Transition-metal-catalyzed allylic substitution and titanocene-catalyzed epoxypolyene cyclization as a powerful tool for the preparation of terpenoids

Article abstract of DOI:10.1002/ejoc.200600389

Many biologically active substances are composed of sesquiterpene units linked to aromatic structures, especially substituted phenols. Here, we describe an efficient synthetic approach to this class of natural product from commercially available substances in a short sequence. The key transformations involve allylic substitution reactions using a palladium or copper catalyst and titanocene-catalyzed epoxypolyene cyclization reactions via radicals. The polycyclic core structures are accessed with high chemo- and stereocontrol. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600389

FULL PAPER
DOI: 10.1002/ejoc.200600389
Transition-Metal-Catalyzed Allylic Substitution and Titanocene-Catalyzed
Epoxypolyene Cyclization as a Powerful Tool for the Preparation of Terpenoids
Andreas Gansäuer,*[a] José Justicia,[a] Antonio Rosales,[a] Dennis Worgull,[a] Björn Rinker,[a]
Juan Manuel Cuerva,*[b] and Juan Enrique Oltra*[b]
Keywords: Copper / Cyclization / Epoxides / Radicals / Titanium
Many biologically active substances are composed of sesqui-
terpene units linked to aromatic structures, especially substi-
tuted phenols. Here, we describe an efficient synthetic ap-
proach to this class of natural product from commercially
available substances in a short sequence. The key transfor-
mations involve allylic substitution reactions using a palla-
dium or copper catalyst and titanocene-catalyzed epoxypoly-
ene cyclization reactions via radicals. The polycyclic core
structures are accessed with high chemo- and stereocontrol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
substituted tetrahydrofurans and the efficient synthesis of
cyclopropanes.
In contemporary natural product synthesis, the use of
reactions that generate structurally complex molecules from
The chlorotrimethylsilane/2,4,6-collidine-mediated cata-
simple starting materials catalytically and with atom econ- lytic conditions introduced by Cuerva and Oltra and their
omy in a tandem sequence is rightfully regarded as a most co-workers have been used in efficient transannular and ep-
powerful strategy.[1] In this context the radical chemistry oxypolyene cyclization reactions.[5] In this manner a
originating from titanocene-mediated or -catalyzed epox- number of natural products have been efficiently synthe-
ide-opening has attracted considerable attention in recent sized in very few steps and with high stereoselectivity. This
years.[2] Nugent and RajanBabu introduced “Cp2TiCl” as radical reaction has advantages over classical cationic poly-
a mild and highly chemoselective reagent for the reductive cyclization reactions[6] because radicals are generated under
opening of epoxides by electron transfer.[3] The first cata- much milder conditions than cations. Most importantly, the
lytic reaction conditions for mediating the reaction were de- tandem cyclization reaction is terminated by a highly re-
veloped by Gansäuer and co-workers using collidine hydro- gioselective β-hydride elimination process to yield exocyclic
chloride.[4] This method has been used for enantioselective olefins, normally the side-products of biosynthesis. Thus,
radical generation and a number of unusual radical reac- the incorporation of functional groups to terminate the cyc-
tions, such as a tandem sequence for the preparation of lization reaction is rendered unnecessary.[7] Moreover,
Scheme 1. Retrosynthetic strategy for the preparation of meroterpenoids.
numerous functional groups are tolerated in titanocene
[a] Kekulé-Institut für Organische Chemie und Biochemie der Uni-
catalysis.
versität Bonn,
Gerhard Domagk Str. 1, 53121 Bonn, Germany
Fax: +49-228-734760
In this publication we describe a short and highly stereo-
selective approach to a class of biologically active com-
pounds containing a sesquiterpene unit linked to substi-
tuted phenols. Our strategy features the pivotal atom-eco-
nomical and highly stereoselective titanocene-catalyzed ep-
oxypolyene cyclization reaction.[5b] The necessary starting
E-mail: andreas.gansaeuer@uni-bonn.de
[b] Department of Organic Chemistry, Faculty of Sciences, Univer-
sity of Granada,
18071 Granada, Spain
Fax: +34-958-248437
E-mail: jmcuerva@ugr.es; joltra@ugr.es
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materials can be readily prepared by catalytic allylic substi- Table 1. Products, yields, and reaction times in the palladium-cata-
tution reactions.[8,9] The total syntheses of zonarol (1) and
lyzed synthesis of compounds 8–17 from 7.
zonarone (2)[10] and the formal total syntheses of umbro-
sone (3),[11] puupehedione (4), and 8-epi-puupehedione (5)
[12]
were completed. These compounds are important be-
cause of their antifungal, antitumor, antiviral, and anti-
biotic properties. The general strategy is outlined in
Scheme 1.
Results and Discussion
Synthesis of the Starting Materials by Allylic Substitution
Reactions
In order to develop an efficient overall synthetic strategy
it is mandatory to elaborate simple starting materials into
the desired products in a short sequence. Thus, we decided
to synthesize arylepoxypolyenes as substrates for the epoxy-
polyene cyclization reaction from epoxygeranyl and epoxy-
farnesyl acetates and carbonates through catalytic allylic
substitution reactions with aromatic nucleophiles. For this
purpose, palladium-catalyzed reactions, for example, the
Stille coupling reaction,[8] and reactions with cuprates[9]
seemed especially attractive as both are known to proceed
with a high degree of retention of olefin geometry, as shown
in Scheme 2.[13]
Scheme 2. Allylic substitution reactions for the preparation of ep-
Encouraged by the stability of the epoxides formed under
oxypolyenes.
the Stille coupling conditions, and trying to overcome the
drawbacks, we turned our attention to the use of cuprates
and the copper-catalyzed coupling reactions of Grignard
One serious point of concern is immediately apparent,
however. It is well documented that epoxides can react with
reagents, as exemplified in Scheme 3.[16]
nucleophiles in the presence of Lewis acids to give ring-
opened products through nucleophilic substitution reac-
tions. This is especially so for cuprate reagents derived from
organolithium compounds or Grignard reagents.[14] There-
fore, the essentially neutral conditions of the Stille-type
coupling of allylic carbonates and trialkyl(aryl)stannanes
Scheme 3. Synthesis of substrates for epoxypolyen cyclization uti-
lizing organolithium or Grignard reagents.
developed by Echavarren and co-workers were investigated
first.[15] The results are summarized in Table 1.[5c] The Stille
coupling yielded the corresponding products with satisfac-
We investigated the ability of the highly reactive epoxy-
tory yields (62–92%, Table 1). The procedure has two draw- geranyl bromide (18) to retard the anticipated epoxide
backs, however. Extended reaction times are required and opening and used Bu2CuLi to increase the range of nucleo-
the coupling is limited to aryl- and alkenylstannanes, philes to alkyl groups. The desired 19 was obtained in good
thereby excluding the preparation of other interesting ep- yield (75%) and with high diastereoselectivity. No allylic
oxypolyenes with saturated groups.
isomer was observed. This finding was even surpassed when
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the stable and readily available epoxygeranyl acetate (6) was cuprates than epoxides. Gratifyingly, the Li2CuCl4-cata-
employed as the substrate. Epoxy olefin 19 was obtained in lyzed (4–5 mol-%) substitution reaction of BuMgBr also
79% yield as essentially a single isomer (dr Ͼ 98:2) with no gave the desired 19 in good yield and high diastereoselectiv-
products arising from epoxide opening. Thus, even rela- ity. This result is even more surprising as in the presence of
tively unreactive allylic acetates are more reactive towards copper salts, Grignard reagents open epoxides even more
swiftly than dialkylcuprates.[14] The reaction also gave satis-
factory results on a larger scale (10 mmol). With 20 a 79%
Table 2. Products and yields from the synthesis of compounds 19,
21, and 23 from cuprates and Grignard reagents.
yield of 21 as a single isomer was obtained, while epoxyfar-
nesyl acetate (22) gave an almost quantitative yield of the
coupling product. These results are summarized in Table 2.
From a practical point of view Li2CuCl4 catalysis is more
convenient as no large excess of the organometallic reagent
has to be used and Grignard reagents are easier to prepare
than the corresponding organolithium compounds.
Using these reaction conditions we synthesized a number
of epoxy olefins containing different and functionalized
alkyl and benzyl substituents from 6 and 22, as shown in
Table 3.
[a] See the Exp. Sect. for Methods A and B.
Table 4. Copper-mediated or Li2CuCl4-catalyzed transfer of aryl
groups to 6 and 22 from cuprates and Grignard reagents.
Table 3. Li2CuCl4-catalyzed transfer of alkyl and benzyl Grignard
reagents to 6 and 22.
[a] Method A was used, see Exp. Sect.
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The reaction proceeded smoothly in all cases. Only dur-
This is a general observation, as similar or better yields
ing the synthesis of 24 were small amounts of the allylic were obtained with Li2CuCl4 in all cases. This protocol is
isomer observed which could be removed by column therefore more practical. Moreover, the stannanes necessary
chromatography. The ether-substituted products are valu- for the Stille coupling reaction are usually prepared from
able intermediates for the synthesis of spirodihydrofuranol- either organolithium compounds or Grignard reagents in
actams from Stachybotry chartarum,[17] for example, stach- an additional step.[5c] However, owing to the mildness of
ybotrylactam.[18]
the Stille protocol, no basic organometallic reagents are
Finally, the transfer of aryl groups was also investigated used during coupling, and therefore we recommend its use
(Table 4). It turned out that the reaction of 6 with PhMgBr in the coupling reactions of epoxypolyene carbonates con-
catalyzed by Li2CuCl4 (4–5 mol-%) gave 8 in a yield and taining sensitive groups, such as alcohols or carbonyl
diastereoselectivity (83%, dr Ͼ 97:3) very similar to the groups.
