Total synthesis of (+)-7,11-helianane and (+)-5-chloro-7,11-helianane through stereoselective aromatic claisen rearrangement

Article abstract of DOI:10.1002/ejoc.201100706

The aromatic bisabolene sesquiterpene of marine origin (+)-7,11-helianane (1) and its moderately cytotoxic halogenated relative (+)-5-chloro-7,11- helianane (3) have been synthesized by a concise, stereoselective route. By capitalizing on a palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) reaction, followed by a thermal (uncatalyzed) aromatic Claisen rearrangement, which allowed for the installation of the required benzylic stereocenter, the aforementioned natural products were secured in 80 % ee, with almost complete transfer of stereochemical information during the [3,3] sigmatropic process. The enantioselective total synthesis confirmed the recently proved (S) absolute configuration for (+)-7,11-helianane (1) and demonstrated the same configuration, for the first time, in the case of (+)-5-chloro-7,11-helianane (3).

Full text of DOI:10.1002/ejoc.201100706

FULL PAPER
DOI: 10.1002/ejoc.201100706
Total Synthesis of (+)-7,11-Helianane and (+)-5-Chloro-7,11-helianane through
Stereoselective Aromatic Claisen Rearrangement
Francesca Quartieri,[a] Laura Elisabetta Mesiano,[a] Daniela Borghi,[a] Viviana Desperati,[a]
Cesare Gennari,[b] and Gianluca Papeo*[c]
Keywords: Antitumor agents / Asymmetric synthesis / Natural products / Sigmatropic rearrangement / Terpenoids / Total
synthesis
The aromatic bisabolene sesquiterpene of marine origin (+)-
7,11-helianane (1) and its moderately cytotoxic halogenated
relative (+)-5-chloro-7,11-helianane (3) have been synthe-
sized by a concise, stereoselective route. By capitalizing on a
palladium-catalyzed asymmetric allylic alkylation (Pd-AAA)
ral products were secured in 80%ee, with almost complete
transfer of stereochemical information during the [3,3] sig-
matropic process. The enantioselective total synthesis con-
firmed the recently proved (S) absolute configuration for (+)-
7,11-helianane (1) and demonstrated the same configuration,
for the first time, in the case of (+)-5-chloro-7,11-helianane
(3).
reaction, followed by
a thermal (uncatalyzed) aromatic
Claisen rearrangement, which allowed for the installation of
the required benzylic stereocenter, the aforementioned natu-
number of benzoxocane ring-containing sesquiterpenes, all
at higher oxidation state compared to compounds 1–3, has
been identified as secondary metabolites of sunflowers
(Helianthus annus).[4]
Heliananes (1–3) contain a single stereogenic center, the
absolute configuration of which was provisionally assigned
as 7S, based upon the existing correlation between the abso-
lute configuration and the optical rotation sign of their pre-
sumed biogenetic precursors.[2–4] However, despite the sim-
ple logic underpinning this designation, still some confusion
is present in the literature, as testified by the large number
of inconsistent drawings representing optically active heli-
ananes.[5]
Introduction
(+)-7,11-Helianane (1),[1] isolated from the marine
sponges Haliclona fascigera[2] and Spirastrella hartmani,[3]
and its halogenated derivatives (+)-5-bromo- (2) and (+)-
5-chloro-7,11-helianane (3), both isolated from the sponge
Spirastrella hartmani,[3] are aromatic bisabolene sesquiterp-
enes featuring a benzoxocane ring (Figure 1). This hitherto
unprecedented molecular topology among marine natural
products has its parallel in terrestrial plants, where a
Whereas (+)-7,11-helianane (1) has not been subjected to
any biological assay so far, (+)-5-chloro-7,11-helianane (3)
showed double-digit micromolar in vitro activity on NSCL
(A549, GI50 37.2 μm), colon (HT29, GI50 37.6 μm), and
breast (MDA-MB-231, GI50 37.6 μm) human cancer cell
lines. (+)-5-Bromo-7,11-helianane (2), on the other hand,
when tested on the same cell lines, proved to be inactive.[3]
The first total synthesis of racemic 7,11-helianane (1) was
reported by Snieckus and Stefanovic in 1998.[6] Later, the
group of Venkateswaran entered the field by publishing
three communications[5a,5b,5e] and two full papers[5c,5d] on
the subject. Remarkably, in their last communication, Venk-
ateswaran et al.[5e] also accomplished the first synthesis of
(Ϯ)-5-bromo- (2) and (Ϯ)-5-chloro-7,11-helianane (3). Very
recently, Shishido and co-workers reported the first enan-
tioselective total synthesis of (+)-helianane (1), confirming
its provisionally assigned, biogenetically based, (S) absolute
configuration.[7]
Figure 1. The helianane family.
