A gold-catalyzed entry into the sesquisabinene and sesquithujene families of terpenoids and formal total syntheses of cedrene and cedrol

Article abstract of DOI:10.1002/chem.200801382

A concise entry into the bicyclic cyclopropyl ketone derivatives 5 and 6 by way of a gold-catalyzed Ohloff-Rautenstrauch-type enyne cycloisomerization is described. The required substrates were prepared by an asymmetric addition of the branched allylzinc reagent 21 to the alkynyl aldehyde 17 mediated by the deprotonated bisoxazoline (BOX) ligand 22. Compounds 5 and 6 were then converted into a host of different members of the sesquisabina- and sesquithuja families of terpenoids, inter alia with the aid of iron-catalyzed cross-coupling reactions. As the relative and absolute configuration of 5 and 6 could be unambiguously established, the synthetic samples allowed the previously unknown stereostructures of various such terpenoids to be unraveled, including cis-sesquisabinene hydrate (33), 7-epi-sesquithujene (36), sesquisabinene B (37) and epoxysesquithujene (45). Moreover, the preparation of 6 also constitutes a formal total synthesis of cedrene (11) and cedrol (12).

Full text of DOI:10.1002/chem.200801382

FULL PAPER
DOI: 10.1002/chem.200801382
A Gold-Catalyzed Entry into the Sesquisabinene and Sesquithujene Families
of Terpenoidsand Formal Total Synthesesof Cedrene and Cedrol
[a]
AloisFürstner* and AndreasSchlecker
Abstract: A concise entry into the bicy-
clic cyclopropyl ketone derivatives 5
into a host of different members of the
sesquisabina- and sesquithuja families
of terpenoids, inter alia with the aid of
iron-catalyzed cross-coupling reactions.
As the relative and absolute configura-
tion of 5 and 6 could be unambiguously
established, the synthetic samples al-
lowed the previously unknown stereo-
structures of various such terpenoids to
be unraveled, including cis-sesquisabi-
nene hydrate (33), 7-epi-sesquithujene
(36), sesquisabinene B (37) and epoxy-
sesquithujene (45). Moreover, the
and
6 by way of a gold-catalyzed
Ohloff–Rautenstrauch-type enyne cy-
cloisomerization is described. The re-
quired substrates were prepared by an
asymmetric addition of the branched
allylzinc reagent 21 to the alkynyl alde-
hyde 17 mediated by the deprotonated
bisoxazoline (BOX) ligand 22. Com-
pounds 5 and 6 were then converted
preparation of
6 also constitutes a
Keywords: cyclopropanes · gold ·
natural products · rearrangement ·
terpenoids
formal total synthesis of cedrene (11)
and cedrol (12).
Introduction
lyzed Ohloff-type reactions open entry into cyclopropyl car-
bonyl derivatives and as such represent a safe and conven-
ient alternative to the cyclization of unsaturated a-diazoke-
tones (Scheme 2).[4–10]
Even though the cycloisomerization of enynes with migrato-
ry participation of a propargylic carboxylate group was orig-
inally discovered by Ohloff with the aid of ZnCl2 as stoi-
chiometric promoter,[1] the true value of such transforma-
tions can only be garnered since the superior performance
of carbophilic p-acid catalysts has been recognized
(Scheme 1).[2,3] In conceptual terms, platinum- or gold-cata-
Scheme 2. Synthetic equivalence of classical a-diazoketone methodology
and noble metal catalyzed propargyl acetate rearrangements.
In pursuit of our previous investigations in this
field,[5,6,8,11–14] we now present a concise approach to bisabo-
lane-type sesquiterpenes by way of stereospecific gold-cata-
lyzed cycloisomerizations (Scheme 3). Since the first isola-
tion of sesquisabinene (7) from pepper (Piper nigrum)[15]
and of sesquithujene (9) as a major constituent of the essen-
tial oil of ginger (Zingiber officinale),[15] many relatives of
these natural products have been isolated which differ from
the parent compounds in the peripheral functionalization
pattern and/or in stereochemical terms;[16] in many cases,
however, remained the stereostructures of these congeners
uncertain or even completely unknown. It is also remark-
able that such bicyclic compounds are not only prevalent in
the plant kingdom but were also isolated from animals as
exemplified by the aggregation pheromone of the bug Ey-
Scheme 1. Comparison of the greatly different efficiencies of a conven-
tional Lewis acid and a p-acidic gold catalyst in the original Ohloff cyclo-
isomerization reaction.
[a] Prof. A. Fürstner, Dipl. Chem. A. Schlecker
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801382.
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9181

sarcoris lewisi (Distant) (8), a severe pest in rice fields in
Northern Japan.[17,18] Finally, it should be mentioned that the
key synthetic intermediate 6 required for the preparation of
sesquithujene and relatives also constitutes a known precur-
sor of cedrene (11) and cedrol (12).[19,20] Our stereoselective
approach to 6 hence represents a formal total synthesis of
these renowned targets too (Scheme 3).
Scheme 4. a) para-Formaldehyde, pyrrolidine, propionic acid, iPrOH,
458C, 88%; (ref. [21]); b) NaBH4, CeCl3·7H2O, MeOH, 08C, 98%;
c) Br2, PPh3, imidazole, CH2Cl2, 08C, 87%; d) see text and Table 1;
e) K2CO3, MeOH.
(BOX) derived ligand set (Scheme 5).[24,25] In this transfor-
mation, however, the best selectivities were observed for ke-
tones bearing bulky R1 substituents (e.g. R1 =adamantyl,
tert-butyl), whereas aldehydes gave rather poor results.[24]
This fact is deemed to reflect the peculiarities of a chair-like
transition state TS1, wherein the massive R1 group forces
the alkynyl moiety into an axial orientation such that it can
be recognized by the local chiral environment of the C2-sym-
metric BOX ligand (Scheme 5).[24] Aldehydes (R1 =H) obvi-
ously will not attain this crucial array; their alkynyl group
prefers the equatorial position in TS2, wherein it points
away from the stereodetermining ligand framework.
Scheme 3. Descent of prototype terpenoids of the sesquisabina and ses-
quithuja families as well as of cedrene and cedrol from the two diastereo-
meric [3.1.0]-bicyclohexanone derivatives 5 and 6.
Results and Discussion
Asymmetric synthesis of the cyclization precursors: The
preparation of the required substrates for the envisaged
noble metal catalyzed cycloisomerization reaction com-
menced with the large scale adaptable methylenation of
(R)-citronellal (13) (Scheme 4).[21] Reduction of the resulting
enal 14[22] and subsequent conversion of alcohol 15 into the
corresponding allylic bromide 16 set the stage for the addi-
tion of a derived organometallic reagent onto aldehyde 17.
Since noble metal-catalyzed rearrangements are known to
transmit the configuration of the propargylic center of
enynes of type 4 into the product stereostructure,[3–9] it was
of utmost importance to control the course of this addition
step. Unfortunately, however, some of the most widely prac-
ticed asymmetric allylation reactions for aldehydes either
failed in this particular case or resulted in disappointingly
low diastereomeric ratios.[23]
Scheme 5. Asymmetric allylation of alkynyl ketones (R1 ¼ H) according
to Nakamura et al., cf. ref. [24].
Even though the recorded data for aldehydes seem to
speak against the use of this method en route to 4, a more
careful analysis is warranted. Nakamura et al. reported the
transfer of unsubstituted allyl groups to aldehydes only,[24]
whereas in our case a large substituent R will reside on the
central carbon atom of the allylzinc reagent. Its presence
should render TS2 highly unfavorable due to a clash of R
with the ligandꢁs phenyl substituent (Scheme 6). As a result,
As a consequence, we faced the need to develop an alter-
native method for the selective preparation of either isomer
of product 4. Inspiration was provided by a paper published
by Nakamura et al., who were the first to describe highly
asymmetric allylations of alkynyl carbonyl derivatives with
the aid of allylzinc reagents endowed with a bisoxazoline
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Natural Product Synthesis
FULL PAPER
Scheme 7. Asymmetric allylation of aldehyde 17 with differently substi-
tuted allylzinc reagents: a) i) Zn, THF; ii) (S,S)-22, nBuLi; iii) aldehyde
17, À1008C.
Table 1. Addition of the allylzinc reagent 21 to aldehyde 17 in the ab-
sence or presence of deprotonated BOX-type ligands.[a]
Entry
1
Ligand
Yield [%]
(S)-18/(R)-18
77[b]
–
1
Scheme 6. Proposed asymmetric allylation of alkynyl aldehydes with sub-
stituted allylzinc reagents (R ¼ H).
2
3
4
74
70
72
8.8:1[c]
10.4:1
1:5.2
a transition-state topology of type TS3 with an inverted
chair might ensue, wherein the R group should engage in a
productive crosstalk with the chiral ligand sphere of the zinc
atom. As this interaction renders the equatorial disposition
of the aldehydeꢁs alkynyl group inconsequential, appreciable
levels of stereoinduction can be expected.[26]
The experimental results nicely matched the predictions
of this model. As evident from Scheme 7, the addition of al-
lylzinc reagents to aldehyde 17 under Nakamura conditions
become increasingly enantioselective with increasing bulk of
the substituent at C2. Likewise, addition of the chiral zinc
reagent 21 to the same aldehyde partner showed appreciable
levels of diastereocontrol (Scheme 8 and Table 1). Whereas
[d]
[e]
5
6
1:1
[a] Unless stated otherwise, all reactions were performed by syringe
pump addition of aldehyde 17 to the organozinc reagent at À1008C in
THF; the material was then desilylated with K2CO3 in MeOH. The yield
refers to the overall yield over both operations; [b] at 08C; [c] at À788C;
[d] as the reaction was unselective according to GC, the product was not
isolated; [e] no reaction.
the reaction of unmodified 21 gave
a
ꢀ1:1 mixture
(entry 1), ligation with deprotonated (S,S)-22[27] provided
the forecasted S-configured alcohol (S)-18 with good selec-
tivity (dr 10.4:1, entry 3). Importantly, the course of the ad-
dition is reagent-controlled, as the (R,R)-configured ligand
furnished the opposite isomer as the major product (dr
1:5.2, entry 4). Separation of the enriched samples by prepa-
rative HPLC followed by cleavage of the silyl group afford-
ed (S)-4 and (R)-4 in diastereomerically pure form each. In
both cases was the configuration of the newly formed chiral
center unambiguously established by the Mosher method
(cf. Supporting Informaton).[28] In line with the proposed
transition-state model, more encumbered BOX-type ligands,
which are unable to acquaint the axial R group for steric
reasons, were found inappropriate (Table 1, entries 5 and 6).
