4.7 Hz, 1H), 0.84 (s, 6H), 0.94 (s, 3H), 1.00-1.49 (m, 5H),
1.15 (s, 3H), 1.92-2.07 (m, 2H), 5.05 (d, J ) 1.7 Hz, 1H); 13C
NMR (benzene-d6) δ 14.32, 20.36, 20.72, 27.53, 29.00, 31.48,
31.68, 37.32, 37.63, 41.98, 45.19, 47.66, 116.69, 118.69 (q, J C,F
) 320 Hz), 151.63; HRMS calcd for C15H21F3O3S (M+) 338.1164,
found 338.1161.
(1a S*,3a S*,6a S*,6b R*)-1a ,2,5,5,6b -P en t a m et h yl-1,1a ,-
3a ,4,5,6,6a ,6b-octa h yd r ocyclop r op a [e]in d en e (37). MeLi
(0.55 mL of 1.6 M in ether) was added to a stirring suspension
of 0.107 g (0.56 mmol) of CuI in 2 mL of THF at -10 °C. The
mixture was stirred at -10 °C for 45 min, and then a solution
of 18.9 mg (56 µmol) of 36 in 1 mL of THF was added via
cannula. The reaction mixture was allowed to warm to 0 °C,
stirred for an additional 75 min, and quenched with saturated
aqueous NH4Cl. After dilution with ether, the organic phase
was washed with saturated aqueous NH4Cl and brine, dried,
and evaporated. The remaining residue was flash chromato-
graphed (pentane) to give 6.8 mg (60%) of 37 as a colorless
oil: 1H NMR (benzene-d6) δ 0.26 (d, J ) 3.6 Hz, 1H), 0.91 (d,
J ) 3.6 Hz, 1H), 1.01 (s, 3H), 1.09 (s, 3H), 1.14 (s, 6H), 1.32
(dd, J ) 13.0, 1.4 Hz, 1H), 1.40 (app t, J ) 11.9 Hz, 1H), 1.60
(m, 1H), 1.68 (dd, J ) 13.0, 7.7 Hz, 1H), 1.81 (br s, 3H), 2.30-
2.38 (m, 2H), 4.86 (br s, 1H); 13C NMR (benzene-d6) δ 17.20,
21.16, 21.66, 22.14, 25.73, 29.14, 32.03, 32.25, 37.69, 38.97,
43.69, 45.59, 48.82, 123.22, 137.72; HRMS calcd for C15H24 (M+)
204.1878, found 204.1876.
(1a R,3a S,6a S,6bR)-1a -Allyl-5,5,6b-tr im eth ylocta h yd r o-
cyclop r op a [e]in d en -2(1H)-on e (40). To a solution of 38
(0.560 g, 1.29 mmol) in 10 mL of CH2Cl2 at room temperature
were added 0.69 mL (3.25 mmol) of HMDS and 0.37 mL (2.60
mmol) of TMSI. The reaction mixture was stirred for 35 min
and, after addition of saturated aqueous NaHCO3, diluted with
ether. The two-phase system was separated, and the organic
layer was washed with saturated aqueous Na2S2O3 and brine.
Drying and evaporation gave an oily residue (0.537 g) which
was treated with MgI2 and HMDS for 1.5 h as described above
for 31. Workup and flash chromatography [10:1 petroleum
ether (bp 40-60 °C)/EtOAc] gave 0.247 g (82%) of 40 as a
colorless oil: [R]20D ) -29° (c 1.85, CHCl3); 1H NMR (benzene-
d6) δ 0.37 (d, J ) 5.0 Hz, 1H), 0.82 (s, 3H), 0.91 (s, 3H), 0.94
(m, 1H), 0.96 (s, 3H), 1.01 (d, J ) 5.0 Hz, 1H), 1.12 (app t, J
) 12.5 Hz, 1H), 1.37 (dd, J ) 13.3, 6.7 Hz, 1H), 1.47 (dd, J )
12.5, 6.5 Hz, 1H), 1.75-2.26 (m, 5H), 2.84 (dd, J ) 14.9, 6.7
Hz, 1H), 5.02 (br d, J ) 10.2 Hz, 1H), 5.07 (br d, J ) 17.0 Hz,
1H), 6.07 (ddt, J ) 17.0, 10.2, 6.6 Hz, 1H); 13C NMR (benzene-
d6) δ 20.60, 26.30, 30.91, 31.42, 32.40, 33.31, 35.56, 37.20,
38.80, 40.85, 43.44, 45.32, 48.98, 115.63, 137.45, 207.50; HRMS
calcd for C16H24O (M+) 232.1827, found 232.1824.
