Synthesis of (-)-cubebol by face-selective platinum-, gold-, or coppercatalyzed cycloisomerization: Evidence of chirality transfer and mechanistic insights

Article abstract of DOI:10.1002/chem.200901292

We describe in detail a direct, stereoselective synthesis of (-)-cubebol based on a Pt-, Au-, or Cu-catalyzed cycloisomerization in which control of the configuration of the propargylic center is essential for the facial selectivity. In addition, we show that cycloisomerization reactions of enantioenriched propargyl pivalates occur with substantial chirality transfer. We confirm a mechanism by means of cyclization followed by an [l,2]-acyl migration for the Pt- and the Au-catalyzed cycloisomerization. So far, no evidence supports that the Cu-catalyzed cycloisomerization follows the same reaction course.

Full text of DOI:10.1002/chem.200901292

FULL PAPER
DOI: 10.1002/chem.200901292
Synthesis of (À)-Cubebol by Face-Selective Platinum-, Gold-, or Copper-
Catalyzed Cycloisomerization: Evidence of Chirality Transfer and
Mechanistic Insights
Charles Fehr,* Beat Winter, and Iris Magpantay[a]
Abstract: We describe in detail a direct, stereoselective synthesis of (À)-cubebol
based on a Pt-, Au-, or Cu-catalyzed cycloisomerization in which control of the
configuration of the propargylic center is essential for the facial selectivity. In addi-
tion, we show that cycloisomerization reactions of enantioenriched propargyl piva-
lates occur with substantial chirality transfer. We confirm a mechanism by means
of cyclization followed by an [1,2]-acyl migration for the Pt- and the Au-catalyzed
cycloisomerization. So far, no evidence supports that the Cu-catalyzed cycloisome-
rization follows the same reaction course.
Keywords:
cyclopropanes · diastereoselectivity ·
homogeneous
natural products
cycloisomerization
·
catalysis
·
Introduction
that develops in the mouth after a delay of approximately 1
to 2 min and lasts for approximately 30 min. It lends itself to
diverse flavor applications, as demonstrated by our collea-
gues at Firmenich.[3]
Recently,[1] we reported a direct, stereoselective synthesis of
(À)-cubebol (1)[2] based on a Pt-, Au-, or Cu-catalyzed
enyne cycloisomerization.
(À)-Cubebol (1), (À)-4-epicubebol (2), and (À)-a- and b-
cubebene (3 and 4) are naturally occurring sesquiterpenes
isolated from the berries of Piper cubeba (Scheme 1).[1]
Shortly after the discovery of this new skeleton, syntheses
of 3 and 4, and 1–4 were reported by the groups of Piers
and Yoshikoshi, respectively.[4] Both syntheses are based on
a cyclopropanation of diazoketone 5 (or the analogous iso-
propenyl compound; Scheme 2). Unfortunately, this route is
not diastereoface-selective, and affords the desired ketone 6
as the minor stereoisomer in only moderate yield. After a
long period without any new developments, Fꢀrstner and
Hannen published a new stereoselective synthesis of (À)-cu-
bebol in 2006[5] that is closely related to ours.[1]
Scheme 1. Constituents of Piper cubeba.
The dried berries containing approximately 2% of cube-
bol or the cubeb oil are appreciated food additives in Indo-
nesia and other Asian countries. Whereas 2 has a very bitter
taste, the almost odorless 1 has a pronounced cooling effect
[a] Dr. C. Fehr, B. Winter, I. Magpantay
Firmenich SA, Corporate R&D Division
P.O. Box 239, 1211 Geneva 8 (Switzerland)
Fax : (+41)22-780-33-34
Scheme 2. Classical and new synthetic approaches towards 6.
E-mail: charles.fehr@firmenich.com
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We realized that the application of the Pt-,[6,7] Au-,[8] or
Cu-catalyzed[9] cycloisomerization of enynol esters 8a,b to
9a,b[10] would represent a direct and efficient access to cube-
bol (Scheme 2). The major concern was the uncertainty
about the stereocontrol.
(10:90) was treated with 2 mol% of PtCl2, the expected tri-
cyclic enol pivalates 9a and 9b (60:40) were formed in 80%
yield (entry 1); the Au-catalyzed reaction gave, in a less
clean reaction, a 47:53 mixture of 9a and 9b (entry 2). In
contrast, the reaction of 8a and 8b (70:30) with PtCl2 af-
forded mainly the desired 9a (9a/9b 86:14; entry 3).
From the results shown in entries 1 and 3, it was anticipat-
ed that pure 8a would afford 9a with excellent facial selec-
tivity.
Results and Discussion
The key precursors 8a and 8b (1:2 diastereomeric mixture)
were readily prepared from (+)-(R,R)-tetrahydrocarvone
(10) in an overall yield of 55% (Scheme 3). A Wittig–
A diastereoselective synthesis of 8a was accomplished by
a reagent-controlled diastereoselective addition (88:12) of 2-
methyl-3-butyn-2-ol to aldehyde 15 using the Zn reagent ob-
tained from (À)-N-methylephedrine (17) and Zn
ACHTUNGRTENN(UNG OTf)2, fol-
lowed by esterification of 18a and 18b and base-catalyzed
cleavage of the carbinol fragment of 19a and 19b, as report-
ed by Carreira and co-workers (Scheme 4).[11,12] The S con-
Scheme 3. Reagents and conditions: a) trimethyl phosphonoacetate
(1.5 equiv), NaH (1.4 equiv), THF, reflux, 15 h; b) KOH (1.7 equiv),
EtOH, H2O, 60 8C, 24 h; c) BuLi (3.0 equiv), TMP (3.15 equiv), THF,
À58C, 30 min, then 12, À258C to RT, 16 h; then 5% HCl; d) LiAlH4
(2 molequiv), Et2O, reflux, 45 min; e) (COCl)2 (1.5 equiv), DMSO
Scheme 4. Reagents and conditions: a) ZnACTHNUTRGENUG(N OTf)2 (2.0 equiv), 17
(2.15 equiv), CH2Cl2, À708C, then EtN
ACHTUNGRTEN(NUNG iPr)2 (6 equiv); f) HCCMgBr
(1.2 equiv), THF, 25–288C, 45 min; g) PivCl (1.1 equiv), NEt3 (1.2 equiv),
DMAP (0.12 equiv), CH2Cl2, 08C, 2 h.
(2.1 equiv), NEt3, toluene, RT, 2 h; then 2-methyl-3-butyn-2-ol
(2.1 equiv), RT, 15 min; then slow addition of 15 in toluene at RT
(15+9 h after addition); b) PivCl (2.2 equiv), NEt3 (1.1 equiv), DMAP
(0.12 equiv), 08C to RT, 15 h; c) K2CO3 (1.2 equiv), [18]crown-6
(0.4+0.4 equiv), toluene, reflux, 19+5 h; d) see Table 1; e) K2CO3
(1.2 equiv), MeOH, RT, 90 min; f) CeCl3 (2.0 equiv), MeLi (2.0 equiv),
THF, À788C, 1 h; then 6, À788C to RT, 2 h.
Horner reaction and saponification afforded the acid 12.
Whereas base-catalyzed deconjugation of ester 11 was unse-
lective, deprotonation of 12 using excess LiTMP (TMP=
2,2,6,6-tetramethylpiperidine), followed by protonation of
the dianion with 5% HCl, selectively furnished b,g-unsatu-
rated 13. LiAlH4 reduction and Swern oxidation then afford-
ed the b,g-unsaturated aldehyde 15. Addition of ethynyl-
MgBr and esterification with pivaloyl (Piv) chloride pro-
duced 8a and 8b as a 1:2 diastereomeric mixture.
Chromatographic purification
figuration of the newly formed stereogenic center is in
agreement with the above-cited work of Carreira and co-
workers. A mixture of pivalates 8a and 8b (88:12) was used
for the cycloisomerization step.
of the alcohols 16a,b and
esterification of the fractions
Table 1. Cycloisomerization of 8a and 8b.
enriched in 16a or 16b gave
access to the pivalates 8a,b, en-
riched in 8a and 8b, respective-
ly. These were then submitted
separately to the Pt- or Au-cat-
alyzed cycloisomerization reac-
Entry
8a/8b
Conditions[a]
9a/9b
Yield [%]
1
2
3
4
5
6
10:90
10:90
70:30
88:12
98:2
PtCl2 (2 mol%), DCE, 708C, 9 h
AgSbF6/ACHTNUGRTNENUG[AuClACHUTNGTREN(NUNG PPh3)] (2 mol%), CH2Cl2, 208C, 40 min
PtCl2 (2 mol%), DCE, 708C, 9 h
PtCl2 (2 mol%), DCE, 708C, 9 h
PtCl2 (2 mol%), DCE, 708C, 9 h
60:40
47:53
86:14
94:6
99:1
99:1
80
65
–
81
–
98:2
[Cu
N
77[b]
tion
(Table 1,
entries 1–3).
When a mixture of 8a and 8b [a] DCE=1,2-dichloroethane. [b] 90% conversion.
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(À)-Cubebol Synthesis
FULL PAPER
Indeed, PtCl2-catalyzed cycloisomerization of 8a
and 8b (88:12) afforded 9a and 9b with a 94:6 selec-
tivity (Table 1, entry 4), and chromatographically en-
riched 8a (98% stereochemical purity) afforded 9a
with excellent facial selectivity (99:1; entry 5). Inter-
estingly, inexpensive [CuACTHUNTRGNE(UNG CH3CN)4]BF4 (2 mol%) also
efficiently catalyzed the cycloisomerization (99:1; 77%
isolated yield after 90% conversion).[9] Prolonged re-
action times or higher temperatures (708C) favored
the formation of byproducts.
Hydrolysis of 9a afforded the known ketone 6, and
diastereoselective (97:3) addition of MeLi/CeCl3 fur-
nished (À)-cubebol (1) in 95% yield, identical in all
respects with an authentic sample isolated at Firme-
nich.[3]
The choice of the pivaloyl group in 8a was based on
the reasoning that this bulky group would preferably
occupy the least hindered position, thus bringing the
acetylene moiety in closer contact with the cyclohex-
ene unit. Propargylic pivalates had also been used by
Toste and co-workers in the Rautenstrauch rearrange-
ment.[13] However, the choice of the ester group does
not appear to be crucial, as the PtCl2-catalyzed cycloi-
somerization of the corresponding acetate, reported by
Fꢀrstner and Hannan,[5] proceeded with equal efficien-
cy and stereoselectivity.
Scheme 6. Reagents and conditions: a) K2CO3 (1.2 equiv), MeOH, RT, 90 min. Per-
centages of 32 and 33 refer to relative amounts (GC analysis); [A] DCE, 708C,
8 h; [B] toluene, 708C, 8 h, [C] toluene, 508C, 4 h, 50% conversion starting from
27 (69% ee); [D] DCE, 508C, 90 min; [E] DCE, 708C, 90 min; 66% yield.
The different diastereoface selectivities observed for
the cycloisomerizations of 8a and 8b prompted us to
examine the chirality transfer of the enantioenriched prop-
argyl pivalates 23 and 27, readily accessible from aldehydes
20[14] and 24[15] (Scheme 5). Pt- or Cu-catalyzed rearrange-
ment of 23 (95% ee) afforded 28, which gave, after hydroly-
sis, ketone 29 with 57–61% ee (Scheme 6, expt 1 and 2).[16]
The ee values of 23 and 27 remained unaltered throughout
the course of the reaction, as shown by measurements taken
after 50% conversion.
enol pivalate 30 (À21 to 13% ee), variable amounts of the
isomeric non-rearranged enol pivalate 31 (79–88% ee;
expt 3–6), as shown by conversion of 30 and 31 into the ke-
tones 32 and 33, respectively. The different ee values and
ratios of products may be due to the variable quality of
PtCl2. Indeed, in experiments 5 and 6 we had to add more
catalyst to achieve full conversion. Using [CuACTHNUTRGNE(UNG CH3CN)4]BF4
(2 mol%), the expected acyl transposition product 30 was
highly favored over 31 (expt 7 and 8). A much higher reac-
tivity and better chirality transfer was noticed in 1,2-di-
chloroethane (DCE) compared with toluene. The Au-cata-
lyzed reaction also afforded a mixture of 30 and 31 (expt 9).