[a] Department of Chemical Core Technologies,
Nerviano Medical Sciences,
Viale Pasteur 10, 20014 Nerviano (MI), Italy
[b] Università degli Studi di Milano, Dipartimento di Chimica
Organica e Industriale, Centro Interdipartimentale C.I.S.I.,
Via G. Venezian 21, 20133 Milano, Italy
[c] Department of Medicinal Chemistry,
Nerviano Medical Sciences,
Viale Pasteur 10, 20014 Nerviano (MI), Italy
Fax: +39-0331-581347
E-mail: gianluca.papeo@nervianoms.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100706.
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Eur. J. Org. Chem. 2011, 6794–6801

Synthesis of (+)-7,11-Helianane and (+)-5-Chloro-7,11-helianane
position of the crude reaction mixture allowed rapid com-
parison of the conditions, in terms of both regio- and
stereoselectivity (Table 1).
Results and Discussion
The envisioned retrosynthetic analysis of (S)-7,11-helian-
ane (1) and (S)-5-chloro-7,11-helianane (3) starts with the
well-documented (in its racemic form)[5b,5c] dialdehyde pre-
cursor 4 and entails Trost’s palladium-catalyzed asymmetric
allylic alkylation (Pd-AAA)[8,9] on meta-cresol, followed by
a stereoselective aromatic Claisen rearrangement as the key
steps to install the required stereogenic center (Scheme 1).
Robust literature precedents, based upon the concept of dy-
namic kinetic asymmetric transformation (DYKAT),[8,9]
support the feasibility of the planned asymmetric alkylation
of the starting phenol.[10] In contrast, the challenge of ac-
complishing a stereoselective aromatic Claisen rearrange-
ment can be appreciated by looking at the paucity of exam-
ples reported so far.[10–12] The asymmetric version of this
[3,3] sigmatropic rearrangement is complicated by the coex-
istence of nonsynchronized concerted and ionic mecha-
nisms (the latter often enhanced by Lewis acids), and by the
potential presence (especially under the vigorous thermal
conditions required for the reaction to occur) of competing
chair-like and boat-like transition states;[13] ortho/para as
well as ortho/orthoЈ (in the case of meta-substituted allyl
aryl ethers) regioselectivity issues further complicate the
picture, alongside abnormal Claisen rearrangement.[13a]
Table 1. Claisen rearrangement of (Ϯ)-6; optimization of the reac-
tion conditions.
Entry
1
Reagents and conditions
[Eu(fod)3], CHCl3, reflux
Time Regioisomers;[a]
[h]
yield [%] (E/Z)[b]
48
5; 59 (3:1)
7; 18 (3:1)
8; 14
2
3
[Eu(fod)3], DCE, 80 °C
[Eu(hfc)3], DCE, 80 °C
48
72
5; 64 (4:1)
7; 25 (4:1)
8; 8
5; 62 (3:1)
7; 32 (3:1)
8; 3
4
5
SnCl4, CH2Cl2, 0 °C to r.t.
2
4
extensive
decomposition
5; 67 (7:1)
7; 17 (7:1)
8; 13
N,N-diethylaniline, 190 °C
[a] All regioisomers are racemic. [b] Yields and E/Z ratios were de-
1
termined by H NMR spectroscopic analysis of the crude reaction
mixture.
