Concise total syntheses of the sesquiterpenoids (-)-homalomenol A and (-)-homalomenol B

Article abstract of DOI:10.1021/jo961605+

The conjugate additions of the organocopper(I) reagents 22 and 27 to the enantiomerically homogeneous bicyclic enone 4 provided, after epimerization (NaOMe, MeOH) of the resultant product mixtures and appropriate chromatographic separations, the bicyclo[4.3.0]nonan-2-ones 24 and 28. Compounds 24 and 28 were readily converted, via two synthetic steps in each case, into the sesquiterpenoids (-)-homalomenols B (2) and A (1), respectively.

Full text of DOI:10.1021/jo961605+

J . Org. Chem. 1996, 61, 8439-8447
8439
Con cise Tota l Syn th eses of th e Sesqu iter p en oid s (-)-Hom a lom en ol
A a n d (-)-Hom a lom en ol B
Edward Piers* and Renata M. Oballa
Department of Chemistry, University of British Columbia, 2036 Main Mall, University Campus,
Vancouver, British Columbia, Canada V6T 1Z1
Received August 19, 1996X
The conjugate additions of the organocopper(I) reagents 22 and 27 to the enantiomerically
homogeneous bicyclic enone 4 provided, after epimerization (NaOMe, MeOH) of the resultant product
mixtures and appropriate chromatographic separations, the bicyclo[4.3.0]nonan-2-ones 24 and 28.
Compounds 24 and 28 were readily converted, via two synthetic steps in each case, into the
sesquiterpenoids (-)-homalomenols B (2) and A (1), respectively.
Sch em e 1
In tr od u ction
The sesquiterpenoids homalomenols A (1) and B (2)
have been isolated from the chloroform extract of the
roots of Homalomena aromatica (Roxb.) Schott (Arace-
ae).1 These roots are used in Vietnamese folk medicine
as an anti-inflammatory agent, as a tonic drug, and for
the treatment of stomach diseases.1 On the basis of
evidence from circular dichroism measurements,1 it is
likely that the absolute configurations of (+)-homalom-
enols A and B are enantiomeric with those shown by the
structural formulas 1 and 2, respectively. This initial
assignment of absolute configuration is now confirmed
by the enantiocontrolled syntheses of (-)-homalomenols
A (1) and B (2). A natural product very similar in
structure to the homalomenols, oppositol (3), has been
isolated from the marine red alga Laurencia subopposita
Setchell.2 The absolute stereochemistry of 3 was deter-
mined via a single-crystal X-ray diffraction analysis.2
Although the total syntheses of homalomenols A and
B have not been reported previously, a biomimetic
synthesis3a of (()-3 from germacrene-D, an arduous 28-
step synthesis3b of (()-3, and a formal total synthesis3c
of (-)-3 have been described. We report herein relatively
short total syntheses of (-)-homalomenols A (1) and B
(2) via routes in which the key steps involve stereoselec-
tive conjugate addition reactions to the intermediate
bicyclo[4.3.0]non-9-en-2-one 4 (Scheme 1). The stereo-
chemical outcomes of these additions were predicted to
parallel those obtained in the previously reported con-
jugate addition reactions of the organocopper(I) reagent
6 to the enones 5 (Scheme 2).4
Sch em e 2
Interestingly, prior to our work,4 very little was known
about the stereochemical outcome of the conjugate ad-
dition of organocopper(I) reagents to bicyclo[4.3.0]non-
9-en-2-ones.5 We have found that the conjugate addition
of reagent 6 to enones of general structure 5 proceeds
completely stereoselectively, with the 3-(trimethylger-
myl)-3-butenyl group being introduced trans to the
angular R′ group (Scheme 2).4 In all cases, except when
both R and R′ ) Me, the major cis-fused isomer 7 initially
isolated from the reaction mixture could be equilibrated
with NaOMe/MeOH to produce a mixture of epimers in
which the trans-fused substance 8, the thermodynami-
cally more stable of the two epimers, predominates.
These equilibration results are consistent with those
reported in the literature for structurally related com-
pounds.6
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) Sung, T. V.; Steffan, B.; Steglich, W.; Klebe, G.; Adam, G.
Phytochemistry 1992, 31, 3515.
(2) Hall, S. S.; Faulkner, D. J .; Fayos, J .; Clardy, J . J . Am. Chem.
Soc. 1973, 95, 7187.
(3) (a) Shizuri, Y.; Yamaguchi, S.; Terada, Y.; Yamamura, S.
Tetrahedron Lett. 1986, 27, 57. (b) Fukuzawa, A.; Sato, H.; Masamune,
T. Tetrahedron Lett. 1987, 28, 4303. (c) Sato, Y.; Mori, M.; Shibasaki,
M. Tetrahedron: Asymmetry 1995, 6, 757.
The bicyclo[4.3.0]non-9-en-2-one 4 was to be derived
from the enone 9 via a five-membered ring annulation
(4) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5857.
(5) Wang, X.; Paquette, L. A. Tetrahedron Lett. 1993, 34, 4579.
(6) Cicero, B. L.; Weisbuch, F.; Dana, G. J . Org. Chem. 1981, 46,
914.
S0022-3263(96)01605-2 CCC: $12.00 © 1996 American Chemical Society

8440 J . Org. Chem., Vol. 61, No. 24, 1996
Piers and Oballa
Sch em e 3
Sch em e 5
Sch em e 4
In the preparation of the racemic acetate 10 described
in the literature,8 the crude epoxide 14 was immediately
converted to the allylic alcohol rac-15 with Et3N (Scheme
5). We discovered that rac-15 is quite unstable to
purification and cannot be stored without decomposition
for any length of time. Consequently, a modified proce-
dure that allowed direct conversion of the epoxide 14 into
the allylic acetate rac-10 was developed (Scheme 4). To
that end, treatment of the epoxide 14 with acetic anhy-
dride in the presence of i-Pr2NEt and 4-(dimethyl-
amino)pyridine (DMAP) provided, after flash chroma-
tography of the crude product and distillation of the
acquired oil, the stable racemic acetate 10 in 84% yield.
The kinetic resolution of racemic 10 was accomplished
according to the procedure of Polla and Frejd.8 Thus,
treatment of rac-10 with the enzyme pig liver esterase
(PLE)9 in the presence of a 0.3 M Tris-HCl buffer (pH 7)
and 25% DMSO resulted in the isolation of the (R)-allylic
alcohol (+)-15 and the unreacted (S)-allylic acetate (-)-
10. If the reaction was allowed to proceed to ∼36%
conversion, the enantiomeric excess recorded for the
alcohol (+)-15 was only 88%.10 However, in line with
other findings of Polla and Frejd,8 we were able to obtain
(-)-10 in higher ee by increasing the degree of conver-
sion.11 By hydrolyzing rac-10 with PLE to an extent of
59%, the unreacted acetate (-)-10 was isolated in 40%
yield and >99% ee. The enantiomeric excess of (-)-10
was determined by hydrolyzing this material with Na2-
CO3 in MeOH and esterifying the resultant alcohol (-)-
15 with (-)-menthoxyacetic acid (16) (Scheme 4).12 The
1H NMR spectrum of the ester 17 in the presence of 0.1-
0.2 equiv of Eu(fod)3 revealed the presence of only one
diastereomer. Since the (S)-allylic acetate (-)-10 could
be obtained in an enantiomeric purity significantly higher
than that of the (R)-allylic alcohol (+)-15 (>99 vs 88%
ee, respectively), we elected to carry out the syntheses
of (-)-homalomenols A and B rather than those of the
naturally occurring (+)-homalomenols.
sequence (Scheme 3). Intermediate 9, in turn, was
envisaged to be obtained from a protecting group ma-
nipulation sequence involving the known homochiral
allylic acetate (-)-10.
(b) P r ep a r a tion of th e Bicyclic En on e 4. For the
synthesis of the intermediate bicyclic enone 4, the acetyl
function of (-)-10 was replaced by a more chemoresistant
group, namely, a tert-butyldiphenylsilyl (TBDPS) protect-
ing group (Scheme 6). Thus, base hydrolysis of (-)-10
was followed immediately by conversion of the resultant,
rather unstable (vide supra) alcohol (-)-15 into the
TBDPS ether 9 (80% overall yield).
Resu lts a n d Discu ssion
(a ) P r ep a r a tion of (S)-(-)-4-Acetoxy-3-m eth yl-2-
cycloh exen -1-on e ((-)-10). The synthesis of the enan-
tiomerically pure allylic acetate (-)-10 was readily
accomplished via the route outlined in Scheme 4. Reduc-
tion (Li/NH3, t-BuOH)7 of commercially available 3-meth-
ylanisole (11) afforded the (crude) enol ether 12, which
was hydrolyzed with aqueous oxalic acid to yield 3-meth-
yl-3-cyclohexen-1-one (13) in 84% overall yield. Although
Polla and Frejd reported8 that the enone 13 could be
transformed into the epoxide 14 with peroxyacetic acid
(Scheme 5), we found that employing m-chloroperoxy-
benzoic acid (m-CPBA) as the epoxidation reagent in
place of AcO2H afforded the epoxide 14 in 94% yield
(Scheme 4).