The absolute configurations of 32 and 33 were determined
by chemical correlation (see below).
Surprisingly, Pt-catalyzed cycloisomerization of 27
(92% ee) afforded, in addition to the expected rearranged
Mechanism: Prior to our work[1] and that of Fꢀrstner and
co-workers,[5] the Pt- or Au-catalyzed cycloisomerizations of
secondary enynol esters were generally believed to proceed
by an initial [1,2]-acyl shift of the metal-complexed acety-
lene A and subsequent cyclopropanation of the achiral tran-
sient vinyl carbene C (pathway (a); Scheme 7).[6] This path-
way is certainly operative when the cyclization is slow
enough to allow the [1,2]-acyl shift to occur. This is the case
in intermolecular reactions[17] and medium-sized ring closur-
es.[6e] The proof for such a reaction course was recently es-
tablished by the enantioselective cycloisomerization of
chiral, racemic propargylic esters.[8b]
However, on the basis of the highly stereoselective cycloi-
somerization of pivalate 8a to 9a in the cubebol synthesis,
Scheme 5. Reagents and conditions: for a) to c) see Scheme 4a) to c).
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C. Fehr et al.
acyl shift.[6d] They also proposed pathway (c) for the acyl
shift. In one case, intermediate G (Scheme 7) allows the ra-
tionalization of the predominant formation of a cyclohexa-
diene.
However, Soriano and Marco-Contelles[18] have studied
our system computationally (with R=acetyl (Ac)) and pro-
pose that pathway (b) is operative for both the acyl transpo-
sition and the H shift. Indeed, as the chirality transfer is not
perfect (loss of ee) in the cycloisomerization of 27 to 30 and
31, two diastereomeric intermediates of type E are formed
that exhibit different activation barriers for both the acyl
shift (leading to 30) and the H shift (leading to 31). Since
our preliminary report,[1] we have determined the absolute
configurations of 30 and 31 (see below). Therefore it makes
sense to verify how the amounts of (6R)-30, (6S)-30, (6R)-
31, and (6S)-31 agree with the work of Soriano and Marco-
Contelles.[18] However, it should be kept in mind that R
Scheme 7. ACHTUNGTRENNUNG[1,2]-Acyl versus [1,2]-H shift: different mechanistic pathways
for the cycloisomerization of enynol esters.
equals COCACTHUNTRGNE(UNG CH3)3 in the experiments, whereas R is COCH3
in the calculations.[19]
The calculations of Soriano and Marco-Contelles show
that the Pt-catalyzed cycloisomerization of 27 is favored
from the “top-face”, thereby leading preferentially to inter-
mediate (6R)-E (Scheme 8). The difference in activation
and the unselective reaction of 8b, pathway (a) can be dis-
missed. In support of this, a substantial chirality transfer was
observed in the cycloisomerization of 23 (95% ee) to 28
(57–61% ee). The loss in ee certainly reflects an imperfect
stereocontrol and not a racemization, as the ee values of 23
and 28 both remained constant during the reaction. A com-
peting reaction through a vinyl carbene C (pathway (a))
cannot be excluded. The behavior of pivalate 27 is more
complex, as two reaction pathways are followed, giving the
regioisomeric enol pivalates 30 and 31 in variable propor-
tions and ee values, depending on the reaction conditions
(see below).
The obtained results again show that cyclopropanation of
the electron-rich olefin with the metal-complexed acetylene
A has to (mostly) take place prior to the loss of the propar-
gylic stereogenic center. The most plausible pathway is cy-
cloisomerization of A to E, followed by [1,2]-acyl migration
(pathway (b)). This mechanism has also been proposed by
Soriano et al.[7] on the basis of a DFT computational study,
and is consistent with the mechanism of the related cycloiso-
merization of 5-en-1-yn-3-ols[6a,c,8,9] as shown by us[9] and re-
ported by Soriano et al.[7b] Another possibility that was pro-
posed in our preliminary account[1] is a cyclopropanation of
a vinyl metal species B whose ester function is “half-trans-
posed” but still contains the chiral information (pathway
(c)).
As mentioned already, Cu-catalyzed cycloisomerization of
27 leads almost exclusively to the expected product 30,
whereas Pt- or Au-catalyzed cycloisomerization gives the re-
gioisomeric enol pivalates 30 and 31 in variable proportions
and ee values. The proposition that pathway (b) leads to the
formation of 31 and pathway (c) to the formation of 30
would be consistent with the different ee values measured.
Incidentally, pathway (c) is closely related to the mechanism
proposed for the Rautenstrauch rearrangement.[13] Interest-
ingly, Malacria and co-workers recently described other ex-
amples in which the [1,2]-H shift competes with the [1,2]-
Scheme 8. ACHTUNTRGNEU[GN 1,2]-Acyl versus [1,2]-H shift. The numbers on the arrows rep-
resent activation barriers (in kcalmolÀ1); the numbers in parentheses rep-
resent free-energy differences in solution (DCE; in kcalmolÀ1) relative to
PtCl2-complexed 27.
energy of 0.75 kcalmolÀ1 at a reaction temperature of 708C
should favor (6R)-E over (6S)-E in a proportion of approxi-
mately 67:33. Intermediate (6R)-E then preferentially under-
goes a [1,2]-H shift (18.78 vs. 20.87 kcalmolÀ1 for the acyl
shift). Indeed, the free-energy difference of 2.04 kcalmolÀ1
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(À)-Cubebol Synthesis
FULL PAPER
is expected to induce a ratio of 19:1 for (6R)-31/(6R)-30. In
contrast, (6S)-E exclusively undergoes the acyl shift to
afford (6S)-30. With a free-energy difference of 5.23 kcal
molÀ1, the alternative [1,2]-H shift can be neglected.
(Scheme 9). The allylation of (+)-(1R,6S)-34 by means of
Claisen rearrangement of the allyl enol ether 35 afforded 36
with high diastereoselectivity, together with minor amounts
Table 2, entry 1 shows the expected product distribution
based on a starting material 27 of 100% ee. Entries 2 to 5
Table 2. Calculated (entry 1) and experimental (entries 2–8) isomer dis-
tributions for 30 and 31.
Entry
(6R)-30 (6R)-31 (6R)-E (6S)-E (6S)-30 (6S)-31
1 (ref. [18])
2 (Pt)
3 (Pt)
4 (Pt)
5 (Pt)
6 (Cu)
7 (Cu)
8 (Au)
3
11.5
14
24.5
33
37
64
66.5
62
48
41
trace
trace
34
67
78
76
72.5
74
37
21
70
33
22
24
27.5
26
63
79
30
33
18.5
19
25.5
25
63
0
3.5
5
2
1
trace
trace
1
Scheme 9. Reagents and conditions: a) HCACTHNUTRGNENUG(OMe)3 (1.14 equiv), cat. HCl,
21
36
79
29
MeOH, À78C to RT, 2 h; then cat. NaOAc, allyl alcohol (2 equiv), cat.
CF3CO2H, 80–1508C, 16 h; b) PdCl2 (10 mol%), CuCl2 (10 mol%), 1,2-
dimethoxyethane, H2O, O2, RT, 56 h; c) KOH (2.2 equiv), MeOH, RT,
15 h; d) H2, Pd/C EtOH, RT, 5 h.
show our experimental results using PtCl2 (also extrapolated
to 27 of 100% ee). Unexpectedly, larger amounts of catalyst
had to be used for attaining full conversion in two experi-
ments (3% of PtCl2 in entry 4; 5% in entry 5). These data
are in agreement with the proposed mechanism and the
product distribution reported in entries 2 and 3 are close to
the calculated values. The product distribution in entries 4
and 5 is slightly different from the calculations, but, interest-
ingly, this can again be traced back to almost the same ratio
for intermediates (6R)-E and (6S)-E (ca. 3:1). This is also
true for the Au-catalyzed cycloisomerization (entry 8).
Conversely, the Cu-catalyzed cycloisomerization of 27
shows a completely different reaction profile. If the same re-
action pathway is followed, (6S)-E is favored with respect to
(6R)-E, and both (6R)-E and (6S)-E undergo almost exclu-
sively the acyl shift (entries 6 and 7). It is important to note
that in the cycloisomerizations of 8a and 23, the same face
selectivity is favored, regardless of the metal used (Cu, Pt,
or Au catalysis). The calculations of Soriano and Marco-
Contelles[18] show that the observed face selectivities are dic-
tated by steric factors and, for 8a, 8b, and 23, by the posi-
tive interaction between the vinylic hydrogen and the ether
oxygen of the ester group.
of 37 (36/37 90:10). The trans relationship between the allyl
and the methyl group in 36 was unambiguously established
by NOE. Wacker oxidation of 36 afforded the crystalline
keto aldehyde 38, which underwent smooth intramolecular
aldolization/dehydration. Finally, the resulting enone 39 was
hydrogenated to generate spiro ketone 40.
Hydrogenation of (6S)-32 (Scheme 6, entry 5; 18% ee by
chiral GC; the absolute configuration was determined from
this study), afforded two diastereomeric spiro ketones, 40
and 41 (Scheme 10). At this stage, correlation with enantio-
In conclusion, the detailed results strongly support path-
way (b) for the Pt- or Au-catalyzed cycloisomerization of
8a, 8b, 23, and 27, but are inconclusive for the Cu-catalyzed
reaction. Nevertheless, it should be kept in mind that the
acyl transposition (pathway (a)) and in particular step A to
B (pathway (a) or (c)) possess a low activation energy and
therefore the followed pathway and the outcome of the cy-
cloisomerizations may depend on a multitude of factors,
such as the substrate and the nature of the catalyst.[20]
Scheme 10. Reagents and conditions: a) H2, Pd/C, AcOH, RT, 24 h;
b) LiAlH4 (1.1 equiv), Et2O, RT, 1 h; c) Ac2O, pyridine, RT, 4 h.
merically pure 40 (Scheme 9) was not possible, as only three
peaks were visible by chiral GC. Fortunately, without the
need of a separation, ketones 40 and 41 could be trans-
formed by reduction and acetylation into a mixture of four
Determination of the absolute configurations of 32 and 33:
In an independent study, one of us (B.W.) has synthesized
enantiopure spiro ketone 40 from (+)-(1R,6S)-34[21]
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C. Fehr et al.
diastereomeric acetates (46–49) that separated on chiral
GC. The resolved 8 enantiomers and their superimposition
on the racemic compound mixture and with the enantiomer-
ically pure 46/47 mixture are shown in Figure 1. It can be
Figure 2. Chiral GC (chiral cap. column: CP-Chirasil-DEX CB (25 mꢂ
0.25 mm) (Chrompack)) of 51 and 53. a) (Æ)-51, b) (Æ)-53/(Æ)-51 88:12,
c) (6R)-53 (96% ee)/(6R)-51 (96% ee) 60:40, d) (6R)-51 (21% ee). From
left to right: peak 1) (6S)-53; peak 2) (6R)-53; peak 3) (6S)-51; peak
4) (6R)-51.
Figure 1. Chiral GC (chiral cap. column: CP-Chirasil-DEX CB (25 mꢂ
0.25 mm) (Chrompack)) of acetates 46–49: a) % racemic mixture of 46–
49, b) 46–49 (18% ee), c) 46 and 47 (100% ee) from (+)-40 (100% ee).
sequence starting from (6R)-33 (88% ee) we used the
mother liquor of (6R)-52 and obtained (6R)-51 and (6R)-53
(12:88; 96% ee). As shown in Figure 2, by superimposition
of the chiral chromatograms, the major enantiomer of hy-
drocarbon 51 obtained from 33 (Scheme 6, expt 6) is identi-
cal to (6R)-51 derived from (6R)-32.
seen that our major enantiomers 46 and 47 (18% ee) corre-
spond to the enantiopure enantiomers 46 and 47 derived
from enantiomerically pure (+)-40.