Scheme 8. Reagent-controlled asymmetric allylation: a) Zn, THF, 408C;
Gold-catalyzed cycloisomerizations, stereochemical calibra-
tion, and total synthesis of the insect aggregation phero-
mone 8: Conversion of the propargylic alcohols (S)-4 and
(R)-4 into the corresponding p-nitrobenzoates (S)-23 and
b) see Table 1; c) K2CO3, MeOH, 99%.
The stereochemical relationship between the newly
formed cyclopropane ring and the methyl branch in the side
chain of 5 and 6 is by no means trivial to assign because of
the conformational freedom in this part of the molecules.
Even the detailed analysis of high field NMR spectra and
(R)-23, respectively, followed by AuCl
3(pyridine)[29]-cata-
A
lyzed cycloisomerization furnished the desired [3.1.0]bicyclo-
hexane derivatives 5 and 6 after hydrolysis of the enol esters
primarily formed (Scheme 9).[30,31]
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9183

A. Fürstner and A. Schlecker
was sought. To this end, we turned our attention to the ag-
gregation pheromone 8 produced by male Eysarcoris lewisi
(Distant) bugs, which cause severe damage in rice fields in
Japan.[17] Mori and coworkers have previously prepared this
compound and could determine its stereostructure by chi-
roptical means.[18] Therefore 8 constitutes an additional ste-
reochemical calibration point.
Its synthesis from ketone (+)-5 was accomplished by a
minor modification of the published route (Scheme 11).[18]
The analytical and spectroscopic properties of our samples
of synthetic 8 were in excellent agreement with the reported
data,[18] including the [a]D. This comparison firmly estab-
lishes the stereochemical course of the gold-catalyzed cyclo-
A
Scheme 9. a) 4-Nitrobenzoyl chloride, pyridine, DMAP, CH2Cl2, 08C !
RT, 58 % (S)-23; 62% (R)-23; b) AuCl3(pyridine) (10 mol%), CH2Cl2,
73% (dr 19:1); c) LiOH, THF/H2O, 91%; d) AuCl3(pyridine)
(10 mol%), CH2Cl2, 76% (dr 15:1); e) LiOH, THF/H2O, 89%.
sound basis for the preparation of all other sesquiterpenoids
of the sabina- and thuja series.
AHCTREUNG
ꢀ
ACHTREUNG
NOESY data remains ambiguous. These difficulties also
transpire from previous isolation papers, wherein the stereo-
structure of several members of the sesquisabina- or sesqui-
thuja families either remained undetermined or were merely
inferred by analogy to sister compounds which themselves
are more or less well characterized; in these cases, the as-
signed structures should be met with caution (see below).
As 5 and 6, however, constitute the corner stones of our
projected synthesis of all natural products of these classes of
terpenes, it was of utmost importance to determine the ste-
reochemical course of the gold-catalyzed cycloisomerization
beyond doubt. The assignments shown in Scheme 9 were ini-
tially made by analogy to recorded cases.[8] Additional infor-
mation was gathered by conversion of (À)-(S)-20c into
sabina ketone (+)-(1R,5S)-28,[32,33] a product of known ster-
eostructure and parent compound of the entire family of ter-
Scheme 11. a) O3, CH2Cl2, À788C, then Me2S, Et3N, 84%; b) 30, NaH,
THF, À788C ! 08C; c) [Ph3PCH3]Br, nBuLi, THF, À788C ! RT, 50 %
(over both steps); d) Dibal-H, toluene/THF, À788C, 88%.
Total synthesis of sesquisabinene, sesquithujene and rela-
tives: With the stereostructure of ketone 5 being secured, it
required only the treatment of this compound with Ph3P=
CH2 in THF to obtain (À)-7 (Scheme 12). Its spectroscopic
data are in full agreement with those of sesquisabi-
nene.[15,16,34] It is unfortunate, however, that the rotatory
power of this natural product has not been reported in the
penoids embodying
(Scheme 10).
a
bicyclo[3.1.0]hexane skeleton
A
Scheme 10. a) K2CO3, MeOH, 89%; b) 4-nitrobenzoyl chloride, DMAP,
CH2Cl2, pyridine, 08C RT, 91%; c) AuCl3(pyridine) (10 mol%),
CH2Cl2, 89%; d) LiOH, THF/H2O, 53%.
!
ACHTREUNG
Scheme 12. a) Ph3P=CH2, THF, À788C ! RT, 69 %; b) Hg
C
Even though this example provides compelling evidence,
further confirmation for the assignments made in Scheme 9
THF, À788C, then 2-pyridyl-NTf2, 08C; e) MeMgBr, Fe
(10 mol%), THF/NMP, À308C, 60% (over both steps).
A
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Natural Product Synthesis
FULL PAPER
literature. Therefore we cannot decide whether (À)-7 corre-
sponds to the natural product or its enantiomer.
Amyris diatrypta Sprengel, was previously unknown.[16] Sub-
sequent hydroxymercuration gave 7-epi-trans-sesquisabinene
hydrate (38),[35,42] whereas direct addition of MeMgBr fur-
nished the diastereomeric alcohol 7-epi-cis-sesquisabinene
hydrate (39),[16,34] both of which are found inter alia in Heli-
chrysum oil. The iron catalyzed cross coupling of enol tri-
flate 40 derived from 6 provided sesquithujene (9) itself.[15,16]
Because we lack information on the rotatory power of all of
these naturally occurring sesquiterpenes,[43] their absolute
stereochemistry cannot be assigned at this point.
Reaction of ketone 5 with MeMgBr in Et2O at 08C af-
forded alcohol 33 as a single isomer in high yield. Its spectra
matched those of cis-sesquisabinene hydrate, an ingredient
of the essential oils of Zingiber officinale,[15] Hedychium
gardnerianum Roscoe (“Kahili ginger”),[35] Nectandra globo-
sa (“Ayou” or “canella preta”),[36] and the sub-Himalayan ar-
omatic shrub Strobilanthes auriculatus.[37] Whereas the [a]D
of synthetic (À)-33 and the natural product are in good
agreement, the literature actually depicts the opposite enan-
tiomer.[37] Our synthesis, however, is unambiguous in stereo-
chemical regard; therefore the previously proposed configu-
ration of cis-sesquisabinene hydrate is incorrect and needs
to be revised to what is shown in Scheme 12.
The diastereomeric alcohol 34 was obtained by hydroxy-
mercuration[38] of synthetic sesquisabinene A (7). The NMR
spectra are sufficiently different from those of 33 and were
found to be in accord with the data of trans-sesquisabinene
hydrate published in the literature.[35,36] As no chiroptical
data of this particular natural product are available, the as-
signment of the absolute configuration must remain open.
Finally, ketone 5 was transformed into the corresponding
enol triflate 35 which underwent an iron-catalyzed cross-
coupling with MeMgBr to give endocyclic olefin derivative
(+)-36. This methodology had previously been developed in
our laboratory as a cheap, effective and benign alternative
to established cross-coupling protocols and already served
other total syntheses with considerable success.[39–41] Com-
parison of the NMR data shows that synthetic 36 is identical
with 7-epi-sesquithujene, the stereostructure of which was
previously unknown.[16,34] However, as the [a]D of natural 36
has not been communicated, we cannot establish the abso-
lute configuration of this volatile component produced by
the Brazilian tree Phoebe porosa.
Epoxysesquithujene: Epoxysesquithujene was recently iso-
lated from the fresh roots of Valeriana hardwickii var. hard-
wickii, a rare aromatic Himalayan herb used in traditional
medicine.[44] Interestingly, this compound represents about
50% of the essential oil extracted from this plant but had
previously never been found in any other Valeriana sp.
While its constitution could be firmly established, the ste-
reochemical relationship between the cyclopropane, the
methyl branch and the remote epoxide remained undeter-
mined.[44] To answer this question, we first prepared a mix-
ture of all four possible isomers 42–45 by epoxidation of a
1:1 mixture of 5 and 6 with mCPBA followed by conversion
of the ketone groups in 41a–d into the corresponding endo-
cyclic olefins (Scheme 14). Gratifyingly, the 13C NMR spec-
tra of 42–45 are sufficiently resolved such that all four com-
pounds are discernable in the mixture. Next, the epoxidation
was performed with the aid of the d-fructose derived cata-
lyst 46, which delivers isomers 41a,b as the major products
according to its well established facial selectivity in oxida-
tions of trisubstituted alkenes.[45] None of the two epoxides
Next, the diastereomeric ketone 6 derived from (R)-4 was
subjected to the same set of reactions (Scheme 13). Wittig
olefination delivered (+)-37, which corresponds to sesquisa-
binene B according to its spectral data. The relative stereo-
structure of this compound isolated from the leaves of
Scheme 14. a) mCPBA, 85%; b) i) LDA, THF, À788C, then 2-pyridyl-
NTf2, 08C; ii) MeMgBr, Fe
A
Scheme 13. a) Ph3P=CH2, THF, À788C ! RT, 66 %; b) Hg
C
(for 41d ! 45); c) 46 (0.5 equiv), Oxone, Bu4NHSO4, Na2B4O7·7H2O,
K2CO3, dimethoxymethane, MeCN/H2O, 51%; d) ent-46 (2 equiv),
Oxone, Bu4NHSO4, Na2B4O7·10H2O, K2CO3, dimethoxymethane, MeCN/
H2O, 74% (dr 8:1).
