Stereocontrolled syntheses of (-)-cubebol and (-)-10-epicubebol involving intramolecular cyclopropanation of a-lithiated epoxides

Article abstract of DOI:10.1021/jo9022974

Figure Presented Formylation of (-)-menthone (11) with LDA and HCO ₂CH₂CF₃ avoids loss of configurational integrity at the isopropyl group, giving hydroxymethylenementhone 12. Lithium 2,2,6,6-tetramethylpiperidideinduced intramolecular cyclopropanation of derived unsaturated terminal epoxide 17 (and chlorohydrin 16), efficiently generates a substituted tricyclo[4.4.0.0^1.5]decan-4-ol 18, which is used in a concise synthesis of (-)-cubebol (1). In contrast, isopropyl group inversion during formylation of menthone with NaOMe and HCO₂Et led, by a similar strategy, to syntheses of 7-epicubebol (33) and (from(+)-menthone) of naturally occurring (-)-10-epicubebol (39), confirming the original structural assignment. Computational studies support the origin of the inversion as being rate-determining formylation of cis-enolate 27 from amixture of rapidly interconverting enolates. In the synthesis of 7-epicubebol (33), allylic tertiary C-H insertion is observed as a significant competing reaction in the intramolecular cyclopropanation of unsaturated terminal epoxide 22.

Full text of DOI:10.1021/jo9022974

pubs.acs.org/joc
Stereocontrolled Syntheses of (-)-Cubebol and (-)-10-Epicubebol
Involving Intramolecular Cyclopropanation of r-Lithiated Epoxides
David M. Hodgson,*,† Saifullah Salik,† and David J. Fox‡
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford,
OX1 3TA, United Kingdom and Department of Chemistry, University of Warwick, Gibbet Hill Road,
Coventry, CV4 7AL, United Kingdom
‡
david.hodgson@chem.ox.ac.uk
Received October 27, 2009
Formylation of (-)-menthone (11) with LDA and HCO2CH2CF3 avoids loss of configurational
integrity at the isopropyl group, giving hydroxymethylenementhone 12. Lithium 2,2,6,6-tetramethyl-
piperidide-induced intramolecular cyclopropanation of derived unsaturated terminal epoxide 17
(and chlorohydrin 16), efficiently generates a substituted tricyclo[4.4.0.01,5]decan-4-ol 18, which is
used in a concise synthesis of (-)-cubebol (1). In contrast, isopropyl group inversion during
formylation of menthone with NaOMe and HCO2Et led, by a similar strategy, to syntheses of
7-epicubebol (33) and (from (þ)-menthone) of naturally occurring (-)-10-epicubebol (39), confirming
the original structural assignment. Computational studies support the origin of the inversion as being
rate-determining formylation of cis-enolate 27 from a mixture of rapidly interconverting enolates. In the
synthesis of 7-epicubebol (33), allylic tertiary C-H insertion is observed as a significant competing
reaction in the intramolecular cyclopropanation of unsaturated terminal epoxide 22.
Introduction
co-workers in 1960,4 with the structure and full stereochemi-
stry subsequently being supported by the first total synthesis
of (-)-cubebol by Yoshikoshi and co-workers in 1969.5 The
early syntheses of cubebol5,6 and closely related, by formal
dehydration, R- and β-cubebenes5,7,8 proceed by way of
norcubebanone (2)9 as a common late stage intermediate.
In all these syntheses, an unsaturated R-diazoketone (eg, 3)
was used to generate the embedded cyclopropane; however,
cyclopropanation yields were moderate, and the diastereo-
facial selectivities were poor and in favor of undesired
isomer. Recently, in 2006, independent syntheses of cubebol
Sesquiterpenes constitute a rich pool of structurally div-
erse synthetic challenges, and are often selected as targets to
illustrate the advantages and examine the limits of newly
developed methodology.1 (-)-Cubebol (1) (Scheme 1) is
principally found as one of the major constituents of cubeb
oil, the latter being obtained from the berries of cubeb (Piper
cubeba) grown in the Indonesian archipelago.2 Cubeb has
long found medicinal and culinary uses, and more recently
Firmenich patented the use of cubebol as a sustained cooling
and refreshing agent in the field of flavors.3 The gross
structure of cubebol was originally proposed by Sorm and
(4) Vonasek, F.; Herout, V.; Sorm, F. Collect. Czech. Chem. Commun.
1960, 25, 919–926.
(1) (a) Pirrung, M. C.; Morehead, A. T., Jr. In The Total Synthesis of Natural
Products; Goldsmith. D., Ed.; Wiley: New York, 1997; Vol. 10, pp 1-160.
(b) Pirrung, M. C.; Morehead, A. T., Jr.; Young, B. G. In The Total Synthesis
of Natural Products; Goldsmith. D., Ed.; Wiley: New York, 2000; Vol. 11,
pp 1-1455.
(5) (a) Tanaka, A.; Tanaka, R.; Uda, H.; Yoshikoshi, A. Chem. Commun.
1969, 6365–6370. (b) Tanaka, A.; Tanaka, R.; Uda, H.; Yoshikoshi, A.
J. Chem. Soc., Perkin Trans. 1 1972, 1721–1727.
(6) Torri, T.; Okamoto, T. Bull. Chem. Soc. Jpn. 1976, 49, 771–774.
(7) (a) Piers, E.; Britton, R. W.; de Wall, W. Tetrahedron Lett. 1969, 1251–
1253. (b) Piers, E.; Britton, R. W.; de Wall, W. Can. J. Chem. 1971, 49, 12–19.
(8) Vig, O. P.; Bhatia, M. S.; Verma, A. K.; Matta, K. L. J. Indian Chem.
Soc. 1970, 47, 277–281.
(2) Gunther, E. The Essential Oils; Van Nostrand: London, UK, 1952;
Vol. 5, pp 148-157.
(3) Velazco, M. I.; Wuensche, L.; Deladoey, P. U.S. Patent, 6214788,
2001; Chem. Abstr. 2000, 133, 265959.
(9) Thiessen, W. E. Acta Crystallogr. 1977, B33, 3838–3842.
DOI: 10.1021/jo9022974
r
Published on Web 01/11/2010
J. Org. Chem. 2010, 75, 2157–2168 2157
2010 American Chemical Society

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SCHEME 1. Synthetic Approaches to (-)-Cubebol (1)
Although commercially available, (-)-menthone (11)
(Scheme 3) was conveniently synthesized, without loss of
configuration at the i-Pr bearing stereocenter, by oxidation
(93%) of inexpensive (-)-menthol (99% ee) with Ca(OCl)2.17
Formylation of menthone, under now standard alkoxide/
formate ester conditions, was originally reported by Claisen,18
and was also initially examined in the first synthesis of (-)-
cubebol by Yoshikoshi, but the approach was abandoned due
to the formation of “an inseparable mixture of epimers”.5b
Subsequently, Tolman19 noted the generation of a 7:93 epi-
meric mixture during formylation of menthone using NaOMe/
HCO2Et and, in a key study, Kashima and co-workers found
an identical ratio to Tolman with the (currently undesired) cis-
isomer predominating, when starting with menthone (or
isomenthone) and using NaH/HCO2Et.20 However, Kashima
also observed that the use of LDA (-78 °C) followed by
HCO2Et led to a 75:25 mixture in favor of the trans isomer.
The latter result could be improved in our hands to give
hydroxymethylenementhone (12) (55%, S:R = 98:2 at C-6,
Scheme 3) by using HCO2CH2CF3, which was introduced by
Zayia for “kinetic formylation”.21
were reported by Furstner10 and by Fehr11 in 14 and 13 steps,
€
respectively, similarly starting from (R)-carvone (4). In these
latter syntheses, the key cyclopropanation involved metal-
catalyzed cycloisomerization of propargylic esters 5 (R =
Me, t-Bu) and facial selectivity was controlled by the con-
figuration at the propargylic stereocenter. In the present
paper, we describe an alternative stereocontrolled and more
concise synthesis of (-)-cubebol (1) using a lithiated epoxide
6 (X = Li) to effect cyclopropanation,12-14 together with
strategically related syntheses of 7- and 10-epicubebol.
SCHEME 3. Synthesis of Allylic Alcohol 13
Results and Discussion
All but one of the previous syntheses of (-)-cubebol (1)
and R- and β-cubebenes noted above start from (R)-car-
vone (4), and all involve relatively lengthy sequences of
transformations to generate a side chain suitable for intra-
molecular cyclopropanation. In seeking a more concise
approach to our cyclopropanation substrate, epoxide 6
(Scheme 1, X = H), we were attracted to the synthesis of
β-cubebene (10) claimed (but see below) by Vig and co-
workers (Scheme 2),8 in which allylic bromide 9 (X = Br,
stereochemistry not indicated in Vig’s work) was prepared in
three steps by formylation of ketone 7. We anticipated
copper-catalyzed reaction of a corresponding Grignard
reagent 9 (X = MgHal) with epichlorohydrin15,16 should
allow a comparatively short access to our desired epoxide
substrate 6 (X = H).
Aware that the subsequent steps from hydroxymethylene-
menthone (12) to an allylic halide 9 (X = Hal) might not
parallel Vig’s study (Scheme 2), since the cis isomer was likely
carried through in Vig’s sequence (ultimately resulting in a
synthesis of 7-epi-β-cubebene), we carried out the reduction
of 12 using LiAlH4 as described and were pleased to obtain a
desired allylic alcohol 13 in 50% yield, after chromatogra-
phy. The structure of allylic alcohol 13 was established by
X-ray crystallographic analysis of the 3,5-dinitrobenzoate
derivative 14 (Figure 1).22 The reduction of hydroxymethy-
lenementhone (12) likely23 proceeds by exocyclic hydride
delivery to deprotonated 12, followed by β-elimination of
an (aluminum-complexed) oxygen and finally 1,2-hydride
delivery in an axial24 manner to the resulting enone.
SCHEME 2. Vig’s Approach to β-Cubebene (10)8
€
(10) Furstner, A.; Hannen, P. Chem.;Eur. J. 2006, 12, 3006–3019.
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(b) Fehr, C.; Winter, B.; Magpantay, I. Chem.;Eur. J. 2009, 15, 9773–9784.
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2004, 126, 8664–8665. (b) Hodgson, D. M.; Chung, Y. K.; Nuzzo, I.; Freixas,
G.; Kulikiewic, K. K.; Cleator, E.; Paris, J.-M. J. Am. Chem. Soc. 2007, 129,
4456–4462.
FIGURE 1. Crystal structure representation of 3,5-dinitrobenzo-
ate derivative 14.
(13) Preliminary communication: Hodgson, D. M.; Salik, S. Synlett
2009, 1730–1732.
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(18) Bishop, A. W.; Claisen, L.; Sinclair, W. Liebigs Ann. Chem. 1894,
281, 314–398.
(14) For a recent example in natural product synthesis, see: Tashiro, T.;
Mori, K. Tetrahedron: Asymmetry 2008, 19, 1215–1223.
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(16) Linstrumelle, G.; Lorne, R.; Dang, H. P. Tetrahedron Lett. 1978,
4069–4072.
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Conversion of the allylic alcohol 13 to the allylic chloride
15 (79%) was achieved in a one-flask operation with use of
MsCl/Et3N followed by addition of LiCl (Scheme 4);25 use of
SCHEME 5. Synthesis of (-)-Cubebol (1)
26
SOCl2 or AcCl in EtOH27 was less satisfactory. Allylic
transposition was observed, despite the orthogonal disposi-
tion of the π-system and C-O bond evident in the all-
equatorial 3,5-dinitrobenzonate derivative 14 (Figure 1) of
allylic alcohol 13. Reaction of the Grignard reagent from
allylic chloride 15 with commercially available (R)-epichlo-
rohydrin under copper catalysis15,16 gave the unsaturated
chlorohydrin 16 (49%), which was then ring-closed to epoxide
17 (82%, Scheme 4).
