Platinum- and gold-catalyzed rearrangement reactions of propargyl acetates: Total syntheses of (-)-α-cubebene, (-)-cubebol, sesquicarene and related terpenes

Article abstract of DOI:10.1002/chem.200501299

Propargyl acetates, in the presence of catalytic amounts of late transition-metal salts such as PtCl₂ or AuCl₃, represent synthetic equivalents of α-diazoketones. This notion is corroborated by a concise approach to various sesquiterpene natural products starting from readily available substrates. Specifically, (+)-carvomenthone (17) is converted into propargyl acetate (S)-26 by a sequence involving Stille cross-coupling of its kinetic enol triflate 18, regioselective hydroboration/oxidation of the resulting 1,3-diene 19, and addition of an alkynyl cerium reagent to aldehyde 21 thus obtained. Since the latter step was found to be unselective, the configuration of the reacting propargyl acetate was unambiguously set by oxidation followed by diastereoselective transfer hydrogenation by using Noyori's catalyst 25. Compound (5)-26, on treatment with PtCl₂ in toluene, converted exclusively to the tricyclic enol acetate 27, which was sap onified to give norcubebone 11 in excellent overall yield. The conversion of this compound into the sesquiterpene alcohol (-)-cubebol (6) was best achieved with MeCeCl₂ as the nucleophile, whereas the formation-of the parent hydrocarbon (-)-α-cubebene (4) was effected in excellent yield by recourse to iron-catalyzed cross coupling methodology developed in this laboratory. Since norketone 11 has previously been transformed into (-)-β-cubebene (5) as well as (-)-4-epicubebol 8, our approach constitutes formal total syntheses of these additional natural products as well. Along similar lines, the readily available propargyl acetates 1, 33 and 47 were shown to give access to 2-carene 44, sesquicarene 39, and episesquicarene 51 in excellent overall yields. In this series, however, the cy cloisomerization reaction was best achieved with catalytic amounts of AuCl₃ in 1,2-dichloroethane as the solvent. In addition to these preparative results, our data provide some insight into the mechanism of these remarkable skeletal rearrangement reactions. Transformations of this type are likely triggered by initial coordination of the alkyne unit of the substrate to the carbophilic transition-metal cation. Formal attack of the alkene moiety onto the resulting π-complex engenders the formation of an electrophilic cyclopropyl carbene species which subsequently reacts with the adjacent acetate unit to give the final product. The alternative phasing of events, implying initial attack of the acetate (rather than the alkene moiety) onto the metal-alkyne complex, is inconsistent with the stereochemioal data obtained during this total synthesis campaign.

Full text of DOI:10.1002/chem.200501299

DOI: 10.1002/chem.200501299
Platinum- and Gold-Catalyzed Rearrangement Reactions of Propargyl
Acetates: Total Syntheses of (ꢀ)-a-Cubebene, (ꢀ)-Cubebol, Sesquicarene
and Related Terpenes
Alois Fürstner* and Peter Hannen[a]
Abstract: Propargyl acetates, in the
presence of catalytic amounts of late
transition-metal salts such as PtCl2 or
AuCl3, represent synthetic equivalents
of a-diazoketones. This notion is corro-
borated by a concise approach to vari-
ous sesquiterpene natural products
starting from readily available sub-
strates. Specifically, (+)-carvomen-
thone (17) is converted into propargyl
acetate (S)-26 by a sequence involving
Stille cross-coupling of its kinetic enol
triflate 18, regioselective hydrobora-
tion/oxidation of the resulting 1,3-diene
19, and addition of an alkynyl cerium
reagent to aldehyde 21 thus obtained.
Since the latter step was found to be
unselective, the configuration of the re-
acting propargyl acetate was unambig-
uously set by oxidation followed by dia-
stereoselective transfer hydrogenation
by using Noyoriꢀs catalyst 25. Com-
pound (S)-26, on treatment with PtCl2
in toluene, converted exclusively to the
tricyclic enol acetate 27, which was sap-
onified to give norcubebone 11 in ex-
cellent overall yield. The conversion of
this compound into the sesquiterpene
alcohol (ꢀ)-cubebol (6) was best ach-
ieved with MeCeCl2 as the nucleophile,
whereas the formation of the parent
hydrocarbon (ꢀ)-a-cubebene (4) was
effected in excellent yield by recourse
to iron-catalyzed cross coupling meth-
odology developed in this laboratory.
Since norketone 11 has previously
been transformed into (ꢀ)-b-cubebene
(5) as well as (ꢀ)-4-epicubebol 8, our
approach constitutes formal total syn-
theses of these additional natural prod-
ucts as well. Along similar lines, the
readily available propargyl acetates 1,
33 and 47 were shown to give access to
2-carene 44, sesquicarene 39, and epi-
sesquicarene 51 in excellent overall
yields. In this series, however, the cy-
cloisomerization reaction was best ach-
ieved with catalytic amounts of AuCl3
in 1,2-dichloroethane as the solvent. In
addition to these preparative results,
our data provide some insight into the
mechanism of these remarkable skele-
tal rearrangement reactions. Transfor-
mations of this type are likely triggered
by initial coordination of the alkyne
unit of the substrate to the carbophilic
transition-metal cation. Formal attack
of the alkene moiety onto the resulting
p-complex engenders the formation of
an electrophilic cyclopropyl carbene
species which subsequently reacts with
the adjacent acetate unit to give the
final product. The alternative phasing
of events, implying initial attack of the
acetate (rather than the alkene moiety)
onto the metal–alkyne complex, is in-
consistent with the stereochemical data
obtained during this total synthesis
campaign.
Keywords: carbenes · gold · natural
products · platinum · terpene
Introduction
authors proposed a possible mechanism for this unusual
transformation,[2] the reaction remained unoptimized and its
scope unexplored, even when Rautenstrauch rediscovered
this type of cycloisomerization during studies on PdCl2-cata-
In 1976, Ohloff et al. reported the serendipitous discovery
that treatment of propargyl acetate 1 with ZnCl2 in benzene
at 808C afforded small amounts (ca. 5%) of 2-acetoxy-2-
carene (3) in addition to carvenone (2) formed as the major
product under these conditions (Scheme 1).[1] Although the
[a] Prof. A. Fürstner, Dipl.-Chem. P. Hannen
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
Scheme 1. Ohloffꢀs original discovery of a transition metal catalyzed cy-
cloisomerization with concomitant 1,2-acetyl shift.
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FULL PAPER
lyzed Nazarov-type reactions of certain acetoxylated
enynes.[3]
lished endo-cyclization process (path II). Subsequent attack
of the adjacent acetyl group onto the electrophilic carbene
center affords F via oxatricyle E. Computational studies sug-
gest that both reaction coordinates are feasible and similar
in energy, with path II being only slightly favored in the gas
phase,[14] thus making an unambiguous decision impossible
as to which mode is operative in solution.
Outlined below we describe what are believed to be the
first applications of noble metal-catalyzed propargyl acetate
rearrangements to natural-product synthesis.[15] Moreover,
the preparative data allow us to distinguish between the two
mechanistic scenarios outlined above and provide strong
evidence for path II playing the major role under the chosen
reaction conditions.
Only very recently has the preparative potential of this
particular skeletal reorganization been appreciated, which is
accompanied by a characteristic 1,2-acyl shift.[4–6] This devel-
opment came alongside the increasing understanding for the
activation of unsaturated substrates by late transition metals
which act as efficient “carbophilic” Lewis acids in a variety
of cases.[7] Specifically, complexation to soft noble metal cat-
ions such as PtII, AuI, or AuIII renders alkynes susceptible to
attack by (tethered) nucleophiles including alkenes, arenes,
ethers or carbonyl groups. The cyclopropyl–carbene com-
plexes primarily formed as reactive intermediates evolve
along different pathways that are best rationalized if these
species are seen as latent “non-classical” carbocations com-
plexed to a transition-metal template.[8] This rationale readi-
ly explains the highly diverse set of product structures acces-
sible by this user-friendly methodology. From the prepara-
tive point of view it is noteworthy that such skeletal reor-
ganizations engender a significant increase in molecular
complexity, while being operationally simple, safe and con-
venient to perform.[4–13]
This global picture allows to rationalize the outcome of
the “Ohloff–Rautenstrauch” rearrangement without difficul-
ties; at a closer look, however, two slightly different scenar-
ios must be considered (Scheme 2). Path I assumes that the
tethered acetyl group initially attacks the electrophilic h2-
metal–alkyne complex A with formation of a polarized oxa-
cycle B; the latter evolves into a vinyl–carbene species C ef-
fecting the cyclopropanation of the lateral alkene moiety to
give the observed bicyclic product F. Alternatively, it is con-
ceivable that the olefin acts as the primary nucleophile, fur-
nishing a cyclopropyl–carbene complex D by a well estab-
Results and Discussion
Total synthesis of cubebene and cubebol: Hydrolysis of the
enol ester initially formed by noble metal-catalyzed prop-
argyl acetate cycloisomerizations delivers a cyclopropyl car-
bonyl derivative (Scheme 3). Since compounds of this type
are usually prepared by intramolecular cyclopropanation of
unsaturated a-diazoketones, one may conclude that the
“Ohloff–Rautenstrauch” rearrangement represents an at-
tractive and less hazardous synthetic equivalent to classical
diazocarbonyl chemistry.[16,17]
Scheme 3. Synthetic equivalence of classical a-diazoketone methodology
and noble metal catalyzed propargyl acetate rearrangements. The labels
visualize the positioning of the propargylic atoms in the product.
A total synthesis of cubebene and related cadinane ses-
quiterpenes was planned to scrutinize this aspect
(Scheme 4). The isomeric alkenes (ꢀ)-a-cubebene (4) and
(ꢀ)-b-cubebene (5) together with the tertiary alcohol (ꢀ)-
cubebol (6)[18] are important components of the essential oil
of Piper cubeba L. from which they were originally isolat-
ed.[19] Interestingly enough, the same compounds were later
found in taxonomically unrelated organisms as different as
brown algae, gorgonians and liverworts.[20]
Furthermore it is noteworthy that compound 8, featuring
an epimeric configuration of the tertiary alcohol center at
C-4, and even the enantiomeric terpene (+)-a-cubebene
(ent-4) have also been isolated from natural sources.[21] In
addition to these parent sesquiterpenes, a variety of deriva-
tives is known, amongst which the glycoside 9, the ether de-
rivative 10 and compound 7 bearing a rare isothiocyanate
motif are most remarkable.[22]
The cubebane family shares
a
common tricy-
clo[4.4.0.01,5]decane skeleton with a variety of other bioac-
tive natural products, some of which are depicted in
Scheme 2. Two conceivable mechanisms of the “Ohloff–Rautenstrauch”
rearrangement proceeding via electrophilic metal carbene intermediates.
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3007

A. Fürstner and P. Hannen
Scheme 6. a) [(PPh3)3RhCl] cat., H2 (3 atm), benzene, 98%; b) Pd/C
(10% w/w), H2 (1 atm), MeOH, dr 1:1; c) NaOMe, MeOH, 90%, dr 9:1;
d) lithium 2,2,6,6-tetramethylpiperidinide, THF, ꢀ788C, then N-(5-
chloro-2-pyridyl)bistrifluoromethanesulfonimide
(Comins
reagent),
Scheme 4. Representative members of the cubebane family of tricyclic
sesquiterpenes.
ꢀ788C ! 08C, 87%; e) H2C=CHSn-Bu3, [Pd(PPh3)4] cat., LiCl, THF,
reflux, 85%; f) 9-BBN, THF, then aq. H2O2, aq. NaOH, 87%; g) Dess–
ꢁ
Martin periodinane, CH2Cl2, 86%; h) Me3SiC CH, BuLi, then CeCl3,
THF, ꢀ788C, 93%, dr 65:35; i) TBAF, THF.
Scheme 5.[23] This highly condensed carbocyclic framework
invites construction by cyclopropanation techniques; in fact,
all known syntheses of the cubebenes rely on intramolecular
a-diazoketone cyclization reactions in the presence of suita-
ble metal catalysts.[24] However, these transformations invar-
iably afforded mixtures of the required norketone 11 and
isomers thereof; moreover, all published routes require sep-
aration of isomeric compounds by preparative GC at some
stage of the synthesis.[24] In view of these obvious shortcom-
ings, it seemed appropriate to target cubebene and cubebol
by the envisaged cycloisomerization route in order to assess
its preparative potential.
ic enol triflate 18 in high yield and purity. Sterically less
encumbered
bases
(LDA,
cyclohexyl(isopropyl)NLi,
LiHMDS) gave inferior results. Stille cross-coupling of 18
with commercial vinylstannane provided diene 19 in high
yield, the terminal alkene of which was regioselectively hy-
droborated with 9-BBN to give alcohol 20 after oxidative
work-up.[28] Exposure to Dess–Martin periodinane[29] cleanly
afforded the corresponding aldehyde 21 which reacted with
[30,31]
ꢁ
the alkynylcerium reagent Me3SiC CCeCl2
to give a
mixture of both possible propargyl alcohols 22 in a 65:35 dia-
stereomeric ratio. Cleavage of the silyl group followed by
acetylation of the alcohol 23 under standard conditions gave
propargyl acetate 26, thus setting the stage for the envisaged
cycloisomerization.