and 22.0 mg (159 µmol) of K2CO3 in 2 mL of EtOH was heated
at 60 °C for 2 h. Upon cooling to room temperature, ether was
added, and the organic phase was washed with brine, dried,
and evaporated. The remaining residue was flash chromato-
graphed [5:1 petroleum ether (bp 40-60 °C)/EtOAc] to give
28.3 mg (76%) of 42 as a 10:1 mixture of E and Z isomers,
respectively. Repeated flash chromatography [5:1 petroleum
ether (bp 40-60 °C)/EtOAc] gave the E isomer in pure form
along with an almost pure sample of the Z isomer. E isomer:
1
[R]20 ) +20° (c 1.16, CHCl3); H NMR (400 MHz, benzene-
D
d6) δ 0.82 (s, 3H), 0.90 (s, 3H), 0.90 (d, J ) 5.2 Hz, 1H), 0.93
(s, 3H), 1.05 (dd, J ) 13.2, 3.8 Hz, 1H), 1.11 (app t, J ) 12.5
Hz, 1H), 1.14 (d, J ) 5.2 Hz, 1H), 1.41 (ddd, J ) 13.2, 7.3, 0.8
Hz, 1H), 1.48 (dd, J ) 12.5, 6.6 Hz, 1H), 1.65 (dd, J ) 6.5, 1,6
Hz, 3H), 1.89-1.99 (m, 2H), 2.16 (dt, J ) 12.4, 7.0 Hz, 1H),
2.23 (m, 1H), 5.31 (dq, J ) 15.5, 6.5 Hz, 1H), 6.09 (dd, J )
15.5, 1.6 Hz, 1H); 13C NMR (100 MHz, benzene-d6) δ 18.20,
20.54, 24.79, 30.60, 31.22, 35.79, 36.45, 37.42, 41.37, 42.12,
43.30, 45.90, 49.73, 127.40, 127.62, 206.98; HRMS calcd for
C16H24O (M+) 232.1827, found 232.1825. Z isomer: 1H NMR
(benzene-d6) δ 0.58 (d, J ) 4.8 Hz, 1H), 0.83 (s, 3H), 0.93 (s,
3H), 0.96 (s, 3H), 0.99-1.53 (m, 4H), 1.28 (d, J ) 4.8 Hz, 1H),
1.63 (br d, J ) 6.8 Hz, 3H), 1.69-2.03 (m, 2H), 2.05-2.41 (m,
2H), 5.40 (br d, J ) 10.6 Hz, 1H), 5.80 (dq, J ) 10.6, 6.8 Hz,
1H); 13C NMR (benzene-d6) δ 14.78, 21.25, 28.68, 30.68, 31.42,
33.19, 35.87, 37.27, 38.36, 40.87, 42.91, 45.27, 48.97, 126.97,
131.26, 204.76; HRMS calcd for C16H24O (M+) 232.1827, found
232.1825.
(1a S,3a R,6a S,6bR)-5,5,6b-Tr im eth yl-1a -[(1E)-1-p r op e-
n yl]-1,1a ,3a ,4,5,6,6a ,6b-octa h yd r ocyclop r op a [e]in d en -2-
yl Tr iflu or om eth a n esu lfon a te (45). To a solution of 66.6
mg (287 µmol) of 42 (E isomer) and 205.0 mg (573 µmol) of
Tf2NPh in 5 mL of THF, cooled to -78 °C, was added KHMDS
(1.15 mL of 0.5 M in toluene). After being stirred at -78 °C
for 1 h, the reaction mixture was quenched with brine, allowed
to come to room temperature, and diluted with ether. The
organic layer was washed with brine, dried, and evaporated.