To establish that the configuration of the epoxide was the
sole factor determining facial selectivity during cyclopropa-
nation, the intramolecular cyclopropanation of epoxide 19
[available from allylic chloride 15 and (S)-epichlorohydrin]22
was carried out, which gave cyclopropyl alcohol 20 (90%,
Scheme 6). Oxidation of cyclopropyl alcohol 20 gave known
ketone 21, which possessed data consistent with the litera-
ture.10 The identical yields obtained for the intramolecular
cyclopropanations of epoxides 17 and 19 also indicate that
the presence of the isopropyl group on the same face of the
alkene which undergoes cyclopropanation in epoxide 19
does not reduce the efficiency of this transformation.
SCHEME 4. Synthesis and Intramolecular Cyclopropanation of
Epoxide 17
SCHEME 6. Intramolecular Cyclopropanation of Epoxide 20
The unsaturated epoxides 22 and 23 (Figure2) werenextexa-
mined to further probe the effect on intramolecular cyclopro-
panation of tethered alkenes bearing additional stereocenters.
Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced
intramolecular cyclopropanation of epoxide 17 under our
previously developed conditions12 gave a single cyclopropyl
alcohol 18 in excellent yield (90%, Scheme 4). Cyclopropyl
alcohol 18 could also be obtained from epoxide 17 with use of
n-BuLi (2 equiv) and a catalytic12b amount of 2,2,6,6-tetra-
methylpiperidine (TMP, 0.5 equiv), in 86% yield, and more
directly15 from chlorohydrin 16 in 71% yield, using n-BuLi
(3.5 equiv) and TMP (2.5 equiv, Scheme 4). Oxidation of
cyclopropyl alcohol 18 with 5 mol % TPAP-NMO (2 equiv)
gave norcubebanone (2) (95%, Scheme 5); the spectral data
for 2 were in full accord with the literature,10,11 which
confirms the facial selectivity in the cyclopropanation to be
that shown in Scheme 4. The origin of the facial selectivity
from the intermediate R-lithiated epoxide 6 (X = Li) likely
parallels that previously discussed for simpler systems.12
Reaction of MeLi/CeCl3 with norcubebanone (2) according
FIGURE 2. Further cyclopropanation substrates.
Following the discussion earlier on the formylation of (-)-
menthone (11), it was anticipated that reaction under classi-
cal conditions (alkoxide/formate ester) would lead predomi-
nantly by i-Pr epimerization to the cis configuration required
in the cyclohexene portion of epoxides 22 and 23. In our
hands, formylation gave mainly hydroxymethyleneisome-
nthone (28) (83%, 93:7 inseparable mixture with hydroxy-
methylenementhone (12), Scheme 7), in agreement with the
prior observations of Tolman19 and of Kashima.20 The
origin of the almost complete i-Pr epimerization during the
formylation of menthone with alkoxide and a formate ester
(also observed during Claisen-Schmidt condensations)28 is
not obvious; indeed, several applications of this chemistry
erroneously assume the configuration is unchanged during
this process.17b,23c,29 Subjecting hydroxymethylenementhone
to Furstner10 and Fehr11 gave (-)-cubebol (1) (85%).
€
(19) (a) LeCloux, D. D.; Tolman, W. B. J. Am. Chem. Soc. 1993, 115,
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SCHEME 7. Overview Analysis of Alkoxide-Induced
Formylation of Menthone (11)
to the ring methyl group resulting in unfavorable steric
interactions with the ester (trans-TS2). The methoxy group
of the ester can attempt to swing out of the way to reduce this
steric clash (trans-TS1), but this orientation is less favorable
on stereoelectronic grounds:34 the ground state conforma-
tional preference of methyl formate (20 kJ/mol) is reflected in
the reaction transition state (6.2 kJ/mol for the cis-enolate).
The more stable ester geometry seen in transition structure
trans-TS2 also has the most significant steric interactions
between the enolate and ester methyl groups, raising its
energy. Overall, assuming non-rate-determining enolate iso-
merization, it can be seen that the cis product forming
reactions will be faster than the trans product forming
reactions, consistent with the results observed experimen-
tally. By using the four calculated transition state energies,
the relative rate of formation of cis to trans product was
determined to be 94:6 at 298 K, in good agreement with that
observed experimentally.
Epoxides 22 and 23 were synthesized from hydroxymethy-
leneisomenthone (28) without incident by analogous appli-
cation of the chemistry shown in Schemes 3 and 4, and
epoxide 23 was found to undergo LTMP-induced intramole-
cular cyclopropanation in excellent yield (89%, 87% with
catalytic (0.5 equiv) TMP and n-BuLi (2 equiv)).22 However,
in contrast to the smooth intramolecular cyclopropanation
of epoxides 17, 19, and 23, reaction of epoxide 22 (epimeric to
17 at the i-Pr group) reproducibly led to a mixture of the
anticipated cyclopropyl alcohol 29 together with an approxi-
mately equal amount of bicyclic alcohol 30 and lesser
quantities of aldehyde 31 (Scheme 8). In this case, intramo-
lecular cyclopropanation is likely retarded by the presence of
substituents at two allylic sites on the same face of the alkene
which undergoes cyclopropanation, thus allowing intramole-
cular C-H insertion35 at a tertiary allylic position to compete.
The aldehyde very likely arises from hydrolysis of the corre-
sponding 2,2,6,6-tetramethylpiperidinylenamine, the latter being
generated from interception of the lithiated epoxide inter-
mediate by LTMP.36
(12) to the classical formylation conditions for 3 days returned,
as expected, mainly starting material (12:28, 80:20). This
experiment shows that epimerization following formylation is
not the origin of hydroxymethyleneisomenthone (28) from
(-)-menthone. Under the classical formylation conditions,
alkoxide-induced epimerization at the i-Pr group will occur to
give isomenthone (25) (Scheme 7); however, it is well-known
that menthone is preferred (though not strongly) over iso-
menthone at equilibrium (∼70:30).30 This analysis indicates
that the activation energy barrier for formylation of the
isomenthone-derived enolate 27 will be less than that for
menthone-derived enolate 26, and this may be due to stereo-
electronically preferred axial formylation occurring away from
the Me group in enolate 27.31
This explanation proposed above for the preferential
formation of the cis-menthone derivative 28 was investigated
by DFT calculations at the B3LYP/6-31G(d) level32 with use
of PC-GAMESS/Firefly.33 Making the reasonable assump-
tion20 (see above) that cis- and trans-menthone (11 and 25)
are in pre-equilibrium, then the relative rates of cis and trans
product formation will be controlled by the relative energies
of the cis and trans product forming transition states. Four
anionic transition states were calculated with methyl for-
mate. In all cases the two oxygens of the formate are oriented
away from the enolate oxygen, mimicking the conformation
expected for an “open” aldol-like transition structure stabi-
lized by numerous hydrogen bonds to the solvent. In addi-
tion, all transition states involve axial attack onto the
halfchair-like enolate with the isopropyl group occupying a
pseudoequatorial position. This requirement forces the dif-
ferent enolate diastereoisomers to be attacked from different
faces. For the isomenthone-derived cis-enolate 27, attack
occurs anti to the methyl substituent (Figure 3, cis-TS1 and
cis-TS2), but for the trans isomer attack must occur syn
SCHEME 8. Reaction of Epoxide 22 with LTMP
As the cooling effect of almost odorless cubebol is sensitive
to the precise stereochemistry of the tricyclic alcohol
(for example, 4-epicubebol has a very bitter taste),3,11 it
was of interest to examine 7-epicubebol (33), prepared from
(30) (a) Rickborn, B. J. Am. Chem. Soc. 1962, 84, 2414–2417. (b) Takahashi,
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FIGURE 3. Computational analysis of formylation of menthone and isomenthone enolates, and conformational preference of methyl
formate.
cyclopropyl alcohol 29 by way of ketone 32 as shown in
SCHEME 10. Synthesis of (-)-10-Epicubebol (39)
Scheme 9. 7-Epicubebol (33) (structure confirmed by X-ray
crystallographic analysis)22 was examined at Firmenich, but
was found to be bitter, terpenic, and without much of a
cooling effect compared with cubebol.
SCHEME 9. Synthesis of 7-Epicubebol (33)
The successful intramolecular cyclopropanation of unsa-
turated epoxide 23 prompted us to work in the enantiomeric
series, starting from commercially available (þ)-menthol,
so as to confirm the structure proposed for (-)-10-epicu-
bebol (39) (Scheme 10; note: stereochemical assignment of
alcohol 34 is discussed in the Experimental Section). (-)-
10-Epicubebol (39) was identified in 199637 in the leaf oil of
Chamaecyparis obtuse, an important timber tree in
Japan, and assigned the structure shown on the basis of
similar spectral data to the aglycon of 10-epicubebolxylo-
side,38 with the latter structure being assigned by NOE
studies and spectral comparisons with cubebol and
1
4-epicubebol. The H and 13C data for synthetically ob-
tained (-)-10-epicubebol (39) were in perfect agreement
with the literature data37 for the natural isolate.22 Analysis
of the taste of 10-epicubebol at Firmenich found it to be
slightly bitter.
(37) (a) Hieda, T.; Tazaki, M.; Morishita, Y.; Aoki, T.; Nagahama, S.
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Embedded cyclopropanes fused to 5- and 6-membered
carbocycles are widely found in natural products, and there
has been considerable interest in the synthesis of such
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JOCArticle
systems, especially in a stereocontrolled manner. The above
work has described an efficient intramolecular cyclopropa-
nation strategy of unsaturated terminal epoxides to the
stereocontrolled syntheses of cubebols. These applications
of our cyclopropanation methodology exemplify the latter’s
utility as a fundamentally important alternative to classical
intramolecular cyclopropanation of unsaturated R-diazo-
carbonyl compounds, because of the relative ease of con-
struction of the highly enantioenriched epoxide substrates,
and the experimentally straightforward protocol with use of
commercially available reagents. Significantly, despite ster-
eochemistry variation in the tethered alkene, in all these
syntheses the facial selectivity of cyclopropanation is con-
trolled solely by the epoxide stereochemistry. Aside from the
most concise synthesis of cubebol reported to date, this
Article also discloses the first synthesis of naturally occurring
(-)-10-epicubebol, confirming the original structural assign-
ment. Furthermore, arising out of these studies, the origins
of the unusual and almost complete i-Pr epimerization
during the formylation of menthone with alkoxide and a
formate ester (a reaction originally reported by Claisen, in
1894) have been clarified with supporting computational
studies, and a method established to formylate menthone
with preservation of the original stereocenter.
(1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added over 70 min to a
stirred solution of the unsaturated terminal epoxide (148 mg,
0.71 mmol) and 2,2,6,6-tetramethylpiperidine (0.06 mL, 0.35
mmol) in t-BuOMe (4 mL) at 0 °C. The stirring was continued
for 8 h and the mixture then quenched with MeOH (0.3 mL), and
purified as in General Procedure 2 to give the cyclopropyl
alcohol.
General Procedure 4 (Intramolecular Cyclopropanation of
Unsaturated Chlorohydrins with LTMP). n-BuLi (1.6 M in
hexanes, 2.2 mL, 3.5 mmol) was added over 5 min to a stirred
solution of the unsaturated chlorohydrin (245 mg, 1.0 mmol)
and 2,2,6,6-tetramethylpiperidine (0.42 mL, 2.5 mmol) in
t-BuOMe (8 mL) at -78 °C. The solution was warmed to rt
over 4 h and then left at rt for a further 16 h. The mixture was
then quenched with MeOH (0.5 mL), and purified as in General
Procedure 2 to give the cyclopropyl alcohol.
General Procedure 5 (Oxidation of Cyclopropyl Alcohol
to Ketone). To a stirred solution of the cyclopropyl alcohol
(521 mg, 2.5 mmol) in dry CH2Cl2 (20 mL) were added oven-
˚
dried powdered MS 4 A (500 mg), N-methylmorpholine N-oxide
(585 mg, 5.0 mmol, 2 equiv), and tetra-n-propylammonium
perruthenate (47 mg, 0.13 mmol, 0.05 equiv) at rt. The mixture
was then stirred at rt for 90 min, diluted with Et2O (30 mL) and
filtered through a pad of silica to give the crude ketone, which
was purified by column chromatography (25% Et2O in light
petrol).