Although a rapid conversion took place on exposure of
this substrate to PtCl2 in toluene at 808C, a product mixture
containing an isomeric compound in addition to the desired
enol ester 27 was obtained, which turned out to be difficult
to separate by routine measures. For the sake of practicality
it was therefore necessary to find a more selective entry into
the tricyclic cubebene skeleton.
Monitoring of the course of the PtCl2-catalyzed cycloiso-
merization reaction indicated that the diastereomeric prop-
argyl acetates 26 react with different rates and likely differ-
ent selectivities; therefore it was decided to investigate the
behavior of the individual isomers separately (Scheme 7).
To this end, oxidation of alcohol 22 to the corresponding
ketone 24 followed by chemo- and stereoselective transfer
hydrogenation[32] gave access to (S)-26 and (R)-26, both of
which could be obtained in highly enriched form (dr
95:5).[33] Gratifyingly, (S)-26 derived thereof underwent a re-
markably clean cycloisomerization in the presence of cata-
lytic amounts of PtCl2 in toluene, forming enol acetate 27
exclusively, which was isolated in 92% yield as a diastereo-
merically pure compound (Scheme 8). Subsequent ester
cleavage afforded the known norketone 11, the spectroscop-
Scheme 5. Norketone skeleton of the cubeban family (11) and other nat-
ural products with a tricyclo[4.4.0.01,5]decane skeleton.
Our synthesis started from (R)-(ꢀ)-carvone 15 which was
converted to carvomenthone 17 by a two-step reduction pro-
tocol followed by isomerization of the a-methyl group
(Scheme 6).[25] This procedure minimizes double-bond trans-
position and concomitant racemization and ensures that 17
is obtained with high diastereoselectivity (dr 90:10), superior
to that obtained by alternative methods.[26] Enolization of
ketone 17 also required careful optimization. With the aid
of lithio 2,2,6,6-tetramethylpiperidinide as base and Comins
reagent[27] as electrophile it was possible to obtain the kinet-
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Scheme 9. a) MeLi, CeCl3, THF, ꢀ788C, 91%; b) LDA, THF, ꢀ788C,
then N-(5-chloro-2-pyridyl)bistrifluoromethanesulfonimide (Comins re-
agent), ꢀ788C ! RT, 91%; c) MeMgBr, [Fe(acac)3] (10 mol%), THF/
NMP, ꢀ308C, 90%; d) ref. [24d]; e) Ph3P=CH2, DMSO, 99%, ref. [24b].
Scheme 7. a) Dess–Martin periodinane, CH2Cl2, 94%;
b ) R(,R)-25
(5 mol%), isopropanol, 93% (dr 85:15); c) (S,S)-25 (5 mol%), isopropa-
nol, 94% (dr 86:14); d) TBAF, THF, 88%; e) TBAF, THF, 89%; f)
Ac2O, Et3N, DMAP cat., CH2Cl2, 81%; g) Ac2O, Et3N, DMAP cat.,
CH2Cl2, 93%.
Comins reagent[27] gave triflate 28 which was alkylated with
MeMgBr in the presence of [Fe(acac)3] as the precatalyst of
choice.[35] (ꢀ)-a-Cubebene 4 was thus obtained in 90% iso-
lated yield, thus corroborating the notion that iron-based
cross coupling reactions hold considerable promise as effi-
cient, cheap and benign alternatives to established method-
ology.[36–38]
Mechanistic implications: While the diastereoselective plati-
num-catalyzed cycloisomerization of (S)-26 paved an effi-
cient way to the cubebane sesquiterpenes as outlined above,
the corresponding reaction of its (R)-configured isomer pro-
vided valuable mechanistic information. Under the same
conditions, (R)-26 afforded a mixture of 27 and a diastereo-
meric compound 29 in a ~1:1 ratio (GC) (Scheme 10). The
structure of the latter was unambiguously established after
hydrolytic cleavage of its enol ester moiety with K2CO3 in
MeOH. Careful analysis of the NMR spectra (400 MHz) of
Scheme 8. a) PtCl2 (2 mol%), toluene, 808C, 92%; b) K2CO3, MeOH,
76%.
ic data of which were identical to those previously reported
in the literature.[24,34]
While the conversion of ketone 11 into (ꢀ)-b-cubebene 5
is known to be high yielding, requiring a routine Wittig
methylenation only,[24] the literature procedures for its con-
version into (ꢀ)-cubebol 6 and (ꢀ)-a-cubebene 4 are hardly
satisfactory. Addition of either MeLi of MeMgBr to 11 is re-
ported to give the desired alcohol 6 in 47–49% only.[24d,e] As-
suming that competing enolization might be responsible for
this rather low yield, MeLi was first transmetallated with
CeCl3 before ketone 11 was added to the mixture (Sche-
me 9).[30b,31] In fact, the less basic MeCeCl2 thus formed be-
haved exceptionally well, affording (ꢀ)-cubebol 6 as a single
diastereomer in 91% isolated yield. NOESY spectra con-
firmed that the attack of the methyl donor onto the carbon-
yl group occurred exclusively from the face opposite to the
adjacent cyclopropane ring.
Likewise, the formation of (ꢀ)-a-cubebene from norke-
tone 11 could also be significantly improved over prior art.
Specifically, deprotonation of 11 with LDA at low tempera-
ture followed by quenching of the resulting enolate with
Scheme 10. a) PtCl2 (2 mol%), toluene, 808C, 79%; b) K2CO3, MeOH,
80%.
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A. Fürstner and P. Hannen
the resulting ketone 30 shows the presence of the tricy-
clo[4.4.0.01,5]decane skeleton,[39] which must be isomeric to
that found in 11 with regard to the stereochemistry of the
ring junction.
The striking difference between the stereoselective cyclo-
isomerization of (S)-26 on the one hand and the unselective
transformation of (R)-26 on the other hand shows that the
configuration of the stereogenic center carrying the acetate
unit translates into the stereochemistry of the product.
Hence, this position cannot be planarized before cyclopropa-
nation has occurred. According to our present understand-
ing of such reactions (Schemes 2 and 11), path I involves a
vinyl carbene intermediate C prior to cyclization and hence
implies that both isomers lead to the same product distribu-
tion, whereas path II is consistent with the observed stereo-
divergent behavior. We are therefore inclined to believe
that path II, which was slightly favored in previous computa-
tional studies in the gas phase,[14] is in fact operative under
the chosen experimental conditions.[40,41]
ꢁ
Scheme 12. a) HC CMgBr, THF, 08C ! RT, 96 %; b) Ac2O, DMAP,
Et3N, 98%; c) AgBF4, DME, 76%; d) AuCl3 (5 mol%), 1,2-dichloro-
ethane; e) K2CO3, MeOH, dr 6.7:1, 74% (over two steps); f) LiAlH4,
THF, 08C ! RT, 60% (over two steps).
the desired compound 35 by any of the conventional meth-
ods, we chose to optimize this catalytic system further.
Amongst the host of metal salts screened,[47] AgBF4 led to
the exclusive formation of allene 34 which could be isolated
in 76% yield,[48,49] whereas the use of AuCl3 (5 mol%)[11] in
1,2-dichloroethane at ambient temperature showed by far
the best selectivity in favor of the desired carene framework.
Under these conditions, enol ester 35 was formed in excel-
lent yield and purity (ca. 95%), with only marginal amounts
of allenyl acetate 34 being detectable in the crude reaction
mixture. No cyclopropanation of the distal double bond of
33 was observed, thus showing that the cyclization of the
conceivable 10-membered ring does not compete with the
kinetically and thermodynamically more favorable forma-
tion of the sesquicarane skeleton during the AuCl3-catalyzed
process.
Since compound 35 is rather labile, it was immediately hy-
drolysed with K2CO3 in MeOH to give sesquicarone 36 as a
mixture of diastereomers (74%, > 96% pure by GC). It is
interesting to note that a reductive rather than hydrolytic
cleavage of the ester bond in 35 with LiAlH4 in THF afford-
ed the endo isomer of 36 exclusively, although in lower yield
(60% over cycloisomerization/reduction). The assignment of
the stereochemistry at the quarternary center of this com-
pound is based on the observed NOE data.
Scheme 11. Path II of the proposed cyclization mechanism is consistent
with the observed stereodivergent behavior of (R)- and (S)-26, whereas
path I assuming a vinyl carbene intermediate would imply a stereoconver-
gent course (the stereogenic center of the substrate marked * is planar-
ized before the chiral centers of the cyclopropane unit are generated, cf.
red label).
2-Sesquicarene: This successful implementation of the noble
metal catalyzed rearrangement spurred our efforts to im-
prove Ohloffꢀs original access to the carane skeleton[1] upon
replacement of ZnCl2 by a more appropriate catalyst.[15,42]
The results summarized in Schemes 12 and 13 are consis-
tent with this conjecture. Sesquicarene 39, a component of
the essential oil of the fruit Schisandra chinensis,[43] was
chosen as our initial target because this compound allows
one to address additional questions concerning the regiose-
lectivity of the skeletal rearrangement reaction.[44,45] The re-
quired propargyl acetate 33 was prepared by two routine op-
erations from commercial geranylacetone 31. Although ex-
posure of this substrate to catalytic amounts of PtCl2 in vari-
ous solvents resulted in the formation of the desired bicyclo-
[4.1.0]heptane skeleton 35 in decent yield [GC: 62%
(toluene), 86% (DME), 75% (1,2-dichloroethane), 48%
(MeCN)], allenyl acetate 34 formed by a competing [3,3]-
sigmatropic rearrangement[46] of the substrate was invariably
formed as a byproduct. Since 34 is difficult to separate from
Even though the conversion of ketone 36 into sesquicar-
ene 39 seems trivial, this step had been a major hurdle in
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previous syntheses of this target. It is reported in the litera-
ture that a variety of approaches is plagued by concomitant
cleavage of the cyclopropane ring even under seemingly
mild conditions. The “best” method turned out to be the py-
rolysis of the tosylhydrazone salts derived from ketone 36
which furnished a complex mixture from which the desired
product 39 could be obtained in only 15–22% yield by prep-
arative GC.[44a,b]
This unacceptable solution prompted us to reinvestigate
the transformation (Scheme 13). Two different approaches
were pursued: First, endo-36 was reduced with l-Selectride
ꢁ
Scheme 14. a) HC CMgBr, THF, 08C ! RT, 87 %; b) Ac2O, DMAP,
Et3N, 97%; c) AuCl3 (5 mol%), 1,2-dichloroethane, 98%; d) K2CO3,
MeOH, 60% (dr 5:1); e) LDA, THF, ꢀ788C, then N-(5-chloro-2-pyri-
dyl)bistrifluoromethanesulfonimide (Comins reagent), ꢀ788C ! RT; f)
[Pd(PPh3)4] cat., LiCl, Bu3SnH, THF, 608C, 45% (over two steps) (see
text).