The remaining residue was flash chromatographed [10:1
petroleum ether (bp 40-60 °C)/EtOAc] to give 98.4 mg (94%)
of 45 as a colorless oil: [R]20D ) -37° (c 0.51, CHCl3); 1H NMR
(benzene-d6) δ 0.82 (d, J ) 4.8 Hz, 1H), 0.84 (s, 3H), 0.86 (s,
3H), 0.93 (d, J ) 4.8 Hz, 1H), 0.95 (s, 3H), 1.07 (dd, J ) 13.3,
1.4 Hz, 1H), 1.22 (m, 1H), 1.39-1.52 (m, 2H), 1.60 (dd, J )
3.5, 1.2 Hz, 3H), 1.95-2.10 (m, 2H), 5.08 (br s, 1H), 5.40-
5.51 (m, 2H); 13C NMR (benzene-d6) δ 17.68, 20.59, 26.65,
28.89, 29.46, 31.50, 31.75, 37.34, 37.78, 41.12, 45.15, 47.65,
116.96, 119.20 (q, J C,F ) 320 Hz), 125.99, 131.75, 150.47;
HRMS calcd for C17H23 F3O3S (M+) 364.1320, found 364.1321.
(1a R ,3a R ,6a S ,6b R )-1a -(H yd r oxym e t h yl)-5,5,6b -t r i-
m eth yl-1,1a ,3a ,4,5,6,6a ,6b-octa h yd r ocyclop r op a [e]in d en -
2-yl Tr iflu or om eth a n esu lfon a te (49). A solution of 34.1 mg
(94 µmol) of 45 in 5 mL of CH2Cl2 was cooled to -78 °C, and
O3 was bubbled through the solution until the solution turned
faintly blue. Dry N2 was then bubbled through the stirring
solution until the blue color disappeared, and at that moment
a few drops of DMS were added.46 After 10 min, 18.5 mg of
NaBH4 (0.49 mmol) and 5 mL of MeOH were added, and the
reaction mixture was allowed to come to room temperature
and stirred for 40 min. The reaction mixture was then
quenched with 1 M aqueous HCl and diluted with ether. The
organic layer was washed with brine, dried, and evaporated.
The remaining residue was flash chromatographed [3:1 pe-
troleum ether (bp 40-60 °C)/EtOAc] to afford 12.9 mg (39%)
of 49 as a colorless oil: [R]20D ) -31° (c 0.25, CHCl3); 1H NMR
(benzene-d6) δ 0.34 (d, J ) 4.8 Hz, 1H), 0.46 (br s, OH), 0.79
(d, J ) 4.8 Hz, 1H), 0.84 (s, 3H), 0.93 (s, 3H), 0.98 (s, 3H),
1.05 (dd, J ) 13.3, 1.5 Hz, 1H), 1.36-1.49 (m, 3H), 1.90-2.02
(m, 2H), 2.90 (br ABd, J ) 12.1 Hz, 1H), 4.11 (br ABd, J )
(46) Quenching with DIBAL-H instead of DMS gave 49 (35%) along
with some impure aldehyde 44: 1H NMR (major peaks, benzene-d6) δ
0.76 (s, 3H), 0.84 (s, 3H), 0.85 (s, 3H), 5.10 (d, J ) 2.2 Hz, 1H), 9.60 (s,
1H). Reduction of the impure fraction containing 44 with NaBH4 gave
another portion of 49 through which the total yield of 49 in this two-
step reaction amounted to 50%.