Synthesis of (-)-Cubebol (1). (2S,5R)-2-Isopropyl-5-methyl-
cyclohexanone (11). L-Menthol (5.0 g, 32 mmol) was dissolved in
MeCN:AcOH (3:2, 42 mL) and added dropwise over a period of
30 min to a cooled (0 °C) and stirred solution of calcium
hypochlorite (4.0 g, 28 mmol) in water (65 mL). The stirring
was continued for 3 h, then water (65 mL) was added in one
portion. The solution was extracted with CH2Cl2 (3 ꢀ 50 mL)
and the combined organic layers were washed with 10% aq
NaHCO3 (2ꢀ50 mL), dried (MgSO4), and concentrated under
reduced pressure. (-)-Menthone (11) (4.6 g, 93%) was obtained
as a colorless oil, which was used in the next step without further
purification; Rf 0.4 (4% ether in light petrol); [R]25D -27.9 (c 1.0,
CHCl3) (lit.40 [R]25D -28.5) ; IR (cm-1) 2961 s, 2931 s, 2872 m,
1712 s, 1455 w, 1369 w, 1315 w, 750 w; 1H NMR (400 MHz) 2.30
(ddd, J=12.5, 3.5, 2.0 Hz, 1 H), 2.15-2.07 (m, 1 H), 2.05-1.98
(m, 2 H), 1.94-1.75 (m, 3 H), 1.39-1.25 (m, 2 H), 0.96 (d, J=6.0
Experimental Section
General Experimental Information. Details can be found in
the Supporting Information.
General Procedure 1 (Ring-Opening of Epichlorohydrin with
Grignard Reagents). Mg turnings (486 mg, 20 mmol) were
activated by rapid stirring overnight under argon.39 To a
suspension of the activated Mg in THF (8 mL) at rt was added
1,2-dibromoethane (3 drops), followed by syringe pump addi-
tion of the allylic chloride (935 mg, 5.0 mmol) in THF (7 mL)
over a period of 2 h. On completion of the addition, the mixture
was stirred for a further 2 h at rt, and afterward the solids were
allowed to settle for 30 min. The resulting Grignard reagent was
added dropwise within 30 min to a mixture of CuI (95 mg,
0.5 mmol) and epichlorohydrin (0.31 mL, 4 mmol) in dry THF
(7 mL) at -78 °C. The resulting solution was gradually warmed
to 0 °C over 90 min and then stirred at 0 °C for a further 90 min.
The reaction was then quenched with saturated aq NH4Cl
solution (3 mL) and extracted with Et2O (2 ꢀ 25 mL). The
combined organic layers were dried (MgSO4), evaporated under
reduced pressure, and purified by column chromatography
(18% Et2O in light petrol) to give the unsaturated chlorohydrin.
General Procedure 2 (Intramolecular Cyclopropanation of
Unsaturated Terminal Epoxides with LTMP). n-BuLi (1.6 M in
hexanes, 3.75 mL, 6.0 mmol) was added to a stirred solution of
2,2,6,6-tetramethylpiperidine (1.0 mL, 6.0 mmol) in t-BuOMe
(30 mL) at -78 °C. The resulting pale yellow solution of LTMP
was stirred at rt for 10 min and then cooled to 0 °C in an ice bath.
To a stirred solution of the unsaturated terminal epoxide (593 mg,
2.85 mmol) in t-BuOMe (14 mL) at 0 °C was added the above
LTMP solution dropwise via cannula over 2 h. The resulting
mixture was stirred at rt for 16 h, then quenched with MeOH
(3 mL) and concentrated under reduced pressure. The residue was
dry-loaded onto a small amount of silica and purified by column
chromatography (SiO2, gradient elution, 20% to 35% Et2Oinlight
petrol) to give the cyclopropyl alcohol.
Hz, 3 H), 0.87 (d, J=6.5 Hz, 3 H), 0.81 (d, J=6.5 Hz, 3 H); 13
C
NMR (100 MHz) 212.3 (C-1), 55.8 (C-2), 50.8 (C-6), 35.4 (C-5),
33.9 (C-4), 27.8 (C-3), 25.8 (CMe2), 22.2 (CMe), 21.2 (CMeMe),
18.7 (CMeMe); HRMS (CIþ) m/z [MH]þ calcd for C10H19O
155.1436, found 155.1436.
(3R,6S,Z)-2-(Hydroxymethylene)-6-isopropyl-3-methylcyclo-
hexanone (12). To a solution of diisopropylamine (0.43 mL, 3.0
mmol) in Et2O (4 mL) at -40 °C was added n-BuLi (1.6 M in
hexanes, 2.25 mL, 3.6 mmol) dropwise over 2 min. After 30 min,
the solution was cooled to -78 °C and then a solution of (-)-
menthone (11)22 (462 mg, 3.0 mmol) in Et2O (3 mL) was added
dropwise over 30 min. The solution was stirred at -78 °C for an
additional 2 h, then HCO2CH2CF3 (1.75 mL, 18 mmol, 6 equiv)
was added in one portion and the mixture was stirred at -78 °C
for a further 3 h. The reaction was quenched with H2SO4
(550 mg, 5.6 mmol) and water (15 mL) was added. The organic
phase was extracted with Et2O (3 ꢀ 25 mL) and the combined
organic layers were washed with saturated aq NH4Cl (20 mL)
and extracted with 1% aq NaOH (4 ꢀ 25 mL). The combined
basic extracts were cooled to 0 °C (ice bath), acidified to pH 1 by
dropwise addition of 10% aq HCl, and then extracted with
CH2Cl2 (3 ꢀ 25 mL). The combined organic layers were dried
(MgSO4) and concentrated to give hydroxymethylenementhone
General Procedure 3 (Intramolecular Cyclopropanation of
Unsaturated Terminal Epoxides with Catalytic TMP). n-BuLi
ꢀ
(40) Adje, N.; Breuilles, P.; Uguen, D. Tetrahedron Lett. 1992, 33, 2151–
2154.
(39) Baker, K. V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton, A.
J. Org. Chem. 1991, 56, 698–703.
2162 J. Org. Chem. Vol. 75, No. 7, 2010

Hodgson et al.
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1
12 (300 mg, 55%, 12:28 = 98:2 by integration of dCHOH H
NMR signals22) as an orange oil, which was used in the next step
without further purification; Rf 0.4 (5% Et2O in light petrol);
[R]26D -96.0 (c 1.5, CHCl3); IR (cm-1) 2961 s, 2931 m, 2873 w,
in CH2Cl2 (10 mL) at 0 °C was added Et3N (0.84 mL, 6 mmol),
then MsCl (0.47 mL, 6 mmol) dropwise over 5 min. The reaction
mixture was allowed to stir for 30 min at 0 °C, before addition of
anhyd LiCl (1.3 g, 10 equiv) in dry acetone (20 mL) over 2 min. The
reaction mixture was stirred overnight, then quenched with H2O
(20 mL), washed with 2 M aq NaOH (20 mL), and extracted with
CH2Cl2 (3 ꢀ 25 mL). The combined organic layers were dried
(MgSO4), concentrated under reduced pressure, and purified by
column chromatography (pentane) to give the allylic chloride 15
(407 mg, 79%) as a colorless oil; Rf 0.9 (pentane); IR (cm-1) 2959 s,
2870 s, 1712 w, 1662 m, 1384 m, 1366 m, 1206 s, 1017 w; 1H NMR
(400 MHz) 5.73 (br s, 1H, CHdC), 4.24 (d, J=11.0 Hz, 1 H, CH2-
Cl), 3.94 (d, J = 12.0 Hz, 1 H, CH2-Cl), 2.44-2.35 (m, 1 H),
2.32-2.21 (m, 2 H), 2.18-2.13 (m, 1 H), 1.98-1.87 (m, 3 H), 1.06
1
1734 w, 1703 m, 1633 br, 1466 m, 1388 w, 1181 w; H NMR
(400 MHz) 15.44 (d, J=4.0 Hz, 1 H, dCHOH), 8.56 (d, 1 H, J=
4.0 Hz, dCHOH), 2.5-2.45 (m, 1 H, CHMe), 2.34-2.32 (m,
1 H, CHMe2), 1.83-1.76 (m, 2 H, CH2), 1.53-1.44 (m, 1 H, CH-
i-Pr), 1.32-1.21 (m, 2 H, CH2), 1.15 (d, J = 6.5 Hz, 3 H, Me),
0.11 (d, J = 7.0 Hz, 3 H, CHMeMe), 0.82 (d, J = 7.0 Hz, 3 H,
CHMeMe); discernible data for 28: 8.73 (br s, dCHOH); dis-
cernible data for aldehyde tautomer: 9.71 (d, J = 4 Hz, CHO),
2.81 (dd, J=11.5 Hz, 4, CHCHO); 13C NMR (100 MHz) 191.6
(CdO), 183.7 (CH-OH), 115.2 (C), 47.6 (C-i-Pr), 31.3 (CH2),
29.1 (CMe2), 28.2 (CMe), 21.4 (CMe), 20.5 (CH2), 20.3
(CMeMe), 17.7 (CMeMe); discernible data for aldehyde tauto-
mer: 210.0, 201.1, 69.2, 56.5, 36.0, 33.1, 28.0, 25.7, 21.1, 18.6;
HRMS (CIþ) m/z [MH]þ calcd for C11H19O2 183.1385, found
183.1383.
(d, J=7 Hz, 3 H, CHMe), 0.90 (dd, J=12, 7 Hz, 6 H, CMe2); 13
C
NMR (100 MHz) 138.6 (C), 131.9 (CHdC), 48.8 (CH2-Cl), 42.3
(CH-i-Pr), 32.1 (CHMe2), 31.8 (CMe), 30.2 (CH2), 24.5 (CH2),
19.8 (CMe), 19.4 (CMeMe), 18.9 (CMeMe); HRMS [M]þ found
186.1175, C11H19Cl requires 186.1187.
(1S,3R,6S)-6-Isopropyl-3-methyl-2-methylenecyclohexanol (13).
Hydroxymethylenementhone 12 (219 mg, 1.2 mmol) was added
dropwise to a stirred solution of LiAlH4 (90 mg, 2.4 mmol, 2 equiv)
in dry Et2O (10 mL) at rt. The solution was heated to gentle reflux
overnight, then cooled and carefully quenched with 20% aq
Na2CO3 (3 mL). The organic phase was extracted with Et2O (3ꢀ
15 mL), dried (Na2SO4), and evaporated under reduced pressure.
Purification of the residue by column chromatography gave the
allylic alcohol 13 (101 mg, 50%) as a colorless oil; Rf 0.4 (6% Et2O
in light petrol); [R]25D -100.9 (c 1.4, CHCl3); IR (cm-1) 3480 br,
3067 w, 2958 s, 2933 s, 2870 m, 1644 w, 1475 w, 1450 w, 1029 m, 948
m, 905 s; 1H NMR (400 MHz) 5.02 (d, J= 1.0 Hz, 1 H, dCH2),
4.73 (d, J = 1.5 Hz, 1 H, dCH2), 3.83 (br s, 1 H, CHOH),
2.29-2.20 (m, 1 H, CHMe2), 2.03-1.94 (m, 1 H, CHMe),
1.84-1.79 (m, 1 H, H-4a), 1.71-1.62 (m, 1 H, H-5a), 1.56 (d,
J=5.5 Hz, 1 H, OH), 1.29-1.17 (m, 2 H, H-5b, H-6), 1.09 (d, J=
6.5Hz, 3H, CHMe), 1.02-0.95 (m, 1 H, H-4b), 0.93 (d, J=7.0Hz,
3 H, CHMeMe), 0.87 (d, J=7.0 Hz, 3 H, CHMeMe); 13C NMR
(100 MHz) 156.9 (dC), 100.6 (dCH2), 74.3 (COH), 51.9 (C-6),
36.7 (CHMe), 35.9 (C-4), 26.5 (CHMe2), 23.0 (C-5), 20.9
(CMeMe), 18.1 (CHMe), 15.8 (CMeMe); HRMS (CIþ) m/z
[M-OH]þ calcd for C11H19 151.1487, found 151.1488.