Conversion of the enone 9 into the bicyclic substance
4 was accomplished by employing a modified version of
the five-membered-ring annulation sequence reported by
(9) PLE was purchased as a suspension in 3.2 M (NH4)2SO4, pH 8,
from Sigma.
(10) In Polla and Frejd’s work,8 the alcohol (+)-15 was obtained in
90% ee following a 45% enzymatic conversion. These workers explored
the use of a number of other enzyme systems, but the enantiomeric
excess of (+)-15 could not be improved upon.8
(11) For a quantitative treatment of biochemical kinetic resolution,
see: Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.
(7) Rubottom, G. M.; Gruber, J . M. J . Org. Chem. 1977, 42, 1051.
(8) Polla, M.; Frejd, T. Tetrahedron 1991, 47, 5883.
(12) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.

(-)-Homalomenol A and (-)-Homalomenol B
J . Org. Chem., Vol. 61, No. 24, 1996 8441
Sch em e 6
Sch em e 7
resonances at δ 3.76-3.80 (dd, J ) 11, 4 Hz, H-5) and
6.42-6.66 (dd, J ) 2.5, 2.5 Hz, H-9).
(c) Syn th esis of (-)-Hom a lom en ol B (2). For the
synthesis of (-)-2, the stereoselective conjugate addition
of the organocopper(I) reagent 22 to the bicyclic enone 4
was required (Scheme 7). Initial attempts to prepare
reagent 22 by reaction of methallyl bromide with either
magnesium or t-BuLi failed due to the sole formation of
the coupled product, 2,5-dimethyl-1,5-hexadiene.19 How-
ever, following the procedure reported by Lipshutz and
co-workers,20 the organocopper(I) reagent 22 was pre-
pared from 2-methyl-3-(tri-n-butylstannyl)propene (21)21
by sequential treatment of the latter substance with
n-BuLi and LiCl/CuI. For this convenient procedure to
work well, it was found necessary to use freshly recrys-
tallized CuI.22
Helquist and co-workers.13 Copper(I)-catalyzed conjugate
addition of the Grignard reagent 1814 to 9 in the presence
of HMPA and TMS-Cl15 provided, after an appropriate
workup procedure, the keto acetal 19, accompanied by a
small amount of the diacetal 20 (Scheme 6). Flash
chromatography of this mixture and subsequent crystal-
lization of 19 from the mixed fractions afforded the
desired acetal 19 in 88% yield. Only one stereoisomer
1
was evident in the H NMR spectrum of 19. Thus, the
The conjugate addition of reagent 22 to the bicyclic
enone 4 in the presence of TMS-Br23 provided, after
hydrolysis of the resultant silyl enol ether, a mixture of
epimeric adducts 23 and 24 in a ratio of 7:1 (overall yield
aforementioned copper-catalyzed Grignard addition had
proceeded in the precedented8,16 stereoselective manner,
trans to the oxygen substituent at carbon 4. The con-
figuration of the product 19 was subsequently confirmed
(vide infra).
In attempts to effect the conversion of the keto acetal
19 into the enone 4, the conditions reported by Helquist
and co-workers13 (HCl/H2O/THF) could not be employed
because the TBDPS ether would, in all likelihood, be
hydrolyzed.17 Initial attempts to promote the aldol
cyclization resulted in the nearly quantitative recovery
of starting material.18 Hanessian and Lavallee17 have
shown that TBDPS ethers are stable to 50% aqueous CF3-
CO2H in dioxane at room temperature; however, these
conditions also failed to effect the cyclization. On the
other hand, heating a mixture of the keto acetal 19 in
80% aqueous CF3CO2H/dioxane (1:2) for 16 h accom-
plished the required cyclization reaction and produced
the bicyclic enone 4 in 82% yield (Scheme 6). The IR
spectrum of enone 4 revealed absorbances at 1687 and
1618 cm-1, characteristic of an R,â-unsaturated ketone.
of 93%, see Scheme 7). It was gratifying to find that the
conjugate addition had proceeded stereoselectively, as
expected (vide supra). The cis- and trans-fused epimers
23 and 24 were easily separated by flash chromatography
of the mixture on silica gel, and their relative configura-
(19) Allylic halides are known to be quite reactive and prone to
Wurtz coupling. See: Lipshutz, B. H.; Crow, R.; Dimock, S. H.;
Ellsworth, E. L.; Smith, R. A. J .; Behling, J . R. J . Am. Chem. Soc. 1990,
112, 4063. Katzenellenbogen, J . A.; Lenox, R. S. J . Org. Chem. 1973,
38, 326. Seyferth, D.; Weiner, M. A. Organolithium Compd. 1961, 26,
4797.
1
The H NMR spectrum (400 MHz, CDCl3) of 4 revealed
a three-proton signal at δ 1.20 (s, Me-10) and one-proton
(20) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A.
J . J . Am. Chem. Soc. 1990, 112, 4404.
(21) The allylstannane 21 was prepared from the commercially
available 3-chloro-2-methylpropene and tri-n-butylstannyl chloride as
described by: Keck, G. E.; Enholm, E. J .; Yates, J . B.; Wiley, M. R.
Tetrahedron 1985, 41, 4079.
(22) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 9.
(23) The use of TMS-Br instead of TMS-Cl was found to increase
the overall yield of the conjugate addition reaction by 16%. For the
use of TMS-Br as an additive in conjugate addition reactions, see:
Cahiez, G.; Venegas, P.; Tucker, C. E.; Majid, T. N.; Knochel, P. J .
Chem. Soc., Chem. Commun. 1992, 1406. Bergdahl, M.; Lindstedt, E.-
L.; Nilsson, M.; Olsson, T. Tetrahedron 1989, 45, 535.
(13) Bal, S. A.; Marfat, A.; Helquist, P. J . Org. Chem. 1982, 47, 5045.
Marfat, A.; Helquist, P. Tetrahedron Lett. 1978, 4217.
(14) Stowell, J . C. J . Org. Chem. 1976, 41, 560. Stowell, J . C. Chem.
Rev. 1984, 84, 409.
(15) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025.
(16) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015.
(17) Hanessian, S.; Lavallee, P. Can. J . Chem. 1975, 53, 2975.
(18) Conditions that failed to promote the cyclization are as fol-
lows: PPTS, aqueous acetone, heat, 15 h; 80% aqueous AcOH, THF,
rt, 4 h; p-toluenesulfonic acid, CH2Cl2, heat, 5 h; 50% aqueous CF3-
CO2H, dioxane, rt, 4 h.

8442 J . Org. Chem., Vol. 61, No. 24, 1996
Piers and Oballa
Sch em e 8
Sch em e 9
Sch em e 10
tions were confirmed by the following 1H NMR NOE
difference experiments.
For the major cis-fused epimer 23, irradiation of the
signal at δ 1.18 (Me-10) caused an enhancement of the
signal at δ 2.49-2.52 (H-1) and vice versa (see 23a ).
These experiments confirmed the cis-fused nature of the
ring junction. Irradiation of the signal at δ 3.74-3.77
(H-5) caused an enhancement of the signal at δ 1.56-
1.70 (H-11), thereby verifying that reagent 22 had
introduced the methallyl group trans to the angular
methyl group, as predicted. For the minor trans-fused
epimer 24, irradiation of the signal at δ 0.89 (Me-10)
caused an enhancement of the signal at δ 2.44-2.51 (H-
9) and vice versa (see 24a ). In addition, saturation of
the resonance at δ 3.33-3.44 (H-5) increased the inten-
sity of the H-1 signal (δ 1.87-1.90). Collectively, these
experiments not only confirmed the stereochemical out-
come of the conjugate addition reaction but also verified
that the ring junction in 24 is trans-fused.24
The epimer required for the synthesis of (-)-2 was, in
fact, the minor product 24. According to our previous
studies4 and results reported by Dana and co-workers,6
24 should be thermodynamically more stable than the
corresponding cis-fused epimer 23. In fact, treatment of
23 with NaOMe in MeOH resulted in a 7:1 mixture of
24 and 23, respectively (see Scheme 7). These two
diastereomers were separated by flash chromatography
on silica gel, and the recovered cis-fused epimer 23 was
resubjected to the epimerization conditions. The total
yield of the desired synthetic intermediate 24 after two
such epimerizations and chromatographic separations
was 87%, based on the enone 4.
acetate/petroleum ether provided a colorless, crystalline
solid, mp 94-95 °C (lit.1 mp 78-81 °C). The IR, 1H NMR,
13C NMR, and HRMS data derived from the synthetic
(-)-2 are identical with those of natural (+)-homalomenol
B.1 That the absolute configuration of the synthetic
material is opposite to that of the natural product was
confirmed by the sign of the specific optical rotation
(observed [R]20 -43.0 (c 1.71, CHCl3) for the synthetic
D
material; reported1 [R]20 +20.4 (c 1.745, CHCl3) for the
D
natural product). Thus, the synthesis of (-)-2 was
accomplished in a concise and enantioselective manner.