For the determination of the absolute configuration of 33,
both (6R)-32 (13% ee) and (6R)-33 (88% ee) (Scheme 6;
expt 6) were converted into the same hydrocarbon 51 by
Shapiro reaction of the corresponding hydrazones (6R)-50
and (6R)-52 (Scheme 11). The sequence was at first tested
with racemic substrates. Thus, (Æ)-32 was converted into re-
crystallized hydrazone (Æ)-50 and submitted to a Shapiro
reaction. The obtained hydrocarbon (Æ)-51 readily separat-
ed on chiral GC (Figure 2). Likewise, (Æ)-33 afforded re-
crystallized hydrazone (Æ)-52 that, upon treatment with
BuLi, afforded a mixture of hydrocarbons (Æ)-51/(Æ)-53
(40:60). When we repeated these reactions with (6R)-32
(13% ee), we obtained (6R)-51 (9% ee) from recrystallized
(6R)-50 (21% ee from the mother liquor of (6R)-50). In the
Conclusion
In conclusion, we have succeeded in a direct, stereoselective
synthesis of (À)-cubebol (1) based on a Pt-, Au-, or Cu-cata-
lyzed cycloisomerization in which control of the configura-
tion of the propargylic center is essential for the facial selec-
tivity. In addition, complementary cycloisomerization reac-
tions of enantioenriched propargyl pivalates occur with sub-
stantial chirality transfer. A proposed mechanism by means
of cyclization followed by an [1,2]-acyl migration is consis-
tent with the calculations of Soriano and Marco-Contelles
for the Pt- and the Au-catalyzed cycloisomerization.[18] Con-
versely, the Cu-catalyzed cycloisomerization may follow a
different reaction course. Special calculations would be
needed for more accurate
mechanistic predictions.
Note added in proof: After
submission of this manuscript,
a new stereoselective synthesis
of (À)-cubebol was pub-
lished.[22]
Experimental Section
General: For bulb-to-bulb distillation,
a
Bꢀchi GKR-51 glass oven was
used, with boiling point correspond-
ing to the oven temperature. For
TLC, silica gel F-254 plates (Merck)
were used; detection with EtOH/ani-
saldehyde/H2SO4 18:1:1. For column
chromatography, silica gel 60 (Merck;
0.063–0.2 mm, 70–230 mesh, ASTM)
Scheme 11. Reagents and conditions: a) NH2NHTs (1.1 equiv; Ts=tosyl), MeOH, cat. AcOH, reflux, 2 h;
b) BuLi (4.0 equiv), TMEDA, À788C (or À508C) to RT, 80 min; [A] 9% ee from crystallized (6R)-50; 21% ee
from mother liquor of (6R)-50; [B] from mother liquor of (6R)-52.
9778
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Chem. Eur. J. 2009, 15, 9773 – 9784

(À)-Cubebol Synthesis
FULL PAPER
was used. A Varian instrument model 3500 was used for GC; cap. col-
umns: DB1 30 W (15 mꢂ0.319 mm), DB-WAX 15 W (15 mꢂ0.32 mm);
chiral cap. column: CP-Chirasil-DEX CB (25 mꢂ0.25 mm) (Chrompack),
carrier gas He at 0.63 bar. Optical rotations were measured using a
Perkin–Elmer 241 polarimeter (1 mL cell); c in g100 mLÀ1 solution. A
Bruker WH 400 (400 MHz) spectrometer was used for 1H and 13C NMR
spectroscopy. For MS, a Hewlett Packard MSD 5972 automated GC–MS
instrument was used (electron energy 70 eV).
Et2O). The aqueous phase was acidified with concentrated HCl (3.6 mL,
43.2 mmol) and acid 13 was extracted (2ꢂEt2O), washed (H2O, then satu-
rated aqueous NaCl), dried (Na2SO4), and concentrated. Bulb-to-bulb
distillation (oven temp. 1308C/0.01 mbar) afforded approximately 97%
pure 13 (5.40 g, 92% yield). 1H NMR (CDCl3): d=0.86 (d, J=6.8 Hz,
3H), 0.89 (d, J=6.8 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H), 1.17–1.31 (m, 2H),
1.59 (m, 1H), 1.67 (m, 1H), 1.85 (m, 1H), 1.95 (m, 1H), 2.25 (m, 1H),
2.96 (d, J=15.2 Hz, 1H), 3.16 (brd, J=15.2 Hz, 1H), 5.48 (s, 1H), 10.3–
11.8 ppm (br, 1H); 13C NMR (CDCl3): d=19.3 (q), 19.6 (q), 19.8 (q),
24.4 (t), 32.1 (t), 32.2 (d), 32.6 (d), 40.8 (t), 42.3 (d), 131.2 (d), 135.0 (s),
178.8 ppm (s); MS: m/z (%): 196 (11) [M]+, 153 (20), 136 (37), 107 (18),
93 (100), 91 (20), 79 (15).
(+)-Tetrahydrocarvone ((+)-10):
A solution of (+)-10 (cis/trans 4:1;
203.0 g, 1.32 mol; flavor ingredient from Firmenich SA) in NaOMe/
MeOH (prepared from 20 mL of MeOH and 0.753 g of NaOMe (=
13.24 mmol)) was stirred for 2 h at RT. The clear brown cis-enriched
product mixture ((+)-10; cis/trans 9:1) was extracted (Et2O/H2O),
washed (H2O, then aqueous NaCl, then saturated aqueous NaCl), dried
(Na2SO4), and concentrated (204.5 g).
(+)-2-[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]ethanol (14):
A
solution of 13 (5.38 g, 27.5 mmol) in Et2O (50 mL) was added dropwise
(in 5 min) to a suspension of LiAlH4 (2.09 g, 55.0 mmol). During addi-
tion, the reaction mixture warmed up to reflux. Refluxing was main-
tained for 45 min, after which the cooled (208C) reaction mixture was
successively treated dropwise with H2O (2.1 mL), 5% aqueous NaOH
(2.1 mL), and H2O (6.3 mL). The slurry was stirred for 40 min and fil-
tered through Celite. Concentration and bulb-to-bulb distillation (oven
temp. 100–1258C/0.01 mbar) afforded approximately 97% pure 14
(4.80 g, 96%). [a]2D0 =+34 (c=2.20 in CHCl3) (lit. [5]: [a]2D0 =+39.3
An aliquot of the extracted product (+)-10 (cis/trans 9:1; 98.1 g,
637 mmol) was added under vigorous stirring to a suspension of sodium
trimethylphosphonoacetate (obtained from trimethylphosphonoacetate
(25.7 g, 141 mmol; 0.22 equiv) and NaH (5.55 g; 55% in oil; washed 3ꢂ
with pentane; 127 mmol; 0.2 equiv) in THF (70 mL)) and heated at
reflux for 90 min. After cooling and quenching (5% HCl) the product
mixture was extracted (2ꢂpentane), washed (H2O, then saturated aque-
ous NaHCO3, then saturated aqueous NaCl), dried (Na2SO4), and con-
centrated (102.4 g).
1
(CH2Cl2)). The H NMR, 13C NMR, and MS spectra are in perfect agree-
ment with those reported.[5]
The remaining (+)-10 was separated from the diastereomeric mixture of
11 by Vigreux distillation. This afforded a main fraction of (+)-10
(73.7 g; 95% pure, cis/trans 98:2; b.p. 80–838C; 5 mbar).
(+)-2-[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]acetaldehyde
(15): Oxalyl chloride (4.88 g (3.31 mL), 38.5 mmol) was added at À788C
to
a solution of DMSO (4.29 g (3.91 mL), 55.0 mmol) in CH2Cl2
ACHTUNGTRENNUNG[(2R,5R)-5-Isopropyl-2-methylcyclohexylidene]acetic acid (12) (E/Z
(105 mL). After 15 min, a solution of 14 (4.66 g, 25.6 mmol) in CH2Cl2
(30 mL) was added dropwise (in 20 min) at À708C. After 15 min, the
white suspension was treated with N-ethyldiisopropylamine (19.8 g
(26.8 mL), 154 mmol). After addition, the reaction mixture was allowed
to warm up to 08C. After 5 min the reaction mixture was poured into
water, extracted (2ꢂEt2O), and washed (saturated aqueous NaHCO3,
then saturated aqueous NaCl). As GC indicated 3% of remaining 14 (in-
complete deprotonation of the Swern intermediate), the organic phase
was treated with saturated aqueous NaHCO3 (150 mL) and vigorously
stirred under N2 for 2 h. The phases were separated, and the organic
phase was washed (saturated aqueous NaCl), dried (Na2SO4), and con-
centrated. Bulb-to-bulb distillation (oven temp. 808C/0.01 mbar) afforded
approximately 97% pure 15 (4.29 g, 93% yield), which was stored in the
refrigerator. A sample was purified by column chromatography (silica
gel; cyclohexane/AcOEt 95:5). [a]2D0 =+110 (c=1.30 in CHCl3) (lit. [5]:
[a]2D0 =+99.4 (CH2Cl2)). The 1H NMR, 13C NMR, and MS spectra are in
perfect agreement with those reported.[5]
88:12): (+)-10 (cis/trans 98:2; 35.0 g; 95% pure; 227 mmol) was added
under vigorous stirring to a suspension of sodium trimethylphosphonoa-
cetate (obtained from trimethylphosphonoacetate (62.05 g, 341 mmol)
and NaH (13.9 g; 55% in oil; washed 3ꢂ with pentane; 318 mmol) in
THF (950 mL)) and heated at reflux for 15 h. After cooling and quench-
ing (5% HCl), the product mixture was extracted (2ꢂEt2O), washed
(H2O, then saturated aqueous NaHCO3, then saturated aqueous NaCl),
dried (Na2SO4), and concentrated.
The crude ester 11 (48.1 g) was dissolved in EtOH (335 mL), treated with
an aqueous solution of KOH (from KOH (15.2 g, 272 mmol) and H2O
(95 mL)), and heated at 608C for 15 h. As the saponification was incom-
plete (due to concomitant formation of the corresponding ethyl ester
(20%)), more aqueous KOH was added (from KOH (4.80 g, 85.7 mmol)
and H2O (30 mL)), and heating continued for 5 h (90% conversion).
Again, more aqueous KOH was added (from KOH (2.00 g, 35.7 mmol)
and H2O (12 mL)) and heating continued for 5 h (98% conversion). The
cooled reaction mixture was concentrated at the rotavapor and the neu-
tral parts (3.5 g) were separated by extraction (Et2O/H2O). The aqueous
phase was acidified with concentrated HCl (39.4 mL, 472 mmol) and the
acid 12 extracted (2ꢂEt2O), washed (H2O, then saturated aqueous
NaCl), dried (Na2SO4), and concentrated. Bulb-to-bulb distillation (oven
temp. 1508C/0.01 mbar) afforded pure 12 (E/Z 88:12; 42.2 g; 95% yield
from (+)-10). 1H NMR (CDCl3): d=0.89 (d, J=6.7 Hz, 3H), 0.91 (d, J=
6.7 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H), 1.13 (m, 1H), 1.28 (m, 2H), 1.47–
1.60 (m, 2H), 1.75 (m, 1H), 1.96 (m, 1H), 2.15 (m, 1H), 3.93 (brd, J=
12.6 Hz, 1H), 5.58 (s, 1H), 11.9–12.3 ppm (br, 1H); 13C NMR (CDCl3):
d=17.9 (q), 19.5 (q), 19.8 (q), 29.2 (t), 32.8 (d), 34.3 (t), 37.2 (t), 40.3 (d),
46.8 (d), 109.7 (d), 170.5 (s), 173.1 ppm (s).