Stille reaction without producing toxic stannane waste.
Titanocene-Catalyzed Epoxypolyene Cyclization Reactions
Table 5. Cp2TiCl-catalyzed cyclization of epoxypolyenes (see Exp.
Sect. for details).
Titanocene(III)-catalyzed cyclization reactions of epoxy-
polyenes have recently been developed as a unique tool in
natural product synthesis, taking advantage of the particu-
lar behavior of the radical intermediates involved.[2d]
We found that a substoichiometric quantity of commer-
cial Cp2TiCl2 (20 mol-%), Mn dust, and Me3SiCl/2,4,6-col-
lidine in dry THF at room temperature are the best reaction
conditions for carrying out epoxypolyene cyclization reac-
tions yielding the corresponding terpenoid carbocycles. One
of the main features of this transformation is the termina-
tion of the process by the regioselective formation of an
exocyclic olefin through a β-hydride elimination process.
This clearly has advantages over the cationic reactions in
which mixtures of olefins are usually obtained. Moreover,
these cyclization reactions proceed with high stereoselecti-
vity giving only one of the many possible stereoisomers. A
number of pertinent examples of titanocene-catalyzed ep-
oxypolyene cyclization reactions are summarized in Table 5.
Another important feature of the application of the tit-
anocene-catalyzed protocol to natural product synthesis is
related to the inertness of aromatic rings as radical traps
under our conditions. Thus, as opposed to cationic pro-
cesses, the arenes, including strongly activated aromatic
compounds, remain intact after the radical cyclization.
Therefore, the cyclization products can be converted into
valuable key intermediates for natural product synthesis un-
der very mild conditions, as exemplified below.
Total and Formal Syntheses of Natural Products
Exocyclic olefins are present in a number of pertinent
natural products. Thus, some of the cyclization products
can readily be further elaborated into natural products or
key intermediates for their synthesis. This specific advan-
tage results in overall sequences much shorter than synthe-
ses reported to date.
As pointed out above, the epoxide’s stereocenter is an
essential and highly beneficial control element for the highly
stereoselective formation of all the other stereocenters of
the cyclization products. Gratifyingly, the resulting hydroxy
group is also present in a large number of natural products.
Besides this obvious usefulness, our cyclization products
can, after deoxygenation, be readily employed in the prepa-
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ration of a large number of natural compounds containing catalyzed epoxypolyene cyclization of 37 followed by deoxy-
the reduced decalin structure. genation according to the Barton–McCombie protocol, as
Both of these points are demonstrated by the very short depicted in Scheme 5. As the configuration of the only
preparation of zonarone (2) and zonarol (1) from 49, as stereocenter remaining in 53 is controlled by the absolute
depicted in Scheme 4. Both natural products possess inter- configuration of 47, our method offers a straightforward
esting antifungal properties.[10]
approach to enantiomerically pure 3 from enantiomerically
After the high-yielding Barton–McCombie deoxygen- pure epoxygeranyl acetate (6).
ation[19] of 49 (79% over two steps) zonarone (2) was ob-
The presence of the exocyclic olefin in the cyclization
tained by oxidation of the arene with CAN in 85% yield. products is also of paramount interest for the further func-
Reduction of 2 by Na2S2O4 yields zonarol (1) in 75% yield. tionalization of the epoxypolyene cyclization products. In
Thus, starting from epoxyfarnesyl acetate (22), zonarone (2) this respect the formation of cyclic ethers, such as benzodi-
and zonarol (1) can be prepared in just four or five steps, hydropyrans, by the addition of phenolic hydroxy groups to
respectively. The previously described syntheses require sig- the double bond is of special relevance. This heterocyclic
nificantly more steps.[20] Direct demethylation of 52 with element is present in a number of important natural prod-
acids or Lewis acids was not attempted to avoid suspected ucts, such as taondiol, K-76, kampanol A, puupehedione,
benzodihydropyran formation.
and its unnatural 8-epimer, and is therefore of some inter-
A very short synthesis of the key intermediate 53 in the est.[5c]
synthesis of umbrosone (3) by Ghatak[21] can be ac-
Our epoxypolyene cyclization approach offers a straight-
complished in an overall yield of 35% by the titanocene- forward solution to the existing problems of the regio- and
Scheme 4. Preparation of zonarone (2) and zonarol (1) from 49.
Scheme 5. Preparation of the key intermediate 53 in Ghatak’s synthesis of umbrosone (3).
Scheme 6. Regioselective benzodihydropyran synthesis from epoxypolyene cyclization products.
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stereoselectivity of benzodihydropyran synthesis. With the activity.[12] Interestingly, the unnatural 5 is the more potent
endocyclic olefins obtained from cationic cyclization reac- compound and is therefore an interesting target for syn-
tions or natural sources, selective generation of the desired thetic studies.
tertiary cation is difficult to achieve and thus mixtures of
The key feature of our synthetic approach is the use of
benzodihydropyrans and furans are usually obtained. With the cyclization product 50 as a common intermediate for
our compounds, upon addition of a proton or other electro- the preparation of both 4 and 5, as shown in Scheme 7.
philes, only the tertiary cation is generated, and thus ether
synthesis is expected to occur with high regioselectivity, as Barton–McCombie conditions[19] described above to give
shown in Scheme 6. 54 in high yield. Cleavage of the OMOM group proceeded
To this end, 50 was deoxygenated in two steps using the
We have chosen puupehedione (4) and its 8-epimer (5) to smoothly using pTsOH in MeOH. Phenol 55 thus obtained
demonstrate the validity of our approach. Both 4 and 5 was then selectively converted into either of the epimeric
are pertinent for their antitumor, antiviral, and antibiotic benzodihydropyrans, as shown in Scheme 8, by varying the
Scheme 7. Retrosynthetic strategy for the preparation of puupehedione (4) and its 8-epimer 5 from 50.
Scheme 8. Completion of the formal syntheses of 4 and 5.
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perature for 30 min. Then a solution of epoxypolyene (0.5–1 mmol)
was added and the new mixture was stirred at room temp. over-
night. Satd. aq. NH4Cl was added and the mixture was extracted
with EtOAc, the extract dried with MgSO4, and the solvent re-
moved. The residue was purified by flash chromatography (mix-
tures of CH/EA) to yield the coupling product. Method B: A 0.1 
solution of Li2CuCl4 in THF (0.04 mmol) was added dropwise to
a solution of epoxypolyene (1 mmol) in THF (9 mL) at 0 °C. Then
a solution of Grignard reagent (2–4 mmol) was added dropwise
over 20 min. The mixture was stirred at 0 °C for 3 h and then at
room temp. overnight. Satd. aq. NH4Cl was added and the mixture
was extracted with EtOAc, the extract dried with MgSO4, and the
solvent removed. The residue was purified by flash chromatography
(mixtures of CH/EA) to yield the coupling product.
electrophilic reagent for attack on the exocyclic double
bond.
It turned out that the protocol described by Katoh and
co-workers[22] for the synthesis of kampanol A [N-(phen-
ylseleno)phthalimide, SnCl4, followed by reduction of the
selenide with Bu3SnH] yielded 57 in good overall yield
(69%), completing the formal synthesis of puupehedione
(4). From a 1:3 mixture of 57 and 58, 4 was obtained by
Barrero et al. by oxidation with DDQ and pTsOH in 1,4-
dioxane.[12b]
From a mixture of isomers of 58 (dr = 73:27), 8-epi-pu-
upehedione (5) was synthesized by Yamamoto and co-
workers in three steps [DDQ, 1,4-dioxane; B(C6F5)3,
Et3SiH; DDQ, 1,4-dioxane, H2O] and an overall yield of
91%.[23]
Compound 14: Yield 110 mg, 68% from 6 (0.74 mmol) by Method
A; CH/EA, 9:1; colorless oil. 1H NMR (400 MHz, CDCl3): δ =
7.22 (d, J = 1.2 Hz, 1 H), 6.27 (dd, J = 3.1, 1.2 Hz, 1 H), 5.96 (dd,
J = 3.1, 0.9 Hz, 1 H), 5.38 (tq, J = 7.1, 1.2 Hz, 1 H), 3.35 (d, J =
7.1 Hz, 2 H), 2.70 (t, J = 6.2 Hz, 1 H), 2.28–2.19 (m, 2 H), 1.70 (s,
3 H), 1.69–1.63 (m, 2 H), 1.28 (s, 3 H), 1.25 (s, 3 H) ppm. 13C
Conclusions
We have devised a short and efficient approach to a NMR (100 MHz, CDCl3): δ = 155.14 (C), 141.08 (CH), 136.76 (C),
120.14 (CH), 110.29 (CH), 104.86 (CH), 64.19 (CH), 58.44 (C),
36.39 (CH2), 27.45 (CH2), 27.14 (CH2), 24.96 (CH3), 18.86 (CH3),
16.22 (CH3) ppm. HRMS (70 eV): calcd. for C14H20O2 [M]+
number of natural products and biologically active sub-
stances containing sesquiterpenes linked to arenes, espe-
cially phenols. Our strategy relies on allylic substitution re-
actions employing stannanes, Grignard reagents, or cup-
rates and titanocene-catalyzed epoxypolyene cyclization re-
actions as the key transformations. These reactions proceed
under mild conditions and with high stereo- and chemose-
lectivity. The products obtained by this route are valuable
intermediates for organic synthesis, as demonstrated by
short and efficient syntheses and formal syntheses of a
number of natural products.