(R)-1-Chloro-4-((3S,6R)-3-isopropyl-6-methylcyclohex-1-enyl)-
butan-2-ol (16). Allylic chloride 15 (934 mg, 5 mmol) was reacted
according to General Procedure 1 to give the unsaturated chlo-
rohydrin 16 (479 mg, 49%) as a colorless oil; Rf 0.4 (18% Et2O in
light petrol); [R]25D þ20.4 (c0.7, CHCl3);IR(cm-1) 3584 br, 2978 s,
2871 s, 1714 m, 1470 s, 1366 m, 1255 m, 1050 s, 906 s, 740 s; 1H
NMR (400 MHz) 5.34 (br s, 1 H, CHdC), 3.86-3.80 (m, 1 H,
CHOH), 3.67 (dd, J = 11.0, 3.0 Hz, 1 H, CH2Cl), 3.52 (dd, J =
11.0, 6.5 Hz, CH2Cl), 2.25-2.04 (m, 3 H, CHMe, CH2,),
1.94-1.81 (m, 2 H, CH-i-Pr, CH2), 1.75-1.51 (m, 4 H, CHMe2,
CH2), 1.25-1.14 (m, 2 H, dC-CH2, CH2-CHOH), 0.99 (d, J =
7.0 Hz, 3 H, CHMe), 0.88 (d, J=7.0 Hz, 3 H, CMeMe), 0.84 (d,
J=7.0 Hz, 3 H, CMeMe); 13C NMR (100 MHz) 141.2 (C), 126.3
(CHdC), 71.5 (CH-OH), 50.1 (CH2-Cl), 42.1 (CH-i-Pr), 32.4
(CH2), 32.3 (CHMe), 32.2 (dC-CH2), 32.1 (CHMe2), 31.2 (CH2),
24.6 (CH2), 19.75 (CMe), 19.7 (CMeMe), 19.3 (CMeMe); HRMS
(CIþ) m/z [MH]þ calcd for C14H26OCl 245.1672, found 245.1683.
(R)-2-(2-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)ethyl)-
oxirane (17). Powdered NaOH (91 mg, 2.27 mmol) was added to a
stirred solution of unsaturated chlorohydrin 16 (464 mg, 1.9 mmol)
in MeOH (2.5 mL) at 0 °C. The resulting mixture was stirred at rt
for 90 min, then diluted with Et2O (20 mL) and washed with water
(20 mL). The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification of the residue
by column chromatography (8% Et2O in light petrol) gave epoxide
17 (323 mg, 82%) as a colorless oil; Rf 0.4 (8% Et2O in light petrol);
[R]25D þ26.8 (c 1.6, CHCl3);IR (cm-1) 2955 s, 2929 s, 2851 m, 1463
(1S,3R,6S)-6-Isopropyl-3-methyl-2-methylenecyclohexyl 3,5-
dinitrobenzoate (14). To a stirred solution of allylic alcohol 13
(168 mg, 1.0 mmol) and 3,5-dinitrobenzoyl chloride (230 mg,
1.0 mmol) in CH2Cl2 (10 mL) at 0 °C was added dry pyridine
(0.16 mL, 2 equiv) dropwise. The reaction mixture was warmed
to rt and stirred overnight, before quenching with H2O (5 mL).
The solution was neutralized with 1 N HCl, extracted with
CH2Cl2 (3 ꢀ 15 mL), dried (MgSO4), and evaporated under
reduced pressure to give yellowish brown crystals (300 mg,
80%). These crystals were washed twice with CH2Cl2 and
1
w, 1367 w, 918 w, 836 w; H NMR (500 MHz) 5.32 (br s, 1H,
CHdC), 2.95-2.91 (m, 1 H, CHOH), 2.75 (dd, J = 5.0, 4.0 Hz,
1 H, CH2-O), 2.48 (dd, J=5.0, 2.5 Hz, 1 H, CH2-O), 2.24-2.10
(m, 3 H, CHMe, dC-CH2, CH2-CH-O), 1.94-1.89 (m, 2 H, CH-
i-Pr, CH2), 1.67-1.60 (m, 3 H, dC-CH2, CH2), 1.58-1.52 (m, 1 H,
CHMe2), 1.26-1.16 (m, 2 H, CH2), 0.99 (d, J = 7.0 Hz, 3 H,
CHMe), 0.87 (d, J= 7.0 Hz, 3 H, CMeMe), 0.84 (d, J=7.0 Hz,
3 H, CMeMe); 13C NMR (125 MHz) 141.0 (C), 125.8 (CHdC),
52.3 (CH-O), 47.1 (CH2-Cl), 42.1 (CH-i-Pr), 32.35 (CHMe), 32.3
(CMe2), 32.2 (dC-CH2), 31.2 (CH2), 31.1 (CH2), 24.6 (CH2), 19.7
(CMe), 19.65 (CMeMe), 19.3 (CMeMe);HRMS(CIþ) m/z[MH]þ
calcd for C14H25O 209.1905, found 209.1907.
Et2O, then dried under reduced pressure; mp 162 °C; [R]25
D
-17.6 (c 0.6, CHCl3); IR (cm-1) 2950 m, 2831 m, 2870 m, 2401 w,
1710 s, 1575 s, 1354 s, 1012 w; 1H NMR (400 MHz) 9.27-9.26
(m, 1 H, p-Ar), 9.25-9.24 (m, 2 H, o-Ar), 5.44 (d, J = 5.5 Hz,
1 H, CH-O), 4.74 (t, J=1.5, 1 H, CHdC), 4.7 (br s, 1 H, CHdC),
2.22-2.13 (m, 1 H, CH-Me), 1.96-1.89 (m, 2 H, CH2-CHMe,
CH-Me2), 1.86-1.76 (m, 2 H, CH2CHMe, CH2-CH-i-Pr),
1.45-1.34 (m, 1 H, CH2-CH-i-Pr), 1.14 (d, J = 6 Hz, 3 H,
CH-Me), 1.11-1.04 (m, 1 H, CH-i-Pr), 0.96 (d, J = 7 Hz, 3 H,
CH(Me)2), 0.85 (d, J = 7 Hz, 3 H, CH(Me)2); 13C NMR
(100 MHz) 161.6 (CdO), 150.8 (2 ꢀ m-Ar), 148.8 (CdCH2),
133.9 (C-CdO), 129.5 (2ꢀo-Ar), 122.5 (p-Ar), 102.1 (CH2dC),
78.8 (C-O), 49.2 (C-i-Pr), 36.8 (C-Me), 35.4 (CH2), 27.1 (CMe2),
23.1 (CH2), 20.7 (CMe), 17.9 (CMeMe), 16.1 (CMeMe); HRMS
(FIþ) m/z [M]þ calcd for C18H22N2O6 362.1478, found 362.1476.
(3S,6R)-1-(Chloromethyl)-3-isopropyl-6-methylcyclohex-1-ene
(15). To a stirred solution of allylic alcohol 13 (504 mg, 3.0 mmol)
(1R,4R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-ol (18). Unsaturated terminal epoxide 17 (593 mg, 2.85
mmol) was reacted according to General Procedure 2 to give
cyclopropyl alcohol 18 (534 mg, 90%) as a white solid; Rf 0.4
(40% Et2O in light petrol); mp 74-76 °C; [R]25 -10.7 (c 0.33,
D
CHCl3); IR (cm-1) 3608 w, 3447 br, 3018 m, 2958 m, 2928 m, 2870
m, 1385 w, 1371 w, 1216 s; 1H NMR (400 MHz) 4.22 (br s, 1 H,
CHOH), 2.07-2.00 (m, 1 H, H-2a,), 1.88-1.79 (m, 1 H, H-10),
1.65-1.60 (m, 1 H, H-9a), 1.59-1.50 (m, 2 H, CHMe2, H-3a),
1.45-1.38 (m, 3 H, H-2b, H-3b, H-8a), 1.20 (d, J= 4.5 Hz, 1 H,
J. Org. Chem. Vol. 75, No. 7, 2010 2163

Hodgson et al.
JOCArticle
-OH), 1.09-1.02 (m, 1 H, H-7), 1.00 (d, J=6.5 Hz, 3 H, CHMe),
0.93-0.91 (m, 1H, H-5), 0.91 (d, J=7.0 Hz, 3 H, CMeMe), 0.87
(d, J = 7.0 Hz, 3 H, CMeMe), 0.85-0.82 (m, 1 H, H-8b),
0.60-0.52 (m, 1 H, H-9b), 0.38 (t, J = 3.0 Hz, 1 H, H-6); 13C
NMR (100 MHz) 75.1 (C-4), 44.1 (C-7), 35.4 (C-5), 34.5 (C-1),
33.5 (C-10), 31.6 (C-3), 31.4 (C-9), 29.9 (CHMe2), 28.6 (C-2), 26.5
(C-8), 24.6 (C-6), 19.9 (CHMe), 19.6 (CMeMe), 19.1 (CMeMe);
HRMS-CI: m/z [M - OH]þ calcd for C14H23 191.1800, found
191.1811.
40 (574 mg, 49%) as a colorless oil; Rf 0.4 (18% ether in light
petrol); [R]25D þ18.8 (c 0.78, CHCl3); IR (cm-1) 3470 br, 2957 s,
2933 s, 2871 m, 1713 m, 1464 m, 1384 w, 1167 m, 1049 m; 1H NMR
(400 MHz) 5.33 (br s, 1 H, CHdC), 3.79 (tt, J=8.0, 3.9 Hz, 1 H,
CH-OH), 3.63 (dd, J=10.0Hz, 1H, CH2-Cl), 3.52-3.48 (m, 1 H,
CH2-Cl), 2.33-2.25 (m, 1 H, dC-CH2-), 2.02 (br s, 1 H, -OH),
2.10-2.00 (m, 2 H, CHMe, CH2), 1.95-1.88 (m, 1 H, CH-i-Pr),
1.87-1.80 (m, 1 H, CH2), 1.70-1.52 (m, 4 H, CH2, CH2, CHMe2),
1.24-1.15 (m, 2 H, CH2-CHMe), 0.98 (d, J=7.0 Hz, 3 H, CHMe),
0.88 (d, J = 7.0 Hz, 3 H, CMeMe), 0.85 (d, J = 7.0 Hz, 3 H,
CMeMe); 13C NMR (100 MHz) 140.9 (C), 126.5 (CHdC), 71.0
(CH-OH), 50.6 (CH2-Cl), 42.1 (CH-i-Pr), 32.35 (CHMe), 32.3
(CH2), 32.2 (CH2), 32.0 (CMe2), 30.8 (CH2), 24.6 (CH2), 19.7
(CMe), 19.6 (CMeMe), 19.3 (CMeMe); HRMS (CIþ) m/z [M]þ
calcd for C14H25OCl 244.1594, found 244.1606.
Cyclopropyl alcohol 18 was also prepared (129 mg, 86%, data
as above) from unsaturated terminal epoxide 17 (149 mg, 0.71
mmol) following General Procedure 3.
Cyclopropyl alcohol 18 was also prepared (141 mg, 71%, data
as above) from unsaturated chlorohydrin 16 (244 mg, 1 mmol)
following General Procedure 4.