(À)-(2S)-1-[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]5-methyl-3-
hexyne-2,5-diol (18a):
A mechanically stirred mixture of ZnACHTUNGTRENNUNG(OTf)2
(9.80 g, 28.4 mmol) and (À)-N-methylephedrine ((À)-17; 5.08 g,
27.0 mmol) was treated successively with toluene (19.5 mL) and triethyla-
mine (2.86 g (3.97 mL), 28.4 mmol). After 2 h, 2-methyl-3-butyn-2-ol
(2.39 g (2.75 mL), 28.4 mmol) was added. After 15 min a solution of 15
(2.43 g, 12.8 mmol) in toluene (18 mL) was added in 15 h by syringe
pump. As the conversion was incomplete (85%), stirring was continued
for 8 h (97% conversion). The reaction mixture was poured into a vigo-
rously stirred ice-cold solution of 5% aqueous HCl and extracted (2ꢂ
Et2O/H2O). The organic phases were washed (H2O, then saturated aque-
ous NaHCO3, then saturated aqueous NaCl), dried (Na2SO4), and con-
centrated (3.70 g). Flash chromatography, using silica gel (150 g) and cy-
clohexane/AcOEt 4:1 afforded 96% pure 18a/18b (2.73 g, 88:12; 77%).
Pure 18a (18a/18b>98:2) was obtained after subjecting the sample to
(+)-2-[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]acetic acid ((+)-
13): A solution of BuLi (1.40n in hexane; 64.3 mL; 90.0 mmol) was
added at À10–08C to a solution of 2,2,6,6-tetramethylpiperidine (13.32 g,
16.02 mL, 94.5 mmol) in THF (90 mL). After 30 min the solution was
cooled to À258C and treated dropwise (in 10 min) with a solution of 12
(5.88 g, 30.0 mmol). During addition, the temperature rose to À108C.
After complete addition, the cooling bath was removed and stirring con-
tinued at RT for 16 h. The reaction mixture was poured into a vigorously
stirred ice-cold solution of aqueous HCl (from concentrated HCl
(11 mL) and H2O (300 mL)) and extracted (2ꢂEt2O/H2O). The organic
phases were basified with aqueous NaOH (from NaOH (1.44 g,
36.0 mmol) and H2O (15 mL)) and the neutral parts were extracted (2ꢂ
chromatography
a
second time. [a]D20 =À12.4 (c=1.09 in CHCl3);
1H NMR (CDCl3): d=0.86 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H),
1.01 (d, J=7.1 Hz, 3H), 1.22 (m, 2H), 1.51 (s, 6H),1.57 (m, 1H), 1.66 (m,
1H), 1.85 (m, 1H), 1.94 (br, 1H), 2.07 (br, OH), 2.14 (br, 1H), 2.20 (br,
OH), 2.26 (dd, J=13.9, 9.3 Hz, 1H), 2.61 (m, 1H), 4.39 (dd, J=9.1,
4.5 Hz, 1H), 5.47 ppm (brs, 1H); 13C NMR (CDCl3): d=19.4 (q), 19.7
(q), 19.9 (q), 24.5 (t), 31.4 (2q), 31.7 (d), 31.9 (t), 32.2 (d), 42.3 (d), 43.8
(t), 60.0 (d), 65.1 (s), 82.9 (s), 89.2 (s), 130.9 (d), 137.4 ppm (s); MS: m/z
Chem. Eur. J. 2009, 15, 9773 – 9784
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www.chemeurj.org
9779

C. Fehr et al.
(%): 231 (6), 213 (6), 203 (11), 185 (11), 161 (10), 151 (33), 109 (100), 95
(84), 67 (39), 43 (72).
(65) [M]+, 191 (24), 164 (88), 149 (45), 135 (35), 122 (100), 107 (55), 93
(64), 91 (65), 79 (75), 69 (40), 55 (41), 41 (46).
(À)-(1R,4S,5R,6R,7S,10R)-7-Isopropyl-4,10-dimethyltricyclo[4.4.0.01,5]-
decan-4-ol ((À)-1): Dried anhydrous CeCl3 (468 mg, 1.90 mmol) was sus-
pended in THF (3 mL) and stirred for 1 h at RT. The milky suspension
was cooled to À788C and treated dropwise with MeLi (1.55n in Et2O;
1.19 mL, 1.84 mmol). After stirring for 1 h, a solution of 6 (189 mg,
0.92 mmol) in THF (1.5 mL) was added. After 15 min the temperature
was allowed to reach 08C in 30 min. The reaction mixture was poured
into saturated aqueous NH4Cl and the product was extracted (Et2O),
washed (H2O, then saturated aqueous NaCl), dried (Na2SO4), concentrat-
ed, and bulb-to-bulb distilled (100–1258C/0.01 mbar) on CaCO3 to afford
1 (200 mg, 98%) containing 3% of the epimeric alcohol. Crystallization
in acetonitrile afforded highly pure (À)-cubebol (1). M.p. 61–628C
(lit. [4b]: 61–628C; lit. [5]: 59–60.48C); [a]2D0 =À56.5 (c=0.48 in CHCl3)
(lit. [4b]: [a]2D0 =À48.3 (CHCl3); lit. [5]: [a]D20 =À51 (CHCl3)); 1H NMR
spectra are in perfect agreement with those reported.[5] 13C NMR and MS
spectra show very minor differences: 13C NMR (CDCl3): d=18.8 (q),
19.7 (q), 20.1 (q), 22.6 (d), 26.5 (t), 27.9 (q), 29.6 (t), 30.9 (d), 31.7 (t),
33.5 (s), 33.7 (d), 36.4 (t), 39.1 (d), 44.2 (d), 80.4 ppm (s); MS: m/z (%):
222 (2) [M]+, 207 (46), 204 (31), 161 (100), 119 (38), 105 (48), 93 (24), 91
(31), 81 (22), 43 (25). Our data are in all respects identical with an au-
thentic sample isolated at Firmenich.[3]
(À)-(1S)-4-Hydroxy-1-{[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]-
methyl}-4-methyl-2-pentynylpivalate (19a): A solution of 18a/18b (88:12;
96% pure; 2.73 g, 9.92 mmol) and DMAP (160 mg) in CH2Cl2 (25 mL)
was treated with NEt3 (1.15 g (1.60 mL), 11.4 mmol). The stirred, cooled
(08C) solution was treated with pivaloyl chloride (1.31 g (1.33 mL),
10.9 mmol) and stirred at RT for 15 h. The reaction mixture was poured
into 5% aqueous HCl and extracted (2ꢂEt2O/H2O). The organic phases
were washed (H2O, then saturated aqueous NaHCO3, then saturated
aqueous NaCl), dried (Na2SO4), and concentrated at partial and finally at
high vacuum (0.01 mbar) to remove traces of pivaloyl chloride. The oil
19a/19b (88:12; 92% pure; 3.54 g, 95%) was used without further purifi-
cation.
Likewise, pure 19a was obtained from pure 18a. [a]2D0 =À25.2 (c=0.86 in
CHCl3); 1H NMR (CDCl3): d=0.86 (d, J=6.9 Hz, 3H), 0.90 (d, J=
6.6 Hz, 3H); 1.01 (d, J=7.0 Hz, 3H), 1.19 (s, 9H), 1.19 (m, 2H), 1.49 (s,
6H), 1.49 (m, 1H), 1.66 (m, 1H), 1.83 (m, 2H), 2.05 (brs, OH), 2.15 (m,
1H), 2.40 (dd, J=14.4, 8.5 Hz, 1H), 2.57 (m, 1H), 5.44 ppm (m,
2H);13C NMR (CDCl3): d=19.7 (q), 19.9 (q), 20.0 (q), 24.6 (t), 27.0 (q),
31.2 (q), 31.3 (q), 31.9 (d), 32.0 (t), 32.4 (d), 38.7 (s), 40.4 (t), 42.4 (d),
62.4 (d), 65.0 (s), 80.2 (s), 89.4 (s), 129.7 (d), 136.6 (s), 177.5 ppm (s);
MS: m/z (%): 213 (12), 203 (18), 185 (15), 173 (8), 145 (19), 131 (13), 105
(13), 91 (20), 79 (18), 57 (100), 43 (44).
(6,6-Dimethyl-1-cyclohexen-1-yl)acetaldehyde (20): Aldehyde 20 was
prepared in four steps starting from 6,6-dimethylcyclohexanone (50.0 g,
391 mmol). The Wittig–Horner reaction was performed as described
above for 11 and afforded ethyl (2E)-(2,2-dimethylcyclohexylidene)ace-
tate (76.6 g, 100%). 13C NMR (100 MHz, CDCl3): d=14.3 (q), 22.2 (t),
25.8 (t), 27.8 (q), 28.1 (t), 38.2 (s), 42.0 (t), 59.5 (t), 111.2 (d), 167.5 (s),
169.6 ppm (s).
(À)-(1S)-1-{[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]methyl}-2-
propynylpivalate (8a): Powdered K2CO3 (1.38 g, 10.0 mmol) was added
to a solution of 19a/19b (88:12; 92% pure; 3.54 g, 9.37 mmol) and
[18]crown-6 (1.06 g, 4.00 mmol) in toluene (25 mL). After heating at
reflux for 15 h (90% conversion), more K2CO3 (0.69 g, 5.0 mmol) and
[18]crown-6 (0.53 g, 2.00 mmol) was added and heating continued for 2 h
(full conversion). The cooled reaction mixture was poured into H2O and
extracted (2ꢂEt2O/H2O). The organic phases were washed (H2O, then
saturated aqueous NaCl), dried (Na2SO4), and concentrated. Flash chro-
matography using silica gel (140 g) and cyclohexane/AcOEt 95:5 afforded
8a/8b (88:12; 2.18 g, 80%).
Likewise, pure 8a was obtained from pure 19a. [a]2D0 =À14.2 (c=1.2 in
CHCl3); 1H NMR (CDCl3): d=0.86 (d, J=6.8 Hz, 3H), 0.90 (d, J=
6.8 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H), 1.19 (s, 9H), 1.19 (m, 2H), 1.51 (m,
1H), 1.66 (m, 1H), 1.84 (m, 2H), 2.15 (m, 1H), 2.40 (d, J=2.0 Hz, 1H),
2.43 (dd, J=14.2, 8.4 Hz, 1H), 2.63 (m, 1H), 5.42 (m, 1H), 5.46 ppm
(brs, 1H); 13C NMR (CDCl3): d=19.7 (q), 19.9 (q), 20.0 (q), 24.6 (t), 27.0
(q), 31.8 (d), 32.1 (t), 32.4 (d), 38.7 (s), 40.3 (t), 42.5 (d), 62.2 (d), 73.0
(d), 81.8 (s), 129.9 (d), 136.4 (s), 177.5 ppm (s); MS: m/z (%): 188 (9),
173 (19), 145 (75), 117 (35), 105 (25), 91 (34), 57 (100), 41 (53).
A solution of the above ester (20.0 g, 102 mmol) in THF (30 mL) was
added at À25 to À168C to a solution of lithium diisopropylamide (LDA)
in THF (300 mL) (prepared from BuLi (1.48n in hexane; 73.0 mL,
108 mmol) and diisopropylamine (11.5 g (16.0 mL), 114 mmol)). The tem-
perature was allowed to reach 168C and the reaction mixture was poured
into vigorously stirred 5% aqueous HCl. Usual workup afforded ethyl
(6,6-dimethyl-1-cyclohexen-1yl)acetate (16.8 g, 84%). 13C NMR (CDCl3):
d=14.2 (q), 19.1 (t), 26.0 (t), 27.8 (2q), 34.2 (s), 38.3 (t), 39.3 (t), 60.4 (t),
125.7 (d), 138.1 (s), 173.0 ppm (s).
A solution of the above ester (11.8 g, 60.1 mmol) in Et2O (40 mL) was
added dropwise (5 min) into a suspension of LiAlH4 (3.42 g, 90.2 mmol).
During addition, the reaction mixture was warmed up to reflux. After
5 min the formed (6,6-dimethyl-1-cyclohexen-1-yl)ethanol was isolated in
the usual manner and bulb-to-bulb distilled (see 14) (8.90 g; 92% pure;
93%). 13C NMR (100 MHz, CDCl3): d=19.2 (t), 26.0 (t), 28.1 (2q), 34.1
(s), 34.2 (t), 39.5 (t), 62.0 (t), 122.6 (d), 141.0 ppm (s).