The overall yield of (-)-2 from the homochiral acetate
(-)-10 was 42%.
(d ) Syn th esis of (-)-Hom a lom en ol A (1). For the
synthesis of (-)-1, the conjugate addition of the organo-
copper(I) reagent 27 to the enone 4 to produce the ketone
28 was required (Scheme 9). The formation of the
required vinyllithium species 26 was found to occur much
more smoothly from reaction of t-BuLi with 1-iodo-2-
methylpropene26 than from an analogous protocol involv-
ing the corresponding bromide.27 Addition of a solubi-
lized solution of CuCN (1 equiv) and LiCl (2 equiv) in
THF28 to the vinyllithium species 26 produced the desired
organocopper(I) reagent 27. Reaction of 27 with the
bicyclic enone 4 in the presence of TMS-Br23 and BF3‚
Et2O afforded, after hydrolysis of the resultant silyl enol
ethers, a mixture of three isomeric products 28, 29, and
30 in a ratio of 4:62:34, respectively (81% overall yield,
see Scheme 10).
Reaction of 24 with MeLi provided a single tertiary
alcohol in 87% yield (Scheme 8). Since axial approach
of MeLi to the carbonyl moiety of 24 would involve a 1,3-
diaxial interaction between the angular methyl group and
the incoming reagent, it was expected that this process
would involve equatorial attack to produce the axial
alcohol 25.25 The fact that the latter substance was the
By changing the additives used in the conjugate
addition reaction or modifying the nature of the organo-
(26) Takagi, K.; Hayama, N.; Inokawa, S. Chem. Lett. 1978, 1435.
(27) Reaction of 1-bromo-2-methylpropene with t-BuLi in THF,
followed by addition of cyclohexanone, gave a product mixture that
consisted of a 5:1 mixture of the expected product 32 and the diene
alcohol 33, respectively (eq 1).
1
sole product was confirmed by a H NMR NOE difference
experiment in which irradiation of the signal at δ 1.17
(Me-10) caused enhancement of the H-1 resonance at δ
0.79 (see 25a ).
Treatment of 25 with tetrabutylammonium fluoride
(TBAF) in refluxing THF afforded (-)-2 in 95% yield
(Scheme 8). Recrystallization of the product from ethyl
(24) Examination of molecular models indicates that a NOE en-
hancement between H-9 and Me-10 is possible only when the ring
junction is trans-fused.
(25) For an equatorial approach of MeLi to a carbonyl group in a
structurally related compound, see: Reference 3.
(28) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J . J . Org. Chem.
1988, 53, 2390.

(-)-Homalomenol A and (-)-Homalomenol B
J . Org. Chem., Vol. 61, No. 24, 1996 8443
Sch em e 11
copper(I) reagent (e.g., using the higher order cuprate
reagent derived from 2 equiv of 26 and 1 equiv of CuCN),
the ratio of the desired (28 and 29) to undesired (30)
adducts varied from 1.9:1 (Scheme 10) to 1:2.29 When
the mixture of adducts 28, 29, and 30 was treated with
NaOMe/MeOH, the trans- and cis-fused isomers 28 and
29, each possessing the correct (S) configuration at C-9,
were equilibrated to a mixture with a ratio of 1.3:1,
respectively.30 On the other hand, as expected, the cis-
fused compound 30 with the incorrect (R) configuration
at C-9 did not epimerize under these conditions. It is
evident from an examination of molecular models that
the trans-fused epimer of 30 would be notably destabi-
lized by a pseudo-1,3-diaxial interaction between the
2-methyl-1-propenyl group and the angular methyl group.
Fortunately, column chromatography (silica gel) ef-
fected clean separation of 28 from the equilibrated
mixture of 28, 29, and 30. The remaining mixture of cis-
fused adducts 29 and 30 was resubjected to the equili-
bration conditions, and the desired isomer 28 was again
separated by chromatography. After three such epimer-
izations and separations, the overall yield of 28 from the
enone 4 was 43%.
(δ 2.79-2.88) upon irradiation of the H-5 signal (δ 3.86-
3.91) (see 30a ) clearly confirmed that this substance is
cis-fused and that, in the conjugate addition reaction, the
2-methyl-1-propenyl group had been introduced cis to the
angular methyl group.
Stereoselective addition of MeLi to the carbonyl moiety
of 28 provided the tertiary alcohol 31 in 80% yield
(Scheme 11). Treatment of 31 with TBAF in refluxing
THF for 18 h provided, in 87% yield, (-)-1. Recrystal-
lization of this material from diethyl ether/petroleum
ether provided thin, needlelike plates that exhibited mp
99-100 °C (lit.1 reports (+)-homalomenol A as an oil).
The IR, H NMR, 13C NMR, and HRMS data for (-)-1
1
are identical with those of the naturally occurring (+)-
homalomenol A.1 That the absolute configuration of the
synthetic (-)-homalomenol A is opposite to that of the
natural product was confirmed by the sign of the specific
optical rotation (observed [R]20D -51.5 (c 1.30, CHCl3) for
The relative configurations of the three adducts 28, 29,
1
and 30 were confirmed by the H NMR NOE difference
experiments depicted on the conformational formulas
28a , 29a , and 30a . With respect to the desired epimer
the synthetic material; reported1 [R]20 +33.2 (c 1.205,
D
CHCl3) for the natural product).
Con clu sion
The work described in this paper culminated in the
first total syntheses of the two sesquiterpenoids (-)-1 and
(-)-2. The key steps of the overall synthetic sequences
involved the conjugate addition of the organocopper(I)
reagents 27 and 22, respectively, to the enantiomerically
homogeneous bicyclic enone 4. In the synthesis of (-)-
2, the conjugate addition of 22 to 4 proceeded stereose-
lectively, and after equilibration and chromatographic
separation of the epimers 23 and 24, the required adduct
24 was obtained in excellent yield. However, in the
synthesis of (-)-1, 1,4-addition of 27 to 4 exhibited rather
poor stereoselectivity. Nonetheless, the desired inter-
mediate 28 was readily obtained, albeit in moderate yield,
from the mixture of adducts (28, 29, 30) and the synthesis
of 1 was easily completed.
28, the mutual enhancements observed upon irradiation
of the resonances due to Me-10 (δ 0.91) and H-9 (δ 3.03-
3.10), as well as the enhancement of the signal (δ 2.01)
derived from H-1 when either the H-5 (δ 3.87-3.91) or
H-11 (δ 4.78) signals were irradiated, confirmed both the
trans-fused nature of the ring junction and the configu-
rational assignment at C-9.
For the cis-fused adduct 29, mutual signal enhance-
ments were observed upon irradiation of the following
pairs of resonances: δ 1.17 (Me-10) and 2.48-2.51 (H-
1), δ 2.48-2.51 (H-1) and 3.12-3.21 (H-9), and δ 3.77-
3.81 (H-5) and 4.51 (H-11) (see 29a ). Collectively, these
experiments verified the cis-fused nature of this com-
pound and the assigned configuration at C-9.
With respect to the product 30, which possesses the
“incorrect” configuration at C-9, the enhancement of the
Me-10 resonance (δ 1.16) upon irradiation of the H-1
signal (δ 2.00), the mutual enhancements caused by
saturation of the H-1 (δ 2.00) and H-11 (δ 4.92) reso-
nances, and the increase of intensity of the H-9 multiplet
Exp er im en ta l Section
Gen er a l Exp er im en ta l Deta ils. Distillation tempera-
tures, which refer to short-path (Kugelrohr) distillations, and
melting points are uncorrected. 1H NMR and 13C NMR spectra
were recorded using CDCl3 as the solvent, and signal positions
(δ values) were measured relative to the signals for CHCl3 (δ
7.26), unless otherwise noted, and CDCl3 (δ 77.0), respectively.
GLC was performed on instruments equipped with capillary
columns (25 m, HP-5) and flame ionization detectors. TLC
was carried out using commercial aluminum-backed silica gel
60 plates. Flash chromatography31 was carried out with 230-
400 mesh silica gel (E. Merck) or 10-50 µm Type H silica (TLC
grade silica).
Et2O and THF were distilled from sodium/benzophenone,
while CH2Cl2, i-Pr2NEt, DMF, DMSO, HMPA, t-BuOH, and
Me3SiCl were distilled from CaH2. Magnesium was added to
MeOH, and after the mixture had been refluxed, the MeOH
was distilled from the resulting solution of magnesium meth-
oxide and was stored over 4 Å molecular sieves. Acetic
(29) It is known that the use of TMS-X and/or BF3‚Et2O can affect
the stereoselectivity of conjugate addition reactions. See: Reference
16. Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J . J . Am. Chem. Soc.