The shift reagent [Eu(fod)3] was initially used as a cata-
lyst in an attempt to promote the Claisen rearrangement of
allyl phenyl ether (Ϯ)-6, due to the mild reaction conditions
and high diastereoselectivity reported by Trost and Toste
with a similar substrate.[10] Unfortunately, modest yield and
diastereoselectivity [(Ϯ)-5; 59%, E/Z = 3:1] were observed
in this case (Table 1, Entry 1). A slight increase in conver-
sion and diastereoselectivity [(Ϯ)-5; 64%, E/Z = 4:1] was
obtained by working at higher temperature, as suggested for
less electron-rich substrates[10] (Table 1, Entry 2). Attempts
to further improve these results by using a more sterically
demanding europium salt proved unsuccessful (Table 1, En-
try 3). Tin tetrachloride, which was recently claimed to be
effective in catalyzing some Claisen rearrangements[16] and
also influencing the regioselective course of the reaction,[5d]
unfortunately delivered a complex mixture containing negli-
gible amounts of phenol (Ϯ)-5 (Table 1, Entry 4).[17] Grati-
fyingly, the more conventional thermal process, performed
in a polar solvent such as N,N-diethylaniline (Table 1, En-
try 5), resulted in a significant improvement in the dia-
stereoselectivity [(Ϯ)-5; E/Z = 7:1] with a yield (67%) com-
parable to that obtained in the europium-catalyzed reaction
(cf. Table 1, Entries 2 and 5). As expected, the same levels
of diastereoselectivity were observed in allylphenol (Ϯ)-5
and its orthoЈ regioisomer (Ϯ)-7 (Table 1, Entries 1–3 and
5). The effect of the branched (and thus more sterically de-
manding) allylic chain on the equilibrium population of the
ground-state conformers[18] reasonably accounts for the
pleasingly good ortho/orthoЈ regioselectivity that was experi-
mentally observed in the thermal [3,3] sigmatropic re-
arrangement [(Ϯ)-5/(Ϯ)-7 = ca. 4:1; Table 1, Entry 5].
Having identified suitable reaction conditions for the
aromatic Claisen rearrangement of (Ϯ)-6, their application
to the corresponding optically active substrate was then in-
vestigated. To this end, meta-cresol was submitted to a Pd-
Scheme 1. Retrosynthetic approach to heliananes.
The search for optimal Claisen rearrangement conditions
(in terms of conversion, regio- and stereoselectivity) was
undertaken on racemic allyl phenyl ether (Ϯ)-6, which was
prepared in moderate yield by reaction of meta-cresol with
(E)-3-penten-2-ol using a standard Mitsunobu protocol
(Scheme 2). Because the E/Z isomer ratio of (Ϯ)-5 reflects
the diastereoselectivity of the sigmatropic rearrangement
process,[10,11,14,15] a 1H NMR-based assessment of the com-
Scheme 2. Synthesis of (Ϯ)-6 and studies of the Claisen rearrange-
ment.
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G. Papeo et al.
FULL PAPER
AAA reaction in the presence of allyl carbonate 9, catalytic quence of the better diastereoselectivity. Furthermore, the
[Pd2dba3·CHCl3] and (R,R)-Trost ligand (A), delivering 6[19] thermal reaction required significantly shorter reaction time
in excellent isolated yield (90%) and good enantiomeric ex- to go to completion.