(À)-(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.01,5]decan-4-
one ((À)-6): A solution of 8a and 8b (8a/8b 88:12; 1.98 g, 6.83 mmol) in
1,2-dichloroethane (30 mL) was treated with PtCl2 (36 mg, 0.136 mmol)
and heated for 9 h at 708C. The solution was cooled and poured in satu-
rated aqueous NaHCO3. Extraction (Et2O), washing (H2O, then saturat-
ed aqueous NaCl), drying (Na2SO4), concentration and bulb-to-bulb dis-
tillation (100–1208C/0.01 mbar) afforded 9a and 9b (9a/9b 94:6; 1.60 g,
81%). A solution of 9a and 9b (9a/9b 94:6; 1.50 g, 5.17 mmol) in MeOH
(25 mL) was treated with K2CO3 (861 mg, 6.24 mmol) and stirred for
90 min at RT. After partial concentration, the product was extracted
(Et2O/H2O), washed (H2O, then saturated aqueous NaCl), dried
(Na2SO4), concentrated, and bulb-to-bulb distilled (100–1258C/
0.01 mbar) to afford 86% pure 6 (1.13 g, 91%). Purification by chroma-
tography using silica gel (150 g) and cyclohexane/AcOEt 7:3, followed by
crystallization in pentane at À788C, afforded pure 6 (680 mg). M.p. 60–
60.58C (lit. [4b]: 58.5–59.58C; lit. [5]: 57–588C); [a]2D0 =À20.1 (c=1.30 in
CHCl3) (lit. [4b]: [a]2D0 =À23.9 (isooctane); lit. [5]: [a]2D0 =À21.8
(CH2Cl2)); 1H NMR (CDCl3): d=0.59 (m, 1H), 0.90–1.00 (m, 1H), 0.91
(d, J=7.0 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.99 (d, J=6.0 Hz, 3H), 1.19
(m, 1H), 1.27 (t, J=2.5 Hz, 1H), 1.45–1.52 (m, 2H), 1.58–1.70 (m, 2H),
1.78–1.90 (m, 2H), 1.98–2.21 ppm (m, 3H); 13C NMR (CDCl3): d=18.9
(q), 19.4 (q), 19.9 (q), 26.0 (t), 26.6 (t), 30.8 (t), 31.3 (d), 32.5 (d), 33.2
(d), 33.3 (t), 39.7 (d), 40.3 (s), 43.4 (d), 214.6 ppm (s); MS: m/z (%): 206
The oxidation of the above alcohol (4.70 g, 30.7 mmol) to 20 (4.15 g,
89%) was performed as described for 15. 1H NMR (CDCl3): d=0.98 (s,
6H), 1.51 (m, 2H), 1.62 (m, 2H), 2.04 (m, 2H), 2.98 (m, 2H), 5.47 (brt,
J=3.9 Hz, 1H), 9.55 ppm (t, J=3.0 Hz, 1H);13C NMR (CDCl3): d=19.1
(t), 26.2 (t), 27.7 (2q), 34.1 (s), 39.1 (t), 47.3 (t), 127.5 (d), 136.4 (s),
201.7 ppm (d); MS: m/z (%): 152 (21) [M]+, 137 (20), 123 (24), 109 (61),
93 (100), 81 (76), 67 (76), 55 (33), 41 (50).
(À)-(2S)-1-(6,6-Dimethyl-1-cyclohexen-1-yl)-5-methyl-3-hexyne-2,5-diol
(21): Procedure as described for 18a. Starting from 20 (3.13 g,
20.6 mmol), pure 21 (2.50 g, 51%; 95% ee (see 23)) was obtained. [a]D20
=
À16.8 (c=1.01 in CHCl3); 1H NMR (CDCl3): d=1.02 (s, 6H), 1.46 (m,
2H), 1.52 (s, 6H), 1.60 (m, 2H); 2.01 (m, 2H), 2.37 (m, 2H), 2.47 (s,
OH), 4.52 (m, 1H), 5.51 ppm (brt, J=3.9 Hz, 1H);13C NMR (CDCl3):
d=19.1 (t), 26.0 (t), 28.1 (2q), 31.4 (2q), 34.1 (s), 39.5 (t), 40.0 (t), 61.5
(d), 65.1 (s), 83.2 (s), 89.5 (s), 124.5 (d), 140.0 ppm (s); MS: m/z (%): 203
(40) [M]+, 185 (16), 175 (24), 147 (21), 133 (20), 123 (28), 109 (100), 95
(41), 81 (73), 67 (49), 43 (64).
(À)-(1S)-1-[(6,6-Dimethyl-1-cyclohexen-1-yl)methyl]-4-hydroxy-4-
methyl-2-pentynyl pivalate (22): Procedure as described for 19a. Starting
from 21 (2.36 g, 10.0 mmol), 22 (2.90 g, 91%; 95% ee (see 23)) was ob-
tained after concentration at 808C/0.1 mbar. [a]2D0 =À61.8 (c=0.76 in
CHCl3); 1H NMR (CDCl3): d=1.02 (s, 6H), 1.20 (s, 9H), 1.44 (m, 2H),
9780
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9773 – 9784

(À)-Cubebol Synthesis
FULL PAPER
1.49 (s, 6H), 1.57 (m, 2H), 1.96 (m, 2H), 2.16 (s, OH), 2.37 (m, 1H), 2.44
(m, 1H), 5.44 (brt, J=3.8 Hz, 1H), 5.50 ppm (dd, J=8.3, 6.1 Hz, 1H);
13C NMR (CDCl3): d=19.1 (t), 26.0 (t), 27.0 (3q), 28.0 (2q), 31.3 (2q),
34.0 (s), 36.8 (t), 38.7 (s), 39.5 (t), 63.2 (d), 65.0 (s), 80.2 (s), 89.7 (s),
124.5 (d), 138.8 (s), 177.4 ppm (s); MS: m/z (%): 218 (7) [M]+, 217 (7),
203 (29), 185 (10), 175 (13), 149 (15), 133 (16), 105 (10), 85 (12), 57 (100),
41 (19).
2.1 Hz, 1H), 1.80–1.90 (m, 1H), 1.95–2.12 ppm (m, 4H); 13C NMR
(CDCl3): d=18.0 (t), 23.3 (t), 24.6 (t), 24.9 (q), 27.9 (q), 28.4 (d), 29.9 (s),
33.2 (t), 37.3 (t), 41.1 (d), 43.2 (s), 214.8 ppm (s); MS: m/z (%): 178 (26)
[M]+, 163 (9), 136 (16), 135 (16), 121 (30), 110 (100), 107 (25), 93 (28), 91
(22), 79 (33), 69 (40).
Alternatively, a solution of 23 (50 mg, 0.191 mmol) in toluene (1 mL) was
treated with [CuACHTNUTRGNEG(UN CH3CN)4]BF4 (1.2 mg, 0.0038 mmol) and heated for 8 h
at 708C. Proceeding as above afforded (À)-29 (22.0 mg, 65%; 57% ee by
(À)-(1S)-1-[(2,6,6-Dimethyl-1-cyclohexen-1-yl)methyl]-2-propynyl piva-
late (23): Procedure as described for 8a. Starting from 22 (2.78 g,
8.69 mmol), 95% pure 23 (2.05 g, 85%; 95% ee (see 23)) was obtained.
chiral GC (major enantiomer: first peak)).
A
(ent-32)
1
[a]2D0 =À51.0 (c=0.79 in CHCl3); H NMR (CDCl3): d=1.02 (s, 3H), 1.03
(Scheme 6, expt 8): A solution of 27 (224 mg, 92% pure; 0.746 mmol;
92% ee) in 1,2-dichloroethane (8 mL) was treated with [Cu-
AHCTNUGTREN(GUNN CH3CN)4]BF4 (5.0 mg, 0.0159 mmol) and heated for 90 min at 508C. Fil-
tration through silica, washing with CH2Cl2, and evaporation afforded
ent-30 (198 mg, 87% by GC). It was dissolved in MeOH (3 mL), treated
with K2CO3 (103 mg, 0.75 mmol), and stirred for 15 h at RT. The product
was extracted (2ꢂpentane/saturated aqueous NaCl), dried (Na2SO4), con-
centrated, and bulb-to-bulb distilled (1008C/0.04 mbar) to afford of ent-
32 (117 mg; GC: 88%; 72%; 53% ee by chiral GC (major enantiomer:
first peak)).
(s, 3H), 1.20 (s, 9H), 1.45 (m, 2H), 1.57 (m, 2H), 1.96 (m, 2H), 2.41 (d,
J=2.1 Hz, 1H), 2.46 (m, 2H), 5.45 (m, 1H), 5.47 ppm (m, 1H); 13C NMR
(CDCl3): d=19.1 (t), 25.9 (t), 27.0 (3q), 28.0 (2q), 34.0 (s), 36.6 (t), 38.7
(s), 39.5 (t), 62.9 (d), 73.0 (d), 81.9 (s), 124.4 (d), 138.6 (s), 177.4 ppm (s);
MS: m/z (%): 262 (2) [M]+, 178 (13), 163 (7), 160 (9), 145 (74), 117 (15),
108 (22), 91 (19), 57 (100), 41 (26).
(2S)-5-Methyl-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-5-methyl-3-hexyne-
2,5-diol (25): Procedure as described for 18a. Starting from 24 (8.73 g,
52.6 mmol), nonpurified 25 (14.22 g, max. 52.6 mmol; 92% ee (see 27))
was obtained. 1H NMR (CDCl3) (characteristic signals): d=1.03 (s, 6H),
1.52 (s, 6H), 1.70 (s, 3H), 4.56 ppm (dd, J=8.3, 6.2 Hz, 1H); 13C NMR
(CDCl3): d=19.3 (t), 21.2 (q), 28.8 (q), 29.0 (q), 31.4 (2q), 33.1 (t), 34.8
(s), 36.9 (t), 39.9 (t), 62.4 (d), 65.1 (s), 83.4 (s), 89.4 (s), 132.0 (s),
132.5 ppm (s); MS: m/z (%): 232 (5) [M]+, 217 (8), 189 (10), 137 (100),
123 (51), 95 (93), 81 (55).
Starting from 27 (46% ee), the cycloisomerization catalyzed by [Cu-
A
(c=1.02 in CHCl3) (26% ee by chiral GC (major enantiomer: first
peak)).
In another experiment, (Æ)-27 (3.00 g, 93% pure; 10.1 mmol) afforded
(Æ)-32 (1.78 g, 91% by GC; 83%); 1H NMR (CDCl3): d=0.90 (s, 3H),
0.99 (s, 3H),1.00 (s, 3H), 1.07–1.30 (m, 4H), 1.34–1.48 (m, 1H), 1.60–1.70
(m, 2H), 2.15 (d, J=19.5 Hz, 1H), 2.24 (d, J=19.5 Hz, 1H), 2.51 (d, J=
19.5 Hz, 1H), 2.52 ppm (m, 1H); 13C NMR (CDCl3): d=17.1 (q), 18.1 (t),
24.4 (s), 25.6 (d), 27.6 (2q), 30.2 (s), 33.8 (t), 36.8 (s), 37.5 (t), 39.5 (t),
40.5 (t), 220.2 ppm (s); MS: m/z (%): 192 (51) [M]+, 177 (57), 149 (63),
136 (64), 107 (73), 93 (100), 79 (97), 69 (71), 67 (38), 55 (39), 41 (48).
(1S)-4-Hydroxy-4-methyl-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-2-
pentynyl pivalate (26): Procedure as described for 19a. Starting from 25
(14.22 g, max. 52.6 mmol), nonpurified 26 (17.4 g, max. 52.1 mmol;
92% ee (see 27)) was obtained after concentration at 808C/0.1 mbar.