220.1463; found 220.1460. IR (neat): ν = 3379, 2924, 1719, 1455,
˜
1377, 1257, 1012, 883 cm–1.
Compound 19: Yield 119 mg, 75% from 18 (0.75 mmol) and
670 mg, 79% from 6 (4.0 mmol) by Method A; 1520 mg, 72% from
6 (10 mmol) by Method B; CH/EA, 97:3; colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 5.17 (t, J = 7.0 Hz, 1 H), 2.69 (t, J =
6.3 Hz, 1 H), 2.04–2.19 (m, 2 H), 1.97 (q, J = 7.0 Hz, 2 H), 1.70–
1.54 (m, 2 H), 1.60 (s, 3 H), 1.25–1.36 (m, 6 H), 1.29 (s, 3 H), 1.25
(s, 3 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 133.93 (C), 125.65 (CH), 64.38 (CH), 58.41 (C), 36.57
(CH2), 31.72 (CH2), 29.64 (CH2), 28.02 (CH2), 27.69 (CH2), 25.05
(CH3), 22.73 (CH2), 18.92 (CH3), 16.11 (CH3), 14.28 (CH3) ppm.
HRMS (70 eV): calcd. for C14H26O [M]+ 210.1984; found 210.1986.
Experimental Section
General Remarks: All reactions were performed in oven-dried
(100 °C) glassware under Ar. THF was freshly distilled from K,
Et2O from Na/K, while CH2Cl2, MeOH, and benzene were freshly
distilled from CaH2. The products were purified by flash
chromatography on Merck silica gel 50 (eluents are given in paren-
theses, EA refers to ethyl acetate, CH to cyclohexane). Yields refer
to analytically pure samples. Isomer ratios were determined by suit-
able 1H NMR integrals of cleanly separated signals. NMR: Bruker
IR (neat): ν = 2925, 1460, 1375, 1120 cm–1.
˜
Compound 21: Yield 78 mg, 79% from 20 (0.47 mmol) by Method
B; CH/EA, 97:3; colorless oil. 1H NMR (400 MHz, CDCl3): δ =
5.16 (t, J = 7.1 Hz, 1 H), 2.70 (t, J = 6.4 Hz, 1 H), 2.20–2.05 (m,
2 H), 1.97 (q, J = 6.9 Hz, 2 H), 1.69 (s, 3 H), 1.50–1.65 (m, 2 H),
1.25–1.34 (m, 6 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 0.81 (t, J = 6.9 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 133.97 (C), 126.46
(CH), 64.25 (CH), 58.43 (C), 31.74 (CH2), 29.84 (CH2), 28.61
(CH2), 27.95 (CH2), 27.58 (CH2), 25.03 (CH3), 23.44 (CH3), 22.74
(CH2), 18.82 (CH3), 14.17 (CH3) ppm. HRMS (70 eV): calcd. for
1
AMX 300 and AM 400 spectrometers. H NMR: CHCl3 (δ = 7.26
ppm) in the indicated solvent as internal standard in the same sol-
vent. 13C NMR: CDCl3 (δ =77.16 ppm) as internal standard in
the same solvent; integrals in agreement with assignments, coupling
constants are measured in Hz and are always given as J(H,H) coup-
ling constants. An asterisk (*) indicates the signal of the (Z,E) iso-
mer. IR spectra: Perkin-Elmer 1600 series FTIR spectrometer as
neat films on KBr plates. Farnesol was bought from Aldrich in the
form of a mixture of stereoisomers containing 50% of the all-(E)
isomer (GC-MS analysis with an authentic sample as stan-
dard).[5b,24] Geranylgeraniol was obtained from the plant Bellardia
trixago[5b] as an (E,E,E) isomer. The epoxy acetates 6,[5b] 7,[5c]
20,[5b] and 22[5b] were prepared according to known procedures.
Compounds 8–13, 15–17, 43–46, 48, 49, and 51 have been described
previously.[5c]
C H O [M]+ 210.1984; found 210.1985. IR (neat): ν = 2960, 2925,
˜
14 26
2855, 1460, 1375, 1120, 865 cm–1.
Compound 23: Yield 92 mg, 90% from 22 (0.35 mmol) by Method
B as a 1:1 mixture of (E,E) and (Z,E) isomers; CH/EA, 97:3; color-
1
less oil. H NMR (400 MHz, CDCl3): δ = 5.20–5.05 (m, 2 H), 2.69
(dd, J = 12.4, 6.2 Hz, 1 H), 2.68 (t, J = 6.2 Hz, 1 H), 2.20–2.00 (m,
4 H), 1.96 (quintuplet, J = 6.7 Hz, 4 H), 1.68 (m, 2 H), 1.60 (s, 6
H), 1.58 (s, 6 H), 1.35–1.20 (m, 6 H), 1.29* (s, 3 H), 1.28 (s, 3 H),
1.26* (s, 3 H), 1.24 (s, 3 H), 0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 134.65 (C), 134.58 (C), 134.09 (C),
134.06 (C), 125.90 (CH), 125.87 (CH), 125.17 (CH), 125.07 (CH),
64.29 (CH), 64.22 (CH), 58.36 (C), 58.34 (C), 40.03 (CH2), 39.78
(CH2), 36.44 (CH2), 31.98 (CH2), 31.68 (CH2), 31.65 (CH2), 29.67
(CH2), 29.65 (CH2), 28.01 (CH2), 27.99 (CH2), 27.62 (CH2), 27.58
(CH2), 26.74 (CH2), 26.62 (CH2), 25.03 (CH3), 25.00 (CH3), 23.49
General Procedure for Cu-Catalyzed Coupling. Method A: The lithi-
ated compound (2–4 mmol) was added to a solution of CuI (1–
2 mmol) in Et2O at –30 °C and the mixture was stirred at this tem-
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A. Gansäuer, J. M. Cuerva, J. E. Oltra et al.
(CH3), 23.42 (CH3), 22.74 (CH2), 22.72 (CH2), 18.85 (CH3), 18.81 (CH2), 27.07 (CH2), 26.80 (CH2), 26.57 (CH2), 25.04 (CH3), 18.90
FULL PAPER
(CH3), 16.11 (CH3), 16.06 (CH3), 14.19 (CH3), 14.18 (CH3) ppm.
(CH3), 16.23 (CH3) ppm. HRMS (70 eV): calcd. for C16H28O
HRMS (70 eV): calcd. for C19H34O [M]+ 278.2610; found 278.2600.
[M]+ 236.2140; found 236.2145. IR (neat): ν = 2921, 2849, 1447,
˜
IR (neat): ν = 2923, 1458, 1378, 1248, 1120, 864 cm–1.
1375, 1124, 880 cm–1.
˜
Compound 24: Yield 123 mg, 70% from 6 (0.72 mmol); CH/EA,
95:5; colorless oil. 1H NMR (300 MHz, CDCl3): δ = 7.34–7.30 (m,
4 H), 7.29–7.21 (m, 1 H), 5.16 (tq, J = 7.1, 1.2 Hz, 1 H), 4.48 (s, 2
H), 3.45 (t, J = 6.6 Hz, 2 H), 2.68 (t, J = 6.2 Hz, 1 H), 2.20–2.05
(m, 2 H), 1.99 (dd, J = 14.7, 7.4 Hz, 2 H), 1.73–1.60 (m, 3 H), 1.59
(s, 3 H), 1.47–1.35 (m, 3 H), 1.28 (s, 3 H), 1.24 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.81 (C), 134.32 (C), 128.42 (CH),
127.68 (CH), 127.55 (CH), 125.15 (CH), 72.98 (CH2), 70.47 (CH2),
64.27 (CH), 58.35 (C), 36.45 (CH2), 29.51 (CH2), 27.81 (CH2),
27.56 (CH2), 26.46 (CH2), 24.99 (CH3), 18.85 (CH3), 16.08 (CH3)
ppm. HRMS (70 eV): calcd. for C20H30O2 [M]+ 302.2246; found
Compound 29: Yield 124 mg, 68% from 6 (0.67 mmol); CH/EA,
97:3; colorless oil. H NMR (400 MHz, CDCl3): δ = 7.10 (d, J =
1
8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.22 (t, J = 7.0 Hz, 1 H),
3.78 (s, 3 H), 2.69 (t, J = 6.2 Hz, 1 H), 2.60 (d, J = 7.3 Hz, 1 H),
2.58 (d, J = 6.9 Hz, 1 H), 2.28 (q, J = 7.7 Hz, 2 H), 2.20–2.00 (m,
2 H), 1.68–1.59 (m, 2 H), 1.57 (s, 3 H), 1.30 (s, 3 H), 1.26 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 157.88 (C), 134.91 (C),
134.50 (C), 129.44 (CH), 124.45 (CH), 113.82 (CH), 64.27 (CH),
58.40 (C), 55.38 (CH3), 36.44 (CH2), 35.24 (CH2), 30.27 (CH2),
27.60 (CH2), 25.02 (CH3), 18.87 (CH3), 16.11 (CH3) ppm. HRMS
(70 eV): calcd. for C18H26O2 [M]+ 274.1933; found 274.1935. IR
(neat): ν = 2922, 1456, 1377, 782 cm–1. C H O (274.19): calcd.
302.2249. IR (neat): ν = 1613, 1586, 1513, 1462, 1377, 1301, 1247,
˜
˜
18 26
2
1172, 1094, 1036, 820 cm–1. C20H30O2 (302.22): calcd. C 79.42, H
10.00; found C 79.21, H 10.09.