(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-one (2). Following General Procedure 5, cyclopropyl
alcohol 18 (521 mg, 2.5 mmol) gave norcubebanone 2 (495 mg,
95%) as a white crystalline solid; Rf 0.4 (25% Et2O in light
(S)-2-(2-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)ethyl)-
oxirane (19). Powdered NaOH (96 mg, 2.4 mmol, 1.2 equiv) was
added to a stirred solution of unsaturated chlorohydrin 40 (488mg,
2.0 mmol) in MeOH (4 mL) at 0 °C. The resulting mixture was
stirred at rt for 90 min, then diluted with Et2O (20 mL) and washed
with water (25 mL). The organic layer was dried (MgSO4), filtered,
and concentrated under reduced pressure. Purification of the
residue by column chromatography (8% Et2O in light petrol) gave
the epoxide 19 (324 mg, 78%) as a colorless oil; Rf 0.4 (8% Et2O in
petrol); [R]25D þ28.0 (c 0.6, CHCl3); IR (cm-1) 2957 s, 2934 s, 2824
m, 1464 w, 1348 w, 1115 w, 917 w, 734 w; 1H NMR (400 MHz) 5.34
(br s, 1 H, CHdC), 2.96-2.90 (m, 1 H, CH-OH), 2.76 (dd, J=5.0,
4.0 Hz, 1 H, CH2-O), 2.49 (dd, J = 5.0, 3.0 Hz, 1 H, CH2-O),
2.30-2.22 (m, 1 H, CH2CHMe), 2.11-2.03 (m, 2 H, CHMe,
CH2), 1.94-1.87 (m, 1 H, CH2), 1.85-1.80 (m, 1 H, CH-i-Pr),
1.68-1.56 (m, 4 H, CHMe2, CH2), 1.24-1.13 (m, 2 H, CH2), 0.97
(d, J = 7.0 Hz, 3 H, CHMe), 0.84 (dd, J = 12.0, 7.0 Hz, 6 H,
CHMe2); 13C NMR (100 MHz) 140.8 (C), 126.1 (CHdC), 52.1
(CH-O), 47.3 (CH2-O), 42.1 (CH-i-Pr), 32.3 (CHMe), 32.2
(CHMe2), 32.1 (dC-CH2), 31.2 (CH2), 30.8 (CH2-CHMe), 24.6
(CH2), 19.6 (CMe), 19.6 (CMeMe), 19.2 (CMeMe); HRMS (CIþ)
[M-H]þ calcd for C14H23O 207.1749, found 209.1760.
petrol); mp 58-59 °C (lit.10 mp 58.5-60 °C); [R]25 -22.3
D
(c 0.62, CHCl3) (lit.10 [R]25D -21.8 (c 0.72, CH2Cl2)); IR (cm-1
)
2956 m, 2929 m, 2872 w, 1721 s, 1459 w, 1295 w, 1221 m, 913 w; 1H
NMR (500 MHz) 2.13-2.11 (m, 1 H, H-3a), 2.10-2.04 (m, 1 H,
H-2a), 2.02-1.96 (m, 1 H, H-3b), 1.84-1.77 (m, 1 H, H-10),
1.79-1.63 (m, 2 H, H-2b, H-9a), 1.6 (oct, J=6.0 Hz, 1 H, H-11),
1.49-1.37 (m, 2 H, H-5, H-6a), 1.24 (t, J = 2.5 Hz, 1 H, H-6),
1.15-1.13 (m, 1 H, H-7), 0.95 (d, J=6.0 Hz, 3 H, CMeMe), 0.91
(m, 4 H, H-8b, CHMe), 0.87 (d, J= 6.0 Hz, 3 H, CMeMe), 0.55
(ddt, J = 2.5, 11.0, 13.0 Hz, 1 H, H-9b); 13C NMR (125 MHz)
214.6 (C-4), 43.3 (C-7), 40.3 (C-1), 39.7 (C-5), 33.3 (C-3), 33.2
(C-11), 32.5 (C-6), 31.3 (C-10), 30.8 (C-9), 26.6 (C-2), 26.0 (C-8),
19.9 (CMeMe), 19.4 (CMeMe), 18.9 (CHMe); HRMS (CIþ) m/z
[MH]þ calcd for C14H23O 207.1749, found 207.1767.
(1R,4S,5R,6R,7S,10R)-7-Isopropyl-4,10-dimethyltricyclo-
[4.4.0.01,5]decan-4-ol (1) [(-)-Cubebol]. Anhyd CeCl3 (740 mg,
3 mmol) was obtained by dehydrating CeCl3 7H2O (1.1g, 3 mmol)
3
under high vacuum (<0.1 mbar) at 165 °C (oil bath) for 2 h.41 To
this anhyd CeCl3 was added THF (15 mL) and the suspension was
stirred for 2 h at rt. MeLi (1.6 M in Et2O, 1.87 mL, 3 mmol) was
then added to the above suspension at -78 °C, followed after
30 min by a solution of ketone 9(310 mg, 1.5 mmol) in THF (10 mL)
over 10 min. After 90 min, the reaction was quenched with aq
NH4Cl (3 mL) and then warmed to rt. The reaction mixture was
extracted with Et2O (2ꢀ20 mL) and the combined organic layers
were dried (MgSO4) and concentrated under reduced pressure.
Purification of the residue by column chromatography (20% Et2O
in light petrol) gave (-)-cubebol (1) (283 mg, 85%, 97:3 mixture11)
as a crystalline solid; mp 60-61 °C (lit.10 mp 59-60.4 °C); [R]25
(1S,4S,5S,6S,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-ol (20). Unsaturated terminal epoxide 19 (304 mg, 1.46
mmol) was reacted according to General Procedure 2. The crude
product was purified by flash column chromatography (SiO2,
gradient elution, 20-35% Et2O-light petrol) to give cyclopropyl
alcohol 20 (273 mg, 90%) as a colorless oil; Rf 0.4 (40% Et2O-
petroleum ether); [R]25D þ28.0 (c 1.0, CHCl3); IR (cm-1) 3310 br,
2954 s, 2971 s, 2844 m, 1470 m, 1443 w, 1383 w, 1327 w, 1057 w,
1
974 s; H NMR (400 MHz) 4.21 (d, J = 5.0 Hz, 1 H, CHOH),
2.03-1.95 (m, 1 H, H-2a), 1.94-1.88 (m, 1 H, H-10), 1.69-1.72
(m, 1 H, H-3a), 1.62-1.46 (m, 3 H, H-7, H-8a, H-9a), 1.43-1.32
(m, 3 H, CHMe2, H-2b, H-3b), 1.08 (d, J=7.0 Hz, 3 H, CHMe),
1.01 (d, J=3.5 Hz, 1 H, H-5), 0.92 (d, J=6.5 Hz, 3 H, CHMeMe),
0.89 (d, J = 6.5 Hz, 3 H, CHMeMe), 0.88-0.86 (m, 1 H, H-9b),
0.84-0.71 (m, 1 H, H-8b), 0.68 (t, J=4.0 Hz, 1 H, H-6); 13C NMR
(100 MHz) 75.6 (C-4), 40.3 (C-7), 33.1 (C-10), 33.0 (C-3), 32.8
(C-5), 32.4 (C-1), 31.4 (C-2), 31.2 (CHMe2), 28.6 (C-9), 23.55(C-6),
23.5 (C-8), 20.8 (CMeMe), 20.7 (CMeMe), 20.4 (CMe); HRMS
(CIþ) m/z [M-OH]þ calcd for C14H23 191.1800, found 191.1806.
(1S,5S,6S,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-one (21). Following General Procedure 5, cyclopropyl
alcohol 20 (166 mg, 0.8 mmol) gave ketone 21 (158 mg, 95%) as
a colorless oil; Rf 0.4 (25% Et2O in light petrol); [R]25D -1.0 (c0.54,
CHCl3); IR (cm-1) 2972 m, 2872 m, 1725 s, 1471 w, 1420 w, 1285
w, 1187 w, 915 m; 1H NMR (500 MHz) 2.15-2.11 (m, 1 H, H-2a),
2.08-2.05 (m, 1 H, H-3a), 2.04-1.99 (m, 1 H, H-2b), 1.99-1.95
(m, 2 H, H-3b, H-10), 1.65-1.59 (m, 1 H, H-9a), 1.58-1.53 (m,
4 H, H-5, H-8a, H-6, H-7), 1.45-1.37 (m, 1 H, H-11), 1.10 (d, J=
7.0Hz, 3H, CHMe), 1.00-0.95 (m, 1 H, H-9b), 0.94 (d, J=7.0Hz,
3 H, CHMeMe), 0.90 (d, J = 6.5 Hz, 3 H, CMeMe), 0.78-0.69
(m, 1 H, H-8b); 13C NMR (125 MHz) 215.2 (C-4), 40.5 (C-7), 37.6
-59.6 (c 0.6, CHCl3) (lit.10 [R]25D -48.3 (c 1.0, CHCl3)); IR (cm-1D
)
3350 br, 2951 m, 2860 m, 1490 w, 1142 m, 910 w; 1H NMR (400
MHz): 1.82-1.8 (m, 1 H, H-2a), 1.32-1.26 (m, 1 H, H-10),
1.62-1.59 (m, 1 H, H-11), 1.58-1.55 (m, 1 H, H-9a), 1.53-1.49
(m, 2 H, H-3a, H-2b), 1.4 (s, 1 H, H-16), 1.35-1.32 (m, 2 H, H-8a,
H-3b), 1.25 (d, J=1.0 Hz, 3 H, H-15), 0.96-0.93 (m, 10 H, H-7,
CHMe, CMeMe, CMeMe), 0.80-0.77 (m, 3 H, H-10, H-6, H-8b),
0.49-0.46 (m, H-9b); 13C NMR (100 MHz) 80.3 (C-4), 44.1 (C-7),
39.0 (C-5), 36.3 (C-3), 33.6 (C-11), 33.4 (C-1), 31.7 (C-9), 30.8
(C-10), 29.5 (C-2), 27.9 (C-15), 26.4 (C-8), 22.6 (C-6), 20.1
(CMeMe), 19.6 (CMeMe), 18.7 (CHMe), discernible data for
4-epi-(1): 80.8, 44.6, 39.9, 36.6, 34.9, 31.8, 30.2, 29.7, 27.1, 25.3,
25.0, 20.1, 19.2; HRMS (CIþ) m/z [MH]þ calcd for C15H27O
223.2062, found 223.2069.
(S)-1-Chloro-4-((3S,6R)-3-isopropyl-6-methylcyclohex-1-enyl)-
butan-2-ol (40). Allylic chloride 15 (1.1 g, 6.0 mmol) was reacted
according to General Procedure 1 to give unsaturated chlorohydrin
(41) Hodgson, D. M.; Kloesges., J.; Evans, B. Org. Lett. 2008, 10, 2781–
2783.
2164 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
(C-1), 37.5 (C-5), 32.9 (C-3), 32.8 (C-11), 32.2 (C-6), 32.1 (C-9),
30.6 (C-10), 26.8 (C-2), 23.1 (C-8), 20.6 (CMeMe), 20.5 (CMeMe),
18.7 (CMe); HRMS (CIþ) m/z [MH]þ calcd for C14H23O
207.1749, found 207.1762.
CHMe2), 1.41-1.36 (m, 1 H, CH-i-Pr), 1.13 (d, J=7.0 Hz, 3 H,
CHMe), 0.97 (dd, J = 11.0, 6.5 Hz, 6 H, CHMe2); 13C NMR
(125 MHz) 161.6 (CdO), 148.7 (CdCH2), 148.2 (2 ꢀ o-Ar),
134.5, 129.2 (2 ꢀ C-NO2), 122.2 (p-Ar), 114.8 (CdCH2), 79.2
(C-O), 48.5 (C-i-Pr), 35.7 (C-Me), 32.0 (CH2), 28.7 (CHMe2),
21.1 (CMe), 20.9 (CMeMe), 20.8 (CMeMe), 20.7 (CH2); HRMS
(FIþ) m/z [M]þ calcd for C18H22N2O6 362.1478, found 362.1476.
Comparison of 14 J1,6 (5.5 Hz) with 41 J1,6 (2.5 Hz) for 3,5-
DNB derivatives of allylic alcohols 13 and ent-34, respectively,
led to assignment of the cis configuration for 3,5-DNB deriva-
tive of ent-34.