Finally, the effect of the geometry of the reacting double
bond on the outcome of the intramolecular cyclopropana-
tion was investigated (Scheme 15). For this purpose, neryl-
Scheme 13. a) l-Selectride, THF, ꢀ788C ! RT, 93%; b) PPh3, DEAD,
THF, 70%; c) LDA, THF, ꢀ788C, then N-(2-pyridyl)bistriflimide, ꢀ788C
! RT; d) [Pd(PPh3)4] cat., LiCl, Et3SiH, THF, 608C, 74%.
to alcohol 37, which reacted with PPh3 and DEAD at ambi-
ent temperature to give sesquicarene 39 as the major prod-
uct (70%).[50] Although this method constitutes an improve-
ment over prior art, the isolation of this hydrocarbon prod-
uct in analytically pure form still required prep-GC. Gratify-
ingly, however, this cumbersome purification method could
be avoided upon conversion of sesquicarone 36 into enol tri-
flate 38 followed by palladium catalyzed reduction using
Et3SiH as the optimal hydride donor.[51,52] Under these con-
ditions, sesquicarene 39 was obtained in 74% yield in pure
form after routine flash chromatography of the crude reac-
tion mixture. Therefore it remains to conclude that the over-
all efficiency as well as the practicality of our new route to
2-sesquicarene 39 is far superior to that of the a-diazoke-
tone based approaches previously reported in the litera-
ture.[44]
ꢁ
Scheme 15. a) HC CMgBr, THF, 08C ! RT, 96 %; b) Ac2O, DMAP,
Et3N, 92%; c) AuCl3 (5 mol%), 1,2-dichloroethane; d) K2CO3, MeOH,
dr 4.5:1, 65% (over two steps); e) LDA, THF, ꢀ788C, then N-(5-chloro-
2-pyridyl)bistriflimide, ꢀ788C ! RT; f) [Pd(PPh3)4] cat., LiCl, Et3SiH,
THF, RT, 75% (over both steps).
acetone 45 was converted to propargyl acetate 47 on reac-
tion with ethynylmagnesium bromide followed by acetyla-
tion under standard conditions.[53] Treatment of compound
47 containing a (Z)-configured double bond in its backbone
with catalytic amounts of AuCl3 in 1,2-dichloroethane at am-
bient temperature afforded enol ester 48, which is isomeric
at C-7 to product 35 derived from the geranyl series
(Scheme 12). Therefore it must be concluded that the Au-
catalyzed skeletal rearrangement proceeds stereospecifically,
translating the configuration of the reacting alkene into the
stereochemistry of the emerging cyclopropane unit. Com-
pound 48 could then be converted into episesquicarene 51
by the established route via ketone 49 and the enol triflate
50 derived thereof.[54]
2-Carene and episesquicarene: In view of the foregoing, it
comes as no surprise that the truncated substrate 1 cyclized
equally effectively in the presence of AuCl3 (5 mol%), af-
fording carenyl acetate
3 in almost quantitative yield
(Scheme 14). This exemplifies that the change of the catalyst
from ZnCl2 originally used by Ohloff[1] to the soft and car-
bophilic AuIII cation upgrades the cycloisomerization proc-
ess from a minor side reaction to an exquisitely productive
yet user-friendly method. Conversion of enol acetate 3 to 2-
carene 44 essentially followed the sequence outlined above.
The fact that the final palladium-catalyzed reduction of enol
triflate 43 gave only 45% isolated yield is mainly due to the
volatility of the resulting hydrocarbon.
Chem. Eur. J. 2006, 12, 3006 – 3019
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3011

A. Fürstner and P. Hannen
Conclusion
Experimental Section
General: All reactions were carried out under Ar in flame-dried glass-
ware. The solvents used were purified by distillation over the drying
agents indicated and were transferred under Ar: THF, Et2O (Mg/anthra-
cene), CH2Cl2, 1,2-dichloroethane (P4O10), MeCN, Et3N, NMP (CaH2),
MeOH, iPrOH (Mg), hexane, benzene, toluene (Na/K). Flash chromatog-
raphy: Merck silica gel 60 (230–400 mesh). NMR: Spectra were recorded
on a Bruker DPX 300 or AV 400 spectrometer in the solvents indicated;
chemical shifts (d) are given in ppm relative to TMS, coupling constants
(J) in Hz. The solvent signals were used as references and the chemical
The results outlined above highlight the remarkable catalyt-
ic reactivity of late transition metal cations such as PtII or
AuIII for fully atom economical and complexity-inducing cy-
cloisomerization reactions that can be applied with confi-
dence in natural product synthesis. Although some empirical
optimization of the catalyst system is mandatory, propargyl
acetates in general can be viewed as synthetic equivalents of
a-diazoketones for intramolecular cyclopropanation process-
es; thereby, the reacting olefin can be mono-, di- or even tri-
substituted. Comparison of the cyclization of the geranyl de-
rived substrate 33 with the analogous compound 47 belong-
ing to the neryl series reveals that the cycloisomerization
proceeds stereospecifically, translating the geometry of the
reacting double bond to the configuration of the resulting
cyclopropane derivative. At the same time, these examples
show that proximal alkenes react selectively in the presence
of distal alkenes with the same degree of substitution. In
contrast to this flexibility with respect to the reacting olefin,
the methodology is presently limited to propargylic sub-
strates of terminal alkynes. This is evident from the exam-
ples compiled in Scheme 16, amongst which the terminal
acetylene derivative 52 is the only substrate to convert to
the corresponding bicyclo[4.1.0]heptane 53[4b] under the
chosen reaction conditions.
ꢁ
shifts converted to the TMS scale (CDCl3: dC 77.0 ppm; residual CHCl3
ꢁ
ꢁ
in CDCl3: dH
7.24 ppm; CD2Cl2: dC
53.8 ppm; residual CH2Cl2 in
ꢁ
CD2Cl2: dH 5.32 ppm). Where indicated, the signal assignments are un-
ambiguous; the numbering scheme is arbitrary and is shown in the in-
serts. The assignments are based upon 1D and 2D spectra recorded using
the following pulse sequences from the Bruker standard pulse program li-
brary: DEPT; COSY (cosygs and cosydqtp); HSQC (invietgssi) opti-
mized for 1J(C,H)=145 Hz; HMBC (inv4gslplrnd) for correlations via
nJ(C,H); HSQC-TOCSY (invietgsml) using an MLEV17 mixing time of
120 ms. IR: Nicolet FT-7199 spectrometer, wavenumbers (n˜) in cmꢀ1. MS
(EI): Finnigan MAT 8200 (70 eV), ESI-MS: Finnigan MAT 95, accurate
mass determinations: Bruker APEX III FT-MS (7 T magnet). Melting
points: Büchi melting point apparatus B-540 (corrected). Elemental anal-
yses: H. Kolbe, Mülheim/Ruhr. All commercially available compounds
(Fluka, Lancaster, Aldrich) were used as received.
Cubebene series
(+)-(2R,5R)-5-Isopropyl-2-methylcyclohexanone
[(+)-carvomenthone,
17]: An autoclave was charged with a solution of (ꢀ)-(R)-carvone (15)
(4.0 g, 26.6 mmol) and [Rh(PPh3)3Cl] (246 mg, 0.266 mmol) in benzene
(25 mL) and the resulting solution was stirred for 40 h at 258C under an
atmosphere of H2 (3 atm). After venting the autoclave, the solvent was
evaporated and the residue was purified by flash chromatography (hex-
anes/ethyl acetate 10:1) to give product 16 as a colorless liquid (3.95 g,
98%). To a solution of this product in MeOH (40 mL) was added Pd/C
(195 mg, 5%) and the resulting suspension was stirred for 6 h under H2
(1 atm). Filtration over a pad of silica gel and evaporation of the filtrate
yielded product 17 as a 1:1 mixture of diastereomers (3.81 g, 96%). Equi-
libration was effected by stirring a solution of this mixture in MeOH
(15 mL) in the presence of NaOMe (267 mg, 4.94 mmol) for 30 min, fur-
nishing the desired trans-isomer as a colorless liquid after standard work
up (3.42 g, 90%, dr ꢂ 90:10). [a]D23
=
+13.48 (c=3, EtOH); 1H NMR
(400 MHz, CDCl3): d=2.39 (ddd, J=2.3, 3.4, 13.0 Hz, 1H), 2.31 (dddd,
J=1.2, 6.4, 13.1, 13.1 Hz, 1H), 2.06 (m, 2H), 1.85 (dddd, J=2.8, 2.8, 5.4,
12.4 Hz, 1H), 1.55 (m, 2H), 1.42 (m, 1H), 1.29 (ddd, J=3.3, 12.8,
15.6 Hz, 1H), 1.01 (d, J=6.5 Hz, 3H), 0.90 (d, J=4.2 Hz, 3H), 0.88 (d,
J=4.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=212.7, 45.7, 44.5, 44.1,
34.3, 31.9, 28.1, 18.7, 18.5, 13.5; IR (KAP): n˜ =2960, 2931, 2871, 1710,
1455, 1428, 1387, 1368, 1315, 1240, 1220, 1197, 1127 cmꢀ1
.
Scheme 16. Present limitations of PtCl2-catalyzed cycloisomerizations:
Effect of the substituent on the alkyne moiety.
(3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl-trifluoromethanesulfonate
(18): nBuLi (1.55m in hexanes, 5.02 mL, 7.78 mmol) was added dropwise
to 2,2,6,6-tetramethylpiperidine (1.42 mL, 8.43 mmol) in THF (15 mL) at
08C and the resulting solution was stirred for 30 min before it was cooled
to ꢀ788C and a solution of carvomenthone 17 (1.0 g, 6.48 mmol) in THF
(7 mL) was added dropwise with a syringe pump. After stirring for 2 h at
ꢀ788C, a chilled solution of N-(5-chloro-2-pyridyl)bistriflimide (3.05 g,
7.78 mmol) in THF (15 mL) was introduced and the resulting mixture
was allowed to reach ambient temperature over the course of 2 h. For
work up, the solvent was evaporated and the residue purified by flash
The preparative data obtained during this total synthesis
campaign, which led to 2-carene, sesquicarene, episesquicar-
ene, cubebol, a-cubebene, b-cubebene and 4-epicubebol,
also shed light onto the mechanism of noble metal catalyzed
cycloisomerizations in general. Not only do they confirm
previous mechanistic assumptions implying electrophilic car-
benes as key intermediates, but also provide more detailed
information concerning the individual steps by which such
reactive species might form and evolve. This growing mech-
anistic understanding guides our ongoing investigations on
the use of noble metal salts as selective “p-acidic” catalysts
for a host of skeletal rearrangement reactions.[5,8,10]
chromatography (pentane) yielding product 18 as
a colorless liquid
(1.61 g, 87%). [a]D20 +418 (c=1.2, CH2Cl2); 1H NMR (300 MHz,
=
CDCl3): d=5.64 (s, 1H), 2.51 (m, 1H), 2.15 (m, 1H), 2.01 (td, J=5.5,
10.6 Hz, 1H), 1.68 (m, 2H), 1.32 (m, 2H), 1.12 (d, J=6.9 Hz, 3H), 0.90
(d, J=6.8 Hz, 3H), 0.898 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=153.6, 122.0, 118.7 (q, JCF =318 Hz), 42.3, 33.2, 32.1, 32.0,
24.1, 19.5, 19.4, 18.0; IR (KAP): n˜ =2963, 2940, 2876, 1677, 1415, 1246,
1201, 1141, 1048, 1027, 1008, 938, 894, 875, 861, 828 cmꢀ1; MS (EI): m/z
(%): 286 (10) [M +], 243 (64), 153 (7), 113 (16), 93 (100), 69 (36), 55 (22),
3012
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3006 – 3019

Natural Products
FULL PAPER
41 (36); elemental analysis calcd (%) for C11H17F3O3S (286.31): C 46.14,
H 5.98; found: C 46.08, H 6.04.
THF (15 mL) at ꢀ788C. After stirring for 30 min, the resulting solution
of 2-trimethylsilylethynyllithium was transferred via cannula to the CeCl3
suspension, which was previously cooled to ꢀ788C. The resulting mixture
(3S,6R)-3-Isopropyl-6-methyl-1-vinylcyclohex-1-ene (19):
A suspension
was stirred for 30 min before
a solution of aldehyde 21 (562 mg,
of [Pd(PPh3)4] (307 mg, 0.265 mmol) and LiCl (675 mg, 15.93 mmol) in
THF (12 mL) was stirred for 10 min before a solution of triflate 18
(1.52 g, 5.31 mmol) and tributyl(vinyl)stannane (1.55 mL, 5.31 mmol) in
THF (4 mL) was added. The mixture was refluxed for 4 h, diluted with
pentane and poured onto sat. aq. NH4Cl and 10% aq. NH3. After stirring
for 30 min, the organic phase was washed with water and brine before
being dried over Na2SO4. The solvent was evaporated and the residue pu-
rified by flash chromatography (hexanes) to yield the desired product as
3.12 mmol) in THF (20 mL) was added dropwise. After stirring for 2.5 h
at that temperature, excess alkynylcerium dichloride was quenched by
addition of sat. aq. NH4Cl. The mixture was warmed to ambient tempera-
ture and the precipitate dissolved by addition of aq. HCl (1m). Standard
extractive work up followed by purification of the crude product by flash
chromatography (hexanes/ethyl acetate gradient, max. 15% ethyl ace-
tate) gave compound 22 as a colorless oil (803 mg, 93%, dr 65:35). See
below for a compilation of the physical data of the individual isomers.
a
colorless liquid (737 mg, 85%). [a]D20
= +172.38 (c=2, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=6.25 (ddd, J=0.4, 10.9, 17.7 Hz, 1H),
5.69 (d, J=3.4 Hz, 1H), 5.11 (d, J=17.7 Hz, 1H), 4.94 (d, J=11.0 Hz,
1H), 2.50 (m, 1H), 1.93 (m, 1H), 1.81 (m, 1H), 1.71 (m, 1H), 1.61 (dddd,
J=6.7, 6.7, 6.7, 13.4 Hz, 1H), 1.35 (m, 2H), 1.08 (d, J=7.0 Hz, 1H), 0.93
(d, J=6.8 Hz, 1H), 0.89 (d, J=6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=141.6, 139.5, 132.5, 110.8, 41.7, 32.7, 29.7, 28.7, 22.3, 20.5,
20.37, 20.35; IR (KAP): n˜ =2957, 2927, 2871, 1635, 1600, 1462, 1384,
1367, 1164, 1113, 989, 892 cmꢀ1; MS (EI): m/z (%): 164 (29) [M +], 121
(100), 93 (69), 79 (43), 55 (26), 41 (22); elemental analysis calcd (%) for
C12H20 (164.29): C 87.73, H 12.27; found: C 87.64, H 12.22.