C 78.79, H 9.55; found C 78.64, H 9.57.
Compound 30: Yield 125 mg, 54% from 6 (0.9 mmol); CH/EA, 97:3;
colorless oil. 1H NMR (300 MHz, CDCl3): δ = 7.20–6.90 (m, 4 H),
5.24 (t, J = 7.1 Hz, 1 H), 2.69 (t, J = 6.2 Hz, 1 H), 2.60 (dd, J =
8.3, 7.5 Hz, 2 H), 2.33, (s, 3 H), 2.30–2.00 (m, 4 H), 1.73–1.61 (m,
2 H), 1.59, (s, 3 H), 1.30 (s, 3 H), 1.26 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 142.34 (C), 137.88 (C), 134.93 (C), 129.40
(CH), 128.28 (CH), 126.59 (CH), 125.57 (CH), 124.50 (CH), 64.29
(CH), 58.41 (C), 36.46 (CH2), 36.12 (CH2), 30.10 (CH2), 27.63
(CH2), 25.03 (CH3), 21.54 (CH3), 18.88 (CH3), 16.12 (CH3) ppm.
HRMS (70 eV): calcd. for C18H26O [M]+ 258.1984; found 258.1984.
Compound 25: Yield 93 mg, 74% from 6 (0.37 mmol); CH/EA, 96:4;
colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.7 Hz,
2 H), 6.85 (d, J = 8.7 Hz, 2 H), 5.15 (tq, J = 7.0, 1.1 Hz, 1 H), 4.40
(s, 2 H), 3.78 (s, 3 H), 3.28 (dd, J = 9.1, 6.7 Hz, 1 H), 3.20 (dd, J
= 9.1, 6.7 Hz, 1 H), 2.68 (t, J = 6.2 Hz, 1 H), 2.19–1.80 (m, 4 H),
1.80–1.60 (m, 3 H), 1.59 (s, 3 H), 1.50–1.42 (m, 1 H), 1.28 (s, 3 H),
1.24 (s, 3 H), 1.19–1.15 (m, 1 H), 0.91 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.19 (C), 134.03 (C), 131.04
(C), 129.18 (CH), 125.33 (CH), 113.84 (CH), 75.73 (CH2), 72.75
(CH2), 64.28 (CH), 58.37 (C), 55.35 (CH3), 36.44 (CH2), 33.82
(CH2), 33.23 (CH), 27.57 (CH2), 25.47 (CH2), 24.98 (CH3), 18.86
(CH3), 17.22 (CH3), 16.06 (CH3) ppm. HRMS (70 eV): calcd. for
IR (neat): ν = 2922, 1377, 780 cm–1. C H O (258.19): calcd. C
˜
18 26
83.62, H 10.14; found C 83.15, H 10.05.
Compound 31: Yield 95 mg, 65% from 22 (0.50 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 96:4; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 5.33–5.21 (m, 2 H), 2.55 (t, J =
6.2 Hz, 1 H), 2.22–2.00 (m, 10 H), 1.85–1.62 (m, 6 H), 1.60* (s, 3
H), 1.59 (s, 3 H), 1.55* (s, 3 H), 1.54 (s, 3 H), 1.52–1.44 (m, 2 H),
1.14 (s, 3 H), 1.11* (s, 3 H), 1.10 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 134.98 (C), 134.78 (C), 134.27 (C), 134.07
(C), 125.93 (CH), 125.08 (CH), 124.49 (CH), 124.40 (CH), 64.31
(CH), 64.24 (CH), 58.41 (C), 58.36 (C), 46.46 (CH2), 40.70 (CH),
40.65 (CH), 40.12 (CH2), 39.87 (CH2), 34.16 (CH2), 34.13 (CH2),
32.43 (CH2), 32.41 (CH2), 32.06 (CH2), 31.94 (CH2), 27.63 (CH2),
27.59 (CH2), 26.75 (CH2), 26.63 (CH2), 25.49 (CH2), 25.27 (CH2),
25.04 (CH3), 25.02 (CH3), 23.56 (CH3), 23.44 (CH3), 18.86 (CH3),
18.83 (CH3), 16.21 (CH3), 16.15 (CH3) ppm. HRMS (70 eV): calcd.
C22H34O2 [M]+ 346.2508; found 346.2525. IR (neat): ν = 2957,
˜
1613, 1513, 1462, 1377, 1301, 1247, 1172, 1095, 820 cm–1.
Compound 26: Yield 119 mg, 73% from 6 (0.52 mmol); CH/EA,
95:5; colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.30 (m,
4 H), 7.28–7.23 (m, 1 H), 5.16 (tq, J = 7.1, 1.2 Hz, 1 H), 4.48 (s, 2
H), 3.45 (t, J = 6.6 Hz, 2 H), 2.68 (t, J = 6.2 Hz, 1 H), 2.19–2.03
(m, 2 H), 1.98 (dd, J = 13.4, 6.7 Hz, 2 H), 1.72–1.61 (m, 4 H), 1.74
(s, 3 H), 1.38–1.33 (m, 4 H), 1.28 (s, 3 H), 1.24 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 138.82 (C), 134.10 (C), 128.40 (CH),
127.67 (CH), 127.53 (CH), 125.32 (CH), 72.95 (CH2), 70.54 (CH2),
64.26 (CH), 58.34 (C), 36.44 (CH2), 29.79 (CH2), 29.73 (CH2),
27.97 (CH2), 27.55 (CH2), 25.99 (CH2), 24.98 (CH3), 18.84 (CH3),
16.05 (CH3) ppm. HRMS (70 eV): calcd. for C21H32O2 [M]+
for C20H34O [M]+ 290.2610; found 290.2618. IR (neat): ν = 2951,
316.2402; found 316.2401. IR (neat): ν = 1495, 1454, 1377, 1249,
˜
˜
1204, 1104, 1027, 901, 873, 735, 697 cm–1.
1449, 1377, 1247, 1211, 871, 680 cm–1.
Compound 27: Yield 67 mg, 61% from 6 (0.50 mmol); CH/EA, 92:8;
colorless oil. H NMR (400 MHz, CDCl3): δ = 5.38 (tq, J = 7.2,
Compound 32: Yield 92 mg, 66% from 22 (0.46 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 9:1; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 5.21–5.09 (m, 2 H), 2.70* (t, J =
6.4 Hz, 1 H), 2.69 (t, J = 6.4 Hz, 1 H), 2.21–1.97 (m, 6 H), 1.69*
(s, 3 H), 1.68 (s, 3 H) 1.66–1.64 (m, 2 H), 1.63* (s, 3 H), 1.61 (s, 3
H), 1.59–1.54 (m, 2 H), 1.30* (s, 3 H), 1.29 (s, 3 H), 1.27* (s, 3 H),
1.25 (s, 3 H), 1.23–0.82 (m, 11 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 135.24 (C), 135.14 (C), 134.11 (C), 134.08 (C), 125.11
(CH), 125.08 (CH), 123.75 (CH), 123.64 (CH), 64.33 (CH), 64.25
(CH), 58.43 (C), 58.37 (C), 43.62 (CH), 40.17 (CH2), 39.92 (CH2),
38.77 (CH), 36.45 (CH2), 35.93 (CH2), 35.91 (CH2), 35.81 (CH2),
33.46 (CH2), 33.38 (CH2), 33.37 (CH2), 30.34 (CH2), 28.68 (CH2),
27.64 (CH2), 27.60 (CH2), 27.06 (CH2), 27.04 (CH2), 26.82 (CH2),
1
1.3 Hz, 1 H), 2.70 (t, J = 6.2 Hz, 1 H), 2.23–2.09 (m, 2 H), 1.99 (t,
J = 6.9 Hz, 2 H), 1.88–1.63 (m, 5 H), 1.61 (s, 3 H), 1.59–1.42 (m,
4 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.20–1.08 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 134.08 (C), 124.95 (CH), 64.35 (CH), 58.44
(C), 40.63 (CH), 36.60 (CH2), 34.21 (CH2), 32.48 (CH2), 32.46
(CH2), 27.64 (CH2), 25.28 (CH2), 25.05 (CH3), 18.89 (CH3), 16.23
(CH3) ppm. HRMS (70 eV): calcd. for C15H26O [M]+ 222.1984;
found 222.1985. IR (neat): ν = 2951, 1451, 1377, 1121, 872 cm–1.
˜
Compound 28: Yield 68 mg, 63% from 6 (0.46 mmol); CH/EA, 9:1;
1
colorless oil. H NMR (400 MHz, CDCl3): δ = 5.20 (tq, J = 7.3,
1.2 Hz, 1 H), 2.70 (t, J = 6.3 Hz, 1 H), 2.21–1.98 (m, 2 H), 1.87 (t,
J = 6.9 Hz, 2 H), 1.75–1.61 (m, 6 H), 1.60 (s, 3 H), 1.29 (s, 3 H), 26.80 (CH2), 26.76 (CH2), 26.68 (CH2), 26.60 (CH2), 25.04 (CH3),
1.26 (s, 3 H), 1.25–0.85 (m, 7 H) ppm. 13C NMR (100 MHz, 25.03 (CH3), 23.59 (CH3), 23.44 (CH3), 18.89 (CH3), 18.83 (CH3),
CDCl3): δ = 134.54 (C), 124.18 (CH), 64.37 (CH), 58.44 (C), 43.64
(CH), 36.65 (CH2), 35.94 (CH2), 33.38 (CH2), 30.35 (CH2), 27.66
16.23 (CH3), 16.16 (CH3) ppm. HRMS (70 eV): calcd. for C21H36O
[M]+ 304.2766; found 304.2772. IR (neat): ν = 2921, 2849, 1447,
˜
4122
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4115–4127

Preparation of Terpenoids
FULL PAPER
1376, 1121, 873 cm–1. C21H36O2 (304.27): calcd. C 82.83, H 11.92;
found C 83.22, H 11.80.