(3R,6R, Z)-2-(Hydroxymethylene)-6-isopropyl-3-methylcyclo-
hexanone (28). A solution of ethyl formate (47.1 g, 636 mmol) in
toluene (96 mL) was added to a vigorously stirred cooled (0 °C)
solution of NaOMe (34.4 g, 636 mmol) in dry toluene (192 mL)
over a period of 1 h. A solution of menthone 11 (32.7 g, 212 mmol)
in a 1:3 toluene-THF mixture (135 mL) was added dropwise to
the above cooled solution over 1 h. The solution was allowed to
warm to room temperature and then stirring was continued for
72 h. The solution was then neutralized with ice-cooled 15% (w/v)
H2SO4, the organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3ꢀ50 mL). The combined organic layers
were dried (Na2SO4) and evaporated to give a pale red oil, which
was distilled (15 mbar, 125 °C) to give a yellow oil hydroxymethy-
(3R,6R)-1-(Chloromethyl)-3-isopropyl-6-methylcyclohex-1-ene
(ent-35). To a stirred solution of allylic alcohol ent-34 (1.5 g,
9 mmol) in CH2Cl2 (20 mL) at 0 °C was added Et3N (2.5 mL,
18 mmol), then MsCl (1.4 mL, 18 mmol) was added dropwise over
5 min. The reaction mixture was allowed to stir for 30 min at 0 °C,
before the addition of anhyd LiCl (3.8 g, 10 equiv) in dry acetone
(25 mL) over 2 min. The reaction mixture was stirred overnight,
then quenched with H2O (20 mL), washed with 2 M aq NaOH
(40 mL), and extracted with CH2Cl2 (3ꢀ100 mL). The combined
organic layers were dried (MgSO4), concentrated under reduced
pressure, and purified by column chromatography (pentane) to
give the allylic chloride ent-35 (1.27 mg, 76%) as a colorless oil;
Rf 0.9 (pentane); IR (cm-1) 2959 s, 2870 s, 1712 w, 1662 m, 1384 m,
1
lene ketone 28 (31.7 g, 82%, 12:28 = 7:93 by integration of H
NMR signals for dCHOH); Rf = 0.4 (5% ether in light petrol);
[R]26D þ26.8 (c 1.6, CHCl3); IR (cm-1) 3165 br, 3103 br, 2961 s,
2874 s, 1709 s, 1633 w, 1587 w, 1464 m, 1370 m, 1167 br; 1H NMR
(400 MHz) 14.81 (br s, 1 H, dCHOH), 8.72 (br s, 1 H, dCHOH),
2.70-2.59 (m, 1 H, CHMe), 2.54-2.39 (m, 1 H, CHMe2), 2.32-
2.27 (m, 1 H, CH-i-Pr), 1.63-1.51 (m, 4 H, 2 ꢀ CH2), 1.16-1.04
(m, 3 H, CHMeMe), 1.01-0.92 (3 H, CHMeMe), 0.86-0.72 (m,
3H, CHMe), discernible data 15.44 (br s, 1 H, dCHOH), 8.55(brs,
1 H, dCHOH); 13C NMR (100 MHz) 188.8 (CdO), 186.7 (CH-
OH), 115.1 (C), 46.1 (C-i-Pr), 28.5 (CH2), 27.7 (CMe2), 27.6, 23.0
(CMe), 20.2 (CMeMe), 17.2 (CMeMe), 16.3 (CH2); discernible
data for 12: 183.8, 47.5, 31.3; HRMS (CIþ) m/z [MH]þ calcd for
C11H19O2 183.1385, found 183.1383.
1
1366 m, 1206 s, 1017 w; H NMR (400 MHz) 5.70 (br s, 1 H,
CHdC), 4.18 (d, J=11.0 Hz, 1 H, CH2-Cl), 3.97 (d, J=11.0 Hz,
1 H, CH2-Cl), 2.49-2.45 (m, 1 H), 2.37-2.22 (m, 1 H), 2.03-1.93
(m, 1 H), 1.82-1.56 (4 H), 1.04 (d, J=6.5 Hz, 3 H, CHMe), 0.89
(dd, J= 11.0, 6.5 Hz, 6 H, CHMe2); (100 MHz) 139.2 (C), 131.5
(CHdC), 49.0 (CH2-Cl), 42.4 (CH-i-Pr), 31.9 (CHMe), 29.6
(CH2), 28.4 (CMe2), 20.4 (CH2), 19.7 (CMe), 19.3 (CMeMe),
19.2 (CMeMe); HRMS (Clþ) m/z [M]þ calcd for C11H19Cl
186.1175, found 186.1171.
(1S,3R,6R)-6-Isopropyl-3-methyl-2-methylenecyclohexanol
(ent-34). Hydroxymethylene ketone 28 (6.38 g, 35 mmol) was
added dropwise to a stirred solution of LiAlH4 (2.65 g, 70 mmol)
in dry Et2O (210 mL) at rt. The solution was heated to gentle reflux
overnight, then cooled and carefully quenched with 20% Na2CO3
solution (20 mL). The organic phase was extracted with Et2O (3ꢀ
50 mL), dried (Na2SO4), and evaporated under reduced pressure.
Purification of the residue by column chromatography gave the
allylic alcohol ent-34 (3.0 g, 51%) as a colorless oil; Rf 0.4 (5% ether
in petrol); [R]25D -10.4 (c 1.2, CHCl3); IR (cm-1) 3165 br, 2961 s,
(R)-1-Chloro-4-((3R,6R)-3-isopropyl-6-methylcyclohex-1-enyl)-
butan-2-ol (42). Allylic chloride ent-35 (930 mg, 5 mmol) was
reacted according to General Procedure 1 to give unsaturated
chlorohydrin 42 (488 mg, 2 mmol, 50%) as a colorless oil; Rf 0.4
(18% ether in light petrol); [R]25D þ32.9 (c 2.4, CHCl3); IR (cm-1
)
3429 br, 2957 s, 2870 s, 1711 m, 1462 m, 1383 w, 1061 br, 487 w; 1H
NMR (400 MHz) 5.20-5.18 (m, 1 H, CHdC), 3.85-3.8 (m, 1 H,
CH-OH), 3.66 (dd, J=3.5, 1 H, CH2-Cl), 3.51 (dd, J= 11.0, 6.5
Hz, 1 H, CH2-Cl), 2.2-2.0 (m, 5 H), 1.85-1.95 (m, 1 H, CH-i-Pr),
1.75-1.45 (m, 4 H, 2ꢀCH2), 1.39-1.31 (m, 1 H), 1.26 (s, 1 H), 1.0
(d, J=7.0 Hz, 3 H, CHMe), 0.9 (d, J=7.0 Hz, 3 H, CHMeMe),
0.85 (d, J=7.0 Hz, 3 H, CHMeMe); 13C NMR (100 MHz) 141.8
(C), 125.3 (CHdC), 71.6 (CH-OH), 50.3 (CH2Cl), 42.2 (CH-i-Pr),
32.6 (CH2), 32.2 (CH2), 31.5 (CH2), 31.2 (CHMe2), 30.1 (CH2),
20.5 (CH2), 19.7 (CMe), 19.6 (CMeMe), 19.2 (CMeMe); HRMS
(CIþ) m/z [MH]þ calcd for C14H26OCl 245.1672, found 245.1683.
(R)-2-(2-((3R,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)ethyl)-
oxirane (22). Powdered NaOH (91 mg, 2.4 mmol) was added to a
stirred solution of unsaturated chlorohydrin 42 (488 mg, 2.0 mmol)
in MeOH (3.5 mL) at 0 °C. The resulting mixture was stirred at rt
for 90 min, then diluted with Et2O (20 mL) and washed with water
(20 mL). The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification of the residue
by column chromatography (8% Et2O in petrol) gave the epoxide
22 (316 mg, 1.52 mmol, 76%) as a colorless oil; Rf 0.4 (8% Et2O in
light petrol); [R]25D þ47.4 (c 0.7, CHCl3); IR (cm-1) 3381 br, 3046
w, 2959 s, 2872 m, 1713 w, 1659 m, 1462 m, 1409 m, 1257 w; 1H
NMR (400 MHz) 5.27 (br s, 1 H, CHdC), 2.95-2.90 (m, 1 H,
CH-O), 2.75 (t, J=4.5 Hz, 1 H, CH2-O), 2.49 (dd, J=4.5, 2.5 Hz,
1 H, CH2-O), 2.20-2.07 (m, 3 H), 1.93-1.89 (m, 1 H, CHMe),
1.71-1.48 (m, 6 H), 1.38-1.22 (m, 1 H, CH-i-Pr), 1.00 (d, J =
1
2874 s, 1633 w, 1587 w, 1464 m, 700 w; H NMR (400 MHz)
4.88-4.86 (d, J= 2.0 Hz, 1 H, dCH2), 4.8 (dd, J= 2.0 Hz, 1 H,
dCH2), 4.3 (br s,1 H, CH-OH), 2.48-2.42 (m, 1 H, CHMe),
1.73-1.62 (m, 2 H, CH2), 1.57-1.49(m, 3H), 1.4(s, 1H, CH-i-Pr),
1.2 (d, J=7.0 Hz, 3 H, CHMe), 1.15-1.06 (m, 1 H, CH-i-Pr), 0.1
(d, J=6.5Hz, 3H, CHMeMe), 0.9 (d, J=6.5 Hz, 3 H, CHMeMe);
13C NMR(100 MHz) 154.6 (C), 110.0 (dCH2), 74.9 (COH), 49.4
(CH), 36.0 (CH), 32.7 (CH2), 28.2 (CH3), 21.3 (CMeMe), 21.3,
21.0 (CMeMe), 20.2 (CH2); HRMS (CIþ) m/z [MHþ] found
169.1589, C11H20O requires 169.1592.
(1S,3R,6R)-6-Isopropyl-3-methyl-2-methylenecyclohexyl 3,5-
dinitrobenzoate (41). To a stirred solution of allylic alcohol ent-
34 (168 mg, 1.0 mmol), 3,5-dinitrobenzoyl chloride (230 mg,
1.0 mmol), and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (10 mL) at
0 °C was added anhydrous Et3N (0.28 mL, 2 equiv) dropwise.
The reaction mixture was warmed to rt and stirred overnight,
before quenching with aq NaHCO3 solution (5 mL). The
solution was washed with brine (20 mL), extracted with CH2Cl2
(3 ꢀ 15 mL), dried (MgSO4), and evaporated under reduced
pressure. Purification by column chromatography (3% Et2O in
light petrol) gave colorless oil 41 (225 mg, 62%); Rf 0.4 (4%
Et2O in light petrol); [R]25D þ 52.6 (c 1.54, CHCl3); IR (cm-1
)
3104 w, 2962 m, 2932 m, 2871 w, 1729 s, 1629 w, 1547 s, 1344 s,
1272 s, 1167 s, 777 m; 1H NMR (500 MHz) 9.22 (br s, 1 H, p-Ar),
9.13 (d, J=2.0 Hz, 2 H, o-Ar), 5.82 (d, J=2.5 Hz, 1 H, CH-O),
5.17 (s, 1 H, CHdC), 5.04 (s, 1 H, CHdC), 2.63-2.56 (m, 1 H,
CH-Me), 1.87-1.76 (m, 2 H, CH2), 1.73-1.62 (m, 3 H, CH2,
7.0 Hz, 3 H, CHMe), 0.87 (dd, J=16.5, 6.0 Hz, 6 H, CHMe2); 13
C
NMR (100 MHz) 141.5 (C), 124.9 (CHdC), 52.3 (CH-O), 47.2
(CH2-O), 42.2 (CH-i-Pr), 32.2 (CHMe), 31.6 (CH2), 31.4 (CH-
i-Pr), 31.2 (CH2), 30.1 (CH2), 20.5 (CH2), 19.7 (CMe), 19.6
J. Org. Chem. Vol. 75, No. 7, 2010 2165

Hodgson et al.
JOCArticle
(CMeMe), 19.2 (CMeMe); HRMS (CIþ) m/z [MH]þ cald for
C14H25O 209.1907, found 209.1905.
2 mmol) under high vacuum (<0.1 mbar) at 165 °C (oil bath) for
2 h.41 To this anhyd CeCl3 was added THF (10 mL) and the
suspension was stirred for 2 h at rt. MeLi (1.6 M in Et2O, 1.25 mL,
2 mmol) was then added to the above suspension at -78 °C,
followed after 30 min by a solution of ketone 32 (206 mg, 1.0 mmol)
in THF (7 mL) over 10 min. After 90 min, the reaction was
quenched with aq NH4Cl (3 mL) and then warmed to rt. The
reaction mixture was extracted with Et2O (2 ꢀ 20 mL), and the
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. Purification by column chromatography
(20% Et2O in light petrol) gave the crystalline white solid, alcohol
33 (191 mg, 86%); Rf 0.4 (25% Et2O in light petrol); mp 87-89 °C;
[R]25D -9.8 (c 0.6, CHCl3); IR (cm-1) 3273 br, 2953 s, 2916 s, 2877
m, 2850 m, 1460 w, 1370 w, 1299 w, 1199 w, 1149 w; 1H NMR (400
MHz) 1.95-1.89 (m, 1 H, H-10), 1.74-1.64 (m, 2 H, H-2a, H-3a),
1.56-1.49 (m, 2 H, H-9), 1.41-1.32 (m, 8 H, H-8a, H-2b, H-3b,
H-11, H-5, H-15), 1.21 (t, J=3.5 Hz, 1 H, H-6), 1.14-1.10 (m, 1 H,
H-8b), 1.02 (d, J = 6.5 Hz, 3 H, Me), 0.93-0.91 (m, 4 H, H-7,
CMeMe), 0.84 (d, J=7.0 Hz, 3 H, CMeMe), 0.78-0.71 (m, 1 H,
H-6); 13C NMR (100 MHz) 80.2 (C-4), 40.6 (C-5), 35.9 (C-3), 33.7
(C-1), 32.6 (C-11), 31.7 (C-7), 31.6 (C-2), 29.9 (C-9), 28.4 (C-15),
28.2 (C-10), 21.9 (C-6), 21.3 (C-8), 21.0 (CHMe), 20.7 (CHMeMe),
18.0 (CHMeMe); HRMS (CIþ) m/z [MH]þ calcd for C15H27O
223.2062, found 223.2052.