1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)-4-(trimethyl-silyl)but-3-
yn-2-one (24): Dess–Martin periodinane (1.36 g, 3.2 mmol) was added in
portions at 08C to a solution of alcohol 22 (810 mg, 2.90 mmol) in
CH2Cl2 (30 mL) and the resulting mixture was stirred at ambient temper-
ature for 1 h. For work up, the mixture was diluted with pentane, the pre-
cipitates were filtered through a pad of silica gel (pentane/tert-butyl
methyl ether 4:1), the filtrate was evaporated and the residue purified by
flash chromatography (hexanes/ethyl acetate gradient, max. 10% ethyl
acetate), yielding ketone 24 as a yellow liquid (753 mg, 94%). [a]D20
=
+105.58 (c=1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.50 (s, 1H),
3.29 (ddd, J=1.2, 1.2, 14.8 Hz, 1H), 3.11 (dd, J=0.5, 14.8 Hz, 1H), 2.18
(m, 1H), 1.97 (m, 1H), 1.84 (m, 1H), 1.64 (m, 2H), 1.25 (m, 2H), 0.97
(d, J=7.0 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.22
(s, 9H); 13C NMR (100 MHz, CDCl3): d=186.6, 134.9, 132.5, 102.2, 98.0,
51.8, 42.6, 32.9, 32.5, 32.2, 24.4, 20.0, 19.7, 19.6, ꢀ0.6; IR (KAP): n˜ =
2-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)ethanol (20): A solution
of diene 19 (765 mg, 4.66 mol) in THF (12 mL) was added to a solution
of 9-BBN (568 mg, 2.33 mmol) in THF (30 mL) and the resulting mixture
stirred for 2 h at ambient temperature. The reaction was quenched at
08C by successive addition of aq. NaOH (3m, 1.9 mL) and aq. H2O2
(30%, 1.6 mL) and the resulting mixture was stirred for 12 h before it
was diluted with tert-butyl methyl ether and water. Upon acidification
with 10% aq. HCl, the precipitate dissolved and the water phase was ex-
tracted with tert-butyl methyl ether. The combined organic layers were
washed with brine and dried over Na2SO4. Evaporation of the solvent fol-
lowed by purification of the crude product by flash chromatography (hex-
anes/ethyl acetate gradient, max. 35% ethyl acetate) gave compound 20
2957, 2929, 2872, 1674, 1462, 1368, 1251, 1220, 1110, 1089, 842, 760 cmꢀ1
;
MS (EI): m/z (%): 276 (5) [M +], 261 (36), 234 (31), 191 (27), 136 (22),
125 (100), 97 (34), 95 (45), 93 (45), 73 (63); elemental analysis calcd (%)
for C17H28OSi (276.49): C 73.85, H 10.21; found: C 73.89, H 10.15.
(S)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)-4-(trimethylsilyl)-
but-3-yn-2-ol [(S)-22]:
A degassed solution of ketone 24 (200 mg,
0.723 mmol) in iPrOH (3 mL) was added to a degassed solution of
[(1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylene-diamine-Ru-h6-p-cyme-
ne] [(S,S)-25] (22 mg, 0.036 mmol)[32] in iPrOH (4 mL) and the resulting
mixture was stirred for 4 h. Evaporation of the solvent followed by flash
chromatography (hexane/ethyl acetate 20:1) of the crude product afford-
ed alcohol (S)-22 as a yellow oil (189 mg, 94%, dr 82:18). Careful chro-
matography provided a sample of diastereomerically pure product in
as
a = +39.38 (c=1, CH2Cl2);
colorless oil (737 mg, 87%). [a]D20
1H NMR (300 MHz, CDCl3): d=5.39 (s, 1H), 3.63 (m, 2H), 2.42 (m,
1H), 2.17 (ddd, J=4.1, 7.8, 15.0 Hz, 1H), 2.10 (m, 1H), 1.92 (m, 1H),
1.84 (ddd, J=5.5, 5.5, 10.8 Hz, 1H), 1.65 (m, 1H), 1.55 (m, 2H), 1.21 (m,
2H), 0.99 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=138.4, 128.9, 60.6, 42.4, 38.2, 32.4,
32.2, 32.17, 24.8, 20.0, 19.5, 19.1; IR (KAP): n˜ = 3336, 2955, 2928, 2871,
1462, 1444, 1384, 1367, 1039, 1015, 848 cmꢀ1; MS (EI): m/z (%): 182 (35)
[M +], 139 (71), 121 (90), 93 (100), 79 (58), 67 (24), 55 (26), 41 (39); ele-
mental analysis calcd (%) for C12H22O (182.30): C 79.06, H 12.16; found:
C 79.13, H 12.07.
about 60% yield. [a]D20
=
ꢀ5.38 (c=1, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.48 (s, 1H), 4.37 (dd, J=4.8, 9.3 Hz, 1H), 2.64 (m, 1H), 2.27
(dd, J=9.3, 14.0 Hz, 1H), 2.13 (m, 1H), 1.94 (m, 2H), 1.84 (m, 1H), 1.66
(m, 1H), 1.57 (dddd, J=6.8, 12.4, 12.4, 12.4 Hz, 1H), 1.21 (m, 2H), 1.01
(d, J=7.0 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.17
(s, 9H); 13C NMR (100 MHz, CDCl3): d=137.5, 131.0, 106.7, 89.1, 60.6,
43.8, 42.4, 32.4, 32.1, 31.9, 24.6, 20.0, 19.8, 19.6, 0.0; IR (KAP): n˜ = 3349,
2956, 2928, 2871, 1462, 1443, 1385, 1367, 1249, 1054, 1031, 1012, 894, 838,
759, 735, 698 cmꢀ1; MS (EI): m/z (%): 278 (1) [M +], 173 (13), 145 (12),
109 (100), 99 (22), 95 (59), 81 (19), 73 (43), 43 (14); elemental analysis
calcd (%) for C17H30OSi (278.51): C 73.31, H 10.86; found: C 73.46, H
10.77.
2-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)acetaldehyde (21): A sol-
ution of alcohol 20 (722 mg, 3.96 mmol) in CH2Cl2 (10 mL) was added to
a solution of Dess–Martin periodinane (1.85 g, 4.36 mmol) in CH2Cl2
(20 mL). After stirring for 1.5 h, the mixture was diluted with pentane
before it was filtered through a plug of silica gel (pentane/tert-butyl
methyl ether 4:1). The filtrate was evaporated and the residue purified
by flash chromatography (hexanes/ethyl acetate 20:1) to give product 21
as a colorless liquid (611 mg, 86%). [a]D20
= +99.48 (c=1, CH2Cl2);
(R)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)-4-(trimethylsilyl)-
but-3-yn-2-ol [(R)-22]: Prepared analogously using the enantiomeric cat-
alyst (R,R)-25. Pale yellow oil (18.6 mg, 93%, dr 85:15). An analytically
pure sample (dr > 95:5) was obtained by careful chromatography. [a]D20
1H NMR (300 MHz, CDCl3): d=9.58 (t, J=2.7 Hz, 1H), 5.45 (d, J=
0.7 Hz, 1H), 3.10 (m, 1H), 2.96 (ddd, J=0.9, 2.4, 15.6 Hz, 1H), 2.10 (m,
1H), 2.00 (m, 1H), 1.86 (m, 1H), 1.67 (m, 1H), 1.58 (ddd, J=6.8, 12.5,
13.5 Hz, 1H), 1.24 (m, 2H), 0.96 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.8 Hz,
3H), 0.86 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=201.1,
133.8, 132.0, 50.2, 42.6, 33.5, 32.3, 32.1, 24.6, 19.8, 19.7, 19.5; IR (KAP):
n˜ = 2956, 2929, 2872, 1724, 1461, 1385, 1368, 1043 cmꢀ1; MS (EI): m/z
(%): 180 (8) [M +], 136 (23), 95 (16), 93 (100), 81 (10), 67 (13), 55 (9), 41
(19); elemental analysis calcd (%) for C12H20O (180.29): C 79.94, H
11.18; found: C 79.86, H 11.09.
=
+56.28 (c=0.93, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.46 (s,
1H), 4.44 (dd, J=5.3, 7.4 Hz, 1H), 2.62 (m, 1H), 2.27 (dd, J=7.4,
13.7 Hz, 1H), 2.25 (m, 1H), 1.94 (m, 2H), 1.84 (m, 1H), 1.67 (m, 1H),
1.57 (dddd, J=6.8, 12.4, 12.4, 12.4 Hz, 1H), 1.22 (m, 2H), 1.02 (d, J=
7.0 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.15 (s,
9H); 13C NMR (100 MHz, CDCl3): d=137.4, 130.7, 106.9, 89.4, 61.5, 43.0,
42.5, 32.9, 32.5, 32.3, 24.7, 20.1, 20.0, 19.7, ꢀ0.03; IR (KAP): n˜ = 3310,
2956, 2927, 2872, 1460, 1444, 1382, 1367, 1249, 1040, 1013, 894, 839, 759,
734, 698 cmꢀ1; MS (EI): m/z (%): 278 (1) [M +], 217 (12), 173 (10), 145
(11), 136 (11), 109 (100), 99 (22), 95 (58), 73 (43), 43 (19); elemental
analysis calcd (%) for C17H30OSi (278.51): C 73.31, H 10.86; found: C
73.26, H 10.81.
1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)-4-(trimethyl-silyl)but-3-
yn-2-ol (22): A suspension of dry CeCl3 (1.61 g, 6.54 mmol) in THF
(15 mL) was stirred at ambient temperature for 16 h. In another Schlenk
flask, a solution of nBuLi (1.7m in hexanes, 3.12 mL, 5.30 mmol) was
added to a solution of trimethylsilylacetylene (0.793 mL, 5.61 mmol) in
Chem. Eur. J. 2006, 12, 3006 – 3019
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3013

A. Fürstner and P. Hannen
(S)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)but-3-yn-2-ol
[(S)-
work up, the solvent was evaporated and the residue purified by flash
23]: TBAF (1m in THF, 0.66 mL, 0.66 mmol) was added at 08C to a solu-
tion of (S)-22 (154 mg, 0.55 mmol) in THF (4 mL) and the resulting mix-
ture was stirred for 1 h. After dilution with tert-butyl methyl ether, the or-
ganic phase was washed with water and brine before it was dried over
Na2SO4. Evaporation of the solvent followed by flash chromatography
(hexanes/ethyl acetate 10:1) gave the title compound as a yellow liquid
(102 mg, 89%). [a]2D0 = ꢀ13.18 (c=1.05, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.49 (s, 1H), 4.38 (ddd, J=2.1, 4.4, 9.5 Hz, 1H), 2.67 (m,
1H), 2.44 (d, J=2.1 Hz, 1H), 2.28 (dd, J=9.6, 14.1 Hz, 1H), 1.23 (m,
1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.66 (m, 1H), 1.58 (dddd, J=6.8, 12.3,
12.2, 12.2 Hz, 1H), 1.23 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.88 (d, J=
6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
137.2, 131.2, 84.9, 72.7, 59.8, 43.8, 42.5, 32.3, 32.1, 31.8, 24.6, 20.0, 19.8,
19.5; IR (KAP): n˜ = 3411, 3311, 2955, 2927, 2871, 1462, 1443, 1385, 1367,
1297, 1255, 1029, 836 cmꢀ1; MS (EI): m/z (%): 206 (15) [M +], 163 (52),
135 (52), 107 (43), 93 (100), 79 (97), 67 (50), 55 (62), 41 (68).
chromatography (hexanes/ethyl acetate 20:1) to give product 27 as a
yellow oil (92 mg, 92%). [a]D20
=
ꢀ2.88 (c=0.74, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=4.98 (t, J=2.2 Hz, 1H), 2.53 (dd, J=2.1, 17.0 Hz,
1H), 2.20 (td, J=2.7, 17.0 Hz, 1H), 2.14 (s, 3H), 1.79 (sept, J=2 Hz,
1H), 1.62 (m, 1H), 1.60 (m, 1H), 1.40 (ddd, J=2.5, 4.8, 5.1 Hz, 1H), 1.36
(dd, J=2.6, 5.7 Hz, 1H), 1.10 (m, 1H), 0.96 (d, J=6.2 Hz, 3H), 0.95 (d,
J=6.5 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.85 (m, 1H), 0.61 (t, J=2.8 Hz,
1H), 0.51 (m, 1H); 13C NMR (100 MHz, CDCl3): d=168.6, 154.9, 108.1,
43.8, 36.0, 34.3, 33.5, 32.6, 31.4, 31.2, 30.4, 26.3, 21.2, 20.0, 19.7, 19.6; IR
(KAP): n˜ = 2956, 2926, 2870, 2852, 1763, 1649, 1458, 1368, 1202, 1161,
1141 cmꢀ1; MS (EI): m/z (%): 248 (16) [M +], 206 (86), 163 (100), 152
(18), 121 (57), 107 (39), 93 (17), 55 (33), 43 (45); HRMS (ESI): m/z:
calcd for C16H24O2+Na: 271.1666, found 271.1668 [M ++Na].