(1a S,3a S,6a S,6b R)-5,5,6b -Tr im et h yl-1a -[(1-p r op en yl]-
octa h yd r ocyclop r op a [e]in d en -2(1H)-on e (42). A mixture
of 36.8 mg (159 µmol) of 40, 4.7 mg (18 µmol) of RhCl3‚H2O,

Total Synthesis of (+)-Isovelleral
J . Org. Chem., Vol. 66, No. 7, 2001 2357
12.1 Hz, 1H), 5.15 (br s, 1H); 13C NMR (benzene-d6) δ 20.24,
26.65, 28.03, 28.13, 31.60 (2C), 37.41, 37.52, 41.49, 45.01,
47.62, 61.15, 118.29, 119.18 (q, J C,F ) 320 Hz), 150.01; HRMS
calcd for C15H21F3O4S (M+) 354.1113, found 354.1112.
(1a S ,5a S ,8a S ,8b R )-7,7,8b -Tr im e t h yl-5a ,6,7,8,8a ,8b -
h e xa h yd r ocyclop r op a [4,5]in d e n o[5,6-c]fu r a n -4(1H )-
on e (50). Enol triflate 49 (10.4 mg, 29 µmol) was treated with
a mixture of MeOH, Et3N, Ph3P, and Pd(OAc)2 in DMF under
a CO atmosphere for 3.5 h as described for 45.11 Workup and
flash chromatography [3:1 petroleum ether (bp 40-60 °C)/
EtOAc] gave 5.8 mg (85%) of 50 as a white solid: [R]20D ) -16°
(c 0.29, CHCl3); 1H NMR (400 MHz, benzene-d6) δ 0.66 (s, 3H),
0.68 (d, J ) 4.5 Hz, 1H), 0.80-0.86 (m, 2H), 0.82 (s, 3H), 0.83
(s, 3H), 1.14 (dd, J ) 13.4, 1.7 Hz, 1H), 1.21 (m, 1H), 1.48 (dd,
J ) 13.4, 8.4 Hz, 1H), 1.95-2.06 (m, 2H), 3.64 (ABd, J ) 8.8
Hz, 1H), 3.82 (ABd, J ) 8.8 Hz, 1H), 6.18 (d, J ) 2.1 Hz, 1H);
13C NMR (100 MHz, benzene-d6) δ 19.07, 24.97, 26.76, 26.95,
31.70, 31.84, 37.56, 40.12, 42.28, 44.57, 47.30, 69.89, 130.20,
133.50, 168.82; HRMS calcd for C15H20O2 (M+) 232.1463, found
232.1463.
washed with brine. The organic layer was dried and evapo-
rated to give 5.6 mg of ((1aS,3aS,6aS,6bR)-2-(hydroxymethyl)-
5,5,6b-trimethyl-3a,4,5,6,6a,6b-hexahydrocyclopropa[e]inden-
1a(1H)-yl)methanol as a white solid: HRMS calcd for C15H24O2
(M+) 236.1776, found 236.1782. The NMR data were identical
with those reported in the literature.31 This diol (5.6 mg) was
oxidized with oxalyl chloride and DMSO as described.31
Workup and flash chromatography [5:1 petroleum ether (bp
40-60 °C)/EtOAc] afforded 3.2 mg (55%) of 41 as a white
solid: [R]20 ) +234° (c 0.16, CHCl3) (lit.30 [R]20 ) +251°);
D
D
HRMS calcd for C15H20O2 (M+) 232.1463, found 232.1464. The
NMR data were identical with those reported in the litera-
ture. 31
Ack n ow led gm en t. We thank A. van Veldhuizen for
recording NMR spectra and C. J . Teunis and H. J onge-
jan for mass spectral data. In addition, we thank Dr.
H. Zuilhof for carrying out ab initio calculations.
(+)-Isoveller a l (41). To a solution of 5.8 mg (25 µmol) of
50 in 2 mL of ether, cooled to -78 °C, was added DIBAL-H
(125 µL of 1 M in hexane). The solution was stirred at -78 °C
for 15 min and then allowed to warm to room temperature.
Another 50 µL of DIBAL-H was added, and stirring was
continued for an additional 25 min. The reaction mixture was
quenched with 1 M aqueous HCl, diluted with ether, and
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of 6, 11-13, 17-21, 25, 29-31, 38,
39, 43, and 46-48. 1H NMR spectra for all new compounds
and 1H-coupled 13C NMR spectrum of 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0015568