THF, À788C then 2-pyridyl-NTf2, 08C; e) MeMgBr, Fe
(10 mol%), THF/NMP, À308C, 58% (over both steps).
A
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9185

A. Fürstner and A. Schlecker
137.9 ppm; residual toluene in [D]8-toluene: dH =2.09 ppm). IR: Nicolet
FT-7199 spectrometer, wavenumbers (n) in cmÀ1. MS (EI): Finnigan
MAT 8200 (70 eV), ESI-MS: Finnigan MAT 95, accurate mass determi-
nations: Bruker APEX III FT-MS (7 T magnet). Melting points: Büchi
melting point apparatus B-540 (corrected). Elemental analyses: H.
Kolbe, Mülheim/Ruhr. All commercially available compounds (Fluka,
Lancaster, Aldrich) were used as received. Compounds 14 and 15 were
prepared according to literature methods.[21,22] The Supporting Informa-
tion of this paper details the analysis of the Mosher esters derived from
(R)-4 and (S)-4, contains a tabular comparison of the published and the
recorded NMR spectra of the individual natural products, and shows
42 and 43 thus formed, however, corresponds to epoxyses-
quithujene. Therefore, this natural product must be one of
the remaining structures 44 or 45. One of them was then se-
lectively prepared by Shi epoxidation of ketone 6 with the
enantiomeric (formally l-fructose derived)[46] catalyst ent-46
(dr 8:1). Subsequent conversion of the carbonyl group of
the resulting ketone 41d into the corresponding triflate and
cross-coupling with MeMgBr furnished product 45 in 72%
yield after only 5 min reaction time at À358C. The fact that
the iron-based methodology tolerates the reactive oxirane
ring of the substrate is noteworthy and attests to the rele-
vance of this new methodology.[39–41] The NMR spectra of
the major diastereomer of the resulting 8:1mixture of prod-
ucts matched the reported data very well.[44] Therefore we
confidently assign structure 45 to epoxysesquithujene de-
rived from Valeriana hardwickii var. hardwickii.
1
copies of their H and 13C NMR spectra.
Compound 16: Bromine (0.64 mL, 13 mmol) was slowly added to a solu-
tion of Ph3P (3.4 g, 13 mmol) in CH2Cl2 (60 mL) and the resulting mix-
ture was transferred via cannula to a solution of alcohol 15 (2.0 g,
12 mmol) and imidazole (1.0 g, 14 mmol) in CH2Cl2 (80 mL) at 08C.
After stirring for 10 min at that temperature, the mixture was poured
into ice water and stirred for 1h. A standard extractive work up followed
by flash chromatography of the crude material (3% Et2O in pentanes)
gave bromide 16 as a colorless oil (2.4 g, 87%). [a]2D0 =À16.6 (c=1.04 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.21(d, J=0.7 Hz, 1H), 5.12–
5.08 (m, 1H), 5.00 (brs, 1H), 3.99 (brs, 2H), 2.38 (q, J=6.9 Hz, 1H),
2.00–1.94 (m, 2H), 1.69 (d, J=0.9 Hz, 3H), 1.60 (s, 3H), 1.58–1.49 (m,
1H), 1.42–1.32 (m, 1H), 1.10 ppm (d, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=150.4, 131.6, 124.3, 114.2, 36.5, 36.3, 35.9, 25.7,
25.7, 20.0, 17.7 ppm; IR (film): n˜ = 2965, 2919, 2855, 1637, 1452, 1376,
1208, 905 cmÀ1; MS (70 eV): m/z (%): 232 (0.1) [M+], 189 (3), 151 (26),
109 (22), 95 (100), 82 (38), 69 (41), 55 (33), 41 (59); HRMS (EI): m/z:
calcd for C11H23NBr [M+ +NH4]: 248.1014, found: 248.1012; elemental
analysis calcd (%) for C11H19Br (231.2): C 57.15, H 8.28; found: C 57.06,
H 8.26.
Conclusion
A short and efficient entry into the cyclopropyl carbonyl de-
rivatives 5 and 6 was established by combining the power of
asymmetric synthesis with noble metal catalyzed cycloisome-
rization chemistry. Specifically, a conceptual extension of an
allylation method reported by Nakamura and coworkers
using allylzinc derivatives modified by BOX-type ligand 22
allowed the diastereomeric enyne derivatives (R)-4 and (S)-
4 to be formed in good yield and appreciable levels of dia-
Compound (R)-18:
A suspension containing bromide 16 (0.28 g,
1.2 mmol) and zinc dust (0.21 g, 3.0 mmol) in THF (3 mL) was stirred for
1 h at 408C. At this time, GC/MS indicated complete conversion of the
substrate into the allylzinc reagent 19 and the reaction mixture was al-
lowed to cool to ambient temperature. In a second Schlenk tube, nBuLi
(1.6m in hexane, 0.8 mL) was added dropwise to a solution of 2,2’-meth-
ylene-bis-[(4R)-4-phenyl-2-oxazoline] [(R,R)-22, 0.39 g, 1.3 mmol] in THF
(4 mL) at 08C. The solution of the organozinc reagent was then added
via cannula and the resulting mixture was stirred for 30 min at 08C,
before it was cooled to À1008C. A solution of 3-trimethylsilylpropinal
(17; 0.16 mL, 1.1 mmol) in THF (1 mL) was introduced via syringe pump
over a period of 1h. Once the addition was complete, the reaction was
quenched with MeOH/H2O 1:1 (0.8 mL), the mixture was diluted with
Et2O (5 mL) and allowed to warm to ambient temperature. The organic
phase was washed with NaOH (0.5m, 1mL), dried over Na 2SO4, ad-
sorbed on silica gel and purified by flash chromatography (10% Et2O in
pentanes) to give compound (R)-18 as a colorless oil (250 mg, 72%, dr
5.2:1). Analytically pure (R)-18 was obtained by preparative HPLC
(250 mm YMC, 1 30 mm, MeCN/H2O 60:40, 35.0 mLminÀ1, 6.9MPa,
308 K, UV, 210 nm). [a]2D0 =À3.9 (c=0.78 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=5.11–5.07 (m, 1H), 4.93 (s, 1H), 4.92 (d, J=
1.1 Hz, 1H), 4.48 (t, J=6.9 Hz, 1H), 2.43 (dd, J=6.8, 0.5 Hz, 2H), 2.18
(q, J=6.9 Hz, 1H), 1.94 (q, J=7.6 Hz, 2H), 1.79 (brs, 1H), 1.68 (s, 3H),
1.56 (s, 3H), 1.53–1.44 (m, 1H), 1.35–1.26 (m, 1H), 1.04 (d, J=6.9 Hz,
3H), 0.17 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=149.6, 131.5,
124.5, 111.5, 106.4, 89.5, 61.3, 42.8, 39.1, 35.8, 25.8, 25.7, 19.7, 17.7,
À0.2 ppm; IR (film): n˜ = 3349, 2961, 2923, 2176, 1643, 1454, 1376, 1249,
1033, 883, 837, 759 cmÀ1; MS (70 eV): m/z (%): 263 (3), 217 (4), 151 (9),
136 (10), 127 (10), 109 (20), 99 (33), 95 (20), 82 (100), 73 (61), 69 (24), 55
(21), 41 (36); HRMS (ESI): m/z: calcd for C17H30OSiNa [M+ +Na]:
301.1958, found: 301.1955; elemental analysis calcd (%) for C17H30OSi
(278.51): C 73.31, H 10.86; found: C 73.42, H 10.78.
stereocontrol. Catalytic amounts of AuCl
ranged these substrates stereospecifically into the bicyclo-
[3.1.0] ketones 5 and 6 after saponification of the enol ester
3(pyridine) rear-
ACHTREUNG
derivatives primarily formed. These compounds could then
be converted into a host of sesquisabina and sesquithuja de-
rivatives. Since the stereochemistry of the synthetic materi-
als is unambiguous, the as yet unknown structure of several
members of these families of terpenoids could be estab-
lished by comparison with the published data. Moreover, it
should be pointed out that ketone 6 previously served as the
key intermediate en route to cedrene (11) and cedrol
(12).[19] Therefore the new gold-catalyzed access to 6 also
represents a formal total synthesis of these challenging tar-
gets.