(ꢀ)-(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyl-tricyclo[4.4.0.01,5]decane-
4-one (11): K2CO3 (60 mg, 0.43 mmol) was added to a solution of enol
ester 27 (214 mg, 0.86 mmol) in
(R)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)but-3-yn-2-ol [(R)-
23]: Prepared analogously from (R)-22 as a pale yellow oil (89 mg, 88%).
[a]2D0 = +65.68 (c=1.05, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=5.46
(s, 1H), 4.47 (ddd, J=2.1, 5.7, 7.7 Hz, 1H), 2.64 (m, 1H), 2.42 (d, J=
2.0 Hz, 1H), 2.29 (dd, J=7.4, 13.6 Hz, 1H), 2.19 (m, 1H), 1.93 (m, 2H),
1.84 (m, 1H), 1.65 (m, 1H), 1.59 (ddd, J=4.9, 10.2, 13.5 Hz, 1H), 1.22
(m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H), 0.87 (d, J=
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=137.2, 130.7, 84.9, 73.2, 61.1,
43.2, 42.4, 32.8, 32.4, 32.3, 24.5, 20.0, 19.8, 19.5; IR (KAP): n˜ = 3362,
3311, 2955, 2927, 2871, 1462, 1443, 1385, 1367, 1260, 1037, 1014 cmꢀ1; MS
(EI): m/z (%): 206 (12) [M +], 191 (12), 173 (13), 163 (21), 145 (44), 109
(46), 95 (100), 81 (36), 67 (37), 55 (49), 41 (45); elemental analysis calcd
(%) for C14H22O (206.32): C 81.50, H 10.75; found: C 81.37, H 10.65.
MeOH (4 mL). After stirring for
45 min, the mixture was diluted with
tert-butyl methyl ether and water.
Standard extractive work up followed
by flash chromatography (hexanes/
ethyl acetate 20:1) gave ketone 11 as a
yellow oil which slowly crystallized
upon standing (135 mg, 76%). M.p.
58.5–608C (ref.:[24c] 57–588C); [a]2D0
=
ꢀ21.88 (c=0.72, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=2.12 (m, 1H, H-8a), 2.10 (m, 1H, H-7a), 2.00 (m,
1H, H-8b), 1.797 (d(qi), J=6.0, 12.0 Hz, 1H, H-5), 1.796 (m, 1H, H-7b),
1.63 (dddd, J=2.4, 4.8, 5.2, 13.6 Hz, 1H, H-4a), 1.61 (oct, J=6.6 Hz, 1H,
H-11), 1.455 (d, J=2.7 Hz, 1H, H-10), 1.45 (ddt, J=2.4, 4.7, 4.7, 12.8 Hz,
1H, H-3a), 1.23 (t, J=2.6 Hz, 1H, H-1), 1.15 (dddd, J=2.6, 4.8, 6.0,
12.8 Hz, 1H, H-2), 0.95 (d, J=6.6 Hz, 3H, H-14), 0.92 (ddt, J=2.4, 12.8,
12.8, 13.2 Hz, 1H, H-3b), 0.91 (d, J=6.8 Hz, 3H, H-12), 0.88 (d, J=
6.8 Hz, 3H, H-13), 0.55 (ddt, J=2.4, 11.4, 13.2, 13.2 Hz, 1H, H-4b);
13C NMR (100 MHz, CDCl3): d=214.4 (C-9), 43.3 (C-2), 40.3 (C-6), 39.7
(C-10), 33.3 (C-8), 33.2 (C-11), 32.5 (C-1), 31.3 (C-5), 30.8 (C-4), 26.6 (C-
7), 26.0 (C-3), 19.9 (C-12), 19.4 (C-13), 18.9 (C-14); IR (KAP): n˜ = 2947,
2926, 2889, 2859, 1707, 1455, 1249, 1185, 912 cmꢀ1; MS (EI): m/z (%): 206
(97) [M +], 191 (20), 164 (99), 149 (36), 135 (23), 122 (100), 110 (46), 93
(61), 79 (69), 69 (30), 55 (62), 41 (68); HRMS (ESI): m/z: calcd for
C14H22O+Na: 229.1563, found 229.1563 [M ++Na].
(S)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)but-3-yn-2-yl acetate
[(S)-26]: DMAP (127 mg, 1.04 mmol), acetic anhydride (0.295 mL,
3.13 mmol) and Et3N (0.439 mL, 3.13 mmol) were successively added to a
solution of (S)-23 (215 mg, 1.04 mmol) in CH2Cl2 (10 mL). The reaction
mixture was stirred for 40 min before it was diluted with tert-butyl
methyl ether and poured onto ice water. The aqueous phase was repeat-
edly extracted with tert-butyl methyl ether, the combined organic phases
were washed with brine, dried over Na2SO4 and evaporated. Purification
of the residue by flash chromatography (hexanes/ethyl acetate 20:1)
yielded product (S)-26 as a colorless liquid (241 mg, 93%). [a]D20
=
ꢀ25.28 (c=1, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=5.47 (ddd, J=
2.2, 4.8, 9.1 Hz, 1H), 5.41 (s, 1H), 2.63 (m, 1H), 2.43 (d, J=2.1 Hz, 1H),
2.38 (m, 1H), 2.14 (m, 1H), 2.04 (s, 3H), 1.91 (m, 1H), 1.82 (ddd, J=5.7,
5.7, 9.9 Hz, 1H), 1.57 (m, 2H), 1.18 (m, 2H), 0.99 (d, J=6.9 Hz, 3H),
0.87 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=170.0, 136.4, 130.5, 81.8, 73.4, 62.0, 42.4, 40.9, 32.4, 32.1, 31.8,
24.4, 21.1, 20.0, 19.8, 19.4; IR (KAP): n˜ = 3302, 3288, 2956, 2929, 2871,
1741, 1462, 1444, 1431, 1368, 1227, 1024 cmꢀ1; MS (EI): m/z (%): 248
(0.5) [M +], 188 (22), 173 (21), 145 (100), 117 (25), 105 (20), 95 (26), 43
(88); elemental analysis calcd (%) for C16H24O2 (248.36): C 77.38, H 9.74;
found: C 77.45, H 9.71.
(1S,5S,6S,7S,10R)-7-Isopropyl-10-methyl-tricyclo[4.4.0.01,5]decane-4-one
(30): Prepared analogously; the pure compound was isolated from the
mixture of isomeric products by preparative HPLC. 1H NMR (400 MHz,
CDCl3): d=2.10 (m, 1H, H-7a), 2.06
(m, 1H, H-8a), 2.01 (m, 1H, H-7b),
1.98 (m, 1H, H-8b), 1.93 (d(dq), J=
6.2, 6.8, 10.2 Hz, 1H, H-5), 1.59 (m,
1H, H-4), 1.57 (dt, J=3.2, 3.6 Hz, 1H,
H-1), 1.565 (m, 1H, H-3), 1.555 (t, J=
3.2 Hz, 1H, H-10), 1.545 (m, 1H, H-
2), 1.40 (m, 1H, H-11), 1.09 (d, J=
7.1 Hz, 3H, H-14), 0.95 (m, 1H, H-4),
(R)-1-((3S,6R)-3-Isopropyl-6-methylcyclohex-1-enyl)but-3-yn-2-yl-acetate
[(R)-26]: Prepared analogously from (R)-23 as a colorless oil (63 mg,
81%). [a]2D0
=
+788 (c=1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
0.92 (d, J=6.6 Hz, 3H, H-12), 0.89 (d, J=6.6 Hz, 3H, H-13), 0.72 (m,
1H, H-3); 13C NMR (100 MHz, CDCl3): d=215.2 (C-9), 40.5 (C-2), 37.6
(C-6), 37.5 (C-10), 33.0 (C-8), 32.8 (C-11), 32.2 (C-1), 32.1 (C-4), 30.7 (C-
5), 26.8 (C-7), 23.1 (C-3), 20.7 (C-12), 20.5 (C-13), 18.7 (C-14).
5.45 (dd, J=2.4, 6 Hz, 1H), 5.43 (dd, J=2.4, 6 Hz, 1H), 2.63 (ddt, J=1.2,
6.0, 13.6 Hz, 1H), 2.41 (d, J=2 Hz, 1H), 2.32 (dd, J=8.9, 13.4 Hz, 1H),
2.12 (m, 1H), 2.07 (s, 3H), 1.92 (m, 1H), 1.84 (m, 1H), 1.61 (m, 1H),
1.58 (m, 1H), 1.20 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.8 Hz,
3H), 0.85 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.0,
136.4, 130.4, 81.3, 63.2, 42.4, 40.5, 32.4, 32.3, 24.4, 21.2, 19.9, 19.8, 19.4; IR
(KAP): n˜ = 3312, 2956, 2928, 2872, 1740, 1463, 1443, 1370, 1227, 1021,
960 cmꢀ1; MS (EI): m/z (%): 248 (0.7) [M +], 188 (21), 173 (21), 145
(100), 117 (26), 105 (21), 95 (28), 43 (80); HRMS (ESI): m/z: calcd for
C16H24O2+Na: 271.1666, found 271.1668 [M ++Na].
(ꢀ)-(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyl-tricyclo[4.4.0.01,5]dec-3,4-
en-4-yl-acetate (27): A solution of (S)-26 (100 mg, 0.403 mmol) in toluene
(3 mL) was added to a suspension of PtCl2 (2.1 mg, 0.0081 mmol) in tol-
uene (1 mL) and the resulting mixture was stirred at 808C for 3 h. For
(ꢀ)-(1R,4S,5R,6R,7S,10R)-7-Isopropyl-4,10-dimethyl-tricy-
clo[4.4.0.01,5]decane-4-ol [(ꢀ)-cubebol, 6]: A suspension of CeCl3 (50 mg,
0.204 mmol) in THF (1 mL) was stirred
for 16 h at ambient temperature before
MeLi (1.6m in Et2O, 0.118 mL,
0.189 mmol) was added at ꢀ788C.
After 30 min, a solution of ketone 11
(30 mg, 0.145 mmol) in THF (1 mL)
was added dropwise. Stirring was con-
tinued for 45 min before the reaction
3014
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3006 – 3019

Natural Products
FULL PAPER
was quenched by addition of aq. sat. NH4Cl and warmed to room temper-
ature. Standard extractive work up followed by purification of the crude
product by flash chromatography yielded cubebol 6 as a colorless solid
(29.2 mg, 91%). M.p. 59–60.48C (ref.:[24c] 61–628C); [a]D20 = ꢀ518 (c=1,
Carene series
3,7-Dimethyloct-6-en-1-yn-3-ol (41):
A solution of ethynylmagnesium
bromide (0.5m in THF, 10 mL, 5 mmol) was added to a solution of 6-
methyl-5-hepten-2-one (40) (428 mg, 3.39 mmol) in THF (10 mL) at
ꢀ788C. The resulting mixture was allowed to reach ambient temperature
and was stirred for 1 h. After quenching with aq. sat KHSO4, the aqueous
phase was repeatedly extracted with tert-butyl methyl ether, the com-
bined organic layers were washed with brine and dried over Na2SO4
before being concentrated. Purification of the residue by flash chroma-
tography (pentane/diethyl ether 6:1) gave product 41 as a yellow liquid
(447 mg, 87%). 1H NMR (300 MHz, CDCl3): d=5.17 (ddd, J=1.4, 2.8,
8.1 Hz, 1H), 2.46 (s, 1H), 2.27 (ddd, J=7.8, 14.7, 21.5 Hz, 1H), 2.19 (ddd,
J=7.3, 13.8, 21.9 Hz, 1H), 2.07 (s, 1H), 1.70 (t, J=7.6 Hz, 1H), 1.69 (t,
J=10.8 Hz, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.50 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=132.7, 123.8, 87.7, 71.6, 68.4, 43.3, 30.0, 25.8, 23.7,
17.9; IR (KAP): n˜ = 3400, 3307, 2972, 2938, 2856, 1740, 1449, 1375, 1119,
1083, 907 cmꢀ1; MS (EI): m/z (%): 137 (41), 119 (84), 109 (18), 91 (36),
69 (99), 55 (74), 41 (100); HRMS (CI): m/z: calcd for C10H16O: 153.1279;
found: 153.1281 [M ++H].