cess (82%), as determined by chiral HPLC analysis
From these results, it is clear that, regardless of the reac-
(Scheme 3). Attempts to shorten the reaction time (20 h), tion conditions employed, excellent transfer of stereochemi-
by performing the asymmetric allylation under microwave cal information took place during the rearrangement (com-
irradiation, resulted in a comparable yield (88%) but re- pare the 76–80%ee of phenol 5 with the 82%ee of the start-
duced enantiomeric excess (75%). The enantiomerically en- ing ether 6). However, a greater diastereoselectivity was
riched allyl phenyl ether 6 was then subjected to a Claisen achieved under thermal conditions. Success in scaling up
rearrangement (Table 2) according to the optimized reac- (up to 10 mmol) the palladium-catalyzed asymmetric allylic
tion conditions (Table 1). Bearing in mind the possible ste- alkylation/aromatic Claisen rearrangement sequence, pro-
reochemical erosion that could arise from such a vigorous vided enough phenol 5 to complete the synthesis of (S)-
thermal process (Table 1, Entry 5), we decided to run the 7,11-helianane (1) and (S)-5-chloro-7,11-helianane (3) (see
reaction under both the optimized thermal conditions and below).
under the milder Trost–Toste catalytic conditions[10]
(Table 1, Entry 2), in order to compare the resulting 4 (Scheme 1) required, first, the preparation of alkene 10
For this purpose, access to key intermediate dialdehyde
enantiopurities of 5.
(Scheme 4). Deletion of the redundant terminal carbon
atom of 5 was achieved in moderate yield through cross
metathesis, by exposing 5 to an atmosphere of ethylene in
the presence of Grubbs second generation ruthenium cata-
lyst (B). Subsequent straightforward alkylation of the phe-
nol moiety with 2-bromo-2-methylpropanoic acid allowed
the installation of the quaternary carbon in nearly quantita-
tive yield. With the aim of verifying the integrity of the
benzylic stereocenter at this stage, diastereomeric amides
were prepared by coupling acid 11 with (R)-(–)-2-phenylgly-
cine methyl ester, and the resulting crude reaction was ana-
1
lyzed by H NMR spectroscopy. Gratifyingly, despite the
strongly alkaline medium required for the alkylation reac-
tion, no stereochemical erosion was observed (80%ee based
upon the relative intensity of the diastereomeric pro-
tons).[21] Alkene hydroboration with simultaneous carbox-
ylic acid reduction, followed by treatment with hydrogen
peroxide, secured the desired diol 12 (the only solid com-
pound along the synthetic sequence), which was sub-
sequently oxidized to the corresponding dialdehyde 4 using
a standard Swern protocol (Scheme 4).
Scheme 3. Pd-AAA reaction to give enantiomerically enriched 6
(82%ee).
Table 2. Claisen rearrangement of ether 6 (82%ee) to phenol 5.
At this point, an intramolecular pinacol-type McMurry
coupling[22a] of the carbonyl functionalities present in 4 was
envisioned as a promising shortcut to benzooxocene 13.
Unfortunately, reaction of 4 with Ti0, which was generated
in situ, delivered either a complex reaction mixture (with
TiCl3 and freshly prepared Zn/Cu alloy),[22b,22c] or the
Entry
Reagents and conditions
Time
[h]
Isolated yield
[%]
ee
[%]
1
2
[Eu(fod)3], DCE, 80 °C
N,N-diethylaniline, 190 °C
48
4
14
32
76
80
Isolation of the desired (E)-isomer of 5 required, in ad- benzooxepine derivative 14 arising from an intramolecular
dition to classical flash chromatography, a second purifica- aldol condensation (with TiCl3 and LiAlH4)[22d]
tion step with a silver nitrate-impregnated silica gel station- (Scheme 4).