Experimental Section
General methods: All reactions were carried out under argon in flame-
dried glassware. The solvents used were purified by distillation over the
drying agents indicated and were stored and transferred under argon:
THF, Et2O (Mg/anthracene), CH2Cl2, Et3N, hexanes, benzene, toluene
(Na/K), DMF (Desmodur 15, dibutyl tin dilaurate). Flash chromatogra-
phy (FC): Merck silica gel 60 (230–400 mesh). NMR: Spectra were re-
corded on a Bruker DPX 300, AMX 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 shifts converted to the TMS scale (CDCl3: dC =
77.0 ppm; residual CHCl3 in CDCl3: dH =7.26 ppm; CD2Cl2: dC =
53.8 ppm; residual CH2Cl2 in CD2Cl2: dH =5.32 ppm; C6D6: dC =
128.1 ppm; residual C6H6 in C6D6: dH =7.26 ppm; [D]8-toluene: dC =
Compound (S)-18: Prepared analogously using 2,2’-methylene-bis-[(4S)-
4-phenyl-2-oxazoline] (S,S)-20 as the ligand. Colorless oil (290 mg, 70%,
dr 10.4:1). [a]2D0 =À28.9 (c=0.95 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.11–5.07 (m, 1H), 4.94 (brs, 1H), 4.92 (d, J=1.1 Hz, 1H),
4.49 (dd, J=7.2, 6.1Hz, 1H), 2.45–2.42 (m, 2H), 2.18 (q, J=6.9 Hz, 1H),
9186
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9181 – 9191

Natural Product Synthesis
FULL PAPER
1.94 (q, J=7.5 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.53–1.44 (m, 1H),
1.36–1.27 (m, 1H), 1.04 (d, J=6.9 Hz, 3H), 0.17 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=149.7, 131.5, 124.4, 111.5, 106.4, 89.5, 61.2, 42.7,
39.3, 35.7, 25.9, 25.7, 19.9, 17.7, À0.2 ppm; IR (film): n˜ = 3380, 2961,
2923, 2177, 1642, 1454, 1376, 1249, 1034, 883, 839, 759 cmÀ1; MS (70 eV):
m/z (%): 263 (2), 217 (5), 151 (8), 136 (10), 127 (9), 109 (19), 99 (32), 95
(20), 82 (100), 73 (60), 69 (24), 55 (21), 41 (36); HRMS (ESI): m/z: calcd
for C17H30OSiNa [M+ +Na]: 301.1958, found: 301.1957.
Compound (S)-4: Prepared analogously as a colorless oil (190 mg, 99%).
[a]2D0 =À35 (c=1.52 in CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=5.13–
5.08 (m, 1H), 4.94 (brs, 1H), 4.92–4.91 (m, 1H), 4.52–4.47 (m, 1H), 2.50
(d, J=2.1Hz, 1H), 2.45–2.42 (m, 2H), 2.16 (q, J=6.9 Hz, 1H), 2.03 (d,
J=5.1Hz, 1H), 1.95 (q, J=7.5 Hz, 2H), 1.68 (d, J=0.9 Hz, 3H), 1.59 (s,
3H), 1.52–1.43 (m, 1H), 1.37–1.28 (m, 1H), 1.03 ppm (d, J=6.9 Hz, 3H);
13C NMR (100 MHz, CD2Cl2): d=150.2, 131.8, 124.8, 111.5, 85.2, 72.9,
61.0, 43.0, 39.7, 36.0, 26.2, 25.8, 20.0, 17.7 pm; IR (film): n˜ = 3376, 3309,
2963, 2918, 2855, 1643, 1452, 1376, 1029, 896 cmÀ1; MS (70 eV): m/z (%):
206 (0.1) [M+], 145 (6), 109 (8), 95 (19), 82 (100), 67 (32), 55 (23), 41
(41); HRMS (ESI): m/z: calcd for C14H22ONa [M+ +Na]: 229.1563,
found: 229.1561.
(S)-1-(Trimethylsilyl)hex-5-en-1-yn-3-ol [(S)-20a, R=H]: Colorless oil
(93 mg, 70%, ee 57%). The enantiomeric excess was determined by GC
analysis on chiral stationary phase (25 m Hydrodex-B-TBDAc 0.25/df, 1
0.25 mm, 220/105iso, 0.8 bar H2, FID). The absolute stereochemistry was
assigned by comparison of the optical rotation. [a]2D0 =À22.1( c=1.3 in
CHCl3), Lit:[47] [a]DRT =À29 (c=0.85 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.93–5.83 (m, 1H), 5.21–5.19 (m, 1H), 5.17 (brs, 1H), 4.41 (t,
J=6.1Hz, 1H), 2.47 (t, J=7.0 Hz, 2H), 1.79 (brs, 1H), 0.17 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=132.9, 119.0, 105.9, 89.8, 62.0, 42.1,
À0.2 ppm; IR (film): n˜ = 3351, 3073, 2960, 2901, 2175, 1643, 1250, 1027,
837, 759 cmÀ1; MS (70 eV): m/z (%): 168 (0.1) [M+], 127 (98), 99 (100),
Compound (R)-23: Pyridine (0.12 mL, 1.5 mmol), 4-nitrobenzoyl chloride
(0.27 g, 1.5 mmol) and DMAP (30 mg, 0.25 mmol) were successively
added to a solution of compound (R)-4 (100 mg, 0.5 mmol) in CH2Cl2
(5 mL) at 08C and the resulting mixture was allowed to reach ambient
temperature. After stirring for 1h, the reaction was quenched with pH 7
buffer (5 mL) and Et2O (5 mL), the aqueous phase was extracted with
Et2O (3”5 mL), the combined organic layers were washed with brine,
dried over Na2SO4, evaporated and the residue was purified by flash
chromatography (20% Et2O in pentanes) to give product (R)-23 as a col-
orless oil (110 mg, 62%). [a]2D0 =+20.1( c=0.93 in CH2Cl2); 1H NMR
(400 MHz, CD2Cl2): d=8.29 (d, J=9.0 Hz, 2H), 8.21(d, J=9.0 Hz, 2H),
5.75 (ddd, J=7.7, 6.5, 2.1Hz, 1H), 5.12–5.07 (m, 1H), 4.95 (d, J=1.0 Hz,
1H), 4.94 (brs, 1H), 2.72 (dd, J=14.9, 7.2 Hz, 1H), 2.64 (dd, J=14.9,
6.5 Hz, 1H), 2.59 (d, J=2.1Hz, 1H), 2.21 (q, J=6.9 Hz, 1H), 1.98–1.92
(m, 2H), 1.67 (s, 3H), 1.58 (s, 3H), 1.52–1.45 (m, 1H), 1.37–1.27 (m, 1H),
1.04 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=163.9,
151.1, 148.8, 135.6, 131.9, 131.2, 124.7, 123.9, 112.0, 81.1, 74.6, 64.5, 39.8,
39.6, 36.0, 26.2, 25.8, 19.9, 17.8 ppm; IR (film): n˜ = 3293, 2963, 2923,
2855, 1729, 1528, 1345, 1261, 1099, 1014, 872, 718 cmÀ1; MS (70 eV): m/z
(%): 355 (0.3) [M+], 150 (30), 145 (20), 104 (14), 91 (11), 82 (100), 67
(18), 55 (17), 41 (29); HRMS (CI): m/z: calcd for C21H25NO4 [M+]:
356.1862, found: 356.1859.
75 (33), 59 (11), 45 (16); HRMS (CI): m/z: calcd for C9H20NOSi [M+
+
NH4]: 186.1314, found: 186.1316.
(S)-5-Methyl-1-(trimethylsilyl)hex-5-en-1-yn-3-ol [(S)-20b, R=Me]: Col-
orless oil (109 mg, 76%, ee 67%). The enantiomeric excess was deter-
mined by GC analysis on chiral stationary phase (25 m Hydrodex-B-
TBDAc 0.25/df, 1 0.25 mm, 220/105iso, 0.8 bar H2). The absolute stereo-
chemistry was assigned in analogy to (S)-20a. [a]2D0 =À38.5 (c=1.4 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=4.93–4.90 (m, 1H), 4.86–4.83
(m, 1H), 4.49 (t, J=6.6 Hz, 1H), 2.44 (d, J=6.6 Hz, 2H), 1.80 (s, 3H),
0.17 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=140.9, 114.4, 106.3,
89.5, 60.8, 46.1, 22.6, À0.2 ppm; IR (film): n˜ = 3351, 3073, 2961, 2896,
2175, 1647, 1249, 1063, 1019, 883, 837, 759 cmÀ1; MS (70 eV): m/z (%):
182 (1) [M+], 167 (21), 151 (17), 127 (44), 111 (15), 99 (100), 91 (29), 75
(56), 45 (20); HRMS (CI): m/z: calcd for C10H22NOSi [M+ +NH4]:
200.1471, found: 200.1473.
Compound (S)-23: Prepared analogously from (S)-4 (0.13 g, 0.63 mmol)
as
a
colorless oil (0.13 g, 58%). [a]2D0 =À42.7 (c=0.72 in CH2Cl2);
(S)-6-Methyl-5-methylene-1-(trimethylsilyl)hept-1-yn-3-ol [(S)-20c, R=
iPr]: Colorless oil (94 mg, 69%, ee 81%). The enantiomeric excess was
determined by GC analysis on chiral stationary phase (25 m Hydrodex-
B-TBDAc 0.25/df, 1 0.25 mm, 220/90iso, 0.5 bar H2). The absolute ste-
reochemistry was assigned by Mosher-ester analysis. [a]2D0 =À18.1 (c=0.5
in CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=4.93 (brs, 1H), 4.56 (brs,
1H), 4.47–4.43 (m, 1H), 2.45–2.43 (m, 2H), 2.32 (qt, J=6.8 1H), 1.96 (d,
J=5.2 Hz, 1H), 1.04 (dd, J=6.7, 1.1 Hz, 6H), 0.16 ppm (s, 9H);
13C NMR (100 MHz, CD2Cl2): d=151.7, 110.5, 107.1, 89.4, 61.7, 43.5,
34.0, 21.9, 21.8, À0.2 ppm; IR (film): n˜ = 3349, 2961, 2896, 2175, 1642,
1249, 1033, 882, 837, 759 cmÀ1; MS (70 eV): m/z (%): 210 (1) [M+], 195
(26), 167 (21), 151 (59), 127 (44), 111 (11), 105 (25), 99 (95), 84 (79), 73
(100), 69 (95), 55 (20), 41 (32); HRMS (ESI): m/z: calcd for
C12H22ONaSi [M+ +Na]: 233.1332, found: 233.1334.