1988, 110, 4834 and citations therein. Lipshutz, B. H.; Ellsworth, E.
L.; Siahaan, T. J .; Shirazi, A. Tetrahedron Lett. 1988, 29, 6677. Zhao,
S.-K.; Helquist, P. Tetrahedron Lett. 1991, 32, 447. Horiguchi, Y.;
Nakamura, E.; Kuwajima, I. J . Org. Chem. 1986, 51, 4323.
(30) This 1.3:1 equilibrium ratio of 28:29 is in contrast to the 7:1
ratio observed for the trans- and cis-fused adducts 24 and 23 used in
the synthesis of (-)-2. Obviously, the nature of the substituent at C-9
has a significant effect on the relative stabilities of 9-substituted
bicyclo[4.3.0]nonan-2-ones.
(31) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8444 J . Org. Chem., Vol. 61, No. 24, 1996
Piers and Oballa
anhydride was refluxed over and then distilled from phospho-
rus pentoxide. Trimethylsilyl bromide was distilled from
calcium hydride using a Kugelrohr distillation apparatus and
was used immediately. BF3‚Et2O was purified by distillation
from calcium hydride under reduced pressure (60 °C (20 Torr)).
CuBr-Me2S complex was prepared by the method described
by Wuts32 and was stored in a desiccator under an atmosphere
of dry argon.
A solution of NaOMe in dry MeOH was prepared as follows.
To a cold (-78 °C) flask containing dry NaH was added the
appropriate amount of dry MeOH. The mixture was stirred
at -78 °C for 10 min, warmed to rt, and used immediately.
Aqueous NH4Cl/NH4OH (pH 8-9) was prepared by the addi-
tion of ∼50 mL of aqueous NH3 (30%) to ∼950 mL of saturated
aqueous NH4Cl.
mmol). The mixture was stirred at rt for 6 h. EtOAc (100
mL) and saturated aqueous NaHCO3 (100 mL) were added,
and the layers were separated. The aqueous layer was
extracted with EtOAc (2 × 75 mL), and the combined organic
extracts were washed (saturated aqueous NaHCO3, 2 × 100
mL; H2O, 100 mL), dried (MgSO4) and concentrated. The
crude product was flash chromatographed (300 g of silica gel,
1:1 petroleum ether/CH2Cl2), and the oil thus obtained was
distilled (90-94 °C (0.2 Torr)) to provide 4.7 g (84%) of the
allylic acetate rac-10,34 a colorless oil.
(R)-(+)-4-Hyd r oxy-3-m eth yl-2-cycloh exen -1-on e ((+)-
15) a n d (S)-(-)-4-Acet oxy-3-m et h yl-2-cycloh exen -1-on e
((-)-10). To a stirred mixture of rac-10 (4.57 g, 27.2 mmol)
in Tris-HCl buffer,35 pH 7 (0.3 M, 600 mL), and DMSO (200
mL) at rt was added PLE (6 mL of enzyme suspension, 100
mg of protein, ∼1.7 × 104 units of activity). The above
materials were dispensed with glass pipets or with Eppendorf
plastic tips. In order to avoid inactivation of the enzyme, metal
needles were not used. The pH of the solution was monitored
using a pH meter (Fischer Accumet pH meter, Model 140) and
was kept at pH 7 by the appropriate addition of 0.1 M aqueous
NaOH. A total of 155 mL of 0.1 M aqueous NaOH was used,
indicating that the reaction had proceeded to the extent of 57%
(i.e., 57% of the racemic acetate had been hydrolyzed to the
corresponding alcohol). Analysis (GLC) at this time (26 h)
confirmed that ∼59% of the acetate had been hydrolyzed. The
solution was extracted with EtOAc (4 × 600 mL), and the
combined organic extracts were washed (brine, 1 × 200 mL),
dried (MgSO4), and concentrated. Flash chromatography (275
g of silica gel, 3:2 petroleum ether/Et2O to elute the unreacted
allylic acetate, followed by 100% EtOAc to elute the allylic
alcohol) provided fractions containing the allylic acetate fol-
lowed by fractions containing the more polar alcohol. Con-
centration of the first set of fractions provided 1.81 g (40%) of
(-)-4-acetoxy-3-methyl-2-cyclohexen-1-one ((-)-10) as a color-
Unless stated otherwise, all reactions were carried out under
an atmosphere of dry argon using glassware that had been
thoroughly flame- and/or oven-dried (∼140 °C).
3-Meth yl-3-cycloh exen -1-on e (13). To cold (-78 °C),
stirred liquid NH3 (200 mL, distilled from sodium) was added
a solution of 3-methylanisole (11; 8.3 mL, 66 mmol) in dry Et2O
(50 mL). This was followed by the addition of t-BuOH (62 mL,
0.66 mol). Li metal (2.3 g, 0.33 mol) was added in small
portions over a period of 15 min. The blue solution was
refluxed at -33 °C for 3.5 h. The reaction mixture was cooled
to -78 °C, and the excess Li was destroyed by portionwise
addition of solid NH4Cl (52 g, 0.97 mol). The cloudy white
suspension was opened to the atmosphere via an air-cooled
condenser, and the NH3 was allowed to evaporate. Pentane
(150 mL) was added, and the flask was warmed in a water
bath to drive off any residual ammonia. H2O (150 mL) was
added, and the layers were separated. The aqueous layer was
extracted with pentane (2 × 90 mL), and the combined organic
extracts were washed (H2O, 4 × 100 mL), dried (MgSO4), and
concentrated by distillation of the solvent at atmospheric
pressure through a jacketed Vigreux column (20 cm) to avoid
loss of product.
less oil ([R]25 -46.7 (c 1.69, CHCl3); lit.,8 -35.1 (c 0.61,
D
CDCl3)). The spectral data are identical with those derived
from rac-10. Concentration of the late fractions afforded 2.0
g (58%) of (+)-4-hydroxy-3-methyl-2-cyclohexen-1-one ((+)-
15).36
The crude enol ether 12 was dissolved in 130 mL of MeOH/
H2O (3:1), oxalic acid dihydrate (412 mg, 3.30 mmol, 5 mol %
with respect to 11) was added, and the resultant mixture was
stirred at rt for 1.5 h. H2O (200 mL) was added and the
suspension was extracted with CH2Cl2 (6 × 100 mL) until the
extracts no longer contained any product, as indicated by GLC
analysis. The combined organic extracts were washed with
H2O (1 × 100 mL), dried (MgSO4), and concentrated by
distillation of the solvent at atmospheric pressure through a
jacketed Vigreux column (20 cm). The oil thus obtained was
distilled (88 °C (50 Torr)) to give 6.0 g (84%) of 13.33
The enantiomeric excess of the desired (-)-10 was ascer-
tained by converting the acetate to the corresponding alcohol
(-)-15 (vide infra), transforming (-)-15 into the ester 17 by
reaction with (-)-menthoxyacetic acid (16),12 and recording the
1H NMR spectrum of this ester in the presence of 0.1-0.2 equiv
of Eu(fod)3. Only one diastereomer was observed; hence an
ee > 99% was obtained.
(S)-(+)-4-(ter t-Bu tyld ip h en ylsiloxy)-3-m eth yl-2-cyclo-
h exen -1-on e (9). To a solution of the allylic acetate (-)-10
(717 mg, 4.26 mmol) in dry MeOH (43 mL) at rt was added
solid Na2CO3 (2.26 g, 21.3 mmol). The heterogeneous reaction
mixture was stirred at rt for 1.5 h. The resultant pink mixture
was filtered, and the filtrate was concentrated under reduced
pressure. The residue was subjected to flash chromatography
(35 g of silica gel, 3:1 EtOAc/petroleum ether) to afford 538
mg (quantitative yield) of the colorless allylic alcohol (-)-15,
which was used immediately in the next step.
To a solution of (-)-15 (538 mg, 4.26 mmol) in dry DMF
(8.5 mL) at rt was added sequentially imidazole (1.16 g, 17.1
mmol) and TBDPS-Cl (2.2 mL, 8.5 mmol). The reaction
mixture was stirred at rt for 15 h, at which time H2O (10 mL)
was added. The aqueous phase was separated and extracted
with Et2O (2 × 50 mL). The combined organic extracts were
washed (H2O, 5 × 30 mL), dried (MgSO4), and concentrated.
The crude product was subjected to flash chromatography (50
g of silica gel, 9:1 petroleum ether/EtOAc) and the viscous oil
thus obtained, upon heating to 70 °C (0.2 Torr) for 1 h to
remove any residual solvent, provided 1.2 g (80%, based on
1-Meth yl-7-oxa bicyclo[4.1.0]h ep ta n -3-on e (14). To a
cold (0 °C), stirred solution of m-CPBA (purity 50-60%, 4.30
g, 12.5 mmol) in dry CH2Cl2 (90 mL) was added, via a large
cannula, a solution of 13 (1.05 g, 9.53 mmol) in dry CH2Cl2 (5
mL). After the mixture had been stirred at 0 °C for 2.5 h,
excess m-CPBA was destroyed by the addition of saturated
aqueous Na2S2O3 (50 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 100 mL).