(CH), 110.39 (CH), 64.36 (CH), 58.50 (C), 55.46 (CH3), 36.53
(CH2), 28.52 (CH2), 27.57 (CH2), 24.97 (CH3), 18.88 (CH3), 16.21
(CH3) ppm. HRMS (70 eV): calcd. for C17H24O2 [M]+ 260.1776;
Compound 33: Yield 60 mg, 62% from 22 (0.35 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 97:3; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 5.74 (m, 1 H), 5.15–5.00 (m, 2 H),
4.92 (ddd, J = 17.0, 3.7, 1.8 Hz, 1 H), 4.86 (ddt, J = 10.3, 2.2,
1.1 Hz, 1 H), 2.68* (t, J = 6.2 Hz, 1 H), 2.63 (dd, J = 12.4, 6.2 Hz,
found 260.1782. IR (neat): ν = 2966, 2930, 1721, 1599, 1490, 1461,
˜
1379, 1289, 1245, 1027, 753 cm–1.
Compound 37: Yield 75 mg, 68% from 6 (0.45 mmol); CH/EA, 92:8;
colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.09 (d, J = 8.8 Hz,
1 H), 2.10–1.85 (m, 10 H), 1.62 (q, J = 1.4 Hz, 2 H), 1.54* (s, 3 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.38 (tq, J = 7.3, 1.3 Hz, 1 H), 3.78
H), 1.52 (s, 3 H), 1.40–1.30 (m, 2 H), 1.23* (s, 3 H), 1.23 (s, 3 H),
(s, 3 H), 3.31 (d, J = 7.3 Hz, 2 H), 2.71 (t, J = 6.2 Hz, 1 H), 2.26–
1.22 (s, 3 H), 1.20* (s, 3 H), 1.19* (s, 3 H), 1.18 (s, 3 H) ppm. 13C 2.11 (m, 2 H), 1.74 (s, 3 H), 1.71–1.56 (m, 2 H), 1.28 (s, 3 H), 1.26
NMR (100 MHz, CDCl3): δ = 139.12 (CH), 139.11 (CH), 135.14 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.93 (C), 135.02
(C), 135.06 (C), 134.17 (C), 134.13 (C), 125.86 (CH), 125.02 (CH),
(C), 133.73 (C), 129.27 (CH), 124.27 (CH), 113.96 (CH), 64.24
124.68 (CH), 124.59 (CH), 114.42 (CH2), 114.41 (CH2), 64.30 (CH), 58.40 (C), 55.38 (CH3), 36.48 (CH2), 33.44 (CH2), 27.55
(CH), 64.22 (CH), 58.42 (C), 58.37 (C), 40.04 (CH2), 39.79 (CH2), (CH2), 24.97 (CH3), 18.86 (CH3), 16.24 (CH3) ppm. HRMS
36.45 (CH2), 33.48 (CH2), 33.46 (CH2), 29.22 (CH2), 29.21 (CH2), (70 eV): calcd. for C17H24O2 [M]+ 260.1776; found 260.1781. IR
28.67 (CH2), 27.62 (CH2), 27.58 (CH2), 27.48 (CH2), 27.46 (CH2), (neat): ν = 3372, 2959, 1607, 1511, 1460, 1378, 1246, 1175, 1109,
˜
26.73 (CH2), 26.60 (CH2), 25.04 (CH3), 25.02 (CH3), 23.51 (CH3), 1035, 970, 819 cm–1.
23.44 (CH3), 18.87 (CH3), 18.83 (CH3), 16.13 (CH3), 16.11 (CH3)
Compound 38: Yield 725 mg, 76% from 6 (3.00 mmol); CH/EA,
ppm. HRMS (70 eV): calcd. for C19H32O [M]+ 276.2453; found
96:4; colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.81–7.76 (m,
276.2445. IR (neat): ν = 2923, 1451, 1378, 1248, 1121, 908 cm–1.
˜
3 H), 7.62 (s, 1 H), 7.48–7.40 (m, 2 H), 7.33 (td, J = 8.6, 1.3 Hz, 1
H), 5.50 (t, J = 7.3 Hz, 1 H), 3.50 (d, J = 7.2 Hz, 2 H), 2.74 (t, J
= 6.2 Hz, 1 H), 2.31–2.17 (m, 2 H), 1.81 (s, 3 H), 1.76–1.65 (m, 2
Compound 34: Yield 77 mg, 79% from 22 (0.35 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 97:3; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 5.25–5.15 (m, 2 H), 2.69* (t, J = H), 1.29 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
6.2 Hz, 1 H), 2.68 (t, J = 6.2 Hz, 1 H), 2.20–2.0 (m, 6 H), 1.86 (d,
J = 7.7 Hz, 2 H), 1.70 (dq, J = 9.7, 1.1 Hz, 2 H), 1.62 (s, 3 H), 1.58
(s, 3 H), 1.30* (s, 3 H), 1.29 (s, 3 H), 1.25* (s, 3 H), 1.25 (s, 3 H),
0.87 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.11 (C),
δ = 139.17 (C), 135.71 (C), 133.82 (C), 132.15 (C), 128.04 (CH),
127.72 (CH), 127.54 (CH), 127.44 (CH), 126.25 (CH), 126.00 (CH),
125.23 (CH), 123.68 (CH), 64.22 (CH), 58.39 (CH3), 36.54 (CH2),
34.55 (CH2), 27.57 (CH2), 24.98 (CH3), 18.88 (CH3), 16.37 (CH3)
136.04 (C), 134.11 (C), 134.09 (C), 125.09 (CH), 125.08 (CH), ppm. HRMS (70 eV): calcd. for C20H24O [M]+ 280.1827; found
122.25 (CH), 122.12 (CH), 64.33 (CH), 64.31 (CH), 58.42 (C),
58.36 (C), 42.02 (CH2), 41.86 (CH2), 40.41 (CH2), 40.15 (CH2),
36.47 (CH2), 36.45 (CH2), 31.95 (C), 31.82 (C), 29.47 (CH3), 29.41
(CH3), 27.63 (CH2), 27.58 (CH2), 27.06 (CH2), 26.76 (CH2), 25.05
(CH3), 25.03 (CH3), 23.76 (CH3), 23.46 (CH3), 18.88 (CH3), 18.83
(CH3), 16.18 (CH3), 16.16 (CH3) ppm. HRMS (70 eV): calcd. for
280.1820. IR (neat): ν = 3050, 2960, 2920, 1630, 1600, 1440, 1375,
˜
1120, 855, 810, 770, 745, 680 cm–1.
Compound 39: Yield 58 mg, 61% from 22 (0.30 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 95:5; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.16 (t, J = 7.7 Hz, 1 H), 7.13 (d, J
= 7.7 Hz, 1 H), 6.88 (td, J = 7.7, 1.0 Hz, 1 H), 6.84 (dd, J = 7.7,
1.0 Hz, 1 H), 5.32 (t, J = 7.3 Hz, 1 H), 5.17 (t, J = 6.9 Hz, 1 H),
3.83 (s, 3 H), 3.33 (d, J = 7.3 Hz, 2 H), 2.69 (t, J = 6.2 Hz, 1 H),
2.68* (t, J = 6.2 Hz, 1 H), 2.20–2.03 (m, 8 H), 1.74* (s, 3 H), 1.70
(s, 3 H), 1.63* (s, 3 H), 1.61 (s, 3 H), 1.60–1.50 (m, 4 H), 1.30* (s,
3 H), 1.29 (s, 3 H), 1.26* (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR
C H O [M]+ 278.2610; found 278.2603. IR (neat): ν = 2956, 1460,
˜
19 34
1377, 1245, 1122, 871, 681 cm–1.
Compound 35: Yield 111 mg, 48% from 22 (0.7 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 97:3; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.18 (dd, J = 7.6, 1.3 Hz, 1 H), 7.02
(s, 1 H), 7.01 (d, J = 7.6 Hz, 2 H), 5.25–5.15 (m, 2 H), 2.76–2.69 (100 MHz, CDCl3): δ = 157.47 (C), 157.41 (C), 136.13 (C), 136.07
(m, 1 H), 2.65–2.59 (m, 2 H), 2.35 (s, 3 H), 2.40–2.00 (m, 7 H), (C), 134.27 (C), 134.23 (C), 130.24 (C), 130.21 (C), 129.46 (CH),
1.74–1.57 (m, 3 H), 1.65 (s, 3 H), 1.59 (s, 3 H), 1.33* (s, 3 H), 1.32
(s, 3 H), 1.29* (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 142.42 (C), 142.40 (C), 137.83 (C), 137.78 (C), 135.71
(C), 135.62 (C), 134.18 (C), 134.15 (C), 129.37 (CH), 129.34 (CH),
128.26 (CH), 128.22 (CH), 126.56 (CH), 126.51 (CH), 125.55 (CH),
125.51 (CH), 125.00 (CH), 124.91 (CH), 124.03 (CH), 123.95 (CH),
129.37 (CH), 127.02 (CH), 126.97 (CH), 125.03 (CH), 125.01 (CH),
122.77 (CH), 122.67 (CH), 120.58 (CH), 120.56 (CH), 110.35 (CH),
110.34 (CH), 64.36 (CH), 64.27 (CH), 58.44 (C), 58.43 (C), 55.47
(CH3), 55.44 (CH3), 40.09 (CH2), 39.85 (CH2), 36.46 (CH2), 32.01
(CH2), 28.33 (CH2), 28.31 (CH2), 27.63 (CH2), 27.60 (CH2), 26.74
(CH2), 26.70 (CH2), 25.06 (CH3), 25.04 (CH3), 23.63 (CH3), 23.47
64.27 (CH), 64.25 (CH), 58.39 (C), 58.35 (C), 39.99 (CH2), 39.75 (CH3), 18.90 (CH3), 18.84 (CH3), 16.19 (CH3), 16.17 (CH3) ppm.