CHCl3) [[a]2D0
=
ꢀ48.38 (c=3.52, CHCl3)];[24c] 1H NMR (400 MHz,
CDCl3): d=1.82 (ddd, J=8.6, 11.6, 12.6 Hz, 1H, H-7a), 1.63 (d(quint.),
J=6.2, 11.4 Hz, 1H, H-5), 1.60 (oct., J=6.8 Hz, 1H, H-11), 1.57 (dddd,
J=2.2, 4.6, 5.2, 13.6 Hz, 1H, H-4a), 1.51 (ddt, J=0.8, 8.8, 13.2 Hz,
1H, H-8a), 1.50 (ddd, J=0.8, 8.6, 12.6 Hz, 1H, H-7b), 1.42 (s, 1H,
H-16), 1.36 (ddt, J=2.3, 4.4, 12.4 Hz, 1H, H-3a), 1.33 (dddd, J=1.0,
8.6, 11.6, 13.2 Hz, 1H, H-8b), 1.26 (d, J=0.9 Hz, 3H, H-15), 0.97 (dddd,
J=3.2, 4.4, 6.2, 12.4 Hz, 1H, H-2), 0.94 (d, J=6.7 Hz, 3H, H-12), 0.91
(d, J=6.4 Hz, 3H, H-14), 0.90 (d, J=6.7 Hz, 3H, H-13), 0.84 (d,
J=3.2 Hz, 1H, H-10), 0.80 (t, J=3.2 Hz, 1H, H-1), 0.79 (d(dt),
J=2.2, 12.6, 13.6 Hz, 1H, H-3b), 0.49 (dddd, J=2.0, 11.1, 13.2, 13.6 Hz,
1H, H-4b); 13C NMR (100 MHz, CDCl3): d=80.9 (C-9), 44.2 (C-2),
39.1 (C-10), 36.4 (C-8), 33.7 (C-11), 33.5 (C-6), 31.7 (C-4), 31.0 (C-5),
29.6 (C-7), 28.0 (C-15), 26.5 (C-3), 22.6 (C-1), 20.1 (C-12), 19.7 (C-13),
18.8 (C-14); IR (KAP): n˜ = 3279, 2952, 2925, 2865, 1462, 1451, 1384,
1369, 1300, 1184, 1133, 1099, 1032, 929 cmꢀ1; MS (EI): m/z (%): 222 (12)
[M +], 207 (100), 161 (82), 121 (34), 105 (35), 93 (26), 81 (26), 55 (26),
43 (78); HRMS (EI): m/z: calcd for C15H26O: 222.1987, found 222.1984
[M +].
(E)-3,7,11-Trimethyldodeca-6,10-dien-1-yn-3-ol (32): Prepared analogous-
ly from geranyl acetone 31 as a yellow oil (2.16 g, 96%). 1H NMR
(300 MHz, CDCl3): d=5.18 (ddd, J=1.2, 6.8, 7.8 Hz, 1H), 5.08 (ddd, J=
1.4, 5.4, 6.9 Hz, 1H), 2.46 (s, 1H), 2.28 (m, 1H), 2.20 (m, 1H), 2.15–1.96
(m, 5H), 1.72 (m, 2H), 1.68 (d, J=1.2 Hz, 3H), 1.65 (s, 3H), 1.60 (s,
3H), 1.50 (s, 3H); 13C NMR (75 MHz, CDCl3): d=136.4, 131.7, 124.3,
123.7, 87.8, 71.6, 68.4, 43.3, 39.8, 30.0, 26.8, 25.8, 23.6, 17.8, 16.2; IR
(KAP): n˜ = 3358, 3308, 2969, 2917, 1447, 1375, 1109, 907, 838 cmꢀ1; MS
(EI): m/z (%): 220 (0.1) [M +], 205 (10), 187 (13), 159 (14), 136 (15), 123
(13), 105 (38), 93 (35), 81 (19), 69 (100), 55 (18), 41 (83); HRMS (ESI):
m/z: calcd for C15H24O+Na: 243.1725; found: 243.1722 [M ++Na].
(Z)-3,7,11-Trimethyldodeca-6,10-dien-1-yn-3-ol (46):[53] Prepared analo-
gously from neryl acetone 45 as a yellow liquid (2.19 g, 96%). 1H NMR
(300 MHz, CDCl3): d=5.17 (dt, J=1.2, 7.5 Hz, 1H), 5.12 (m, 1H), 2.45
(m, 1H), 2.24 (m, 2H), 2.08 (m, 5H), 1.69 (m, 2H), 1.69 (s, 3H), 1.69 (s,
3H), 1.61 (s, 3H), 1.50 (s, 3H); 13C NMR (75 MHz, CDCl3): d=136.4,
131.8, 124.5, 124.4, 87.7, 71.6, 68.4, 43.6, 32.1, 29.9, 26.7, 25.9, 23.6, 23.5,
17.8; IR (KAP): n˜ = 3350, 3308, 2966, 2928, 2857, 1448, 1375, 1146, 1112,
1024, 907, 833 cmꢀ1; MS (EI): m/z (%): 220 (1) [M +], 205 (8), 187 (9),
159 (10), 133 (9), 119 (11), 105 (22), 93 (25), 81 (15), 69 (100), 55 (14), 41
(74).
(ꢀ)-(1R,5R,6R,7S,10R)-7-Isopropyl-10-methyl-tricyclo[4.4.0.01,5]dec-3,4-
en-4-trifluoromethanesufonate (28): nBuLi (1.55m in hexanes, 0.176 mL,
0.273 mmol) was added dropwise to a solution of (iPr)2NH (0.042 mL,
0.296 mmol) in THF (2 mL) at 08C and the resulting mixture was stirred
for 30 min before it was cooled to ꢀ788C. At that temperature, a solution
of ketone 11 (47 mg, 0.228 mmol) in THF (1 mL) was introduced and stir-
ring continued for 2 h before N-(5-chloro-2-pyridyl)bistriflimide (107 mg,
0.273 mmol) in THF (2 mL) was added and the reaction allowed to reach
ambient temperature. The solvent was evaporated and the residue was
purified by flash chromatography (pentane) to yield product 28 as a col-
orless liquid (70 mg, 91%). 1H NMR (400 MHz, CDCl3): d=5.20 (t, J=
2.2 Hz, 1H), 2.56 (dd, J=2.3, 17.5 Hz, 1H), 2.27 (td, J=2.8 Hz, 17.5 Hz,
1H), 1.80 (sept, 1H), 1.64 (m, 1H), 1.62 (ddd, J=6.5, 13.4, 13.5 Hz, 1H),
1.47 (t, J=2.9 Hz, 1H), 1.42 (m, 1H), 1.15 (m, 1H), 0.96 (d, J=6.5 Hz,
3H), 0.94 (d, J=6.8 Hz, 3H), 0.92 (m, 1H), 0.91 (d, J=6.8 Hz, 3H), 0.70
(t, J=2.7 Hz, 1H), 0.52 (m, 1H); 13C NMR (100 MHz, CDCl3): d=153.1,
117.2 (q, JCF =318 Hz), 113.0, 43.4, 35.4, 34.4, 33.6, 33.4, 31.4, 30.9, 29.3,
26.3, 19.8, 19.77, 19.5; IR (KAP): n˜ = 2959, 2930, 2857, 1643, 1421, 1245,
1203, 1140, 1113, 1098, 905, 855, 821 cmꢀ1; MS (EI): m/z (%): 338 (54)
[M +], 295 (83), 253 (100), 239 (46), 145 (43), 105 (27), 91 (53), 77 (31),
69 (63), 55 (88), 41 (56); HRMS (EI): m/z: calcd for C15H21F3O3S:
338.1165, found 338.1164 [M +].
3,7-Dimethyl-oct-6-en-1-yn-3-yl acetate (1): DMAP (160 mg, 1.3 mmol)
and acetic anhydride (0.62 mL, 6.57 mmol) were added to a solution of
alcohol 41 (200 mg, 1.3 mmol) in Et3N (10 mL). After stirring for 3 h at
ambient temperature, the mixture was poured onto water, the aqueous
phase was extracted with tert-butyl methyl ether, the combined organic
layers were washed with brine, dried over Na2SO4 and evaporated. Flash
chromatography (hexanes/ethyl acetate 5:1) of the residue gave the de-
sired product 1 as a colorless liquid (248 mg, 97%). 1H NMR (300 MHz,
CDCl3): d=5.11 (tddd, J=1.3, 2.7, 5.6, 8.5 Hz, 1H), 2.55 (s, 1H), 2.16 (m,
2H), 2.02 (s, 3H), 1.94 (m, 1H), 1.81 (ddd, J=6.6, 10.2, 13.5 Hz, 1H),
1.68 (s, 6H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3): d=169.5, 132.4,
123.3, 83.9, 74.9, 73.4, 41.5, 26.5, 25.8, 23.0, 22.0, 17.8; IR (KAP): n˜ =
3287, 2971, 2921, 2860, 1743, 1444, 1367, 1230, 1167, 1080, 1014, 940,
830 cmꢀ1; MS (EI): m/z (%): 152 (36), 137 (23), 119 (95), 109 (18), 91
(37), 79 (10), 69 (35), 55 (19), 43 (100); HRMS (CI): m/z: calcd for
C12H18O2: 195.1385; found: 195.1382 [M ++H].
(ꢀ)-(1R,5R,6R,7S,10R)-7-Isopropyl-10,4-dimethyl-tricyclo[4.4.0.01,5]dec-
3,4-ene [(ꢀ)-a-cubebene, 4]: A solution of triflate 28 (54 mg, 0.16 mmol)
in THF (2 mL) was added to
a solution of [Fe(acac)3] (5.6 mg,
0.016 mmol) and 1-methyl-2-pyrrolidinone (NMP, 0.147 mL) in THF
(1 mL). The mixture was cooled to ꢀ308C before a solution of MeMgBr
(3m in Et2O, 0.106 mL, 0.318 mmol) was added dropwise. The resulting
mixture was stirred for 40 min before the reaction was quenched with aq.
sat. NH4Cl. A standard extractive work up followed by purification of
the crude product by flash chromatography (pentane) furnished a-cube-
bene 4 as a colorless oil (29.2 mg, 90%). [a]2D0 = ꢀ18.48 (c=0.7, CHCl3);
1H NMR (400 MHz, CDCl3): d=4.89 (d, J=1.2 Hz, 1H), 2.52 (td, J=2,
16.8 Hz, 1H), 2.15 (ddd, J=2.2, 4.5, 17.1 Hz, 1H), 1.82 (sep, J=6 Hz,
1H), 1.76 (dd, J=2.0, 3.8 Hz, 3H), 1.60 (ddd, J=5.7, 5.7, 13.1 Hz, 1H),
1.60 (ddd, J=6.7, 14.4, 14.5 Hz, 1H), 1.38 (m, 1H), 1.15 (t, J=2.6 Hz,
1H), 1.08 (m, 1H), 0.93 (d, J=6.6 Hz, 6H), 0.91 (m, 1H), 0.89 (d, J=
6.8 Hz, 3H), 0.52 (dddd, J=2.3, 13.4, 13.3, 13.3 Hz, 1H), 0.22 (t, J=
2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=145.9, 120.3, 44.8, 40.6,
36.3, 34.9, 34.5, 33.6, 31.6, 31.3, 26.7, 20.0, 19.8, 19.78, 16.8; IR (KAP):
n˜ = 2955, 2927, 2909, 2870, 2852, 1457, 1444, 1385, 1369, 1319, 1165, 1032,
931, 825, 776 cmꢀ1; MS (EI): m/z (%): 204 (33) [M +], 161 (100), 119
(69), 105 (67), 91 (25), 81 (18), 41 (21); HRMS (EI): m/z: calcd for
C15H24: 204.1881, found 204.1878 [M +].
(E)-3,7,11-Trimethyldodeca-6,10-dien-1-yne-3-yl acetate (33): Prepared
analogously from alcohol 32 as
a pale yellow oil (581 mg, 98%).
1H NMR (300 MHz, CDCl3): d=5.13 (dt, J=1.2, 7.1 Hz, 1H), 5.08 (ddd,
J=1.4, 2.8, 7.0 Hz, 1H), 2.56 (s, 1H), 2.20 (m, 2H), 2.07 (m, 2H), 2.03 (s,
3H), 2.02–1.92 (m, 3H), 1.82 (ddd, J=6.7, 10.2, 13.5 Hz, 1H), 1.69 (s,
3H), 1.68 (d, J=1.2 Hz, 3H), 1.62 (s, 3H), 1.60 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=169.4, 135.9, 131.4, 124.3, 123.0, 83.8, 74.7, 73.3,
41.3, 39.7, 26.7, 26.4, 25.7, 22.8, 21.9, 17.7, 16.0; IR (KAP): n˜ = 3296,
2967, 2916, 1745, 1444, 1367, 1230, 1167, 1085, 1013, 940, 836 cmꢀ1; MS
(EI): m/z (%): 262 (0.3) [M +], 220 (30), 159 (18), 133 (37), 119 (17), 105
(59), 91 (31), 81 (18), 69 (100), 55 (16), 43 (69); HRMS (ESI): m/z: calcd
for C17H26O2: 285.1830; found: 285.1830 [M ++Na].