The combined organic extracts were washed with saturated
aqueous NaHCO3 (5 × 100 mL), dried (MgSO4), and concen-
trated by distillation of the solvent at atmospheric pressure
through a jacketed Vigreux column (20 cm). The oil thus
obtained was distilled (80 °C (32 Torr)) to afford 1.12 g (94%)
of the epoxide 14, a colorless oil: IR (neat) 1713, 1198, 1044
1
cm-1; H NMR (400 MHz) δ 1.36 (s, 3H, Me), 2.14-2.19 (m,
2H), 2.34-2.40 (m, 2 H), 2.56 (d, 1 H, J ) 19 Hz), 2.78 (d, 1H,
J ) 19 Hz), 3.20 (br d, 1 H, J ) 2.5 Hz); 13C NMR (75.3 MHz)
δ 22.1, 22.3, 33.8, 43.8, 56.7, 58.1, 207.7; HRMS calcd for
C7H10O 126.0681, found 126.0677. Anal. Calcd: C, 66.64; H,
7.99. Found: C, 66.51; H, 8.03.
4-Acetoxy-3-m eth yl-2-cycloh exen -1-on e (r a c-10). To a
stirred solution of the epoxide 14 (4.19 g, 33.2 mmol) in dry
CH2Cl2 (110 mL) at rt was added dry Ac2O (6.3 mL, 66 mmol),
DMAP (812 mg, 6.60 mmol), and dry i-Pr2NEt (11.6 mL, 66.5
(34) The spectral data of the allylic acetate 10 are identical with
those reported in ref 8.
(35) The Tris-HCl buffer was prepared by adding 0.3 M aqueous
tris(hydroxymethyl)aminomethane to a stirred aqueous solution of 0.3
M tris(hydroxymethyl)aminomethane hydrochloride until the pH of the
solution reached 7.
(32) Wuts, P. G. M. Synth. Commun. 1981, 11, 139.
(33) The spectral data of 13 are identical with those reported by:
Noyce, D. S.; Evett, M. J . Org. Chem. 1972, 37, 394.
(36) The spectral data of (+)-15 are identical with those reported
in ref 8.

(-)-Homalomenol A and (-)-Homalomenol B
J . Org. Chem., Vol. 61, No. 24, 1996 8445
(-)-10) of the TBDPS ether (+)-937 ([R]25D +8.7 (c 2.05, CHCl3);
lit.,8 +4.7 (c 1.03, CDCl3)).
concentrated, the residue was dissolved in a mixture of dioxane
(16 mL) and 100% CF3COOH (8 mL), and the solution was
heated to 75 °C for 16 h. The reaction mixture was neutralized
with saturated aqueous NaHCO3. The aqueous layer was
separated and extracted with Et2O (3 × 25 mL) and EtOAc (1
× 25 mL). The combined organic extracts were dried (MgSO4)
and concentrated. The residual material was flash chromato-
graphed (25 g of silica gel, 4:1 petroleum ether/Et2O) to yield
a further 81 mg (5%) of (-)-4. The total yield of the enone 4
was 2.14 g (82%): [R]25D -22.2 (c 0.92, CHCl3); IR (neat) 1687,
(3S,4S)-(+)-4-(ter t-Bu tyldiph en ylsiloxy)-3-[2-(1,3-dioxan -
2-yl)eth yl]-3-m eth ylcycloh exa n on e (19). To a stirred sus-
pension of freshly ground Mg turnings (1.01 g, 41.7 mmol) and
I2 (a few crystals) in dry THF (5 mL) at rt was added dropwise
(via a large cannula) a solution of 2-(2-bromoethyl)-1,3-dioxane
(4.06 g, 20.8 mmol) in dry THF (5 mL). Formation of the
Grignard reagent 18 began immediately, and the bromide
solution was added at such a rate that reflux of the reaction
mixture was maintained. After the addition was complete, the
mixture was heated to reflux for an additional 35 min. The
mixture was cooled to rt, diluted with THF (90 mL), and
further cooled to -78 °C. Solid CuBr-Me2S (1.07 g, 5.20
mmol, 25 mol % with respect to 18) was added, and the
resultant cloudy mixture was stirred at -78 °C for 1 h.
Addition of dry HMPA (3.7 mL) was followed by the dropwise
addition (via a large cannula over 10 min) of a solution of the
enone 9 (3.08 g, 8.45 mmol) and TMS-Cl (2.7 mL, 21 mmol) in
dry THF (8 mL). The resultant bright yellow solution was
stirred at -78 °C for 3 h and was then warmed to -50 °C over
a period of 2.5 h, at which point the solution became colorless.
H2O (20 mL) was added, and the mixture was stirred at rt for
2 h, open to the atmosphere, to hydrolyze the silyl enol ether.
Aqueous NH4Cl/NH4OH (pH 8-9, 50 mL) and Et2O (50 mL)
were added, and the mixture was stirred vigorously until the
aqueous phase became bright blue. The layers were separated,
and the aqueous phase was extracted with Et2O (3 × 100 mL).
The combined organic extracts were washed (H2O, 5 × 75 mL),
dried (MgSO4), and concentrated.38 The crude oil thus ob-
tained was subjected to chromatography39 (50 g of TLC grade
silica gel, 5.7:1 petroleum ether/EtOAc), which yielded 3.0 g
of the solid acetal (+)-19, as well as a mixture of 19 and the
byproduct 20. The acetal 19 was separated from this mixture
by crystallization from petroleum ether. The combined acetal
fractions were then recrystallized from petroleum ether to yield
3.6 g (88%) of (+)-19 as a colorless crystalline solid: mp 99-
1
1618, 1428, 1111, 1069, 703 cm-1; H NMR (400 MHz) δ 1.09
(s, 9H), 1.20 (s, 3H), 1.70-1.75 (m, 2H), 1.99-2.08 (m, 3H),
2.26-2.50 (m, 3H), 3.76-3.80 (dd, 1H, J ) 11, 4 Hz, H-5),
6.42-6.43 (dd, 1H, J ) 2.5, 2.5 Hz, H-9), 7.37-7.47 (m, 6H),
7.68-7.72 (m, 4H); 13C NMR (75.3 MHz) δ 17.6, 19.4, 27.0,
29.2, 30.0, 38.1, 40.6, 52.4, 78.2, 127.5, 127.6, 129.6, 129.8,
133.4, 134.5, 135.8, 135.9, 138.3, 147.7, 198.7; HRMS calcd
for C26H32O2Si 404.2171, found 404.2178. Anal. Calcd: C,
77.18; H, 7.97. Found: C, 76.88; H, 7.91.
(1R,5S,6S,9S)-(-)-5-(ter t-Bu tyld ip h en ylsiloxy)-6-m eth -
yl-9-(m et h a llyl)b icyclo[4.3.0]n on a n -2-on e
(23)
a n d
(1S,5S,6S,9S)-(-)-5-(ter t-Bu tyld ip h en ylsiloxy)-6-m eth yl-
9-(m eth a llyl)bicyclo[4.3.0]n on a n -2-on e (24). A suspension
of flame-dried LiCl40 (267 mg, 6.30 mmol) and freshly recrys-
tallized CuI22 (1.20 g, 6.30 mmol) in dry THF (35 mL) was
stirred at rt for 15 min until a clear yellow solution resulted.
The mixture was cooled to -78 °C. To a cold (-78 °C), stirred
solution of 2121 (2.12 g, 6.14 mmol) in dry THF (10 mL) was
added a solution of n-BuLi in hexanes (1.61 M, 3.6 mL, 5.8
mmol). The resultant yellow solution was stirred at -78 °C
for 25 min and was quickly cannulated (via a large cannula)
into the LiCl/CuI/THF solution to produce a clear red solution
containing the organocopper(I) reagent 22. Cannulation of dry
TMS-Br (2.20 g, 14.4 mmol) into the red solution was followed
by the addition of a solution of the enone 4 (829 mg, 2.05 mmol)
in dry THF (5 mL). The reaction mixture was stirred at -78
°C for 5.5 h. H2O (20 mL) was added, and the mixture was
stirred at rt, open to the atmosphere, for 45 min. Aqueous
NH4Cl/NH4OH (pH 8-9, 50 mL) was added, and the mixture
was stirred rapidly until the aqueous layer became bright blue.