1H NMR (CDCl3): d=1.02 (2s, 6H), 1.20 (s, 9H), 1.42 (m, 2H), 1.48 (s,
6H), 1.59 (m, 2H), 1.70 (s, 3H), 1.94 (brt, J=6.5 Hz, 2H), 2.53 (dd, J=
14.5, 7.3 Hz, 1H), 2.59 (dd, J=14.5, 8.0 Hz, 1H), 5.53 ppm (t, J=7.5 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=19.3 (t), 21.2 (q), 27.0 (3q), 28.9
(2q), 31.2 (2q), 33.0 (t), 33.5 (t), 34.6 (s), 38.6 (s), 39.9 (t), 64.2 (d), 65.0
(s), 80.5 (s), 89.6 (s), 131.4 (s), 132.0 (s), 177.6 ppm (s); MS: m/z (%): 316
(1) [M]+, 232 (8), 217 (28), 199 (8), 189 (15), 163 (13), 147 (16), 137 (22),
95 (24), 85 (20), 57 (100).
A
(33)
(Scheme 6, expt 6): A solution of 27 (3.52 g, 12.76 mmol; 92% ee) in 1,2-
dichloroethane (40 mL) was treated with PtCl2 (5.0 mg, 0.256 mmol) and
heated for 2 h at 708C (14% conversion). Another portion of PtCl2 was
added (102 mg, 0.383 mmol) and heating continued for 6 h. Filtration
through silica, washing with CH2Cl2, and evaporation afforded 3.38 g of
30 (53% by GC) and 31 (39% by GC). It was dissolved in MeOH
(40 mL), treated with K2CO3 (1.85 g, 13.4 mmol), and stirred for 2 h at
RT. After partial concentration, the products 32 and 33 were extracted
(2ꢂpentane/saturated aqueous NaCl), dried (Na2SO4), concentrated
(2.28 g), and separated by chromatography (silica gel; cyclohexane/
AcOEt 95:5) to afford successively 33 (744 mg, 34%; 88% ee by chiral
GC (major enantiomer: first peak)) and 32 (1.09 g, 44%; 13% ee by
chiral GC (major enantiomer: second peak)).
Compound 33 (from a previous experiment): [a]2D0 =À29.9 (CHCl3; c=
1.07) (62% ee by chiral GC (major enantiomer: first peak)); 1H NMR
(CDCl3): d=0.95 (s, 3H), 1.05–1.10 (m, 1H), 1.06 (s, 3H), 1.15–1.25 (m,
2H), 1.19 (s, 3H), 1.42 (m, 1H), 1.65 (s, 1H), 1.65–1.87 (m, 3H), 1.96–
2.04 (m, 1H), 2.15–2.28 ppm (m, 2H); 13C NMR (CDCl3): d=18.0 (t),
18.8 (q), 21.9 (t), 26.2 (q), 27.6 (2q), 30.9 (s), 31.8 (s), 34.2 (t), 37.8 (2t),
44.5 (d), 49.3 (s), 215.9 ppm (s); MS: m/z (%): 192 (43) [M]+, 177 (27),
150 (58), 136 (71), 135 (100), 123 (60), 121 (55), 107 (64), 93 (59), 79 (57),
69 (38), 55 (30), 41 (38).
(1S)-1-[(2,6,6-Trimethyl-1-cyclohexen-1-yl)methyl]-2-propynyl
pivalate
(27): Procedure as described for 8a. Starting from 26 (17.4 g, max.
52.1 mmol), pure bulb-to-bulb distilled 23 (12.76 g, 88% from 24;
92% ee) was obtained. A separation of the enantiomers was possible by
chiral GC, but a better separation that gave more accurate values was ob-
tained by injection of the corresponding alcohol (most easily produced
by diisobutylaluminium hydride (DIBAH) reduction in THF). [a]D20
=
À49.2 (c=0.99 in CHCl3); 1H NMR (CDCl3): d=1.02 (s, 3H), 1.03 (s,
3H), 1.21 (s, 9H), 1.42 (m, 2H), 1.59 (m, 2H), 1.71 (s, 3H), 1.95 (brt, J=
6.0 Hz, 2H), 2.40 (d, J=2.3 Hz, 1H), 2.58 (dd, J=14.7, 6.6 Hz, 1H), 2.65
(dd, J=14.7, 8.4 Hz, 1H), 5.49 ppm (m, 1H); 13C NMR (CDCl3): d=19.3
(t), 21.2 (q), 27.0 (3q), 28.9 (2q), 28.9 (q), 33.0 (t), 33.5 (t), 34.6 (s), 38.7
(s), 39.9 (t), 63.9 (d), 73.1 (d), 82.2 (s), 131.7 (s), 177.5 ppm (s); MS: m/z
(%): 276 (1) [M]+, 192 (5), 174 (13), 159 (100), 137 (32), 95 (33), 57 (67),
41 (23).
(À)-(1R,5R,6R)-10-Dimethyl-tricyclo[4.4.0.01,5]decan-4-one ((À)-29):
A
solution of 23 (1.69 g, 6.45 mmol) in 1,2-dichloroethane (26 mL) was
treated with PtCl2 (35 mg, 0.132 mmol) and heated for 8 h at 708C. The
solution was cooled and poured in saturated aqueous NaHCO3. Extrac-
tion (Et2O), washing (H2O, then saturated aqueous NaCl), drying
(Na2SO4), concentration, and bulb-to-bulb distillation (100–1208C/
0.01 mbar) afforded 28 (1.49 g) containing 5% of 29. It was dissolved in
MeOH (25 mL) and treated with K2CO3 (1.08 g, 7.83 mmol) and stirred
for 165 min at RT. After partial concentration, the product was extracted
(Et2O/H2O), washed (H2O, then saturated aqueous NaCl), dried
(Na2SO4), concentrated, and bulb-to-bulb distilled (100–1258C/
0.01 mbar) to afford 29 (853 mg, 74%; 61% ee). [a]2D0 =+24.8 (c=0.56 in
CHCl3) (61% ee by chiral GC (major enantiomer: first peak)); 1H NMR
(CDCl3): d=0.92–1.02 (m, 1H); 0.96 (s, 3H), 1.09 (s, 3H), 1.20–1.30 (m,
2H), 1.35–1.55 (m, 2H), 1.51 (d, J=2.5 Hz, 1H), 1.59 (ddd, J=8.0, 2.5,
AHCTUNGTERG(NNUN 1S,6S)- and (1R,6S)-1-Allyl-2,2,6-trimethylcyclohexanecarbaldehyde (36
and 37): Concentrated HCl (1 mL, 10 mmol) was added to a stirred solu-
tion of (+)-34 (100 g; purity 89% (containing 7% of cis diastereomer);
0.63 mol) and trimethyl orthoformate (Fluka purum; 77.5 g (80.0 mL),
0.72 mol) in MeOH (70 mL) at À78C, and the mixture was stirred at RT
over 2 h. NaOAc (1.7 g, 20 mmol) was added, followed by allyl alcohol
(Fluka purum; 76.6 g (90 mL), 1.23 mol) and trifluoroacetic acid (Fluka
purum; 0.34 g, 3 mmol), and the mixture was slowly heated to 808C (bath
temp.), while the volatiles were distilled through a 20 cm Vigreux column
over 2 h. The temperature of the bath was then raised to 1508C and heat-
ing continued for 16 h. The cooled mixture was diluted with Et2O and
H2O and extracted. The organic phase was washed (10% aqueous HCl,
then H2O, then saturated aqueous NaHCO3, then brine), dried (Na2SO4),
Chem. Eur. J. 2009, 15, 9773 – 9784
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9781

C. Fehr et al.
and concentrated (113 g). Distillation (20 cm Vigreux column) under
vacuum gave a first fraction containing 88% pure product (13.1 g) and a
second fraction (b.p. 598C/0.3 mbar) containing 99% pure product
(82.6 g; total yield 76%). Subsequently, 1H and 13C NMR spectroscopic
analysis showed that fraction 2 consisted of an approximately 9:1 mixture
of 36 and 37. Data for 36: 1H NMR (CDCl3): d=0.84 (d, J=7 Hz, 3H),
0.92 (s, 3H), 1.07 (s, 3H), 1.28–1.35 (m, 4H), 1.50–1.71 (m, 4H), 1.85–
1.95 (m, 2H), 2.41 (dd, J=16, 9 Hz, 1H), 2.50 (dd, J=16, 9 Hz, 1H), 4.98
(dd, J=10, 1 Hz, 1H), 5.07 (dd, J=17, 1 Hz, 1H), 5.85–5.97 (m, 1H),
10.07 ppm (s, 1H; NOE with the two equatorial Me groups, but not with
the axial Me group); 13C NMR (CDCl3): d=17.3 (q), 22.0 (t), 24.6 (q),
27.2 (q), 32.2 (t), 34.2 (d), 34.3 (t), 36.9 (s), 39.0 (t), 56.4 (s), 116.4 (t),
137.1 (d), 208.6 ppm (d); MS: m/z (%): 194 (4) [M]+, 179 (12), 152 (23),
137 (43), 125 (51), 109 (100), 95 (89), 81 (82), 69 (77), 67 (60). 55 (91), 41
(84).
to a suspension of LiAlH4 (0.34 g, 9.5 mmol) in diethyl ether (10 mL) at
RT, and the mixture was stirred at RT over 1 h. The mixture was cooled
to 48C, acetone (1 mL) was added dropwise, followed by 4% aqueous
NaOH (2 mL), and the mixture was stirred at RT over 30 min. Na2SO4
was added, the solids were filtered off, and the filtrate was concentrated
to afford a mixture of 42 and 43 (1.83 g). Crystallization from pentane at
À308C afforded a >99% pure mixture of 42 and 43 (1.68 g, ratioꢀ1:1;
96%) as colorless crystals. M.p. 60–628C; 1H NMR (CDCl3, data for
characteristic signals): d=0.77 (d, J=5 Hz, 1.5H), 0.78 (d, J=5 Hz,
1.5H), 0.87 (s, 1.5H), 0.89 (s, 1.5H), 0.90 (s, 1.5H), 0.91 (s, 1.5H), 4.09–
4.18 (m, 0.5H), 4.19–4.27 ppm (m, 0.5H); 13C NMR (CDCl3): d=18.0
and 18.3 (q); 21.8 and 22.2 (t); 21.8 and 22.8 (q); 23.9 and 24.6 (t); 26.5
and 27.2 (q); 31.1 and 32.0 (t); 35.2 and 36.4 (d); 36.6 and 36.9 (t); 37.0
and 37.1 (s); 37.1 and 37.3 (t); 41.0 and 42.6 (t); 49.6 and 50.8 (s); 74.0
and 74.5 ppm (d); MS: m/z (%): 196 (8) [M]+, 178 (22), 163 (18), 135
(23). 121 (21), 112 (27), 109 (37), 107 (78), 94 (81), 83 (100), 79 (37), 69
(43), 67 (47), 55 (57), 41 (47), 39 (13).
ACHTUNGTRENNUNG(1R,6S)-1-Allyl-2,2,6-trimethylcyclohexanecarbaldehyde (37): Character-
istic signals: 1H NMR (CDCl3): d=0.90 (d, J=7 Hz, 3H), 0.98 (s, 3H),
1.03 (s, 3H), 9.68 ppm (s, 1H); 13C NMR (CDCl3): d=19.0 (q), 24.0 (q),
26.9 (q), 116.1 (t), 137.4 (d), 208.5 ppm (d).
ACHUTNERGN(NUG 5R,10S)-6,6,10-TrimethylspiroHCATUNGTRNEN[UGN 4.5]decalyl-2-acetate (46 and 47): Ac2O
(4 mL) was added to a solution of 42 and 43 (ca. 1:1, 0.85 g, 4.3 mmol) in
pyridine (4 mL), and the mixture was stirred at RT over 4 h. The mixture
was concentrated to afford a colorless oil (1.06 g). Bulb-to-bulb distilla-
tion (oven temp. 1128C/0.3 mbar) afforded a >99% pure mixture of 46
(+)-(1S,6S)-2,2,6-Trimethyl-1-(2-oxopropyl)cyclohexanecarbaldehyde
((+)-38): PdCl2 (4.0 g, 22 mmol) and CuCl2 (3.0 g, 22 mmol) were added
to a solution of 36 and 37 (9:1) (43.7 g, 223 mmol) in 1,2-dimethoxy-
ethane (360 mL) and H2O (40 mL) at RT, and the mixture was stirred
under O2 at RT over 56 h. The mixture was diluted with diethyl ether and
H2O and then extracted. The organic phase was washed (H2O, then
brine), dried (Na2SO4), and concentrated (48 g). Distillation (Widmer
column) under vacuum gave 38 (b.p. 898C/0.14 mbar) as a yellowish
liquid (25 g) which solidified on standing. Crystallization from pentane at
À308C afforded 99% pure (+)-38 (22.7 g, 48%) as colorless crystals.