Chem. Eur. J. 2006, 12, 3006 – 3019
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3015

A. Fürstner and P. Hannen
(Z)-3,7,11-Trimethyldodeca-6,10-dien-1-yne-3-yl acetate (47): Prepared
analogously from alcohol 46 as a colorless liquid (2.23 g, 92%). 1H NMR
(300 MHz, CDCl3): d=5.13 (t, J=7.2 Hz, 1H), 5.12 (t, J=7.0 Hz, 1H),
2.55 (s, 1H), 2.18 (dd, J=7.9, 16.4 Hz, 1H), 2.18 (dd, J=8.0, 15.5 Hz,
1H), 2.06 (m, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.94 (m, 1H), 1.80 (ddd,
J=6.9, 10.0, 13.5 Hz, 1H), 1.69 (m, 3H), 1.687 (s, 3H), 1.68 (s, 3H), 1.62
(s, 3H); 13C NMR (75 MHz, CDCl3): d=169.5, 136.2, 131.8, 124.4, 124.0,
83.9, 74.8, 73.4, 41.8, 32.1, 26.7, 26.5, 25.9, 23.5, 22.8, 22.0, 17.8; IR
(KAP): n˜ = 3308, 2966, 2919, 2858, 1745, 1445, 1367, 1231, 1170, 1085,
1014, 940, 830 cmꢀ1; MS (EI): m/z (%): 220 (21) [M +ꢀAcOH], 187 (11),
159 (12), 136 (28), 119 (15), 105 (32), 93 (22), 81 (16), 69 (100), 55 (13),
43 (77); HRMS (ESI): m/z: calcd for C17H26O2+Na: 285.1830; found:
285.1829 [M ++Na].
7.3 Hz, 1H), 1.83 (dd, J=6.2, 13.4 Hz, 1H), 1.70 (m, 1H), 1.66 (s, 3H),
1.64 (m, 1H), 1.06 (s, 3H), 0.95 (dd, J=4.4, 8.7 Hz, 1H), 0.85 (s, 3H),
0.81 (ddd, J=3.0, 8.1, 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=133.7,
119.6, 28.7, 27.6, 24.2, 24.0, 23.0, 21.2, 17.9, 15.6; IR (KAP): n˜ = 2956,
2924, 2860, 1689, 1450, 1374, 1260, 1213, 1098, 1022, 826, 804 cmꢀ1; MS
(EI): m/z (%): 136 (36) [M +], 121 (79), 105 (21), 93 (100), 79 (43), 65
(9), 53 (11), 41 (28).
(1R*,6S*,7R*)-3,7-Dimethyl-7-(4-methylpent-3-enyl)bicyclo[4.1.0]hept-2-
en-2-yl acetate (35): A flame dried 100 mL two-necked flask was charged
with AuCl3 (57 mg, 0.19 mmol). After adding a solution of acetate 33
(1.0 g, 3.81 mmol) in 1,2-dichloroethane (40 mL) the resulting mixture
was stirred under argon for 4 h during which a characteristic color
change from orange to purple and finally blue was observed. The reac-
tion mixture was filtered through a pad of Celite (hexanes/ethyl acetate
3:1) and the filtrate was evaporated yielding the crude product 35 (~1 g)
which was used without further purification. Characteristic data:
1H NMR (400 MHz, CDCl3): d=5.08 (m, 1H), 2.24 (dd, J=7.9, 16.2 Hz,
1H), 2.15 (s, 3H), 2.08–1.95 (m, 3H), 1.82 (m, 1H), 1.78 (m, 1H), 1.67 (s,
3H), 1.65 (m, 1H), 1.60 (s, 3H), 1.54 (s, 3H), 1.23 (m, 1H), 1.21 (ddd,
J=6.7, 9.3, 13.7 Hz, 1H), 1.10 (m, 1H), 0.97 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=168.5, 140.3, 130.2, 123.7, 118.3, 41.3, 28.8, 28.1,
24.8, 24.6, 23.2, 22.4, 20.0, 16.7, 16.65, 15.2, 12.1; IR (KAP): n˜ = 2966,
2916, 2852, 1753, 1447, 1367, 1209, 1096 cmꢀ1; MS (EI): m/z (%): 262 (24)
[M +], 220 (75), 151 (46), 135 (100), 109 (34), 69 (42), 43 (76); HRMS
(EI): m/z: calcd for C17H26O2: 262.1933; found: 262.1930 [M +].
3,7,7-Trimethylbicyclo[4.1.0]hept-2-en-2-yl acetate (3):
A flame dried
25 mL two-necked flask was charged with AuCl3 (16 mg, 0.052 mmol).
After a solution of acetate 1 (200 mg, 1.03 mmol) in 1,2-dichloroethane
(10 mL) had been added, the mixture was stirred under argon for 12 h.
During the course of the reaction a characteristic color change from
yellow to orange and finally brownish grey occurred. The mixture was fil-
tered through a pad of Celite (hexanes/ethyl acetate 3:1) and the filtrate
was evaporated yielding product 3 as a yellow liquid (197 mg, 98%).
1H NMR (400 MHz, CDCl3): d=2.24 (dd, J=7.6, 15.7 Hz, 1H), 2.16 (s,
3H), 1.83 (m, 1H), 1.78 (m, 1H), 1.64 (m, 1H), 1.53 (s, 3H), 1.09 (m,
2H), 1.06 (s, 3H), 0.99 (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.5,
140.5, 118.1, 29.8, 28.1, 25.0, 24.7, 24.0, 21.1, 17.7, 16.2, 15.8; IR (KAP):
n˜ = 2918, 2865, 1753, 1698, 1449, 1367, 1208, 1165, 1097, 1044, 1009, 922,
889 cmꢀ1; MS (EI): m/z (%): 194 (16) [M +], 152 (100), 137 (58), 119 (5),
109 (46), 95 (17), 81 (7), 67 (12), 55 (9), 43 (42); HRMS (EI): m/z: calcd
for C12H18O2: 194.1307; found: 194.1304 [M +].
(1R*,6S*,7R*)-3,7-Dimethyl-7-(4-methylpent-3-enyl)-bicyclo-
[4.1.0]heptan-2-one (endo-36): A solution of the crude acetate 35 (1.0 g,
3.81 mmol) in THF (5 mL) was added
dropwise at ꢀ788C to a suspension of
3,7,7-Trimethylbicyclo[4.1.0]heptan-2-one
(42):
K2CO3
(17 mg,
LiAlH4 (217 mg, 5.72 mmol) in THF
0.12 mmol) was added to solution of enol acetate
a
3
(100 mg,
(15 mL). The reaction mixture was al-
0.51 mmol) in MeOH (5 mL). After stirring for 16 h at ambient tempera-
ture, the mixture was diluted with water and the aqueous phase was re-
peatedly extracted with tert-butyl methyl ether. The combined organic
layers were washed with brine, dried over Na2SO4 and evaporated and
the residue was purified by flash chromatography (hexanes/ethyl acetate
20:1) to give ketone 42 as a yellow liquid (47 mg, 60% over two steps, dr
5:1). 1H NMR (400 MHz, CDCl3): d=2.14 (ddd, J=5.9, 12.2, 18.1 Hz,
1H), 2.03 (ddd, J=4.4, 6.0, 14.7 Hz, 1H), 2.03 (dd, J=5.5, 14.7 Hz, 1H),
1.83 (dtd, J=2.7, 6.6, 9.3 Hz, 1H), 1.44 (d, J=7.6 Hz, 1H), 1.43 (ddd, J=
6.0, 12.1, 16.2 Hz, 1H), 1.23 (t, J=6.8 Hz, 1H), 1.11 (s, 3H), 1.10 (s, 3H),
1.03 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=211.3, 42.8,
34.3, 30.0, 28.6, 25.8, 23.7, 19.4, 17.8, 14.3; IR (KAP): n˜ = 2931, 2865,
1693, 1455, 1375, 1329, 1217, 1178, 1119, 1072, 1024, 986, 955, 935, 885,
786 cmꢀ1; MS (EI): m/z (%): 152 (27) [M +], 110 (26), 95 (26), 82 (100),
67 (59), 41 (35); HRMS (EI): m/z: calcd for C10H16O: 152.1201; found:
152.1200 [M +].
lowed to reach ambient temperature
overnight before it was quenched by
careful addition of aq. sat. Na2SO4 at
08C. After filtration over Celite and
extensive rinsing of the filter cake with
tert-butyl methyl ether, the combined
filtrates were washed with brine, dried
over Na2SO4 and evaporated, and the residue was purified by flash chro-
matography (hexanes/ethyl acetate 20:1) to give endo-36 as a yellow
liquid (470 mg, 60% over two steps). 1H NMR (400 MHz, CDCl3): d=
5.04 (t(sept), J=1.4, 7.2 Hz, 1H, H-10), 2.13 (d(qi), J=6.4, 12.4 Hz, 1H,
H-3), 2.10 (dddd, J=6.2, 7.0, 12.2, 14.8 Hz, 1H, H-5a), 2.01 (m, 2H, H-
9a,b), 1.98 (dddd, J=1.8, 2.6, 6.0, 14.8 Hz, 1H, H-5b), 1.80 (dddd, J=2.6,
6.2, 7.2, 14.6 Hz, 1H, H-4a), 1.65 (d, J=1.2 Hz, 3H, H-15), 1.58 (d, J=
1.2 Hz, 3H, H-14), 1.40 (d, J=7.6 Hz, 1H, H-1), 1.39 (dddd, J=6.0, 12.0,
12.4, 14.6 Hz, 1H, H-4b), 1.38 (ddd, J=5.8, 9.6, 13.6 Hz, 1H, H-8a), 1.20
(ddd, J=1.6, 6.1, 7.8 Hz, 1H, H-6), 1.05 (s, 3H, H-13), 1.04 (m, 1H, H-
8b), 1.00 (d, J=6.6 Hz, 3H, H-12); 13C NMR (100 MHz, CDCl3): d=
211.2 (C-2), 131.6 (C-11), 124.0 (C-10), 43.8 (C-8), 42.8 (C-3), 33.6 (C-1),
28.6 (C-4), 27.2, 25.7 (C-15), 25.0 (C-6), 24.9, 19.4, 17.6 (C-14), 15.2 (C-
13), 14.2 (C-12); IR (KAP): n˜ = 2963, 2915, 1695, 1450, 1375, 1317, 1250,
1213, 1178, 1099, 1077, 886, 829 cmꢀ1; MS (EI): m/z (%): 220 (14) [M +],
151 (37), 138 (22), 123 (31), 107 (25), 93 (26), 81 (100), 69 (94), 55 (27),
41 (94); HRMS (EI): m/z: calcd for C15H24O2: 220.1827; found: 220.1825
[M +].
3,7,7-Trimethylbicyclo[4.1.0]hept-2-ene (2-Carene, 44): nBuLi (1.6m in
hexanes, 0.484 mL, 0.77 mmol) was added dropwise to a solution of
(iPr)2NH (0.108 mL, 0.77 mmol) in THF (3 mL) at 08C and the resulting
mixture was stirred for 30 min before it was cooled to ꢀ788C. A solution
of ketone 42 (107 mg, 0.7 mmol) in THF (2 mL) was slowly introduced at
that temperature and stirring continued for 16 h before a solution of N-
(5-chloro-2-pyridyl)bistriflimide (276 mg, 0.7 mmol) in THF (3 mL) was
added and the reaction allowed to reach ambient temperature. The mix-
ture was diluted with tert-butyl methyl ether and the organic layer was
successively washed with water, aq. sat. Na2CO3 and brine. Evaporation
of the solvent gave triflate 43 as a yellow oil which was directly used in
the next step.
Solvolytic cleavage of the enol acetate: K2CO3 (35 mg, 0.25 mmol) was
added to a solution of the crude acetate 35 (100 mg, 0.38 mmol) in
MeOH (4 mL) and the resulting mixture was stirred for 16 h before it
was diluted with water and extracted with tert-butyl methyl ether. The
combined organic layers were washed
with brine, dried over Na2SO4 and
evaporated. Purification of the residue
by flash chromatography (hexanes/
ethyl acetate 20:1) furnished product
A solution of this crude triflate (200 mg, 0.7 mmol) in THF (3 mL) was
added to a suspension of [Pd(PPh3)4] (16 mg, 0.014 mmol) and LiCl
(89 mg, 2.11 mmol) in THF (4 mL) followed by addition of Bu3SnH
(0.223 mL, 0.84 mmol). The mixture was stirred at 608C for 16 h before it
was diluted with pentane and repeatedly washed with aq. NH3. The or-
ganic phase was washed with brine, dried over Na2SO4 and evaporated,
and the residue was purified by flash chromatography (hexanes/ethyl ace-
36 as a yellow liquid in a diastereo-
tate 20:1) to give 2-carene 44 as
a
colorless liquid (43 mg, 45%).
meric ratio of 6.7:1 in favor of the exo-
isomer (62 mg, 74% over two steps).