The phases were separated, and the aqueous layer was
extracted with Et2O (3 × 75 mL). The combined organic
extracts were washed (brine, 1 × 100 mL), dried (MgSO4), and
concentrated. 1H NMR spectroscopic analysis of the crude oil
thus obtained indicated a 7:1 ratio of the two isomers 23 and
24, as determined by the integration of their respective vinyl
proton signals. The two isomers were easily separated by flash
chromatography (125 g of silica gel, 11.5:1 petroleum ether/
Et2O). The first compound to be eluted was the adduct 24
possessing the trans ring junction. Concentration of the
appropriate fractions, followed by recrystallization (from Et2O/
petroleum ether) of the solid thus obtained, provided 113 mg
(12%) of the trans-fused compound (-)-24, a colorless crystal-
line solid: mp 98-99 °C; [R]25D -37.1 (c 1.27, CHCl3); IR (KBr)
101 °C; [R]25 +15.72 (c 1.62, CHCl3); IR (KBr) 1704, 1588,
D
1145, 1111, 1088, 706 cm-1; 1H NMR (400 MHz) δ 0.96 (s, 3H),
1.09 (s, 9H), 1.27-1.47 (m, 5H), 1.74-1.79 (br ddd, 2H, J )
7.5, 7.5, 5 Hz), 1.96-2.07 (m, 3H), 2.38-2.43 (br dt, 1H, J )
14, 7.5 Hz), 2.47-2.51 (br d, 1H, J ) 14 Hz), 3.65-3.72, 3.66-
3.73 (ddd, 1H each, J ) 12, 12, 2 Hz for each ddd), 3.81-3.84
(dd, 1H, J ) 5, 5 Hz), 4.03-4.07 (br ddd, 2H, J ) 12, 5, 1 Hz),
4.34-4.36 (dd, 1H, J ) 5, 4.5 Hz), 7.35-7.72 (m, 6H), 7.66-
7.72 (m, 4H); 13C NMR (75.3 MHz) δ 19.6, 21.2, 25.7, 27.2,
28.8, 29.0, 33.1, 36.8, 42.7, 49.2, 66.8, 73.9, 102.4, 127.5, 127.6,
129.7, 129.8, 133.4, 134.3, 135.9, 136.0, 211.4; HRMS calcd
for C29H40O4Si 480.2696, found 480.2668. Anal. Calcd: C,
72.46; H, 8.39. Found: C, 72.57; H, 8.52.
(5S ,6S )-(-)-5-(t er t -Bu t yld ip h e n ylsiloxy)-6-m e t h yl-
bicyclo[4.3.0]n on -9-en -2-on e (4). To a stirred solution of the
acetal 19 (2.04 g, 4.24 mmol) in 1,4-dioxane (57 mL) at rt was
added 80% aqueous CF3COOH (28 mL: 5.5 mL H2O + 22.5
mL of 100% CF3COOH). The mixture was heated at 80 °C
for 16.5 h. The dark brown solution was neutralized by the
careful, dropwise addition (via the condenser) of saturated
aqueous NaHCO3. The aqueous phase was separated and
extracted with Et2O (3 × 75 mL) and EtOAc (1 × 75 mL). The
combined organic extracts were dried (MgSO4) and concen-
trated. Flash chromatography (125 g of silica gel, 4:1 petro-
leum ether/Et2O) of the brown oil thus obtained afforded 1.33
g (77%) of the enone (-)-4 as a viscous, yellow oil.
1
1716, 1649, 1590, 1112, 1094, 704 cm-1; H NMR (400 MHz)
δ 0.89 (s, 3H), 1.06 (s, 9H), 1.14-1.34 (m, 2H), 1.65-1.80 (m,
1H), 1.71 (s, 3H), 1.81-1.95 (m, 5H, one of which is H-1 (d, J
) 11 Hz)), 2.01-2.19 (m, 2H), 2.14-2.19 (br dd, 1H, J ) 14,
4.5 Hz), 2.44-2.51 (m, 1H, H-9), 3.33-3.40 (dd, 1H, J ) 10.5,
5 Hz, H-5) 4.59 (br s, 1H), 4.64 (br s, 1H), 7.36-7.52 (m, 6H),
7.66-7.73 (m, 4H); 13C NMR (75.3 MHz) δ 13.3, 19.4, 22.4,
27.0, 27.1, 32.0, 32.6, 38.4, 39.5, 44.5, 52.4, 62.9, 78.8, 110.6,
127.5, 127.6, 129.6, 129.8, 133.6, 134.5, 135.9, 136.0, 145.2,
209.7; HRMS calcd for C30H40O2Si 460.2798, found 460.2792.
Anal. Calcd: C, 78.21; H, 8.75. Found: C, 78.25; H, 8.78.
The second compound to be eluted was the conjugate
addition product 23 bearing the cis ring junction. Concentra-
tion of the appropriate fractions, followed by removal of traces
of solvent (vacuum pump) from the acquired oil, provided 763
mg (81%) of the cis-fused product (-)-23 as a colorless oil:
[R]25D -73.0 (c 1.79, CHCl3); IR (neat) 1702, 1648, 1590, 1112,
After acquisition of 4 from the chromatography column, the
column was flushed with Et2O (600 mL). The eluate was
(37) The spectral data of the TBDPS ether (+)-9 are identical with
those reported in ref 8.
(38) In the event that the silyl enol ether failed to hydrolyze, the
crude oil was dissolved in THF (1 mL/mmol of starting material) and
treated with 1 equiv of TBAF in THF. The mixture was stirred at rt
for ∼10 min. H2O (10 mL/mmol of starting material) and Et2O (20 mL/
mmol of starting material) were added to the mixture, and the layers
were separated. The aqueous layer was extracted thoroughly with
Et2O, and the combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure. The keto acetal 19 was purified
as described.
(40) LiCl was flame-dried according to the following procedure. A
round-bottomed flask containing solid LiCl was placed under reduced
pressure (vacuum pump) and flame-dried using a Bunsen burner. The
flask was then filled with argon and cooled to rt.
(39) Taber, D. F. J . Org. Chem. 1982, 47, 1351.

8446 J . Org. Chem., Vol. 61, No. 24, 1996
Piers and Oballa
1
704 cm-1; H NMR (400 MHz) δ 1.02-1.21 (m, 1H), 1.07 (s,
1.83 (m, 2H), 1.84-1.94 (m, 1H), 2.24-2.34 (m, 1H), 2.56 (br
d, 1H, J ) 14 Hz), 3.34-3.38 (ddd, 1H, J ) 11.5, 4.5, 4.5 Hz,
collapses to a dd (J ) 11.5, 4.5 Hz) upon addition of D2O), 4.66
(br s, 1H), 4.71 (br s, 1H); 13C NMR (75.3 MHz) δ 14.5, 22.6,
27.7, 28.0, 31.7, 33.3, 38.3, 41.0, 45.8, 47.7, 59.1, 71.8, 79.7,
110.8, 145.4; HRMS calcd for C15H26O2 238.1933, found
238.1927. Anal. Calcd: C, 75.58; H, 10.99. Found: C, 75.80;
H, 11.14.
9H), 1.18 (s, 3H), 1.30-1.38 (m, 1H), 1.41-1.47 (br dd, 1H, J
) 13, 10.5 Hz, H-9), 1.59 (s, 3H), 1.56-1.70 (m, 1H), 1.79-
1.95 (m, 5H), 2.29-2.38 (m, 1H), 2.40-2.48 (m, 1H), 2.49-
2.52 (dd, 1H, J ) 10.5, 2 Hz, H-1), 3.74-3.77 (dd, 1H, J ) 8.5,
3.5 Hz, H-5), 4.48 (br s, 1H), 4.65 (br s, 1H), 7.28-7.50 (m,
6H), 7.66-7.73 (m, 4H); 13C NMR (75.3 MHz) δ 19.4, 21.9, 23.5,
27.1, 27.9, 30.2, 37.9, 39.3, 40.4, 40.7, 49.5, 62.8, 74.1, 111.4,
127.5, 127.7, 129.7, 129.8, 133.3, 134.4, 135.9, 136.0, 143.9,
213.5; HRMS calcd for C30H40O2Si 460.2797, found 460.2804.
Anal. Calcd: C, 78.21; H, 8.75. Found: C, 77.88; H, 8.68.
Ep im er iza tion of 23. To a cold (-78 °C), stirred solution
of the cis-fused compound 23 (264 mg, 0.573 mmol) in dry
MeOH (11.5 mL) was added a solution of NaOMe in MeOH
(0.40 M, 1.1 mL, 0.44 mmol). The pale yellow solution was
warmed to rt and stirred for 19 h. The MeOH was removed
under reduced pressure and H2O (10 mL) and Et2O (20 mL)
were added to the residue. The layers were separated, and
the aqueous phase was extracted with Et2O (3 × 25 mL). The
combined organic extracts were dried (MgSO4) and concen-
trated. 1H NMR spectroscopic analysis of the oil thus obtained
indicated a 7:1 ratio of compounds 24 and 23, respectively.
Flash chromatography of the crude oil (25 g of silica gel, 19:1
petroleum ether/Et2O) yielded 223 mg (84%) of the trans-fused
compound 24 and 35 mg (13%) of the cis-fused compound 23.