(1R,4R,5R,6R,7R,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-ol (29). Unsaturated epoxide 22 (707 mg, 3.4 mmol) was
subjected to General Procedure 2. The crude product was purified
by flash column chromatography (SiO2, gradient elution, 20-35%
Et2O in light petrol) to give cyclopropyl alcohol 29 (304 mg, 1.74
mmol, 43%) as an orange oil; Rf 0.3 (40% Et2O in light petrol);
[R]25D -32.0 (c 0.6, CHCl3); IR (cm-1) 3326 br, 2953 s, 2870 m,
2360 w, 2341 w, 1457 w, 1382 w, 1057 w, 974 w; 1HNMR(400MHz)
4.20 (d, J=4.5 Hz, 1 H, CH-OH), 2.12-2.09 (m, 1 H), 1.91-1.89
(m, 1 H), 1.64 (dd, J = 12.0, 8.0 Hz, 1 H), 1.54-1.49 (m, 1 H),
1.44-1.30 (m, 6 H), 1.26 (br s, 1 H), 1.17-1.13 (m, 1 H), 0.99
(d, J=6.0 Hz, 3 H), 0.90 (dd, J=4.5 Hz, 6 H, 2ꢀMe), 0.81-0.76
(m, 2 H); 13C NMR (100 MHz) 75.8 (C-OH), 40.6 (CH-i-Pr),
34.6 (C), 32.7, 31.2 (CH2), 30.6 (CH2), 29.9 (CH2), 28.5, 27.2,
23.8, 21.5 (CH2), 20.9 (CMe), 20.8 (CMeMe), 18.5 (CMeMe);
HRMS (Clþ) m/z [M]þ calcd for C14H24O 208.1827, found
209.1815.
(2R,6R,8aR)-6-Isopropyl-8a-methyl-1,2,3,4,6,7,8,8a-octahydro-
naphthalen-2-ol (30). The unsaturated alcohol 30 (282 mg, 40%)
was obtained as a major byproduct during the cyclopropanation
of epoxide 22; Rf 0.4 (40% Et2O in light petrol); [R]26 þ 44.6
D
(c 0.56, CHCl3); IR (cm-1) 3336 br, 2956 s, 2930 s,2870 m, 2360 w,
2341 w, 1463 w, 1384 w, 1045 m; H NMR (500 MHz) 5.23 (s,
1
(S)-1-Chloro-4-((3R,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)-
butan-2-ol (ent-36). Allylic chloride ent-35 (1.12 g, 6.0 mmol) was
subjected to General Procedure 1 to give unsaturated chlorohydrin
ent-36 (585 mg, 50%) as a colorless oil; Rf 0.4 (18% Et2O in light
1 H, H-5), 3.97-3.91 (m, 1 H, H-2), 2.25 (tt, J=14, 4.5 Hz, 1 H,
H-8b), 2.11-2.02 (m, 2 H, H-4a, H-8a), 1.95-1.92 (m, 1 H, H-6),
1.84 (ddd, 1 H, J = 12, 4, 2.5 Hz, H-1a), 1.58-1.51 (m, 3 H,
H-3b, H-7b, CHMe), 1.40-1.30 (m, 2 H, H-3a, H-7a), 1.27-
1.18 (m, 2 H, H-4b, -OH), 1.13-1.09 (m, 1 H, H-1a), 1.05 (s,
3 H, Me), 0.86 (dd, J = 15.5, 6.5 Hz, 6 H, CHMe2); 13C NMR
(125 MHz) 141.2 (C-4a), 124.3 (C-5), 67.6 (C-2), 51.0 (C-1),
42.7 (C-6), 39.6 (C-3), 37.3 (C-4), 35.4 (C-8a), 32.1 (CHMe2),
30.9 (C-8), 25.1 (Me), 21.2 (C-7), 19.6 (CMeMe), 19.1 (CMeMe);
HRMS (Clþ) m/z [MH]þ calcd for C14H25O 209.1905, found
209.1909.
4-((3R,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)butanal (31).
The unsaturated aldehyde 31 (10-15%) was obtained as a minor
byproduct during the cyclopropanation of epoxide 22; Rf 0.4 (10%
Et2O in light petrol); IR (cm-1) 3421 br, 2956 s, 2932 s, 2861 m,
1715 w, 1466 w, 1147 m, 949 w; 1H NMR (400 MHz) 9.77 (s, 1 H,
CHO), 5.25 (br s, 1 H, CHdC), 2.44-2.39 (m, 1 H, CdCH2),
2.08-2.05 (m, 2 H, CH2-CHO, CHMe), 1.98-1.90 (m, 2 H, CH2),
1.84-1.69 (m, 1 H, CH2), 1.67-1.46 (m, 6 H, CH2, CHMe2),
1.22-1.21 (m, 1 H, CH-i-Pr), 0.99 (d, J = 7.0 Hz, 3 H, CHMe),
0.88 (d, J = 7.0 Hz, 3 H, CHMeMe), 0.84 (d, J = 7.0 Hz, 3 H,
CHMeMe); 13C NMR (100 MHz) 202.9 (CdO), 141.3 (C), 125.7
(CHdC), 43.5 (CH2), 42.2 (CH-i-Pr), 34.7 (dC-CH2), 32.2 (CH-
Me), 30.9 (CHMe2), 30.1 (CH2), 20.5 (2ꢀCH2), 19.7 (CMe), 19.6
(CMeMe), 19.2 (CMeMe); HRMS (Clþ) m/z [MH]þ calcd for
C14H25O 209.1905, found 209.1898.
petrol); [R]25 þ40.0 (c 0.5, CHCl3); IR (cm-1) 3390 br, 2957 s,
D
2933 s, 2871 m, 1731 m, 1464 w, 1384 w, 1366 w, 1167 w, 1106 w,
1150 w,740 w; H NMR (400 MHz) 5.28 (br s, 1 H, CHdC),
1
3.79-3.73 (m, 1 H, CHOH), 3.64-3.60 (m, 1 H, CH2-Cl),
3.51-3.46 (m, 1 H, CH2-Cl), 2.33 (br s, I H, -OH), 2.19-2.11
(m, 1 H, CH2-CHOH), 2.07-2.03 (m, 2 H, CHMe, dC-CH2),
1.94-1.86 (m, 1 H, CH-i-Pr), 1.71-1.44 (m, 5 H, CHMe2, 2 ꢀ
CH2), 1.37-1.29 (m, 2 H), 0.99 (d, J=7.0, 3 H, CHMe), 0.85 (d,
J = 7.0, 3 H, CHMeMe), 0.82 (d, J = 7.0, 3 H, CHMeMe); 13
C
NMR (100 MHz) 141.5 (C), 125.4 (CHdC), 71.0 (CHOH), 50.5
(CH2-Cl), 42.2 (CH-i-Pr), 32.4 (CHMe), 32.2 (CH2-CHOH), 31.1
(CH2), 30.9 (CMe2), 30.1 (CH2), 20.5 (CH2), 19.7 (CMe), 19.5
(CMeMe), 19.2 (CMeMe); HRMS (CIþ) m/z [MH]þ calcd for
C14H26OCl 245.1672, found 245.1662.
(S)-2-(2-((3R,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)ethyl)-
oxirane (23). To a stirred solution of unsaturated chlorohydrin ent-
36 (585 mg, 2.4 mmol) in MeOH (3 mL) at 0 °C was added pow-
dered NaOH (115 mg, 2.9 mmol). The resulting mixture was stirred
at rt for 90 min, then diluted with Et2O (25 mL) and washed with
water (30 mL). The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification of the residue by
column chromatography (8% Et2O in light petrol) gave the
epoxide 23 (383 mg, 1.84 mmol, 77%) as a colorless oil; Rf 0.4
(8% Et2O in light petrol); [R]D þ33.7 (c 1.0, CHCl3); IR (cm-1
)
25
(1R,5R,6R,7R,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-one (32). Following General Procedure 5, cyclopropyl
alcohol 29 (256 mg, 1.23 mmol) gave ketone 32 (240 mg, 95%)
as a colorless oil; Rf 0.4 (25% Et2O in light petrol); [R]25D -46.4
(c 1.5, CHCl3); IR (cm-1) 2955 m, 2928 m, 2870 w, 1721 s, 1460 w,
1322 w, 1220 w,1043 w; 1H NMR (400 MHz) 2.16-1.97 (m, 5 H),
1.67-1.64 (m, 1 H), 1.57 (d, J=3.0 Hz, 1 H), 1.51-1.42 (m, 3 H),
1.41-1.35 (1 H), 1.21-1.18 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H,
Me), 0.89 (dd, J= 10, 6.5 Hz, 6 H, 2 ꢀ Me), 0.75-0.73 (m, 1 H);
13C NMR (100 MHz) 215.3 (C-4), 41.0 (C-7), 40.5 (C-1), 33.3
(C-5), 33.1 (C-3), 32.4 (C-11), 32.3 (C-6), 29.4 (C-10), 29.1 (C-9),
28.8 (C-2), 21.1 (C-8), 20.7 (CMe), 20.6 (CMeMe), 18.2 (CMeMe);
HRMS (CIþ) m/z [M]þ calcd for C14H22O 206.1671, found
206.1669.
3042 w, 2957 s, 2934 s, 2870 m, 1663 w, 1384 w, 1365 w, 774 w; 1H
NMR (400 MHz) 5.27 (br s, 1 H, CHdC), 2.93-2.88 (m, 1 H, CH-
O), 2.73 (t, J=4.5 Hz, 1 H, CH2-O), 2.46 (dd, J=5.0, 3.9 Hz, 1 H,
CH2-O), 2.20-2.04 (m, 3 H, CHMe, CH2), 1.92-1.85 (m, 1 H,
CH-i-Pr), 1.67-1.57 (m, 3 H, CH2-CH-i-Pr, CH2-CH-O),
1.55-1.45 (m, 3 H, CHMe2, CH2-CHMe), 1.39-1.28 (m, 1 H,
CH2), 0.99 (d, J=7.0 Hz, 3 H, CHMe), 0.87 (d, J=6.5 Hz, 3 H,
CHMe2), 0.83 (d, J=7.0 Hz, 3 H, CHMe2); 13C NMR (100 MHz)
141.3 (C), 125.1 (CHdC), 52.1 (CH-O), 47.3 (CH2-O), 42.2 (CH-
i-Pr), 32.2 (CHMe), 31.5 (dC-CH2), 31.1 (CHMe2), 31.0
(CH2), 30.1 (CH2), 20.5 (CH2), 19.7 (CMe), 19.5 (CMeMe), 19.2
(CMeMe); HRMS (CIþ) m/z [MH]þ calcd for C14H25O 209.1905,
found 209.1905.
(1R,4S,5R,6R,7R,10R)-7-Isopropyl-4,10-dimethyltricyclo-
(1S,4S,5S,6S,7R,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-ol (ent-37). Unsaturated epoxide 23 (304 mg, 1.46 mmol)
was reacted according to General Procedure 2. The crude product
[4.4.0.01,5]decan-4-ol (33) [(-)-7-Epicubebol]. Anhyd CeCl3 (493mg,
2.0 mmol) was obtained by dehydrating CeCl3 7H2O (745 mg,
3
2166 J. Org. Chem. Vol. 75, No. 7, 2010

Hodgson et al.