(CH2), 36.47 (CH2), 36.42 (CH2), 36.19 (CH2), 36.17 (CH2), 30.10 HRMS (70 eV): calcd. for C22H32O2 [M]+ 328.2402; found
(CH2), 30.08 (CH2), 27.62 (CH2), 27.58 (CH2), 26.77 (CH2), 26.61 328.2401. IR (neat): ν = 3350, 2959, 2924, 1596, 1490, 1457, 1377,
˜
(CH2), 25.01 (CH3), 24.99 (CH3), 23.49 (CH3), 22.43 (CH3), 21.50 1243, 1111, 1030, 871, 753 cm–1.
(CH3), 18.87 (CH3), 17.86 (CH3), 16.10 (CH3), 16.09 (CH3) ppm.
Compound 40: Yield 75 mg, 59% from 22 (0.40 mmol) as a 1:1 mix-
HRMS (70 eV): calcd. for C23H34O [M]+ 326.2610; found 326.2608.
ture of (E,E) and (Z,E) isomers; CH/EA, 97:3; colorless oil. 1H
IR (neat): ν = 2945, 1386, 787 cm–1.
˜
NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 8.5 Hz, 2 H), 6.82 (d,
Compound 36: Yield 68 mg, 69% from 6 (0.40 mmol);CH/EA, 92:8;
colorless oil. H NMR (400 MHz, CDCl3): δ = 7.17 (td, J = 7.4,
J = 8.5 Hz, 2 H), 5.32 (t, J = 7.3 Hz, 1 H), 5.17 (t, J = 6.9 Hz, 1
H), 3.78 (s, 3 H), 3.30 (d, J = 7.3 Hz, 2 H), 2.62* (t, J = 6.2 Hz, 1
1
1.5 Hz, 1 H), 7.12 (dd, J = 7.4, 1.5 Hz, 1 H), 6.87 (td, J = 7.4, H), 2.61 (t, J = 6.2 Hz, 1 H), 2.13–1.95 (m, 7 H), 1.74* (s, 3 H),
1.1 Hz, 1 H), 6.77 (br. d, 1 H), 5.36 (tq, J = 7.3, 1.2 Hz, 1 H), 3.82 1.70 (s, 3 H), 1.63* (s, 3 H), 1.62 (s, 3 H), 1.60–1.52 (m, 4 H), 1.30*
(s, 3 H), 3.34 (d, J = 7.3 Hz, 2 H), 2.70 (t, J = 6.2 Hz, 1 H), 2.31– (s, 3 H), 1.29 (s, 3 H), 1.26* (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR
2.05 (m, 2 H), 1.73 (s, 3 H), 1.71–1.57 (m, 2 H), 1.26 (s, 3 H), 1.24
(100 MHz, CDCl3): δ = 158.12 (C), 158.11 (C), 136.14 (C), 136.08
(C), 134.57 (C), 134.53 (C), 134.20 (C), 134.19 (C), 129.51 (CH),
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.45 (C), 135.14
(C), 130.02 (C), 129.45 (CH), 127.08 (CH), 123.35 (CH), 120.58 129.50 (CH), 125.98 (CH), 125.13 (CH), 124.01 (CH), 123.92 (CH),
Eur. J. Org. Chem. 2006, 4115–4127
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4123

A. Gansäuer, J. M. Cuerva, J. E. Oltra et al.
FULL PAPER
113.98 (CH), 113.96 (CH), 64.35 (CH), 64.27 (CH), 58.48 (C),
58.44 (C), 55.44 (CH3), 40.02 (CH2), 39.78 (CH2), 36.48 (CH2),
8.3 Hz, 2 H), 6.80 (d, J = 8.3 Hz, 2 H), 4.81 (s, 1 H), 4.55 (s, 1 H),
3.77 (s, 3 H), 3.50 (dd, J = 9.5, 4.2 Hz, 1 H), 2.91 (dd, J = 14.9,
36.46 (CH2), 33.43 (CH2), 33.34 (CH2), 27.63 (CH2), 27.60 (CH2), 2.8 Hz, 1 H), 2.77 (dd, J = 14.9, 10.8 Hz, 1 H), 2.37 (dt, J = 13.3,
26.71 (CH2), 26.54 (CH2), 25.07 (CH3), 25.05 (CH3), 23.58 (CH3), 5.1 Hz, 1 H), 2.13 (dq, J = 10.8, 1.4 Hz, 1 H), 2.10–1.95 (m, 1 H),
23.48 (CH3), 18.90 (CH3), 18.86 (CH3), 16.26 (CH3), 16.19 (CH3) 1.88 (ddd, J = 12.7, 9.4, 4.9 Hz, 1 H), 1.60 (s, 1 H, OH), 1.62–1.50
ppm. HRMS (70 eV): calcd. for C22H32O2 [M]+ 328.2402; found
(m, 1 H), 1.13 (s, 3 H), 0.87 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.56 (C), 146.72 (C), 134.33 (C), 129.55 (CH),
113.62 (CH), 110.12 (CH2), 77.26 (CH), 55.33 (CH3), 53.08 (CH),
40.76 (C), 32.73 (CH2), 32.18 (CH2), 31.29 (CH2), 26.35 (CH3),
16.21 (CH3) ppm. HRMS (70 eV): calcd. for C17H24O2 [M]+
328.2401. IR (neat): ν = 3352, 2925, 1608, 1510, 1457, 1378, 1245,
˜
1175, 1115, 1034, 822 cm–1.
Compound 41: Yield 131 mg, 62% from 22 (0.74 mmol) as a 1:1
1
mixture of (E,E) and (Z,E) isomers; CH/EA, 9:1; colorless oil. H
260.1776; found 260.1780. IR (neat): ν = 3394, 2934, 1512, 1246,
˜
NMR (400 MHz, CDCl3): δ = 7.29 (br. s, 1 H), 6.19 (br. s, 1 H),
5.88 (br. s, 1 H), 5.33 (t, J = 7.4 Hz, 1 H), 5.22–5.13 (m, 1 H), 3.34
(d, J = 7.4 Hz, 2 H), 2.69 (t, J = 6.1 Hz, 1 H), 2.22–2.03 (m, 10
H), 1.76–1.74 (m, 2 H), 1.69* (s, 3 H), 1.68 (s, 3 H), 1.62* (s, 3 H),
1.62 (s, 3 H), 1.29 (s, 3 H), 1.26* (s, 3 H), 1.25 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.45 (C), 155.44 (C), 141.07 (CH),
137.59 (C), 137.51 (C), 134.47 (C), 134.44 (C), 124.79 (CH), 124.67
(CH), 119.63 (CH), 119.55 (CH), 110.31 (CH), 110.28 (CH), 104.81
(CH), 104.80 (CH), 64.34 (CH), 64.25 (CH), 58.48 (C), 58.43 (C),
39.90 (CH2), 39.66 (CH2), 36.47 (CH2), 28.70 (CH2), 27.62 (CH2),
27.59 (CH2), 27.15 (CH2), 27.06 (CH2), 26.60 (CH2), 26.46 (CH2),
25.06 (CH3), 25.04 (CH3), 23.54 (CH3), 23.46 (CH3), 18.90 (CH3),
18.86 (CH3), 16.25 (CH3), 16.17 (CH3) ppm. HRMS (70 eV): calcd.
1043 cm–1. C17H24O2 (260.17): calcd. C 78.42, H 9.29; found C
78.13, H 9.40.
Compound 50: Yield 141 mg, 41% from 42 (1.71 mmol); CH/EA,
1
9:1; colorless oil. H NMR (300 MHz, CDCl3): δ = 6.68 (s, 1 H),
6.61 (s, 1 H), 5.85 (s, 2 H), 5.09 (s, 2 H), 4.79 (br. s, 1 H), 4.65 (br.
s, 1 H), 3.49 (s, 3 H), 3.28 (dd, J = 11.5, 4.7 Hz, 1 H), 2.70 (d, J =
4.9 Hz, 1 H), 2.69 (s, 1 H), 2.38 (ddd, J = 12.8, 4.3, 2.5 Hz, 1 H),
2.09 (q, J = 4.3 Hz, 1 H), 2.05–1.85 (m, 2 H), 1.78 (sextuplet, J =
2.5 Hz, 1 H), 1.77–1.28 (m, 4 H), 1.17 (dd, J = 12.8, 2.5 Hz, 1 H),
1.01 (s, 3 H), 0.81 (s, 3 H), 0.80 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.73 (C), 147.91 (C), 145.78 (C), 142.15 (C), 123.84
(C), 108.94 (CH), 108.22 (CH2), 101.11 (CH2), 98.30 (CH), 95.80
(CH2), 79.09 (CH), 56.38 (CH3), 56.28 (CH), 55.05 (CH), 39.94
(C), 39.32 (C), 38.21 (CH2), 37.32 (CH2), 28.54 (CH3), 28.10 (CH2),
24.11 (CH2), 23.52 (CH2), 15.65 (CH3), 14.76 (CH3) ppm. HRMS
(70 eV): calcd. for C24H34O5 [M]+ 402.2406; found 402.2413. IR
for C19H28O2 [M]+ 288.2089; found 288.2079. IR (neat): ν = 3330,
˜
2958, 1593, 1457, 1378, 1250, 1119, 1009, 803, 732, 672 cm–1.