The recovered 23 (35 mg, 0.076 mmol) was subjected to the
above epimerization conditions (2.0 mL MeOH, 0.15 mL of a
0.4 M NaOMe/MeOH solution). Flash chromatography (8 g
of silica gel, 19:1 petroleum ether/Et2O) of the crude product
provided a further 24 mg of 24. After one additional epimer-
ization/chromatography sequence, a total of 247 mg (94%) of
the crystalline trans-fused 24 was obtained.
(1S,5S,6S,9S)-(-)-5-(ter t-Bu tyld ip h en ylsiloxy)-6-m eth -
yl-9-(2-m eth yl-1-p r op en yl)bicyclo[4.3.0]n on a n -2-on e (28),
(1R,5S,6S,9S)-(-)-5-(ter t-Bu tyld ip h en ylsiloxy)-6-m eth yl-
9-(2-m eth yl-1-p r op en yl)bicyclo-[4.3.0]n on a n -2-on e (29),
an d (1R,5S,6S,9R)-(-)-5-(ter t-Bu tyldiph en ylsiloxy)-6-m eth -
yl-9-(2-m eth yl-1-p r op en yl)bicyclo[4.3.0]n on a n -2-on e (30).
To a cold (-78 °C), stirred solution of t-BuLi (1.62 M in
pentane, 4.8 mL, 7.8 mmol) in dry THF (40 mL) was added
slowly (over ∼1 h via a small cannula) a solution of 1-iodo-2-
methylpropene
26 (701 mg, 3.85 mmol) in dry THF (8 mL). The
clear yellow solution became a cloudy, colorless mixture. To
the cold (-78 °C), stirred mixture was added (via a large
cannula) a clear yellow solution of LiCl (326 mg, 7.69 mmol)
and CuCN (345 mg, 3.85 mmol) in dry THF (13 mL).28
BF3‚-
Et2O (450 µL, 3.6 mmol) was added to the resultant orange-
red solution containing the organocopper(I) reagent 27. Can-
nulation of dry TMS-Br (558 mg, 3.64 mmol) into the red
solution was followed by the addition of a solution of the enone
4 (245 mg, 0.605 mmol) in dry THF (5 mL). The mixture was
stirred at -78 °C for 6.5 h. The solution was treated at -78
°C with H2O (15 mL), and the mixture was stirred, open to
the atmosphere, for 1 h. Aqueous NH4Cl/NH4OH (pH 8-9,
50 mL) and Et2O (50 mL) were added, and the mixture was
stirred vigorously until the aqueous layer became bright blue.
The layers were separated, and the aqueous phase was
extracted with Et2O (3 × 50 mL). The combined organic
extracts were washed (brine, 1 × 75 mL), dried (MgSO4), and
concentrated. The 1H NMR spectrum of the crude oil thus
obtained indicated that the starting material had been con-
sumed and that the ratio of isomers 28:29:30 was ∼4:62:34.
Flash chromatography (25 g of silica gel, 19:1 petroleum
ether/Et2O) of the crude oil provided 9.4 mg (3.4%) of 28 and
220 mg (78%) of a mixture of 29 and 30. The mixture of 29
and 30 (218 mg, 0.47 mmol) was dissolved in MeOH (9 mL),
and the solution was cooled to -78 °C. A solution of NaOMe
in MeOH (0.40 M, 1.2 mL, 0.48 mmol) was added, and the
solution was warmed to rt and stirred for 17.5 h. The mixture
was worked up (see previous procedure for the epimerization
(1S,2R,5S,6S,9S)-(-)-5-(ter t-Bu t yld ip h en ylsiloxy)-2,6-
d im eth yl-9-(m eth a llyl)bicyclo[4.3.0]n on a n -2-ol (25). To
a cold (-20 °C), stirred solution of the trans-fused 24 (61 mg,
0.13 mmol) in dry Et2O (2.6 mL) was added a solution of MeLi
in Et2O (1.4 M, 140 µL, 0.20 mmol). The solution was warmed
to -5 °C over the course of 1.5 h. A few drops of H2O were
added, and the solution was dried (MgSO4), filtered, and
concentrated. The crude product was flash chromatographed
(8 g of silica gel, 9:1 petroleum ether/Et2O), and after removal
of trace amounts of solvent (vacuum pump) from the resultant
liquid, 55 mg (87%) of the tertiary alcohol (-)-25, a colorless
oil, was obtained: [R]25D -75.2 (c 0.04, CHCl3); IR (neat) 3583,
3481, 3071, 1650, 1590, 1111, 1052, 703 cm-1; H NMR (400
1
MHz) δ 0.79 (br d, 1H, J ) 11 Hz, H-1), 1.05 (s, 9H), 1.00-
1.10 (m, 1H), 1.11-1.20 (m, 2H), 1.17 (s, 3H), 1.20 (d, 3H, J )
0.6 Hz), 1.23-1.36 (m, 2H), 1.42-1.47 (m, 1H), 1.61-1.73 (m,
2H), 1.71 (s, 3H), 1.80-1.93 (m, 2H), 2.24-2.32 (m, 1H), 2.52
(br d, 1H, J ) 14 Hz), 3.37-3.41 (dd, 1H, J ) 11.5, 4.5 Hz),
4.66 (br s, 1H), 4.71 (br s, 1H), 7.34-7.45 (m, 6H), 7.65-7.71
(m, 4H); 13C NMR (75.3 MHz) δ 15.2, 19.5, 22.6, 27.0, 27.9,
28.2, 31.6, 33.4, 39.1, 40.9, 45.8, 48.4, 58.8, 71.8, 81.0, 110.7,
127.3, 127.4, 129.3, 129.5, 134.1, 135.2, 135.9, 136.0, 145.5;
HRMS calcd for C27H35O2Si (M+ - CMe3) 419.2406, found
419.2409. Anal. Calcd for C31H44O2Si: C, 78.10; H, 9.30.
Found: C, 78.12; H, 9.41.
23), and analysis of the crude product mixture by
1H NMR
spectroscopy indicated that the ratio of isomers 28:29:30 was
36:28:36. Flash chromatography (15 g of silica gel, 19:1
petroleum ether/Et2O) of this material provided 64 mg (23%
with respect to the enone 4) of 28 and 140 mg of a mixture of
29 and 30. The remaining mixture (140 mg of 29 and 30) was
resubjected to the epimerization conditions and the desired
isomer 28 was again isolated by flash chromatography. This
process was repeated once more (i.e., three epimerization/
chromatography sequences in total). The overall yield of the
desired isomer (-)-28, based on the enone substrate 4, was
120 mg (43%); [R]25D -8.0 (c 1.05, CHCl3); IR (neat) 1723, 1590,
1112, 1064, 703 cm-1; 1H NMR (400 MHz) δ 0.91 (s, 3H), 1.06
(s, 9H), 0.97-1.48 (m, 4H), 1.60 (br s, 3H), 1.70 (br s, 3H),
1.73-2.07 (m, 5H, one of which is H-1 (d, J ) 10.5 Hz)), 3.03-
3.10 (dddd, 1H, J ) 10.5, 10.5, 10.5, 6.5 Hz, H-9), 3.87-3.91
(dd, 1H, J ) 10.5, 5 Hz, H-5), 4.78 (br d, 1H, J ) 10.5 Hz),
7.36-7.48 (m, 6H), 7.66-7.72 (m, 4H); 13C NMR (75.3 MHz) δ
13.4, 18.2, 19.4, 25.8, 27.0, 28.9, 32.1, 33.8, 38.7, 39.6, 52.5,
63.5, 78.8, 127.5, 127.6, 128.7, 129.6, 129.8, 131.5, 133.6, 134.5,
135.9, 136.0, 209.4; HRMS calcd for C30H40O2Si 460.2797,
found 460.2793. Anal. Calcd: C, 78.21; H, 8.75. Found: C,
78.15; H, 8.81.
(-)-Hom a lom en ol B (2). To a stirred solution of the
tertiary alcohol 25 (52 mg, 0.11 mmol) in dry THF (2.2 mL) at
rt was added a solution of TBAF in THF (1.0 M, 550 µL, 0.55
mmol). The mixture was refluxed for 17 h. The solution was
cooled to rt and H2O (5 mL) and Et2O (10 mL) were added.