1
and 47 (0.98 g, ratioꢀ1:1; 95%). H NMR (CDCl3, data for characteristic
signals): d=0.79 (s, 1.5H), 0.81 (d, J=7 Hz, 1.5H), 0.85 (d, J=7 Hz,
1.5H), 0.88 (s, 1.5H), 0.89 (s, 1.5H), 0.91 (s, 1.5H), 2.00 (s, 1.5H), 2.02 (s,
1.5H), 4.88–4.98 (m, 0.5H), 5.02–5.09 ppm (m, 0.5H). 13C NMR (CDCl3):
d=17.9 and 18.0 (q); 21.3 and 21.4 (q); 21.9 and 22.1 (t); 21.9 and 22.5
(q); 23.5 and 24.9 (t); 26.4 and 27.0 (q); 31.1 and 32.1 (t); 32.8 and 33.9
(t); 35.3 and 36.4 (d); 36.9 and 37.1 (s); 37.2 and 37.3 (t); 38.1 and 38.8
(t); 49.3 and 50.9 (s); 76.2 and 77.4 ppm (d); MS: m/z (%): 178 (87), 163
(12), 135 (20), 122 (18), 107 (100), 94 (88), 82 (37), 79 (20), 69 (25), 67
(32), 55 (27), 43 (43), 41 (26).
1
M.p.=53–558C; [a]2D0 =+52.7 (c=1.00 in CHCl3); H NMR (CDCl3): d=
0.82 (d, J=7 Hz, 3H), 0.92 (s, 3H), 0.98 (s, 3H), 1.27–1.35 (m, 1H), 1.50–
1.58 (m, 1H), 1.60–1.84 (m, 4H), 2.20 (s, 3H), 2.20–2.31 (m, 1H), 2.67 (d,
J=18 Hz, 1H), 2.91 ppm (d, J=18 Hz, 1H); 13C NMR (CDCl3): d=18.2
(q), 21.8 (t), 24.7 (q), 26.8 (q), 31.6 (t), 31.6 (q), 34.3 (d), 36.9 (s), 37.9 (t),
43.5 (t), 56.6 (s), 206.0 (d), 207.8 ppm (s); MS: m/z (%): 195 (1), 167 (1),
153 (12), 137 (15), 123 (20), 109 (44), 81 (22), 67 (20), 55 (28), 43 (100),
41 (55), 39 (25), 29 (22), 27 (15).
Compounds 46–49: A suspension of (S)-32 (60 mg, 0.313 mmol; 18% ee
(from Scheme 6; expt 7), AcOH (0.5 mL), and 10% Pd/C (20 mg) was
stirred under H2. After 24 h, the suspension was filtered over Celite, and
the filter cake was washed with Et2O. The filtrate was washed (H2O, then
saturated aqueous NaHCO3, then saturated aqueous NaCl), dried
(Na2SO4), and concentrated. The product mixture of 40 and 41 (contain-
ing 20% of unreacted (S)-32) was reduced, and the alcohol diastereomers
42–45 were converted into the acetates 46–49 as described above. Super-
imposition with the enantiomerically pure mixture of 46 and 47 on the
chiral GC allowed the determination of the absolute configuration of (S)-
32 (see Figure 1).
(1RS,5RS,6RS)-6,10,10-Trimethyltricyclo[4.4.0.01,5]decan-4-toluenesulfo-
nylhydrazone ((Æ)-50): A solution of (Æ)-32 (1.78 g, 8.42 mmol; 91%
pure), tosylhydrazide (1.72 g, 9.26 mmol), and AcOH (3 drops) in MeOH
(12 mL) was heated at reflux for 3 h. The reaction mixture was half-con-
centrated and stored in the refrigerator for 2 d. The formed crystals were
isolated by filtration and washed with cold MeOH. Yield: 2.52 g (83%).
A sample was recrystallized for analytical purposes. Characteristic signals
(E/Z or Z/E 60:40): 1H NMR (CDCl3): d=0.89 (0.85) (s, 3H), 0.87 (s,
3H), 0.97 (s, 3H), 2.42 (2.41) (s, 3H), 7.29 (m, 2H), 7.84 ppm (m, 2H);
13C NMR (CDCl3): d=17.9 (t), 18.1 (t), 18.6 (q), 19.0 (q), 21.6 (q), 23.1
(t), 24.3 (t), 26.5 (q), 26.6 (q), 27.5 (q), 27.6 (q), 29.6 (t), 30.7 (s), 30.9 (s),
33.4 (t), 33.8 (t), 34.0 (t), 37.5 (t), 37.9 (t), 39.2 (d), 127.9 (2d), 129.6 (2d),
135.4 (s), 135.6 (s), 143.8 (s), 143.9 (s), 171.2 ppm (brs).
(1RS,5RS,6RS)-6,10,10-Trimethyltricyclo[4.4.0.01,5]dec-3-ene ((Æ)-51): A
solution of (Æ)-50 (500 mg, 1.39 mmol) in N,N,N’,N’-tetramethyl-1,2-
ethane (TMEDA; 7 mL) was cooled to À788C and treated dropwise with
BuLi (1.41m; 3.94 mL, 5.56 mmol). The temperature was maintained
below À658C. The red solution was stirred at À708C for 5 min and al-
lowed to reach RT (30 min). Stirring was continued for 80 min. The solu-
tion was then poured into 5% HCl/ice, and the product was extracted
(2ꢂpentane/H2O), washed (4ꢂH2O), dried (Na2SO4), concentrated, and
filtered (silica gel; heptanes) to afford (Æ)-51 (93 mg, 38%). 1H NMR
(CDCl3): d=0.78 (s, 3H), 0.86 (s, 3H), 0.97 (s, 1H), 1.04 (m, 1H), 1.18
(m, 1H), 1.22 (m, 1H), 1.37 (m, 1H), 1.49 (t, J=2.5 Hz, 1H), 1.62 (m,
1H), 1.81 (m, 1H), 1.98 (dq, J=18.0, 2.4 Hz, 1H), 2.46 (d, J=18.0 Hz,
(+)-(5R,10S)-6,6,10-TrimethylspiroACTHNUTRGNEUGN[4.5]dec-3-en-2-one ((+)-39): A solu-
tion of (+)-38 (14.3 g, 67.1 mmol) in 1m methanolic KOH (150 mL) was
stirred at RT over 15 h. The mixture was diluted with diethyl ether and
H2O, and extracted. The organic phase was washed (saturated aqueous
NaHCO3, then H2O), dried (Na2SO4), and concentrated to
a solid
(12.8 g). Crystallization from pentane at À308C afforded 99% pure (+)-
39 (11.0 g, 85%) as colorless crystals. M.p. 67–688C; [a]2D0 =+66.9 (c=
2.00 in CHCl3); 1H NMR (CDCl3): d=0.64 (d, J=7 Hz, 3H), 0.73 (s,
3H), 1.03 (s, 3H), 1.18–1.28 (m, 1H), 1.35–1.39 (m, 1H), 1.57–1.68 (m,
4H), 1.92–2.02 (m, 1H), 2.05 (d, J=18 Hz, 1H), 2.33 (d, J=18 Hz, 1H),
6.21 (d, J=6 Hz, 1H), 7.71 ppm (d, J=6 Hz, 1H); 13C NMR (CDCl3):
d=17.2 (q), 21.8 (t), 23.7 (q), 27.1 (q), 32.2 (t), 35.1 (d), 35.7 (s), 37.1 (t),
43.1 (t), 55.7 (s), 134.6 (d), 167.9 (d), 209.8 ppm (s); MS: m/z (%): 192
(15) [M]+, 177 (11), 149 (16), 135 (9), 122 (37), 108 (81), 91 (52), 79
(100), 77 (63), 69 (27), 55 (46), 53 (37), 41 (87), 39 (49), 29 (27), 27 (25).
(+)-(5R,10S)-6,6,10-Trimethylspiro
[4.5]decan-2-one
((+)-40):
Pd/C
(10%, 200 mg) was added to a solution of (+)-39 (4.00 g, 20.8 mmol) in
EtOH (40 mL) at RT, and the mixture was shaken under H2 (1 atm) over
5 h. The catalyst was filtered off through Celite and the filtrate concen-
trated (4.10 g). Bulb-to-bulb distillation (oven temp. 100–1508C/
0.15 mbar) afforded >99% pure (+)-40 (3.94 g, 97%). Crystallization
from pentane at À308C gave colorless crystals (3.56 g). M.p. 53–548C;
1
[a]2D0 =+60.3 (c=1.00 in CHCl3); H NMR (CDCl3): d=0.77 (d, J=7 Hz,
3H), 0.90 (s, 3H), 0.94 (s, 3H), 1.15 (m, 2H), 1.38–1.59 (m, 4H), 1.80–
1.95 (m, 3H), 1.99 (d, J=18 Hz, 1H), 2.18–2.36 (m, 2H), 2.39 ppm (d,
J=18 Hz, 1H); 13C NMR (CDCl3): d=17.4 (q), 21.6 (t), 21.7 (t), 23.0 (q),
26.4 (q), 30.9 (t), 36.4 (d), 36.4 (t), 36.9 (s), 39.2 (t), 45.9 (t), 48.1 (s),
221.1 ppm (s); MS: m/z (%): 194 (57) [M]+, 123 (72), 110 (58), 95 (23),
83 (100), 69 (43), 67 (37), 55 (49), 41 (45), 39 (17).
(+)-(5R,10S)-6,6,10-Trimethylspiro
ACHTUNGTRENN[UNG 4.5]decane-2-ol (42 and 43): A solu-
tion of (+)-40 (1.74 g, 9.00 mmol) in Et2O (20 mL) was added dropwise
9782
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Chem. Eur. J. 2009, 15, 9773 – 9784

(À)-Cubebol Synthesis
FULL PAPER
1H), 5.49 (m, 1H), 5.64 ppm (m, 1H); 13C NMR (CDCl3): d=15.8 (q),
18.7 (t), 24.7 (s), 26.4 (q), 27.9 (q), 30.6 (s), 33.7 (t), 34.9 (t), 38.5 (t), 38.6
(d), 42.3 (s), 129.6 (d), 130.8 ppm (d); MS: m/z (%): 176 (42) [M]+, 161
(26), 133 (22), 119 (25), 105 (100), 91 (93), 79 (19), 77 (17).
[5] A. Fꢀrstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006.
[6] Pt catalysis: a) E. Mainetti, V. Mouriꢃs, L. Fensterbank, M. Malac-
ria, J. Marco-Contelles, Angew. Chem. 2002, 114, 2236; Angew.
Chem. Int. Ed. 2002, 41, 2132; Y. Harrak, C. Blaszykowski, M. Ber-
nard, K. Cariou, E. Mainetti, V. Mouriꢃs, A.-L. Dhimane, L. Fen-
sterbank, M. Malacria, J. Am. Chem. Soc. 2004, 126, 8656; C. Blaszy-
kowski, Y. Harrak, M.-H. GonÅalves, J.-M. Cloarec, A.-L. Dhimane,
L. Fensterbank, M. Malacria, Org. Lett. 2004, 6, 3771; b) S. Anjum,
J. Marco-Contelles, Tetrahedron 2005, 61, 4793; c) V. Mamane, T.
Gress, H. Krause, A. Fꢀrstner, J. Am. Chem. Soc. 2004, 126, 8654;
d) C. Blaszykowski, Y. Harrak, C. Brancour, K. Nakama, A.-L. Dhi-
mane, L. Fensterbank, M. Malacria, Synthesis 2007, 2037; e) X.