ary phase[20] to separate the E/Z mixture. Despite the sepa-
Failure to synthesize the benzooxocene intermediate 13
ration efficiency demonstrated by this venerable technique, through McMurry coupling prompted us to retrace the fi-
unfortunately, the recovery proved to be lower than ex- nal synthetic steps reported by Venkateswaran et al.[5b,5c]
pected, probably due to some silver-mediated phenol oxi- to access (S)-7,11-helianane (1). Accordingly, double Wittig
dation.[20] However, with the pure (E)-isomer in hand, the olefination of dialdehyde 4 would set the stage for the sub-
enantiomeric excess of 5 was then assessed through 1H sequent ring-closing metathesis, delivering 13. Unexpec-
NMR analysis of the corresponding diastereomeric Mosher tedly, attempts to reproduce the Wittig olefination[5b,5c]
esters.[21] Notably, in addition to a slightly higher enantio- proved to be exceedingly troublesome, affording the desired
meric excess (80 vs. 76%ee; cf. Table 2, Entries 2 and 1), a alkene 15 in an unacceptable 17% yield at best. Similar
doubling of the isolated yield of 5 (32 vs. 14%; cf. Table 2, frustrating outcomes were encountered by employing com-
Entries 2 and 1) was observed in the case of the thermal mercially available Tebbe reagent. Finally, microwave-as-
(uncatalyzed) Claisen rearrangement as a logical conse- sisted[23] Petasis (Cp2TiMe2) olefination[24] secured alkene
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Synthesis of (+)-7,11-Helianane and (+)-5-Chloro-7,11-helianane
Scheme 4. Synthesis of the key precursor dialdehyde 4 and attempts at McMurry coupling.
Scheme 5. (S)-(+)-7,11-Helianane (1) and (S)-(+)-5-chloro-7,11-helianane (3) syntheses completion.
15 in moderate yield (Scheme 5). Ring-closing metathesis that reported for the supposed optically pure natural mate-
with Grubbs second generation ruthenium catalyst (B), fol- rial {[α]D = +80.0 (c = 0.01, CHCl3)}.[3]
lowed by catalytic hydrogenation of the benzooxocene
Accurate biological profiling of (S)-(+)-5-chloro-7,11-
double bond proceeded uneventfully, delivering (S)-7,11- helianane (3) on a number of different cancer cell lines, as
helianane (1) as a colorless oil, the spectroscopic data of well as investigation of its mechanism of action are un-
which matched those reported for both natural and syn- derway, and will be reported in due course.
thetic 1 (Scheme 5). Chiral HPLC analysis (80%ee; see the
Experimental Section) of synthetic (S)-7,11-helianane (1)
demonstrated that no stereochemical erosion had occurred
during the last five steps of the synthesis. Furthermore, op-
Conclusions
tical rotation measurements proved 1 to be dextrorotatory,
A palladium-catalyzed, asymmetric allylic alkylation
thus confirming the recently proved (S) absolute configura- (Pd-AAA) on meta-cresol, followed by a stereoselective aro-
tion for this marine sesquiterpene.[7] In agreement with the matic Claisen rearrangement were the key reactions of a
data reported by Shishido and co-workers,[7] the absolute nine-step synthetic sequence that secured the marine sesqui-
value of the optical rotation of the enantioenriched terpene (S)-(+)-7,11-helianane (1) in good enantiomeric ex-
(80%ee) synthetic (S)-(+)-7,11-helianane (1) {[α]D = +18.9 cess. The reported moderately cytotoxic (S)-(+)-5-chloro-
(c = 0.59, CH2Cl2)} turned out to be dramatically higher 7,11-helianane (3) was also attained, with the same enantio-
than that reported for the supposed optically pure natural meric excess, by simple halogenation of the parent com-
compound {[α]D = +8.0 (c = 1.01, CH2Cl2)}.[2] (S)-(+)-7,11- pound (1). Dynamic kinetic asymmetric transformation
Helianane (1) was then brought forward to the biologically (DYKAT) provided the initial enantioenrichment, which
more appealing (S)-5-chloro-7,11-helianane (3). Thus, halo- was faithfully transferred during the [3,3] sigmatropic pro-
genation of 1 with N-chlorosuccinimide (NCS) in acetoni- cess and preserved throughout the whole synthetic pathway.
trile at 50 °C gave 3 in 85% yield. The conservation of en- The enantioselective total synthesis confirmed the recently
antiopurity of 3 was assessed by chiral HPLC analysis proved (S) absolute configuration for (+)-7,11-helianane (1)
(80%ee; see the Experimental Section), whereas the pro- and demonstrated it for the first time in the case of (+)-5-
posed (S) absolute configuration was confirmed by optical chloro-7,11-helianane (3), despite discrepancies between the
rotation measurements. Quite surprisingly, the absolute absolute values of the optical rotation of the natural and
value of the optical rotation of the enantioenriched synthetic materials. Furthermore, the present work under-
(80%ee) (S)-(+)-5-chloro-7,11-helianane (3) {[α]D = +33.4 lines the power of the diastereoselective aromatic Claisen
(c = 0.36, CHCl3)} proved to be discordantly lower than rearrangement in generating benzylic stereocenters from a
Eur. J. Org. Chem. 2011, 6794–6801
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G. Papeo et al.