1H NMR (300 MHz, CDCl3): d=5.54 (m, 1H), 1.92 (ddd, J=2.2, 6.5,
3016
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3006 – 3019

Natural Products
FULL PAPER
1H NMR (400 MHz, CD2Cl2): d=5.07 (t(sept), J=1.4, 7.2 Hz, 1H, H-10),
2.06 (m, 2H, H-9a,b), 2.03 (m, 1H, H-5a), 1.95 (m, 1H, H-3), 1.81 (m,
1H, H-4a), 1.67 (d, J=1.4 Hz, 3H, H-15), 1.60 (s, 3H, H-14), 1.62–1.50
(m, 3H, H-4b, H-5b, H-6), 1.38 (d, J=7.6 Hz, 1H, H-1), 1.31 (m, 1H, H-
8a), 1.24 (m, 1H, H-8b), 1.17 (s, 3H, H-13), 0.99 (d, J=6.6 Hz, 3H, H-
12); 13C NMR (100 MHz, CD2Cl2): d=211.2 (C-2), 131.9 (C-11), 124.3
(C-10), 43.8 (C-3), 43.7 (C-8), 35.9 (C-4), 34.9 (C-1), 31.49, 31.47 (C-6),
25.7 (C-15), 25.5, 19.2 (C-5), 17.7 (C-14), 15.8 (C-12), 14.1 (C-13).
tic data of the exo-isomer: 1H NMR (400 MHz, CDCl3): d=5.07 (m, 1H),
2.15–1.89 (m, 5H), 1.80 (m, 1H), 1.65 (s, 3H), 1.59 (m, 3H), 1.55 (s, 3H),
1.49 (dd, J=5.4, 11.1 Hz, 1H), 1.44 (d, J=7.6 Hz, 1H), 1.12 (s, 3H), 1.02
(d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=211.8, 132.1, 124.0,
43.6, 35.9, 35.8, 33.1, 32.0, 30.9, 26.7, 25.8, 25.1, 19.1, 17.6, 15.7. Character-
istic data of the endo-isomer: 1H NMR (400 MHz, CDCl3): d=5.07 (m,
1H), 2.19–2.08 (m, 4H), 2.03 (m, 1H), 1.85 (m, 1H), 1.67 (s, 3H), 1.60 (s,
3H), 1.53 (ddd, J=5.2, 11.2, 14.4 Hz, 1H), 1.46 (d, J=7.6 Hz, 1H), 1.42
(m, 1H), 1.26 (m, 1H), 1.25 (m, 1H), 1.11 (s, 3H), 1.04 (d, J=6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=210.3, 130.8, 123.3, 41.9, 34.1, 32.4,
27.9, 27.4, 26.2, 25.6, 24.8, 24.3, 19.0, 16.7, 13.5; IR (KAP): n˜ = 2962,
2928, 2868, 1692, 1452, 1376, 1327, 1181, 1083, 1071, 1000, 889 cmꢀ1; MS
(EI): m/z (%): 220 (3) [M +], 151 (25), 138 (100), 111 (23), 93 (13), 81
(52), 69 (56), 55 (16), 41 (60); HRMS (EI): m/z: calcd for C15H24O:
220.1827; found: 220.1828 [M +].
(1R*,6S*,7R*)-3,7-Dimethyl-7-(4-methylpent-3-enyl)bicyclo[4.1.0]hept-2-
ene (2-sesquicarene, 39): nBuLi (1.6m in hexanes, 0.195 mL, 0.31 mmol)
was added dropwise to a solution of (iPr)2NH (0.048 mL, 0.34 mmol) in
THF (1 mL) at 08C and the resulting mixture was stirred for 30 min at
that temperature before it was cooled to ꢀ788C. A solution of ketone 36
(63 mg, 0.28 mmol) in THF (2 mL) was slowly added and the mixture
stirred for 16 h at that temperature before a solution of N-(2-pyridyl)bis-
triflimide (102 mg, 0.28 mmol) in THF (2 mL) was introduced and the re-
action allowed to reach ambient temperature. The mixture was diluted
with tert-butyl methyl ether and successively washed with water and
brine. The combined organic layers were dried over Na2SO4 and the sol-
vent was evaporated to give enol triflate 38 which was used without fur-
ther purification in the following step.
(1R*,6S*,7S*)-3,7-Dimethyl-7-(4-methylpent-3-enyl)bicyclo[4.1.0]hept-2-
ene (episesquicarene, 51): nBuLi (1.5m in hexanes, 0.4 mL, 0.6 mmol)
was added dropwise to a solution of (iPr)2NH (0.091 mL, 0.65 mmol) in
THF (2 mL) at 08C and the resulting mixture was stirred for 30 min
before it was cooled to ꢀ788C.
0.54 mmol) in THF (1.4 mL) was slowly added and stirring continued for
16 h before solution of N-(5-chloro-2-pyridyl)bistriflimide (235 mg,
A solution of ketone 49 (120 mg,
a
A solution of crude 38 (100 mg, 0.28 mmol) and Et3SiH (0.063 mL,
0.4 mmol) in THF (1 mL) was added to a suspension of [Pd(PPh3)4]
(6.6 mg, 0.0057 mmol) and LiCl (36 mg, 0.85 mmol) in THF (2 mL). The
mixture was stirred at 608C for 1.5 h before it was diluted with pentane
and washed with aq. NaHCO3 and brine. The organic phase was dried
over Na2SO4 and concentrated, and the residue was purified by flash
chromatography (pentane) to give sesquicarene 39 as a colorless liquid
(43 mg, 74% over two steps). 1H NMR (400 MHz, C6D6): d=5.36 (m,
1H), 4.93 (tddd, J=1.3, 2.7, 5.5, 8.5 Hz, 1H), 1.87 (dd, J=7.5, 15.1 Hz,
2H), 1.60 (m, 1H), 1.53 (m, 1H), 1.40 (d, J=0.9 Hz, 3H), 1.36 (ddd, J=
2.9, 5.7, 13.7 Hz, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.25 (m, 1H), 1.10 (m,
1H), 0.95 (ddd, J=7.2, 9.0, 13.4 Hz, 1H), 0.78 (dd, J=4.3, 8.4 Hz, 1H),
0.67 (s, 3H), 0.55 (ddd, J=2.9, 5.0, 10.7 Hz, 1H); 13C NMR (100 MHz,
C6D6): d=132.3, 129.3, 124.0, 118.6, 41.9, 27.1, 26.4, 24.7, 24.5, 22.6, 21.4,
19.4, 16.9, 16.3, 11.5; IR (KAP): n˜ = 2964, 2912, 2853, 1448, 1377, 1209,
1098, 1066, 993, 983, 968, 953, 825 cmꢀ1; MS (EI): m/z (%): 204 (40)
[M +], 189 (4), 161 (15), 147 (9), 134 (21), 119 (100), 107 (36), 93 (78), 79
(36), 69 (31), 55 (37), 41 (68), 29 (15); elemental analysis calcd (%) for
C15H24 (204.35): C 88.16, H 11.84; found: C 88.26, H 11.78.
0.60 mmol) in THF (2 mL) was introduced and the reaction was allowed
reach ambient temperature. The mixture was diluted with tert-butyl
methyl ether and successively washed with water and brine. The com-
bined organic layers were dried over Na2SO4 and the solvent was evapo-
rated to give enol triflate 50 as a pale brown oil which was used without
further purification in the following step.
A
solution of this crude triflate (150 mg, 0.43 mmol) and Et3SiH
(0.680 mL, 4.26 mmol) in THF (1 mL) was added to a suspension of [Pd-
(PPh3)4] (9.8 mg, 0.0085 mmol) and LiCl (54 mg, 1.28 mmol) in THF
(3 mL). The reaction was stirred at ambient temperature for 5 h before it
was diluted with pentane and washed with aq. NaHCO3 and brine. The
combined organic layers were dried over Na2SO4 and evaporated, and
the residue was purified by flash chromatography (pentane) to furnish
episesquicarene 51 as a colorless liquid (83 mg, 75% over two steps).
1H NMR (400 MHz, C6D6): d=5.66 (m, 1H), 5.26 (m, 1H), 2.13 (dd, J=
7.4, 15.8 Hz, 2H), 1.91 (m, 1H), 1.84 (ddd, J=5.9, 11.1, 15.0 Hz, 1H),
1.71 (m, 1H), 1.66 (d, J=0.8 Hz, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.39–
1.34 (m, 3H), 1.04 (s, 3H), 1.02 (m, 1H), 0.81 (ddd, J=3.4, 8.0, 8.1 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=133.9, 130.7, 125.8, 119.9, 30.4,
28.1, 27.9, 26.2, 25.9, 25.8, 24.0, 23.9, 22.1, 18.6, 17.6; IR (KAP): n˜ = 2956,
2912, 2858, 1448, 1376, 1078, 1025, 990, 969, 827 cmꢀ1; MS (EI): m/z (%):
204 (41) [M +], 161 (16), 147 (9), 134 (20), 119 (100), 107 (36), 93 (79), 79
(39), 69 (29), 55 (36), 41 (66), 29 (15); elemental analysis calcd (%) for
C15H24 (204.35): C 88.16, H 11.84; found: C 88.24, H 11.73.
(1R*,6S*,7S*)-3,7-Dimethyl-7-(4-methylpent-3-enyl)bicyclo[4.1.0]hept-2-
en-2-yl acetate (48): A flame dried 25 mL two-necked flask was charged
with AuCl3 (15 mg, 0.05 mmol). After a solution of acetate 47 (262 mg,
1 mmol) in 1,2-dichloroethane (10 mL) had been added, the resulting
mixture was stirred under argon for 4 h during which a characteristic
color change from orange to purple and finally to blue was observed.
The mixture was filtered through a pad of Celite (hexanes/ethyl acetate
3:1) and the filtrate was evaporated yielding crude 48 (258 mg) which
was pure enough for further use without purification. 1H NMR
(300 MHz, CDCl3): d=5.14 (m, 1H), 2.26 (m, 1H), 2.16 (s, 3H), 2.11–
1.94 (m, 2H), 1.82 (m, 2H), 1.69 (s, 3H), 1.65 (m, 1H), 1.61 (s, 3H), 1.53
(s, 3H), 1.35 (m, 1H), 1.31 (ddd, J=5.7, 10.6, 10.8 Hz, 1H), 1.12 (m, 2H),
1.04 (s, 3H); 13C NMR (75 MHz, CDCl3): d=169.6, 141.2, 131.2, 125.2,
119.8, 30.2, 30.0, 28.8, 25.9, 25.4, 25.3, 25.2, 24.2, 21.1, 18.1, 17.6, 16.2; IR
(KAP): n˜ = 2923, 2857, 1753, 1728, 1448, 1368, 1227, 1210, 1095, 1009,
889 cmꢀ1; MS (EI): m/z (%): 262 (24) [M +], 220 (74), 202 (20), 177 (12),
164 (11), 151 (53), 135 (100), 121 (20), 109 (37), 91 (17), 79 (13), 69 (37),
55 (22), 43 (81); HRMS (EI): m/z: calcd for C17H26O2: 262.1933; found:
262.1934 [M +].
Acknowledgements
We thank Dr. R. Mynott and P. Philipps for their invaluable help with
numerous NMR analyses. Generous financial support by the Max-
Planck-Society, the Fonds der Chemischen Industrie, and the Merck Re-
search Council is gratefully acknowledged. Moreover, we thank Umicore
AG & Co KG, Hanau, for a gift of noble metal salts.
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Chem. Eur. J. 2006, 12, 3006 – 3019

Natural Products
FULL PAPER
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PdCl2, InCl, InCl3, RuCl3·nH2O, FeCl3, ZnI2, CoBr2·nH2O, IrCl3,
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[54] It is worth mentioning that isosequicarene, a natural product isolat-
ed from Haplopappus tenuisectus, shows this particular configuration
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[39] As such, compound 30 constitutes the nor-ketone of 6-epi-cubebene,
a natural product that was isolated only recently from the essential
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[40] It should be noted, however, that these data do not allow us to con-
clude that it is the only pathway that is operative; at least theoreti-
Received: October 20, 2005
Published online: February 3, 2006
Chem. Eur. J. 2006, 12, 3006 – 3019
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www.chemeurj.org
3019