Compound 42: Yield 920 mg, 60% from 22 (3.8 mmol) as a 1:1 mix-
ture of (E,E) and (Z,E) isomers; CH/EA, 95:5; colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 6.70 (s, 1 H), 6.63 (s, 1 H), 5.87 (s,
3 H), 5.86* (s, 3 H), 5.29–5.23 (m, 1 H), 5.22–5.13 (m, 1 H), 5.08
(s, 3 H), 3.48 (s, 3 H), 3.47* (s, 3 H), 3.26 (d, J = 7.2 Hz, 2 H),
2.73–2.67 (m, 1 H), 2.20–2.00 (m, 5 H), 1.73 (q, J = 1.2 Hz, 1 H),
1.70* (s, 3 H), 1.69 (s, 3 H), 1.62* (s, 3 H), 1.61 (s, 3 H), 1.30 (s, 3
H), 1.29* (s, 3 H), 1.26* (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.51 (C), 149.50 (C), 146.05 (C), 146.02
(C), 142.34 (C), 142.33 (C), 136.23 (C), 136.17 (C), 134.41 (C),
134.35 (C), 124.91 (CH), 124.85 (CH), 123.70 (C), 123.62 (C),
123.00 (CH), 122.89 (CH), 109.20 (CH), 109.14 (CH), 101.15
(CH2), 98.71 (CH), 98.65 (CH), 95.94 (CH2), 95.93 (CH2), 64.34
(CH), 64.31 (CH), 58.47 (C), 58.41 (C), 56.13 (CH3), 56.12 (CH3),
40.04 (CH2), 39.80 (CH2), 36.46 (CH2), 36.42 (CH2), 28.69 (CH2),
28.25 (CH2), 27.60 (CH2), 27.58 (CH2), 26.67 (CH2), 26.51 (CH2),
25.05 (CH3), 25.03 (CH3), 23.59 (CH3), 23.44 (CH3), 18.87 (CH3),
18.83 (CH3), 16.16 (CH3), 16.13 (CH3) ppm. HRMS (70 eV): calcd.
(neat): ν = 3444, 2938, 1505, 1484, 1209, 1151, 1042, 992, 937,
˜
757 cm–1.
Synthesis of 52: O-Pentafluorophenyl chlorothioformate (225 mg,
0.86 mmol) was added to a stirred solution of 49 (153 mg,
0.43 mmol) and DMAP (156 mg, 1.29 mmol) in CH2Cl2 (3 mL) at
0 °C and the solution was stirred at room temp. for 4 h. Then Ac-
OEt was added and the mixture was washed with water, the organic
layer was dried with MgSO4, and the solvent removed. The residue
was purified by flash chromatography (CH/EA, 97:3) to yield the
xanthate (218 mg, 88%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 6.76–6.62 (m, 3 H), 5.03 (dd, J = 11.9, 4.3 Hz, 1 H),
4.81 (br. s, 1 H), 4.70 (br. s, 1 H), 3.81 (s, 3 H), 3.74 (s, 3 H), 2.80–
2.73 (m, 2 H), 2.45–2.36 (m, 1 H), 2.23 (t, J = 6.8 Hz, 1 H), 2.13–
1.96 (m, 3 H), 1.94–1.68 (m, 3 H), 1.52–1.33 (m, 3 H), 1.04 (s, 3
H), 0.99 (s, 3 H), 0.90 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 191.88 (C), 153.50 (C), 151.86 (C), 147.33 (C), 131.62 (C),
116.53 (CH), 111.10 (CH), 110.22 (CH), 108.68 (CH2), 95.28 (CH),
56.03 (CH3), 55.73 (CH3), 55.68 (CH), 54.99 (CH), 39.72 (CH2),
39.08 (CH2), 38.62 (C), 38.01 (CH2), 36.89 (C), 36.74 (CH2), 28.20
(CH3), 23.13 (CH2), 17.01 (CH3), 14.76 (CH3) ppm (some signals
were not observed). HRMS (70 eV): calcd. for C30H33F5O4S [M]+
for C24H34O5 [M]+ 402.2406; found 402.2408. IR (neat): ν = 2924,
˜
1504, 1484, 1436, 1210, 1152, 1042, 988, 938, 856 cm–1.
General Procedure for Radical Cyclization: THF (15 mL) was added
to a mixture of Cp2TiCl2 (0.2 mmol) and Mn dust (8 mmol) under
Ar and the suspension was stirred at room temp. until it turned
green (about 15 min). Then a solution of 2,4,6-collidine (7 mmol)
and Me3SiCl (4 mmol) in THF (5 mL) was added and the mixture
was stirred for 5 min and a solution of epoxypolyene (1 mmol) in
THF (5 mL) was finally added and the mixture was stirred at room
temp. overnight. Then 2  HCl was added, and the mixture was
extracted with tBuOMe. The combined organic layers were dried
with MgSO4 and the solvent was removed. The residue was dis-
solved in THF and a 1  solution of Bu4NF in THF (1.2 mmol)
was added. The new mixture was stirred for 30 min, diluted with
tBuOMe, and washed with brine. The organic layer was dried with
MgSO4 and the solvent removed. The residue was purified by flash
chromatography (CH/EA) to yield the cyclization compound.
584.2020; found 584.2026. IR (neat): ν = 2947, 1523, 1377, 1306,
˜
1220, 1129, 997, 791, 727 cm–1. The xanthate (240 mg, 0.41 mmol)
was dissolved in benzene (45 mL), and then AIBN (14 mg,
0.08 mmol) and HSnBu3 (347 mg, 1.23 mmol) were added, and the
mixture was stirred at reflux for 4 h. Then, the solvent was re-
moved. The residue was purified by flash chromatography (CH/
1
EA, 99:1) to yield 52 (125 mg, 89%) as a colorless oil. Its H and
13C NMR data match with those previously reported.[20e]
Synthesis of Zonarone (2): 2,6-Dicarboxypyridine N-oxide
(416 mg), H2O (13.7 mL) and a 1  aq. solution of CAN (3.75 mL,
4.5 mmol) were added to a solution of 52 (125 mg, 0.37 mmol) in
a mixture of MeCN/DMF (1:1, 35 mL). The mixture was stirred
at room temp. for 8 min. Then, water was added, the mixture was
extracted with tBuOMe, the combined organic layers were dried
Compound 47: Yield 210 mg, 60% from 37 (1.34 mmol); CH/EA,
1
92:8; colorless oil. H NMR (400 MHz, CDCl3): δ = 7.08 (d, J =
4124
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4115–4127

Preparation of Terpenoids
FULL PAPER
with MgSO4, and the solvent was removed. The residue was puri-
AIBN (9 mg, 0.05 mmol) in benzene (1.5 mL) and the new mixture
was refluxed for 1 h. Then the solvent was removed and the residue
was purified by flash chromatography (CH/EA, 98:2) to yield 54
fied by flash chromatography (CH/EA, 95:5) to yield 2 (95 mg,
1
85%) as a yellow oil. Its H and 13C NMR data match with those
previously reported.[20d]
(89 mg, 93%) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
1
6.68 (s, 1 H), 6.63 (s, 1 H), 5.86 (s, 2 H), 5.10 (d, J = 0.7 Hz, 2 H),
4.77 (br. s, 1 H), 4.62 (br. s, 1 H), 3.50 (s, 3 H), 2.71 (d, J = 1.3 Hz,
1 H), 2.70 (s, 1 H), 2.36 (ddd, J = 12.8, 4.2, 2.5 Hz, 1 H), 2.13 (t,
J = 6.6 Hz, 1 H), 1.99 (ddd, J = 12.9, 12.9, 5.2 Hz, 1 H), 1.87 (dd,
J = 12.9, 1.3 Hz, 1 H), 1.75 (dquint, J = 12.9, 2.6 Hz, 1 H), 1.61
(dt, J = 13.6, 3.3 Hz, 1 H), 1.58–1.10 (m, 6 H), 0.90 (s, 3 H), 0.84
(s, 3 H), 0.81 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
149.73 (C), 148.61 (C), 145.67 (C), 142.13 (C), 124.30 (C), 109.06
(CH), 107.87 (CH2), 101.09 (CH2), 98.35 (CH), 95.93 (CH2), 56.61
(CH3), 56.24 (CH), 55.96 (CH), 42.41 (CH2), 40.23 (C), 39.42
(CH2), 38.47 (CH2), 33.83 (CH3), 33.81 (C), 24.61 (CH2), 23.42
(CH2), 21.97 (CH3), 19.68 (CH2), 14.72 (CH3) ppm. HRMS
(70 eV): calcd. for C24H34O4 [M]+ 386.2457; found 386.2455. IR
Synthesis of Zonarol (1): Na2S2O4 (635 mg, 3.6 mmol) was added
to a solution of 2 (95 mg, 0.3 mmol) in THF/H2O (3:2, 40 mL),
and the mixture was heated at reflux for 30 min. Then, water was
added, the mixture was extracted with AcOEt, the combined or-
ganic layers were dried with MgSO4, and the was solvent removed.