JOCArticle
was purified by flash column chromatography (SiO2, gradient
elution, 20-35% Et2O-petrol) to give cyclopropyl alcohol ent-37
(270 mg, 89%) as a colorless oil; Rf 0.4 (40% Et2O in light petrol);
[R]25D þ25.5 (c 3.0, CHCl3); IR(cm-1) 3350 br, 2974 s, 2851 s, 1470
m, 1385 m, 1264 w, 1072 w, 906 w, 740 m; 1H NMR (400 MHz)
4.23 (d, J=4.5 Hz, 1 H, H-4), 2.11-2.06 (m, 1 H, H-10), 1.82-1.74
(m, 1 H, H-2a), 1.65-1.60 (m, 1 H, H-9a), 1.58-1.50 (m, 2 H, H-
3a, H-11), 1.42-1.23 (m, 4 H, H-3b, H-7, H-2b, H-8a), 1.20-1.13
(m, 1 H, H-9b), 1.11-1.08 (m, 1 H, H-8b), 1.04 (d, J=7.0 Hz, 3 H,
CHMe), 0.99 (d, J=2.5 Hz, 1 H, H-5), 0.89 (d, J=7.0 Hz, 3 H,
CHMeMe), 0.86 (d, J=7.0 Hz, 3 H, CHMeMe), 0.29 (br s, 1H,
H-6); 13C NMR (100 MHz) 75.3 (C-4), 42.4 (C-7), 37.5 (C-10), 33.9
(C-1), 33.6 (C-5), 31.6 (C-3), 29.9 (C-9), 29.3 (C-2), 29.3 (C-11),
22.6 (C-6), 19.8 (C-8), 19.7 (CMeMe), 19.2 (CMeMe), 18.6 (CMe);
HRMS (CIþ) m/z [M - OH]þ calcd for C14H23 191.1800, found
191.1808.
then quenched with 20 mL of H2O, washed with 2 M aq NaOH
(35 mL), and extracted with CH2Cl2 (3 ꢀ 60 mL). The com-
bined organic layers were dried under reduced pressure and
purified by column chromatography (pentane) to give the
allylic chloride 35 as a colorless oil (815 mg, 76%); other data
as ent-35.
(R)-1-Chloro-4-((3S,6S)-3-isopropyl-6-methylcyclohex-1-enyl)-
butan-2-ol (36). Allylic chloride 35 (1.1 g, 5.94 mmol) was reacted
according to General Procedure 1 to give the unsaturated chlo-
rohydrin 36 (568 mg, 49%) as a colorless oil; [R]25D -38.1 (c 0.6,
CHCl3); other data as ent-36.
(1R,4R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-ol (37). Unsaturated chlorohydrin 36 (427 mg, 1.75 mmol)
was reacted according to General Procedure 4. The crude product
was purified by flash column chromatography (SiO2, gradient
elution, 20-35% Et2O in light petrol) to give cyclopropyl alcohol
37 (302 mg, 83%) as a colorless oil; [R]25D -28.8 (c 1.9, CHCl3);
other data as ent-37.
From epoxide 23 (244 mg, 1 mmol), following General
Procedure 3, the cyclopropyl alcohol ent-37 was also prepared
in 87% yield.
(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]-
decan-4-one (38). Following General Procedure 5, the cyclopro-
pyl alcohol 37 (187 mg, 0.9 mmol) gave ketone 38 (178 mg,
96%) as a colorless oil; Rf 0.4 (25% Et2O in light petrol);
[R]25D þ7.76 (c 1.0, CHCl3); IR (cm-1) 2956 s, 2929 s, 2872 m,
1719 s, 1459 w, 1387 w, 1248 w, 1185 m, 936 w; 1H NMR
(400 MHz) 2.16-2.07 (m, 2 H, H-10, H-3a), 2.05-1.97 (m,
2 H, H-3b, H-9a), 1.90-1.82 (m, 1 H, H-2a), 1.68-1.60 (m, 1 H,
H-11), 1.56 (d, J=2.0 Hz, 1 H, H-5), 1.43-1.36 (m, 2 H, H-9b,
H-8a), 1.26-1.15 (m, 4 H, H-8b, H-7, H-2b, H-6), 1.07-1.05
(m, 3 H, H-14), 0.93-0.89 (m, 6 H, CHMe2); 13C NMR
(100 MHz) 214.6 (C-4), 42.1 (C-7), 41.5 (C-5), 39.6 (C-1),
33.3 (C-11), 33.3 (C-3), 30.9 (C-6), 29.1 (C-10), 28.2 (C-9),
28.1 (C-2), 19.6 (CMeMe), 19.1 (C-8), 18.9 (CMeMe), 16.5
(CMe); HRMS (CIþ) m/z [M]þ calcd for C14H22O 206.1671,
found 206.1680.
Synthesis of (-)-10-Epicubebol (39). (2R,5S)-2-Isopropyl-
5-methylcyclohexanone (ent-11). d-Menthol (5.0 g, 32.0 mmol)
was dissolved in MeCN:AcOH (3:2, 42 mL) and added dropwise
over a period of 30 min to a cooled (0 °C) and stirred solution of
calcium hypochlorite (4.0 g, 28.0 mmol) in water (65 mL). The
stirring was continued for 3 h, and then water (65 mL) was added
in one portion. The reaction mixture was extracted with CH2Cl2
(3ꢀ50 mL) and the combined organic layers were washed with
10% aq NaHCO3 (2ꢀ50 mL), dried (MgSO4), and concentrated
under reduced pressure to give d-menthone (ent-11) (4.8 g, 97%)
25
as a colorless oil; Rf 0.4 (4% ether in petrol); [R]D þ29.4 (c 0.4,
CHCl3) (lit.42 [R]20 þ19.0 (c 10.0, EtOH)). Other data as
D
l-menthone 11, see above.
(3S,6R,Z)-2-(Hydroxymethylene)-6-Isopropyl-3-methylcyclo-
hexanone (ent-28). A solution of ethyl formate (7.1 g, 96.0 mmol)
in toluene (15 mL) was added to a vigorously stirred cooled
(0°C) solution of NaOMe (5.2 g, 96.0 mmol) in dry toluene (30 mL)
over a period of 1 h. A solution of d-menthone (ent-11) (5.0 g, 32.0
mmol) in a 1:3 toluene-THF mixture (20 mL) was added dropwise
to the above cooled solution over 1 h. The solution was allowed to
warm to room temperature and then stirring was continued for
72 h. The solution was neutralized with ice-cooled 15% (w/v)
H2SO4, the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (3 ꢀ 40 mL). The combined orga-
nic layers were dried (Na2SO4) and concentrated under vac-
uum and distilled (15 mbar, 125 °C) to give a yellow oil hydro-
xymethylene ketone ent-28 (5.0 g, 84%, 93:7 cis:trans by 1H NMR
analysis of signals of dCH); [R]25D þ9.0 (c 1.9, CHCl3); other data
as 28.
(3S,6R)-6-Isopropyl-3-methyl-2-methylenecyclohexanol (34).
Hydroxymethylene ketone ent-28 (5.0 g, 27 mmol) was
added dropwise to a stirred solution of LiAlH4 (2 g, 54 mmol),
in dry Et2O (160 mL) at rt. The solution was heated to
gentle reflux overnight and then cooled and carefully
quenched with 20% aq NaHCO3. The organic phase was
extracted with Et2O (4 ꢀ50 mL), dried (Na2SO4), and evapo-
rated under reduced pressure. Purification of the residue by
column chromatography gave the allylic alcohol 34 (1.47 g,
32%) as a colorless oil; [R]25D þ6.1 (c 0.3, CHCl3); other data
as ent-34.
(1R,4S,5R,6R,7S,10S)-7-Isopropyl-4,10-dimethyltricyclo-
[4.4.0.01,5]decan-4-ol (39) [(-)-10-Epicubebol]. Anhyd CeCl3 (333
mg, 1.35 mmol) was obtained by dehydrating CeCl3 7H2O (503 mg,
3
1.35 mmol) under high vacuum (<0.1 mbar) at 165 °C (oil bath) for
2 h.41 To this anhyd CeCl3 was added THF (7 mL) and the
suspension was stirred for 2 h at rt. MeLi (1.6 M in Et2O,
0.85 mL, 1.35 mmol) was then added to the above suspension at
-78 °C, followed after 30 min by a solution of ketone 38 (140 mg,
0.67 mmol) in THF (2 mL) over 20 min. After 90 min, the reaction
was quenched with aq NH4Cl (3 mL) and then warmed to rt.
The reaction mixture was extracted with Et2O (2 ꢀ 15 mL), dried
(MgSO4), and concentrated under reduced pressure. Purification
by column chromatography (20% Et2O in light petrol) gave the (-)-
10-epicubebol (39) (130 mg, 86%) as a white solid, mp 99-100 °C
(lit.37a mp 100 °C); [R]25D -64.6 (c 0.175, CHCl3) (lit.37a [R]25
-
D
72.3 (c 3.3, CHCl3)); IR (cm-1) 3390 br, 2956 s, 2935 s, 2862 w,
1447 w, 1368 w, 1320 w, 1193 w, 1151 w, 946 w, 931 w; 1H NMR
(500 MHz) 1.96-1.90 (m, 1 H, H-10), 1.76-1.71 (m, 1 H, H-3a),
1.68-1.59 (oct, 1 H, H-11), 1.56-1.49 (m, 2 H, H-9a, H-3b), 1.45
(br s, -OH), 1.36-1.31 (m, 2 H, H-9b, H-2a), 1.27 (d, J=1.0 Hz,
3 H, H-15), 1.26-1.13 (m, 3 H, H-2b, H-8a, H-8b), 1.9-1.04
(m, 1 H, H-5), 0.98 (d, J = 7.0 Hz, 3 H, CHMe), 0.95 (d, J =
6.5 Hz, 3 H, CHMeMe), 0.93-0.91 (m, 1 H, H-7), 0.92 (d, J =
6.5 Hz, 3 H, CHMeMe), 0.77 (t, J= 3.0 Hz, 1 H, H-6); 13C NMR
(125 MHz) 80.1 (C-4), 42.4 (C-7), 41.1 (C-5), 36.5 (C-3), 33.7 (C-11),
32.8 (C-1), 30.8 (C-9), 29.3 (C-2), 29.3 (C-10), 28.0 (C-15), 20.7
(C-6), 19.9 (CMeMe), 19.7 (C-8), 19.2 (CMeMe), 17.4 (CMe);
HRMS (CIþ) m/z [M - OH]þ calcd for C15H25 205.1956, found
205.1962.
(3R,6S)-1-(Chloromethyl)-3-isopropyl-6-methylcyclohex-1-ene
(35). To a stirred solution of allylic alcohol 34 (1.0 g, 6 mmol) in
CH2Cl2 (20 mL) at 0 °C was added Et3N (1.7 mL, 12 mmol),
then MsCl (0.94 mL, 12 mmol) dropwise over 5 min. The
reaction mixture was then stirred for 30 min at 0 °C, before
addition of anhyd LiCl (2.6 g, 10 equiv) in dry acetone (25 mL)
over 2 min. The reaction mixture was stirred overnight and
Acknowledgment. We thank the Higher Education Commis-
sion of Pakistan for studentship support (to S.S.), the EPSRC for
funding (D.J.F.), Dr. C. Fehr (Firmenich, Switzerland) for useful
(42) Schneider, D. F.; Viljoen, M. S. Tetrahedron 2002, 58, 5307–5315.
J. Org. Chem. Vol. 75, No. 7, 2010 2167

Hodgson et al.
JOCArticle
discussions, and Firmenich for testing of 7-epicubebol and
10-epicubebol. We also thank Dr. K. Harrison (University of
Oxford) for preparing the cover art.
thetic and natural product spectroscopic data for 39, X-ray
data, calculated transition states energies and coordinates,
and 1H and 13C NMR spectra for all compounds. This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
Supporting Information Available: General experimental
details, additional reactions schemes, a comparison of syn-
2168 J. Org. Chem. Vol. 75, No. 7, 2010