1H NMR (400 MHz, CD2Cl2): d=8.29 (d, J=9.0 Hz, 2H), 8.21(d, J=
9.0 Hz, 2H), 5.75 (ddd, J=8.7, 6.6, 2.2 Hz, 1H), 5.10–5.06 (m, 1H), 4.95
(d, J=1.1Hz, 1H), 4.94 (brs, 1H), 2.74–2.63 (m, 2H), 2.59 (d, J=2.1Hz,
1H), 2.45–2.16 (m, 1H), 1.93 (q, J=7.5 Hz, 2H), 1.66 (s, 3H), 1.55 (s,
3H), 1.51–1.44 (m, 1H), 1.39–1.30 (m, 1H), 1.05 ppm (d, J=6.9 Hz, 3H);
13C NMR (100 MHz, CD2Cl2): d=163.9, 151.1, 148.8, 135.6, 131.8, 131.2,
124.7, 123.9, 112.0, 81.1, 74.6, 64.5, 39.8, 39.6, 35.9, 26.2, 25.7, 20.0,
17.7 ppm; IR (film): n˜ = 3289, 2963, 2923, 2855, 1729, 1528, 1345, 1264,
1099, 1014, 872, 718 cmÀ1; MS (70 eV): m/z (%): 355 (0.3) [M+], 150
(31), 145 (21), 104 (14), 91 (11), 82 (100), 67 (19), 55 (17), 41 (29);
HRMS (ESI): m/z: calcd for C21H25NO4 [M+]: 356.1862, found: 356.1858.
Compound 26: Prepared analogously from (S)-25 (29 mg, 0.2 mmol) as a
colorless oil (55 mg, 91%). [a]2D0 =À29.9 (c=0.8 in CH2Cl2); 1H NMR
(400 MHz, CD2Cl2): d=8.31–8.27 (m, 2H), 8.23–8.19 (m, 2H), 5.75 (ddd,
J=8.6, 5.6, 1.2 Hz, 1H), 4.94 (brs, 1H), 4.91 (brs, 1H), 2.78–2.66 (m,
2H), 2.59 (d, J=2.2 Hz, 1H), 2.34 (qt, J=6.8 Hz, 1H), 1.06 (d, J=
6.8 Hz, 3H), 1.06 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CD2Cl2):
d=163.9, 151.1, 150.2, 135.6, 131.2, 123.9, 111.0, 81.0, 74.5, 64.5, 40.2,
34.0, 21.9, 21.7 ppm; IR (film): n˜ = 3293, 2963, 2870, 1727, 1526, 1343,
1259, 1098, 1013, 871, 717 cmÀ1; MS (70 eV): m/z (%): 272 (<1 ) [M+-15],
150 (100), 120 (21), 105 (50), 76 (12), 41 (11); HRMS (CI): m/z: calcd for
C16H18NO4 [M+ +H]: 288.1236, found: 288.1235.
Compound (R)-4: K2CO3 (0.34 g, 2.4 mmol) was added to a solution of
(R)-18 (0.23 g, 0.82 mmol) in MeOH (10 mL) and the resulting mixture
stirred for 2 h before the reaction was diluted with water (10 mL) and ex-
tracted with Et2O (3”10 mL). The combined organic phases were
washed with brine, dried over Na2SO4, evaporated and the residue puri-
fied by flash chromatography (10% Et2O in pentanes) to give product
(R)-4 as a colorless oil (170 mg, 99%). [a]2D0 =+0.4 (c=0.87 in CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=5.13–5.08 (m, 1H), 4.94 (brs, 1H),
4.92–4.91(m, 1H), 4.52–4.47 (m, 1H), 2.50 (d, J=2.1Hz, 1H), 2.44–2.43
(m, 2H), 2.17 (q, J=6.9 Hz, 1H), 2.03 (d, J=5.0 Hz, 1H), 1.95 (q, J=
7.7 Hz, 2H), 1.68 (d, J=1.0 Hz, 3H), 1.59 (s, 3H), 1.52–1.43 (m, 1H),
1.35–1.26 (m, 1H), 1.04 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz,
CD2Cl2): d=150.1, 131.8, 124.8, 111.5, 85.3, 72.9, 61.0, 43.1, 39.5, 36.1,
26.2, 25.8, 19.9, 17.8 ppm; IR (film): n˜ = 3377, 3309, 2964, 2918, 2855,
1643, 1453, 1376, 1031, 896 cmÀ1; MS (70 eV): m/z (%): 206 (0.1) [M+],
145 (6), 109 (8), 95 (19), 82 (100), 67 (32), 55 (24), 41 (42); HRMS (ESI):
m/z: calcd for C14H22ONa [M+ +Na]: 229.1563, found: 229.1561; elemen-
tal analysis calcd (%) for C14H22O (206.32): C 81.50, H 10.75; found: C
81.40, H 10.66.
Compound 24: AuCl3(pyridine) (14 mg, 40 mmol) was added to a solution
E
of compound (S)-23 (0.13 g, 0.37 mmol) in CH2Cl2 (4 mL) and the result-
ing mixture was stirred for 5 h at ambient temperature. Silica gel was
added and the solvent removed under reduced pressure. Purification of
the product by flash chromatography (20% Et2O in pentanes) gave enol
ester 24 as a pale yellow syrup (95 mg, 73%, dr ꢀ19:1). [a]2D0 =+19.4
1
(c=0.75 in CH2Cl2); H NMR (400 MHz, CD2Cl2): d=8.31(d, J=9.1Hz,
2H), 8.25 (d, J=9.1 Hz, 2H), 5.27–5.25 (m, 1H), 5.14–5.10 (m, 1H), 2.50
(dd, J=17.2, 2.4 Hz, 1H), 2.30 (dt, J=14.4, 2.8 Hz, 1H), 2.04 (q, J=
7.5 Hz, 2H), 1.82–1.78 (m, 1H), 1.68 (d, J=0.8 Hz, 3H), 1.61 (s, 3H),
Chem. Eur. J. 2008, 14, 9181 – 9191
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9187

A. Fürstner and A. Schlecker
1.57–1.49 (m, 1H), 1.39–1.23 (m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.88 (dd,
J=7.2, 4.1Hz, 1H), 0.48 ppm (t, J=3.5 Hz, 1H); 13C NMR (100 MHz,
CD2Cl2): d=162.6, 154.4, 151.1, 135.6, 131.6, 131.3, 125.1, 124.9, 110.1,
38.2, 35.3, 32.2, 31.7, 27.3, 26.4, 25.8, 21.3, 17.8, 17.7 ppm; IR (film): n˜ =
2962, 2915, 2870, 1740, 1528, 1347, 1259, 1143, 715 cmÀ1; MS (70 eV): m/z
(%): 355 (7) [M+], 270 (22), 150 (100), 104 (18), 69 (24), 41 (14); HRMS
(ESI): m/z: calcd for C21H25NO4Na [M+ +Na]: 378.1676, found: 378.1677.
101.8, 37.8, 36.7, 34.6, 31.2, 28.8, 26.7, 26.1, 25.7, 18.0, 17.7, 16.1 ppm; IR
(film): n˜
=
3073, 2957, 2927, 2867, 1652, 1446, 1375, 862 cmÀ1; MS
(70 eV): m/z (%): 204 (21) [M+], 161 (49), 133 (30), 120 (30), 109 (19),
93 (60), 79 (23), 69 (100), 55 (30), 41 (58); HRMS (EI): m/z: calcd for
C15H24 [M+]: 204.1878, found: 204.1879.
Sesquisabinene B (37): Prepared analogously as a colorless oil (4.6 mg,
66%). [a]2D0 =+53.6 (c=0.92 in CH2Cl2); 1H NMR (300 MHz, CDCl3):
d=5.13–5.07 (m, 1H), 4.80 (s, 1H), 4.62 (s, 1H), 2.15 (dd, J=15.8, 9.2,
1H), 2.08–1.94 (m, 3H), 1.82–1.71 (m, 1H), 1.68 (s, 3H), 1.65–1.59 (m,
1H), 1.61 (s, 3H), 1.52 (dd, J=8.2, 3.4 Hz, 1H), 1.47–1.35 (m, 1H), 1.30–
1.16 (m, 2H), 0.94 (d, J=6.5 Hz, 3H), 0.74 (dd, J=4.4, 3.5 Hz, 1H),
0.66 ppm (ddd, J=8.2, 4.6, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
154.5, 131.2, 124.9, 101.6, 38.0, 36.8, 35.2, 29.7, 29.0, 26.3, 26.2, 25.7, 18.3,
17.7, 17.4 ppm; IR (film): n˜ = 3073, 2957, 2927, 2867, 1652, 1446, 1375,
862 cmÀ1; MS (70 eV): m/z (%): 204 (19) [M+], 161 (42), 133 (29), 120
(32), 109 (19), 93 (59), 79 (23), 69 (100), 55 (31), 41 (56); HRMS (EI):
m/z: calcd for C15H24 [M+]: 204.1878, found: 204.1880.