The layers were separated, and the aqueous layer was
extracted with Et2O (2 × 10 mL) and EtOAc (2 × 10 mL). The
combined organic extracts were dried (MgSO4) and concen-
trated. The residual oil was flash chromatographed (8 g of
silica gel, 3:2 petroleum ether/EtOAc). Recrystallization (EtOAc/
petroleum ether) of the acquired solid yielded 25 mg (95%) of
(-)-2, a colorless crystalline solid: mp 94-95 °C; [R]20 -43.0
D
(c 1.71, CHCl3); lit.1 [R]20D of (+)-homalomenol B +20.4 (c 1.745,
Subjection of the initially obtained mixture of 29 and 30 to
flash chromatography as described above gave, in the first few
fractions eluted from the column, pure ketone 30, a solid. This
material was recrystallized from petroleum ether/Et2O to
CHCl3); IR (KBr) 3632, 3371, 3070, 1649, 1194, 1024, 894 cm-1
;
1H NMR (400 MHz, referenced at δ 7.24) δ 0.92 (d, 1H, J ) 11
Hz), 1.02 (br d, 3H, J ) 0.9 Hz), 1.09 (br s, 1H, tertiary OH,
exchanges with D2O), 1.15-1.27 (m, 2H), 1.25 (s, 3H), 1.30-
1.37 (m, 2H, one of which is the secondary OH, which
exchanges with D2O), 1.41-1.66 (m, 3H), 1.70 (s, 3H), 1.72-
provide 30 as a colorless crystalline solid: mp 72-74 °C; [R]25
D
-30.0 (c 1.94, CHCl3); IR (KBr) 1709, 1589, 1109, 1093, 704
1
cm-1; H NMR (400 MHz) δ 1.02-1.16 (m, 1H), 1.07 (s, 9H),

(-)-Homalomenol A and (-)-Homalomenol B
J . Org. Chem., Vol. 61, No. 24, 1996 8447
1.16 (s, 3H), 1.23-1.40 (m, 1H), 1.42 (d, 3H, J ) 1 Hz), 1.61
(d, 3H, J ) 1 Hz), 1.57-1.70 (m, 1H), 1.82-1.96 (m, 3H), 2.00
(d, 1H, J ) 11.5 Hz, H-1), 2.12-2.28 (m, 2H), 2.79-2.88 (m,
1H, H-9), 3.86-3.91 (dd, 1H, J )10.5, 4 Hz, H-5), 4.92 (br d,
1H, J ) 9 Hz), 7.36-7.48 (m, 6H), 7.66-7.73 (m, 4H); 13C NMR
(75.3 MHz) δ 18.0, 19.5, 21.2, 25.6, 27.0, 29.7, 31.6, 35.9, 37.6,
42.9, 51.7, 67.8, 73.1, 127.5, 127.7, 129.6, 129.8, 132.1, 133.4,
134.4, 135.9, 136.0, 212.2; HRMS calcd for C30H40O2Si 460.2797,
found 460.2799. Anal. Calcd: C, 78.21; H, 8.75. Found: C,
78.28; H, 8.64.
(m, 1H), 1.62, 1.63 (d, d, 3H each, J ) 1 Hz for each d), 1.79-
1.90 (ddd, 1H, J ) 18, 14, 4.5 Hz), 1.98-2.08 (m, 1H), 2.86-
2.95 (m, 1H), 3.35-3.39 (dd, 1H, J ) 11.5, 4 Hz), 5.00 (br d,
1H, J ) 9.5 Hz), 7.34-7.42 (m, 6H), 7.68-7.70 (m, 4H); 13C
NMR (75.3 MHz) δ 14.9, 18.1, 19.5, 25.7, 27.0, 28.4, 29.5, 30.5,
35.0, 39.4, 40.4, 47.8, 58.8, 71.7, 81.3, 127.3, 127.4, 128.4, 129.3,
129.5, 132.4, 134.1, 135.3, 135.9, 136.0; HRMS calcd for
C31H44O2Si 476.3110, found 476.3103. Anal. Calcd: C, 78.10;
H, 9.30. Found: C, 78.12; H, 9.34.
(-)-Hom a lom en ol A (1). To a stirred solution of 31 (141
mg, 0.296 mmol) in dry THF (6 mL) at rt was added a solution
of TBAF in THF (1.0 M, 2.4 mL, 2.4 mmol). The mixture was
refluxed for 18 h. The solution was cooled to rt; H2O (25 mL)
and Et2O (25 mL) were added, and the layers were separated.
The aqueous layer was extracted with Et2O (2 × 20 mL) and
EtOAc (2 × 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated. The crude oil was flash chromato-
graphed (8 g of silica gel, 3:2 petroleum ether/EtOAc) to yield
61 mg (87%) of (-)-1, a white solid. Recrystallization of this
material from Et2O/petroleum ether provided (-)-1 as thin,
needlelike plates: mp 99-100 °C; [R]20D -51.5 (c 1.30, CHCl3);
Compound 29 was obtained in a pure form from the late
fractions of the above-mentioned flash chromatography. The
oil obtained, upon heating at 80-100 °C (0.2 Torr) for 1 h to
remove residual solvent, provided pure 29: [R]25D -33.5 (c 0.84,
1
CHCl3); IR (neat) 1704, 1590, 1112, 1089, 704 cm-1; H NMR
(400 MHz) δ 1.08 (s, 9H), 1.08-1.17 (m, 1H), 1.17 (s, 3H), 1.31-
1.39 (m, 1H), 1.43 (d, 3H, J ) 0.8 Hz), 1.50 (br s, 3H), 1.74-
2.00 (m, 5H), 2.15-2.19 (m, 1H), 2.48-2.51 (br dd, 1H, J )
10, 2 Hz, H-1), 3.12-3.21 (m, 1H, H-9), 3.77-3.81 (br dd, 1H,
J ) 10.5, 4 Hz, H-5), 4.51 (br d, 1H, J ) 10 Hz), 7.37-7.49 (m,
6H), 7.66-7.75 (m, 4H); 13C NMR (75.3 MHz) δ 18.0, 19.4, 21.6,
25.7, 27.0, 29.0, 31.8, 38.5, 39.6, 41.4, 49.5, 64.8, 73.6, 126.6,
127.4, 127.7, 129.6, 129.8, 133.4, 133.5, 134.5, 135.9, 136.0,
212.7; HRMS calcd for C30H40O2Si 460.2797, found 460.2797.
(1S,2R,5S,6S,9S)-(-)-5-(ter t-Bu t yld ip h en ylsiloxy)-2,6-
d im eth yl-9-(2-m eth yl-1-p r op en yl)bicyclo[4.3.0]n on a n -2-
ol (31). To a cold (-20 °C), stirred solution of the trans-fused
compound 28 (170 mg, 0.369 mmol) in dry Et2O (7 mL) was
added a solution of MeLi in Et2O (1.4 M, 530 µL, 0.74 mmol).
The solution was warmed to -5 °C over the course of 1 h. H2O
(10 mL) was added, and the layers were separated. The
aqueous phase was extracted with Et2O (3 × 15 mL), and the
combined organic extracts were dried (MgSO4) and concen-
trated. The crude oil was flash chromatographed (8 g of silica
gel, 9:1 petroleum ether/Et2O) to afford, after recrystallization
of the acquired solid from Et2O/petroleum ether, 141 mg (80%)
of the (-)-tertiary alcohol 31 as a colorless crystalline solid:
lit.1 for (+)-homalomenol A oil, [R]20 +33.2 (c 1.205, CHCl3);
D
IR (KBr) 3617, 3434, 1581, 1023 cm-1
;
1H NMR (400 MHz,
referenced at δ 7.24) δ 0.93 (s, 1H, OH, exchanges with D2O),
0.99 (d, 1H, J ) 11.5 Hz), 1.04 (d, 3H, J ) 0.7 Hz), 1.10 (s,
3H), 1.19-1.39 (m, 3H), 1.41-1.46 (dd, 1H, J ) 14, 5 Hz),
1.52-1.64 (m, 3H), 1.63, 1.64 (d, d, 3H each, J ) 1.5 Hz for
each d), 1.73-1.84 (m, 1H), 2.00-2.11 (m, 1H), 2.88-2.98 (m,
1H), 3.35-3.38 (dd, 1H, J ) 11.4, 4.1 Hz), 5.05 (br d, 1H, J )
9.5 Hz); 13C NMR (75.3 MHz) δ 14.1, 18.1, 25.7, 27.9, 29.6,
30.7, 34.9, 38.6, 40.6, 47.1, 59.0, 71.7, 80.0, 128.7, 132.1; HRMS
calcd for C15H26O2 238.1933, found 238.1930. Anal. Calcd: C,
75.58; H, 10.99. Found: C, 75.29; H, 11.12.
Ack n ow led gm en t. We gratefully acknowledge the
Natural Sciences and Engineering Research Council of
Canada for financial support and for a Postgraduate
Scholarship (to R.M.O.). We also thank Bio-Me´ga/
Boehringer Ingelheim Research Inc., Laval, Quebec, for
a Scholarship (to R.M.O.).
mp 98-100 °C; [R]25 -43.0 (c 1.71, CHCl3); IR (KBr) 3602,
D
3072, 1590, 1111, 703 cm-1; 1H NMR (400 MHz) δ 0.86 (d, 1H,
J ) 11.5 Hz), 0.97 (s, 1H, OH, exchanges with D2O), 1.01 (s,
3H), 1.04 (s, 9H), 1.01-1.20 (m, 3H), 1.21 (s, 3H), 1.26-1.35
(m, 1H), 1.41-1.45 (ddd, 1H, J ) 14.5, 4.5, 2.5 Hz), 1.62-1.65
J O961605+