The residue was purified by flash chromatography (CH/EA, 8:2) to
afford 1 (72 mg, 75%) as a colorless oil. Its 1H and 13C NMR data
match with those previously reported.[10]
Preparation of Compound 53: DMAP (280 mg, 2.28 mmol) and O-
pentafluorophenyl chlorothioformate (0.244 mL, 1.52 mmol) were
added to a solution of alcohol 47 (200 mg, 0.76 mmol) in CH2Cl2
(8 mL) at 0 °C and the mixture was stirred at room temp. for 2 h.
Then water was added and the mixture was extracted with AcOEt,
the extract dried with MgSO4, and the solvent removed. The resi-
due was purified by flash chromatography (CH/EA, 97:3) to afford
the xanthate (280 mg, 76%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ = 7.05 (d, J = 8.6 Hz, 2 H), 6.80 (d, J = 8.6 Hz, 2 H),
5.22 (dd, J = 7.9, 3.8 Hz, 1 H), 4.83 (s, 1 H), 4.52 (s, 1 H), 3.78 (s,
3 H), 2.93 (dd, J = 14.6, 2.9 Hz, 1 H), 2.74 (dd, J = 14.6, 10.9 Hz,
1 H), 2.50–2.35 (m, 1 H), 2.21 (dd, J = 10.9, 2.9 Hz, 1 H), 2.18–
2.03 (m, 2 H), 1.98–1.83 (m, 1 H), 1.14 (s, 3 H), 1.06 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 191.69 (C), 157.80 (C), 145.05
(C), 133.67 (C), 129.70 (CH), 113.70 (CH), 111.88 (CH2), 92.68
(CH), 55.33 (CH3), 53.98 (CH), 40.12 (C), 31.97 (CH2), 30.45
(CH2), 27.26 (CH2), 26.58 (CH3), 19.12 (CH3) ppm (some signals
were not observed). HRMS (70 eV): calcd. for C24H23O3F5S [M]+
(neat): ν = 2933, 1505, 1483, 1208, 1150, 1043, 993, 938, 858 cm–1.
˜
Preparation of Compound 55: pTsOH (4 mg, 0.021 mmol) was
added to a solution of compound 54 (18 mg, 0.046 mmol) in
MeOH (0.5 mL). The mixture was stirred at room temp. for 48 h.
Then AcOEt was added and the mixture was washed with water.
The organic layer was dried with MgSO4 and the solvent removed.
The residue was purified by flash chromatography (CH/EA, 95:5)
to yield 55 (13 mg, 85%) as a colorless oil. Its 1H and 13C NMR
data match with those previously reported.[12b]
Synthesis of Compound 56: N-(Phenylseleno)phthalimide (102 mg,
0.31 mmol) and a 0.19  solution of SnCl4 in CH2Cl2 (0.15 mL,
0.03 mmol) were added to a solution of 55 (100 mg, 0.29 mmol) in
CH2Cl2 (4 mL) at 0 °C. After stirring for 30 min, the solution was
diluted with satd. aq. NaHCO3 and extracted with tBuOMe. The
combined organic layers were washed with brine, dried with
MgSO4, and the solvent was removed. The residue was purified by
flash chromatography (CH/EA, 95:5) to yield 56 (115 mg, 80%) as
486.1288; found 486.1291. IR (neat): ν = 2950, 1521, 1377, 1305,
˜
1247, 1145, 1038, 998, 948 cm–1. HSnBu3 (0.21 mL, 0.78 mmol)
and AIBN (9 mg, 0.055 mmol) were slowly added to a solution of
the xanthate (130 mg, 0.26 mmol) in benzene (2 mL) and the mix-
ture was refluxed for 1 h. Then the solvent was removed. The resi-
due was purified by flash chromatography (CH/EA, 98:2) to yield
53 (52 mg, 77%) as a colorless oil. Its 1H and 13C NMR data match
with those previously reported.[21]
1
a colorless oil. H NMR (300 MHz, CDCl3): δ = 7.46–7.40 (m, 3
H), 7.22–7.18 (m, 2 H), 6.42 (s, 1 H), 6.24 (s, 1 H), 5.83 (d, J =
7.3 Hz, 1 H), 5.80 (d, J = 7.3 Hz, 1 H), 3.13 (d, J = 12.1 Hz, 1 H),
3.05 (d, J = 12.1 Hz, 1 H), 2.69–2.58 (m, 2 H), 2.19 (dt, J = 13.7,
3.0 Hz, 1 H), 1.85–1.37 (m, 10 H), 1.17 (ddd, J = 13.7, 13.1, 4.0 Hz,
1 H), 0.90 (s, 3 H), 0.81 (s, 3 H), 0.73 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.32 (C), 146.35 (C), 141.56 (C), 133.13
(CH), 131.01 (C), 129.10 (CH), 127.04 (CH), 114.02 (C), 107.45
(CH), 100.83 (CH2), 99.37 (CH), 77.94 (C), 55.19 (CH), 47.06
(CH), 42.03 (CH2), 40.32 (CH2), 38.65 (C), 38.37 (CH2), 37.81
(CH2), 33.82 (CH3), 33.42 (C), 22.65 (CH2), 22.04 (CH3), 18.61
(CH2), 18.27 (CH2), 14.51 (CH3) ppm. HRMS (70 eV): calcd. for
Synthesis of Compound 54: DMAP (109 mg, 0.89 mmol) and O-
pentafluorophenyl chlorothioformate (0.1 mL, 0.58 mmol) were
added to a solution of alcohol 50 (120 mg, 0.29 mmol) in CH2Cl2
(3 mL) at 0 °C. Then the mixture was stirred at room temp. for 2 h.
The reaction was quenched with water, the mixture extracted with
AcOEt, the extract dried with MgSO4, and the solvent removed.
The residue was purified by flash chromatography (CH/EA, 95:5)
to yield the xanthate derivative (170 mg, 94%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 6.69 (s, 1 H), 6.61 (s, 1 H), 5.86
(s, 2 H), 5.11 (s, 2 H), 5.01 (dd, J = 11.9, 4.4 Hz, 1 H), 4.83 (s, 1
H), 4.70 (s, 1 H), 3.50 (s, 3 H), 2.75 (dd, J = 15.3, 9.7 Hz, 1 H),
2.69 (dd, J = 15.3, 3.3 Hz, 1 H), 2.41 (ddd, J = 12.9, 4.0, 2.3 Hz,
1 H), 2.20–1.40 (m, 8 H), 1.35 (dd, J = 12.9, 2.3 Hz, 1 H), 1.03 (s,
3 H), 0.98 (s, 3 H), 0.88 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 191.93 (C), 149.72 (C), 147.44 (C), 145.87 (C), 142.25
(C), 123.53 (C), 108.91 (CH), 108.73 (CH2), 101.16 (CH2), 98.38
(CH), 95.89 (CH2), 95.24 (CH), 56.22 (CH3), 56.15 (CH), 55.11
(CH), 39.74 (C), 39.05 (C), 38.08 (CH2), 36.89 (CH2), 28.21 (CH3),
C28H34O3Se [M]+ 498.1673; found 498.1696. IR (neat): ν = 2929,
˜
1477, 1437, 1181, 1150, 1039, 936, 855, 754 cm–1.
Synthesis of Compound 57: A mixture of HSnBu3 (0.07 mL,
0.25 mmol) and AIBN (14 mg, 0.085 mmol) in benzene (2 mL) was
slowly added to a solution of 56 (85 mg, 0.17 mmol) in benzene
(5 mL) and the mixture was refluxed for 1 h. Then the solvent was
removed and the residue was purified by flash chromatography
(CH/EA, 95:5) to yield compound 57 (50 mg, 86%) as a colorless
oil. Its 1H and 13C NMR data match with those previously report-
ed.[12b]
23.82 (CH2), 23.74 (CH2), 23.11 (CH2), 17.07 (CH3), 14.83 (CH3) Synthesis of Compound 58: BF3·Et2O (101 mg, 0.71 mmol) was
ppm (some signals were not observed). HRMS (70 eV): calcd. for
added to a solution of 55 (121 mg, 0.35 mmol) in CH2Cl2 (4 mL)
and the mixture was stirred at room temp. for 1 h. Then water was
added and the new mixture was extracted with Et2O, the extract
dried with MgSO4, and the solvent removed. The residue was puri-
fied by flash chromatography (CH/EA, 97:3) to yield compound 55
C31H33O6F5S [M]+ 628.1918; found 628.1918. IR (neat): ν = 2958,
˜
1523, 1481, 1381, 1309, 1130, 1036, 996, 928, 852 cm–1. A solution
of the xanthate derivative (160 mg, 0.25 mmol) in benzene (2 mL)
was slowly added to a mixture of HSnBu3 (0.2 mL, 0.76 mmol) and
Eur. J. Org. Chem. 2006, 4115–4127
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4125

A. Gansäuer, J. M. Cuerva, J. E. Oltra et al.
FULL PAPER
(104 mg, 86%) as a colorless oil. Its H and 13C NMR data match
1
J. L. Oller-López, M. Valdivia, A. Haïdour, J. E. Oltra, A. F.
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Acknowledgments
We are grateful to the Spanish Ministerio de Educación y Ciencia
(project no. CTQ2005-08402/BQU) and to the University of Gra-
nada, the Ministerio de Educación y Ciencia, and the Fundación
Ramón Areces for postdoctoral grants. Continuing generous finan-
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Preparation of Terpenoids
FULL PAPER
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[24] The cyclization yields refer to the all-(E) isomer contained in
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not undergo cyclization under our experimental conditions, see
ref.[5b]
Received: May 3, 2006
Published Online: July 11, 2006
Eur. J. Org. Chem. 2006, 4115–4127
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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