Compound 27: Prepared analogously as a pale yellow solid (42 mg,
89%). M.p. 95–978C; [a]2D0 =+7.0 (c=0.9 in CH2Cl2); 1H NMR
(300 MHz, CD2Cl2): d=8.31(d, J=9.1Hz, 2H), 8.25 (d, J=9.2 Hz, 2H),
5.26 (bt, J=2.2 Hz, 1H), 2.51 (dt, J=17.2, 2.4 Hz, 1H), 2.31 (dt, J=17.2,
2.8 Hz, 1H), 1.79–1.74 (m, 1H); 1.55–1.46 (m, 1H), 1.01 (d, J=6.8 Hz,
3H), 0.95 (d, J=7.3 Hz, 1H), 0.94 ppm (d, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CD2Cl2): d=162.6, 154.5, 135.6, 131.4, 131.3, 124.0, 110.0, 33.1,
32.7, 32.6, 26.2, 21.4, 19.9, 19.4 ppm; IR (film): n˜ = 3115, 3060, 2959,
2870, 1735, 1526, 1343, 1262, 1139, 1073, 873, 845, 713 cmÀ1; MS (70 eV):
m/z (%): 287 (6) [M+], 244 (12), 150 (100), 104 (16); HRMS (ESI): m/z:
calcd for C16H17NO4Na [M+ +Na]: 310.1050, found: 310.1052.
cis-Sesquisabinene hydrate (33): MeMgBr (3m in Et2O, 23 mL) was added
to a solution of compound 5 (6.7 mg, 30 mmol) in Et2O (0.5 mL) at 08C
and the resulting mixture stirred for 5 min before it was quenched with
aq. sat. NH4Cl (0.5 mL). The mixture was filtered through Na2SO4 and
the filtrate evaporated to give product 33 in analytically pure form as a
colorless oil (6.8 mg, 95%). [a]2D0 =À10.3 (c=1.2 in CHCl3); [a]2D2 =À10.4
(c=0.4 in CHCl3), lit.:[36] [a]D20 =À1 2 c(=1.3 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.10–5.06 (m, 1H), 2.07–1.98 (m, 1H), 1.95–1.85
(m, 1H), 1.68 (s, 3H), 1.64–1.52 (m, 3H), 1.60 (s, 3H), 1.49–1.38 (m, 2H),
1.35 (s, 3H), 1.30–1.22 (m, 2H), 1.10 (dd, J=7.6, 3.4 Hz, 2H), 0.89 (d, J=
6.8 Hz, 3H), 0.65 (dd, J=4.8, 3.7 Hz, 1H), 0.29 ppm (dd, J=7.6, 5.1Hz,
1H); 13C NMR (100 MHz, CDCl3): d=131.3, 124.8, 79.4, 37.6, 36.1, 34.3,
33.9, 33.2, 28.1, 26.1, 25.8, 25.7, 17.7, 17.1, 11.3 ppm; IR (film): n˜ = 3349,
2959, 2924, 2866, 1451, 1374, 1127, 985, 925 cmÀ1; MS (70 eV): m/z (%):
222 (5) [M+], 207 (36), 189 (10), 161 (30), 151 (11), 137 (26), 119 (60),
109 (29), 93 (54), 82 (82), 69 (100), 55 (43), 29 (11); HRMS (ESI): m/z:
calcd for C15H26ONa [M+ +Na]: 245.1876, found: 245.1877.
Compound 5: LiOH (18 mg, 0.76 mmol) was added to a solution of com-
pound 24 (90 mg, 0.25 mmol) in THF (5 mL) and water (0.5 mL) and the
resulting mixture stirred for 2 h at ambient temperature. Silica gel was
added and the THF removed in vacuo. The loaded silica was added on
top of a silica gel column and the product eluded with 20% Et2O in pen-
tane to give ketone 5 as a colorless oil (47 mg, 91%). [a]2D0 =+16.2 (c=
1.62 in CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=5.10–5.05 (m, 1H),
2.15–1.89 (m, 6H), 1.67 (d, J=0.9 Hz, 3H), 1.61–1.60 (m, 1H), 1.59 (s,
3H), 1.53–1.44 (m, 1H), 1.37–1.28 (m, 2H), 1.12–1.08 (m, 1H), 1.05 (dd,
J=4.5, 3.2 Hz, 1H), 0.96 ppm (d, J=6.5 Hz, 3H); 13C NMR (100 MHz,
CD2Cl2): d=214.4, 131.9, 124.7, 38.9, 37.6, 34.7, 34.6, 33.4, 26.2, 25.7, 23.6,
19.3, 17.7, 17.1 ppm; IR (film): n˜ = 2956, 2916, 2873, 1727, 1450, 1377,
1295, 1181, 1023, 914, 775 cmÀ1; MS (70 eV): m/z (%): 206 (28) [M+],
163 (20), 149 (14), 136 (17), 123 (67), 109 (21), 93 (34), 82 (52), 69 (92),
55 (54), 41(100); HRMS (EI): m/z: calcd for C14H22O [M+]: 271.1671,
found: 271.1669.
Compound 6: Prepared analogously as a colorless oil (33 mg 89%).
7-epi-cis-Sesquisabinene hydrate (39): Prepared analogously from ketone
6 as a colorless oil (6.7 mg, 97%); [a]2D0 =+26.3 (c=1.2 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=5.10–5.07 (m, 1H), 2.00 (q, J=7.6 Hz,
2H), 1.68 (s, 3H), 1.64–1.53 (m, 3H), 1.60 (s, 3H), 1.45–1.36 (m, 2H),
1.34 (s, 3H), 1.30–1.17 (m, 2H), 1.05 (q, J=6.9 Hz, 1H), 1.00 (dd, J=7.5,
3.7 Hz, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.73 (dd, J=4.7, 4.0 Hz, 1H),
0.34 ppm (dd, J=7.9, 5.1Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
131.2, 124.9, 79.4, 37.8, 36.1, 34.9, 33.1, 32.4, 27.9, 26.2, 25.7, 24.6, 17.7,
17.4, 13.1 ppm; IR (film): n˜ = 3359, 2959, 2925, 2865, 1451, 1374, 1125,
985, 925 cmÀ1; MS (70 eV): m/z (%): 222 (3) [M+], 204 (31), 161 (23),
137 (20), 119 (48), 109 (27), 93 (53), 82 (80), 69 (100), 55 (48), 42 (91), 29
(15); HRMS (ESI): m/z: calcd for C15H26ONa [M+ +Na]: 245.1876,
found: 245.1876.
1
[a]2D0 =À27.2 (c=1.36 in CH2Cl2); H NMR (400 MHz, CD2Cl2): d=5.12–
5.08 (m, 1H), 2.14–1.94 (m, 5H), 1.88 (dd, J=10.6, 9.2 Hz, 1H), 1.68 (s,
3H), 1.61 (s, 3H), 1.52 (dd, J=8.9, 3.4 Hz, 1H), 1.48–1.40 (m, 1H), 1.35–
1.23 (m, 2H), 1.19–1.13 (m, 2H), 0.98 ppm (d, J=6.6 Hz, 3H); 13C NMR
(100 MHz, CD2Cl2): d=214.4, 131.8, 124.8, 38.9, 37.8, 34.6, 33.5, 33.5,
26.3, 25.8, 22.7, 21.4, 17.7, 17.6 ppm; IR (film): n˜ = 2962, 2916, 2874,
1724, 1450, 1377, 1294, 1181, 1021, 917, 773 cmÀ1; MS (70 eV): m/z (%):
206 (27) [M+], 163 (22), 149 (13), 136 (16), 123 (55), 109 (21), 93 (34), 82
(53), 69 (96), 55 (75), 41(100); HRMS (EI): m/z: calcd for C14H22O [M+
]: 206.1671, found: 206.1668.
Sabina ketone (28): Prepared analogously as a colorless oil (8 mg, 53%,
ee 80%). [a]2D0 =+18.1 (c=0.8 in CHCl3); Lit:[32] [a]2D5 =+27.3 (c=2.34 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=2.19–2.07 (m, 2H), 1.99–1.95
(m, 2H), 1.64 (dd, J=9.0 Hz, 3.0 Hz, 1H), 1.57 (qt, J=6.8 Hz, 1H), 1.17
(dd, J=8.9, 4.5 Hz, 1H), 1.08–1.05 (m, 1H), 0.98 (d, J=6.8 Hz, 3H),
0.93 ppm (dd, J=6.9 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=214.9,
39.5, 33.8, 33.2, 32.2, 23.6, 19.5, 19.3, 19.1 ppm; IR (film): n˜ = 2960, 2874,
1721, 1466, 1178, 1020, 910, 772 cmÀ1; MS (70 eV): m/z (%): 138 (8) [M+
], 123 (15), 96 (72), 81 (100), 67 (49), 55 (54), 41 (43), 27 (18); HRMS
(ESI): m/z: calcd for C9H14O [M+]: 138.1047, found: 138.1045.
7-epi-Sesquithujene (36): A freshly prepared solution of LDA (1m in
THF, 50 mmol) was added to a solution of ketone 5 (8.0 mg, 40 mmol) in
THF (0.5 mL) at À788C and the resulting mixture was stirred for 30 min
before a solution of 2-pyridyl-NTf2 (Comins reagent, 18 mg, 50 mmol) in
THF (0.5 mL) was introduced. The mixture was allowed to reach ambi-
ent temperature and stirred for 30 min until TLC showed full conversion.