Moreau, J.-P. Goddard, M. Bernard, G. Lemiꢃre, J. M. Lopez-
Romero, E. Mainetti, N. Marion, V. Mouriꢃs, S. Thorimbert, L. Fen-
sterbank, M. Malacria, Adv. Synth. Catal. 2008, 350, 43.
ACHTUNGTRENNUNG
(1R,5R,6R)-6,10,10-Trimethyltricyclo[4.4.0.01,5]dec-3-ene ((6R)-51) from
(6R)-32 (13% ee): Starting from (6R)-32 (1.09 g, 5.68 mmol; 13% ee;
Scheme 6, expt 6), 1.60 g (78%) of crystalline (6R)-50 (9% ee; see
below) and 485 mg of mother liquor containing (6R)-50 (21% ee; see
below) were obtained. The crystals and the mother liquor were separate-
ly converted into (6R)-51 of 9% ee (98 mg, 30%) and 21% ee, respec-
tively (chiral GC: second peak major in both cases).
(1RS,5RS,6RS)-6,10,10-Trimethyltricyclo[4.4.0.01,5]decan-3-toluenesulfo-
nylhydrazone (Æ)-52: A solution of (Æ)-33 (1.00 g, 5.21 mmol), tosylhy-
drazide (1.07 g, 5.73 mmol) and AcOH (3 drops) in MeOH (10 mL) was
heated at reflux for 2 h. The reaction mixture was cooled to RT and
stored in the freezer for 15 h. The formed crystals were isolated by filtra-
tion and washed with cold MeOH. Yield: 1.44 g (77%). A sample was re-
crystallized for analytical purposes. Characteristic signals (E/Z or Z/E
[7] a) E. Soriano, P. Ballesteros, J. Marco-Contelles, Organometallics
2005, 24, 3182; b) E. Soriano, J. Marco-Contelles, J. Org. Chem.
2005, 70, 9345.
1
[8] Au catalysis: a) A. Fꢀrstner, A. Schlecker, Chem. Eur. J. 2008, 14,
9181; A. Fꢀrstner, P. Hannen, J. Chem. Soc. Chem. Commun. 2004,
2546; F. Gagosz, Org. Lett. 2005, 7, 4129; N. Marion, P. de Frꢄmont,
G, Lemiꢃre, E. D. Stevens, L. Fensterbank, M. Malacria, S. P.
Nolan, Chem. Commun. 2006, 2048; N. Marion, G. Lemiꢃre, A.
Correa, C. Costabile, R. S. Ramon, X. Moreau, P. de Frꢄmont, R.
Dahmane, A. Hours, D. Lesage, J.-C. Tabet, J.-P. Goddard, V.
Gandon, L. Cavallo, L. Fensterbank, M. Malacria, S. P. Nolan,
Chem. Eur. J. 2009, 15, 3243; b) I. D. G. Watson, S. Ritter, F. D.
Toste, J. Am. Chem. Soc. 2009, 131, 2056 and reference [6c,e]
[9] C. Fehr, I. Farris, H. Sommer, Org. Lett. 2006, 8, 1839.
[10] Recent reviews on enyne cycloisomerizations: H. C. Shen, Tetrahe-
dron 2008, 64, 7847; E. Jimꢄnez-Nunez, A. M. Echavarren, Chem.
Rev. 2008, 108, 3326; V. Michelet, P. Y. Toullec, J.-P. GenÞt, Angew.
Chem. 2008, 120, 4338; Angew. Chem. Int. Ed. 2008, 47, 4268; B.
Crone, S. F. Kirsch, Chem. Eur. J. 2008, 14, 3514; A. Fꢀrstner, P. W.
Davies, Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed. 2007,
46, 3410; E. Jimꢄnez-Nunez, A. M. Echavarren, Chem. Commun.
2007, 333; D. J. Gorin, D. Toste, Nature 2007, 446, 395; N. Marion,
S. P. Nolan, Angew. Chem. 2007, 119, 2806; Angew. Chem. Int. Ed.
2007, 46, 2750; J. Marco-Contelles, E. Soriano, Chem. Eur. J. 2007,
13, 1350; L. Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006,
348, 2271; C. Nieto-Oberhuber, S. Lopez, E. Jimꢄnez-Nunez, A. M.
Echavarren, Chem. Eur. J. 2006, 12, 5916; S. Ma, S. Yu, Z. Gu,
Angew. Chem. 2006, 118, 206; Angew. Chem. Int. Ed. 2006, 45, 200;
C. Bruneau, Angew. Chem. 2005, 117, 2380; Angew. Chem. Int. Ed.
2005, 44, 2328; A. M. Echavarren, C. Nevado, Chem. Soc. Rev. 2004,
33, 431; C. Aubert, O. Buisine, M. Malacria, Chem. Rev. 2002, 102,
813.
60:40): H NMR (CDCl3): d=0.68 (0.69) (s, 3H), 0.87 (0.88) (s, 3H), 0.93
(0.94) (s, 3H), 2.42 (s, 3H), 7.30 (m, 2H), 7.83 ppm (m, 2H); 13C NMR
(CDCl3): d=16.4 (q), 16.5 (q),18.1 (t), 21.6 (q), 23.9 (s), 24.0 (s), 27.5 (q),
27.5 (d), 27.6 (d), 29.2 (t), 30.1 (t), 30.6 (s), 33.8 (t), 34.0 (t), 35.0 (t), 37.9
(t), 38.0 (t), 38.5 (s), 39.4 (s), 127.9 (2d), 129.6 (2d), 135.6 (s), 143.9 (s),
168.6 (s), 168.8 ppm (s).
(1RS,5RS,6RS)-6,10,10-Trimethyltricyclo[4.4.0.01,5]dec-3-ene
((Æ)-51)
and (1RS,5RS,6RS)-6,10,10-trimethyl-tricyclo[4.4.0.01,5]dec-2-ene ((Æ)-
53): Procedure as described for (Æ)-51. Starting from (Æ)-52 (500 mg,
1.39 mmol), (Æ)-51/53 (12:88; 76 mg, 31%) was isolated. Analytical data
1
of 53: H NMR (CDCl3): d=0.81 (s, 3H), 0.87 (s, 3H), 1.13 (s, 1H), 1.05–
1.25 (m, 3H), 1.30–1.45 (m, 2H), 1.62 (m, 1H), 1.72 (m, 1H), 2.07 (d, J=
18.0 Hz, 1H), 2.47 (m, 1H), 5.51 (m, 1H), 5.64 ppm (m, 1H); 13C NMR
(CDCl3): d=16.0 (q), 18.4 (t), 25.6 (s), 28.6 (q), 28.9 (q), 29.5 (d), 29.8
(s), 33.3 (t), 33.7 (t), 38.7 (t), 50.7 (s), 130.1 (d), 132.5 ppm (d); MS: m/z
(%): 176 (36) [M]+, 161 (50), 133 (34), 119 (42), 105 (100), 91 (90), 79
(22), 77 (19).
ACHTUNGTRENNUNG
(1R,5R,6R)-6,10,10-Trimethyltricyclo[4.4.0.01,5]dec-3-ene ((6R)-51) and
(1R,5R,6R)-6,10,10-trimethyltricyclo[4.4.0.01,5]dec-2-ene ((6R)-53) from
(6R)-33 (88% ee): Starting from (R)-33 (744 mg, 3.87 mmol; 88% ee;
Scheme 6, expt 6), 101 mg (7%) of crystalline 52 (probably racemic; see
below) and 1.34 g of mother liquor containing (R)-52 (max. 93% yield;
96% ee; see below) were obtained. Proceeding as described for (Æ)-51,
but at a temperature of À40 to À508C instead of À788C, the mother
liquor (600 mg, max. 1.61 mmol) was converted into a mixture of (6R)-51
and (6R)-53 (40:60) of 96% ee (129 mg, 82% pure; 37% over 2 steps)
(chiral GC: second peaks major) (see Figure 2).
[11] D. Boyall, F. Lopez, H. Sasaki, D. Frantz, E. M. Carreira, Org. Lett.
2000, 2, 4233; J. W. Bode, E. M. Carreira, J. Org. Chem. 2001, 66,
6410.
[12] Despite the slow addition of 15, it accumulates during the reaction.
Diminishing the amount of reagents leads to a slower reaction and
to the formation of byproducts.
Acknowledgements
We thank Dr. X. Chillier (University of Geneva, Switzerland) and Pro-
fessor J. Lacour (University of Geneva, Switzerland) for critical reading
of the manuscript.
[13] X. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 5802.
[14] Synthesis of 20: see the Experimental Section.
[15] For the synthesis of 24, see: O. Isler, M. Montavon, R. Rꢀegg, P.
Zeller, Helv. Chim. Acta 1956, 39, 259; G. L. Olson, H.-C. Cheung,
K. D. Morgan, R. Borer, G. Saucy, Helv. Chim. Acta 1976, 59, 567.
Compound 24 is also commercially available (Aldrich).
[16] The indicated absolute configuration of 29 is based on the stereose-
lectivity observed in the cycloisomerization of 8a (cubebol synthe-
sis).
[1] C. Fehr, J. Galindo, Angew. Chem. 2006, 118, 2967; Angew. Chem.
Int. Ed. 2006, 45, 2901.
[2] F. Vanasek, V. Herout, F. Sorm, Coll. Czech. Chem. Commun. 1960,
25, 919; Y. Ohta, K. Ohara, Y. Hirose, Tetrahedron Lett. 1968, 9,
4181, and references therein.
[3] M. I. Velazco, L. Wuensche, P. Deladoey (Firmenich SA), US patent
6214788, 1999; [Chem. Abstr. 2000, 133, 265959].
[17] M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J. Am. Chem.
Soc. 2005, 127, 18002.
[4] a) E. Piers, R. W. Britton, W. de Waal, Tetrahedron Lett. 1969, 10,
1251; E. Piers, R. W. Britton, W. de Waal, Can. J. Chem. 1971, 49,
12; b) A. Tanaka, R. Tanaka, H. Uda, A. Yoshikoshi, J. Chem. Soc.
Perkin 1 1972, 1721; A. Tanaka, H. Uda, A. Yoshikoshi, J. Chem.
Soc. Chem. Commun. 1969, 308; c) See also: S. Torii, T. Okamoto,
Bull. Chem. Soc. Jpn. 1976, 49, 771.
[18] E. Soriano, J. Marco-Contelles, J. Org. Chem. 2007, 72, 2651.
[19] A referee asked for an explanation why this study was done with
the pivalate and not the acetate. Originally, we supposed that a
crowded ester group would favor the desired reactive conformer
(placing the carbonyl group in the vicinity of the alkynyl group) and
Chem. Eur. J. 2009, 15, 9773 – 9784
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www.chemeurj.org
9783

C. Fehr et al.
had used the pivalates prior to the study by Soriano and Marco-
Contelles (see ref. [18]). As can be seen from the work of Fꢀrstner
and Hannen (see ref. [5]), the cycloisomerizations of the acetates
corresponding to the pivalates 8a and 8b exhibit the same selectivi-
ties. Nevertheless, we prepared the acetate corresponding to 27
(92% ee) and submitted it to the conditions of Scheme 5, expt 5.
The results are in line with those of the pivalate: 32: 37% (1% ee);
33: 63% (87% ee). This gives the following values for Table 2: (6R)-
30: 18.5; (6R)-31: 59; (6R)-E: 77.5; (6S)-E: 22.5; (6S)-30: 18.5; (6S)-
31: 4.
[20] A. Correa, N. Marion, L. Fensterbank, M. Malacria, S. P. Nolan, L.
Cavallo, Angew. Chem. 2008, 120, 730; Angew. Chem. Int. Ed. 2008,
47, 718.
[21] C. Chapuis, R. Brauchli, Helv. Chim. Acta 1993, 76, 2070.
[22] D. M. Hodgson, S. Salik, Synlett 2009, 1730.
Received: May 14, 2009
Published online: August 18, 2009
9784
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Chem. Eur. J. 2009, 15, 9773 – 9784