The solution was then cooled to À308C before NMP (35 mL, 0.39 mmol)
and Fe(acac)3 (1.4 mg, 4mmol) were introduced. MeMgBr (3m in Et2O,
R
Sesquisabinene (7): A solution of ketone 5 (7.0 mg, 30 mmol) in THF
(0.5 mL) was added to a solution of Ph3P=CH2 (14 mg, 50 mmol) in THF
(1mL) at À788C and the resulting mixture was allowed to warm to ambi-
ent temperature. After stirring for 45 min, the reaction was quenched
with aq. sat. NH4Cl (1mL) and extracted with Et 2O (3”2 mL). The com-
bined organic phases were dried over Na2SO4, adsorbed on silica gel and
purified by flash chromatography (pentanes) to give product 7 as a color-
less oil (4.8 mg, 69%). [a]2D0 =À48.5 (c=1.22 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d=5.12–5.06 (m, 1H), 4.80 (s, 1H), 4.62 (s, 1H), 2.14
(dd, J=16.1, 7.3 Hz, 1H), 2.06–1.92 (m, 3H), 1.77–1.66 (m, 2H), 1.68 (d,
J=1.1 Hz, 3H), 1.60 (brs, 4H), 1.51–1.42 (m, 1H), 1.35–1.18 (m, 2H),
0.93 (d, J=6.7 Hz, 3H), 0.66 (dd, J=4.3, 3.5 Hz, 1H), 0.57 ppm (ddd, J=
0.6, 4.6, 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=154.2, 131.1, 125.0,
40 mL) was added dropwise and the resulting mixture stirred for 45 min
at that temperature. A standard extractive work up followed by flash
chromatography (pentanes) afforded product 36 as
a colorless oil
(4.7 mg, 60%). [a]2D0 =+30.2 (c=0.7 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=5.13–5.06 (m, 1H), 4.95 (brs, 1H), 2.40–2.33 (m, 1H), 2.18–
2.10 (m, 1H), 2.00–1.93 (m, 2H), 1.75 (q, J=1.9 Hz, 3H), 1.68 (d, J=
1.1 Hz, 3H), 1.59 (s, 3H), 1.51–1.38 (m, 2H), 1.35–1.13 (m, 2H), 0.93 (d,
J=6.7 Hz, 3H), 0.68 (dd, J=7.5, 3.5 Hz, 1H), 0.01ppm (t, J=3.2 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=145.0, 131.0, 125.2, 120.9, 38.0, 36.1,
35.2, 33.2, 32.5, 26.1, 25.7, 21.5, 18.1, 17.6, 16.3 ppm; IR (film): n˜ = 3043,
2963, 2913, 2855, 1448, 1376, 1025, 1009, 806, 778 cmÀ1; MS (70 eV): m/z
(%): 204 (7) [M+], 119 (100), 105 (17), 93 (89), 77 (20), 69 (32), 56 (15),
9188
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9181 – 9191

Natural Product Synthesis
FULL PAPER
41(29); HRMS (EI): m/z: calcd for C15H24 [M+]: 204.1878, found:
204.1878.
NH4Cl, the entire mixture adsorbed on silica gel and product 31 eluded
with 50% Et2O in pentanes. This material was used in the next step with-
out further characterization. A solution of Ph3P=CH2 (14 mg, 0.05 mmol)
in THF (1mL) was added to a solution of compound 31 thus obtained in
THF (0.5 mL) at À788C and the mixture allowed to reach ambient tem-
perature. After stirring for 45 min, the reaction was quenched with aq.
sat. NH4Cl, the mixture adsorbed on silica gel and the product eluded
with 20% Et2O in pentanes to give compound 32 as a colorless oil
(22 mg, 50%). [a]2D0 =À53.8 (c=1.44 in CH2Cl2); 1H NMR (400 MHz,
CD2Cl2): d=5.89 (qt, J=7.4, 1.3 Hz, 1H), 4.78 (brs, 1H), 4.61 (brs, 1H),
4.16 (q, J=7.1H, 2H), 2.46–2.32 (m, 2H), 2.17–2.10 (m, 1H), 2.05–1.94
(m, 1H), 1.86 (dd, J=2.7, 1.3 Hz, 3H), 1.76–1.67 (m, 2H), 1.61–1.50 (m,
2H), 1.41–1.34 (m, 1H), 1.28 (t, J=7.1 Hz, 3H), 1.25–1.21 (m, 1H), 0.93
(d, J=6.8 Hz, 3H), 0.66 (dd, J=4.3, 3.4 Hz, 1H), 0.58 ppm (dd, J=8.0,
4.3 Hz, 1H); 13C NMR (100 MHz, CD2Cl2): d=168.3, 154.5, 142.8, 127.5,
101.9, 60.3, 38.4, 37.0, 34.5, 31.4, 29.1, 28.1, 27.1, 20.8, 17.9, 16.3,
14.5 ppm; IR (film): n˜ = 3073, 2954, 2931, 2868, 1714, 1651, 1456, 1372,
1220, 1185, 1139, 1098, 1026, 862 cmÀ1; MS (70 eV): m/z (%): 262 (6)
[M+], 216 (12), 141 (16), 133 (16), 119 (100), 105 (19), 93 (65), 77 (28), 67
(16), 55 (18), 41 (22), 29 (17); HRMS (ESI): m/z: calcd for C17H26O2Na
[M+ +Na]: 285.1825, found: 285.1823.
Sesquithujene (9): Prepared analogously from ketone 6 as a colorless oil
(4.6 mg, 58%). [a]2D0 =À8.9 (c=0.6 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.15–5.08 (m, 1H), 4.94 (brs, 1H), 2.43–2.35 (m, 1H), 2.15–
2.00 (m, 3H), 1.77–1.75 (m, 3H), 1.69 (d, J=1.0 Hz, 3H), 1.60 (s, 3H),
1.49–1.38 (m, 1H), 1.34–1.23 (m, 2H), 1.19–1.11 (m, 1H), 0.93 (d, J=
6.6 Hz, 3H), 0.76 (dd, J=7.5, 3.5 Hz, 1H), 0.10 ppm (t, J=3.3 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=145.2, 131.0, 125.1, 120.9, 38.1, 35.5,
35.3, 33.1, 30.9, 26.2, 25.7, 23.7, 17.9, 17.6, 16.3 ppm; IR (film): n˜ = 2963,
2913, 2851, 1641, 1447, 1376, 1026, 779 cmÀ1; MS (70 eV): m/z (%): 204
(7) [M+], 119 (100), 105 (20), 93 (94), 77 (22), 69 (34), 56 (16), 41 (32);
HRMS (EI): m/z: calcd for C15H24 [M+]: 204.1878, found: 204.1877.
trans-Sesquisabinene hydrate (34): A solution of compound 7 (3 mg,
15 mmol) in THF (0.1mL) was added to a solution of Hg (OAc)2 (4.6 mg,
R
15 mmol) in water (0.1mL) and THF (0.1mL). The yellow color of the
reaction mixture disappeared instantaneously and the reaction was
quenched after 5 minutes upon addition of aq. NaOH (3m, 0.1mL) and
NaBH4 (0.5m in 3m NaOH, 0.1mL). A standard extractive work up gave
product 34 as a colorless oil (1.7 mg, 53%). [a]2D0 =À7.8 (c=0.84 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=5.12–5.06 (m, 1H), 2.10–1.94
(m, 2H), 1.89–1.78 (m, 1H), 1.67 (d, J=1.0 Hz, 3H), 1.62 (d, J=8.1Hz,
1H), 1.60 (s, 3H), 1.57–1.43 (m, 2H), 1.39 (brs, 1H), 1.35–1.23 (m, 2H),
1.30 (s, 3H), 1.21–1.14 (m, 1H), 1.09 (ddd, J=8.3, 4.8, 3.5 Hz, 1H), 0.91
(d, J=6.7 Hz, 3H), 0.34 (ddd, J=8.4, 5.2, 0.7 Hz, 1H), 0.22 ppm (dd, J=
5.1, 3.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=131.2, 124.9, 80.6, 37.3,
36.5, 34.9, 34.3, 26.1, 25.8, 25.7, 25.2, 17.7, 13.6 ppm; IR (film): n˜ = 3387,
2962, 2927, 2866, 1452, 1374, 1106, 916 cmÀ1; MS (70 eV): m/z (%): 222
(1) [M+], 204 (38), 161 (20), 137 (16), 121 (80), 107 (30), 93 (65), 82
(100), 69 (84), 55 (39), 43 (73), 29 (10); HRMS (ESI): m/z: calcd for
C15H26ONa [M+ +Na]: 245.1876, found: 245.1874.
Compound 8: Dibal-H (1.0m in toluene, 0.12 mL) was added to a solu-
tion of compound 32 (20 mg, 0.08 mmol) in THF (1mL) at À788C and
the mixture was allowed to warm to 08C. After stirring for 5 min, addi-
tional Dibal-H (1.0m in toluene, 0.08 mL) was introduced and stirring
continued for 30 min. The reaction was quenched by the slow addition of
MeOH (1mL) followed by an aq. sat. solution of Rochelle salt (1mL).
After stirring for 30 min, a clear separation of the phases was reached.
The aqueous layer was extracted with Et2O, the combined organic phases
were evaporated and the product purified by flash chromatography
(20% Et2O in pentanes) to give alcohol 8 as a colorless oil (15 mg,
88%). [a]D27 =À38.9 (c=1.1 in hexanes), lit.:[18a] [a]2D7 =À37.9 (c=1.19 in
hexanes); 1H NMR (300 MHz, C6D6): d=5.18 (t, J=7.3 Hz, 1H), 5.00
(brs, 1H), 4.79 (brs, 1H), 3.97 (s, 2H), 2.10–1.86 (m, 4H), 1.76 (d, J=
1.2 Hz, 3H), 1.67–1.55 (m, 2H), 1.51–1.39 (m, 2H), 1.29–1.17 (m, 1H),
1.08–1.01 (m, 2H), 0.86 (d, J=6.7 Hz, 3H), 0.58 (dd, J=4.2, 3.5 Hz, 1H),
0.42 ppm (ddd, J=7.7, 4.6, 1.1 Hz, 1H); 13C NMR (75 MHz, C6D6): d=
153.8, 135.1, 102.5, 61.5, 38.1, 36.6, 35.3, 31.8, 29.1, 26.7, 25.9, 21.4, 18.3,
16.3 ppm; IR (film): n˜ = 3310, 3073, 2954, 2928, 2867, 1709, 1652, 1455,
1375, 1251, 1110, 1005, 862, 837 cmÀ1; MS (70 eV): m/z (%): 220 (17)
[M+], 161 (17), 145 (10), 133 (32), 121 (52), 105 (26), 93 (100), 79 (46), 69
(40), 55 (34), 43 (79), 20 (17); HRMS (EI): m/z: calcd for C15H24O [M+]:
220.1827, found: 220.1825.
7-epi-trans-Sesquisabinene hydrate (38): Prepared analogously from
alkene 37 as a colorless oil (1.6 mg, 49%). [a]2D0 =+24.6 (c=1.66 in
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=5.11–5.07 (m, 1H), 2.01 (q, J=
7.5 Hz, 2H), 1.90–1.82 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.56–1.50 (m,
2H), 1.47–1.39 (m, 2H), 1.31–1.19 (m, 2H), 1.29 (s, 3H), 1.16–1.08 (m,
1H), 1.01–0.98 (m, 4H), 0.41 (dd, J=7.7, 5.3 Hz, 1H), 0.31ppm (dd, J=
5.1, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=131.2, 124.9, 80.5, 37.5,
36.6, 35.4, 34.0, 33.8, 26.2, 25.7, 24.9, 24.8, 17.8, 17.7, 15.5 ppm; IR (film):
n˜ = 3399, 2963, 2926, 2866, 1452, 1375, 1115, 918 cmÀ1; MS (70 eV): m/z
(%): 222 (9) [M+], 204 (29), 161 (21), 137 (20), 121 (59), 107 (27), 93
(58), 82 (100), 69 (93), 55 (41), 43 (79), 29 (11); HRMS (ESI): m/z: calcd
for C15H26ONa [M+ +Na]: 245.1876, found: 245.1874.
Compound 41d: Ketone ent-46 (50 mg, 0.2 mmol), Bu4NHSO4 (3.4 mg,
0.01mmol) and Na 2B4O7·10H2O (0.05m in Na2EDTAaq (0.4 mm), 2.4 mL)
were successively added to a solution of compound 6 (20 mg, 0.1mmol)
in dimethoxymethane/MeCN (2/1, 2 mL). The resulting mixture was vigo-
rously stirred at 08C while solutions of K2CO3 (0.15 g, 1.1 mmol) in H2O
(1.2 mL) and Oxone (0.17 g, 0.3 mmol) in aq. Na2EDTA (0.4 mm,
1.2 mL) were added dropwise. Once the addition was complete, the reac-
tion was allowed to stir for 20 min at 08C before it was diluted with
water (1mL). The aqueous phase was extracted with Et 2O (3”5 mL),
the combined organic layers were dried over Na2SO4 and evaporated,
and the residue purified by flash chromatography (40% Et2O in pen-
tanes) to give compound 41d as a colorless oil (17 mg, 74%). The diaste-
reomeric ratio (dr 8:1) was determined by GC (50 m SE-54 0.32/0.53df
G/358, 1 0.32 mm, 220/105 410 min, 8 min 320, 5 min 3508C, 0.63 bar
H2). [a]2D0 =À29.1( c=0.5 in CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=
2.68–2.64 (m, 1H), 2.20–1.84 (m, 4H), 1.67–1.52 (m, 4H), 1.43–1.30 (m,
2H), 1.27 (s, 3H), 1.24 (s, 3H), 1.20–1.14 (m, 2H), 1.00 ppm (d, J=
6.6 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=214.2, 64.5, 58.2, 38.8,
38.3, 33.5, 33.4, 31.3, 27.5, 25.0, 22.7, 21.3, 18.8, 17.5 ppm; IR (film): n˜ =
2959, 1875, 1719, 1459, 1378, 1177, 1119, 1023, 863, 775 cmÀ1; MS (70 eV):
m/z (%): 222 (0.2) [M+], 136 (100), 123 (71), 107 (13), 93 (20), 79 (33),
67 (26), 55 (26), 41(73), 27 (32); HRMS (EI): m/z: calcd for C14H22O2Na
[M+ +Na]: 245.1512, found: 245.1510
Compound 29: Ozone was bubbled through a solution of compound 5
(45 mg, 0.22 mmol) in CH2Cl2 (2 mL) at À788C until a pale blue color
persisted. The mixture was purged with argon to remove excess ozone
before Me2S (36 mL, 0.44 mmol) and Et3N (60 mL, 0.42 mmol) were intro-
duced. After stirring for 10 min at À788C, the mixture was allowed to
reach ambient temperature and additional Et3N (60 mL, 0.42 mmol) was
added. After stirring for 30 min, the mixture was adsorbed on silica and
the product eluded with 50% Et2O in pentanes to give compound 29 as a
colorless oil (33 mg, 84%). [a]2D0 =+37.5 (c=2.0 in CH2Cl2); 1H NMR
(400 MHz, CD2Cl2): d=9.73 (t, J=1.5 Hz, 1H), 2.51–2.35 (m, 2H), 2.16–
2.01 (m, 2H), 1.98–1.95 (m, 2H), 1.86–1.77 (m, 1H), 1.65–1.55 (m, 2H),
1.39–1.30 (m, 1H), 1.11 (tdd, J=9.0, 4.7, 1.1 Hz, 1H), 1.07 (dd, J=4.7,
3.3 Hz, 1H), 0.97 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CD2Cl2):
d=214.0, 202.4, 42.2, 38.4, 37.5, 34.5, 33.3, 26.4, 23.6, 19.0, 17.0 ppm; IR
(film): n˜ = 2956, 2933, 2875, 2723, 1714, 1461, 1446, 1379, 1259, 1176,
1025, 916, 776 cmÀ1; MS (70 eV): m/z (%): 180 (7) [M+], 147 (23), 136
(88), 123 (73), 105 (13), 96 (33), 79 (79), 67 (77), 55 (100), 41 (86), 29
(54); HRMS (EI): calcd for C11H16O2Na [M+ +Na]: 180.1150, found:
180.1151.
Compound 32: NaH (6 mg, 0.23 mmol) was added to a solution of phos-
phonate 30 (91mg, 0.25 mmol) [48] in THF (0.5 mL) at 08C and the result-
ing mixture stirred for 30 min before it was transferred via cannula into a
solution of 29 (30 mg, 0.17 mmol) in THF (0.5 mL) at À788C. The mix-
ture was stirred for 30 min and then allowed to reach 08C. After stirring
for 1h, the reaction was quenched with the minimum amount of aq. sat.
Compound 45: A freshly prepared solution of LDA (0.1m in THF,
0.5 mL) was added to a solution of compound 41d (dr 8:1, 11 mg,
Chem. Eur. J. 2008, 14, 9181 – 9191
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9189

A. Fürstner and A. Schlecker
50 mmol) in THF (0.5 mL) at À788C. After stirring for 20 min at this tem-
perature, 2-pyridyl-NTf2 (Comins reagent, 24 mg, 60 mmol) was intro-
duced and the resulting mixture allowed to reach ambient temperature.
Stirring was continued for 30 min before the mixture was cooled to
2005, 24, 3182–3191; c) A. Correa, N. Marion, L. Fensterbank, M.
Malacria, S. P. Nolan, L. Cavallo, Angew. Chem. 2008, 120, 730–733;
Angew. Chem. Int. Ed. 2008, 47, 718–721; d) O. N. Faza, C. S.
López, R. lvarez, A. R. de Lera, J. Am. Chem. Soc. 2006, 128,
2434–2437; e) E. Soriano, J. Marco-Contelles, J. Org. Chem. 2005,
70, 9345–9353; f) E. Soriano, J. Marco-Contelles, J. Org. Chem.
2007, 72, 1443–1448; g) E. Soriano, P. J. Marco-Contelles, J. Org.
Chem. 2007, 72, 2651–2654.
À358C. NMP (46 mL, 0.50 mmol), Fe
A
(3m in Et2O, 27 mL) were then added successively and the ensuing cross
coupling reaction quenched after 5 min at À358C by addition of aq. sat.
NH4Cl (100 mL). The mixture was adsorbed on silica which was placed
on top of a flash column packed with silica gel. The product was eluded
with 10% Et2O in pentanes to give compound 45 as a colorless oil (8 mg,
dr 8:1, 72%). [a]2D0 =À17.9 (c=0.5 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.94 (brs, 1H), 2.73–2.70 (m, 1H), 2.40 (dt, J=17.0, 2.2 Hz,
1H), 2.14–2.09 (m, 1H), 1.76 (d, J=1.7 Hz, 3H), 1.65–1.57 (m, 3H),
1.36–1.30 (m, 2H), 1.31 (s, 3H), 1.27 (s, 3H), 1.20–1.16 (m, 1H), 0.95 (d,
J=6.8 Hz, 3H), 0.76 (dd, J=7.5, 3.5 Hz, 1H), 0.11ppm (t, J=3.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=145.1, 120.9, 64.7, 58.1, 38.4, 35.4,
33.1, 31.9, 31.0, 27.1, 24.9, 23.7, 18.7, 17.8, 16.3 ppm; IR (film): n˜ = 3038,
2959, 2925, 2846, 1687, 1641, 1447, 1377, 1220, 1126, 776 cmÀ1; MS
(70 eV): m/z (%): 220 (1) [M+], 145 (19), 132 (84), 119 (72), 105 (47), 93
(100), 77 (36), 71 (35), 55 (19), 43 (38), 29 (10); HRMS (EI): m/z: calcd
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Acknowledgement
Generous financial support by the MPG and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank our NMR and chroma-
tography departments for excellent support, Dr. T. Yamamoto, Takasago,
for a gift of enantiopure citronellal, and Umicore AG & Co KG, Hanau,
for a gift of noble metal salts.
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9190
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9181 – 9191

Natural Product Synthesis
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Received: July 8, 2008
Published online: September 11, 2008
Chem. Eur. J. 2008, 14, 9181 – 9191
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9191