FULL PAPER
(125.7 MHz, [D6]DMSO, 25 °C):
(CH3CH), 53.8 (OCH3), 74.0 (CHCH3), 128.3 (CH=CHCH3),
130.4 (CH=CHCH3), 154.8 (OCO2CH3) ppm.
δ
=
16.9 (CH3CH=), 19.7
given chiral allyl phenyl ether precursor. Despite a number
of potential setbacks and the lack of a full comprehension
of the mechanistic details, which has probably contributed
to its limited use in wider applications, this functional group
compatible [3,3] sigmatropic rearrangement is one of the
1-Methyl-3-[(2R,3E)-pent-3-en-2-yloxy]benzene (6): Carbonate
(3 g, 20.8 mmol) was dissolved in anhydrous CH2Cl2 (40 mL) under
9
least expensive, experimentally simplest, and efficient strate- an inert atmosphere, then [Pd2(dba)3·CHCl3] (220 mg, 0.212 mmol)
and (R,R)-Trost ligand (A; 440 mg, 0.637 mmol) were subsequently
added at room temperature. As soon as the obtained red mixture
turned yellow (nearly 40 min), a solution of m-cresol (3.35 mL,
32 mmol) in anhydrous CH2Cl2 (40 mL) was added dropwise. The
reaction was monitored by TLC (hexane/AcOEt = 98:2). After 4 h,
further [Pd2(dba)3·CHCl3] (220 mg, 0.212 mmol) and ligand A
(440 mg, 0.637 mmol) were added. The reaction was stirred at room
temperature overnight, then filtered through a pad of Celite and
the volatiles were removed under reduced pressure. Compound 6
was isolated by flash column chromatography (hexane) as a color-
less oil (3.28 g, 90%). 82%ee (Chiral HPLC, column: Daicel Chi-
ralpak AD, 4.6ϫ250 mm, 10 μm; eluent: 100% hexane; flow:
0.2 mL/min; detector: UV 254 nm). For 1H, 13C NMR, and
HRMS, see (Ϯ)-6.
gies for the transfer of stereochemical information.
Experimental Section
General: All solvents were reagent grade and all reagents were used
as supplied. Flash chromatography was performed with silica gel
60 Å (particle size 230–400 mesh) supplied by Aldrich. Melting
points were recorded with a Buchi 535 instrument. NMR spectra
were recorded at 25, 28, and 50 °C in [D6]DMSO and CDCl3 with
a Varian Inova 500 spectrometer equipped with 5 mm 1H{13C,15N}
z-axis-PFG indirect detection cold probe and with a Varian Inova
400 spectrometer equipped with 5 mm 1H{15N-31P} z-axis-PFG in-
direct detection probe. Residual solvent signal was used as refer-
ence (δ = 2.50 and 7.24 ppm for 1H and δ = 39.5 and 77.2 ppm
for 13C). Standard two-dimensional sequences provided by Varian
(COSY, gradient-enhanced HSQC and HMBC) were used to assign
proton and carbon resonances. Exact mass data ESI(+) high-reso-
lution mass spectra (HRMS) were obtained with a Waters Q-Tof
Ultima spectrometer directly connected to a micro HPLC 1100 Ag-
ilent instrument, as described previously.[25] Optical rotation mea-
surements were performed with a Perkin–Elmer 241 polarimeter.
5-Methyl-2-[(2S,3E)-pent-3-en-2-yl]phenol (5)
Thermal Claisen Rearrangement:
A solution of 1-methyl-3-
[(2R,3E)-pent-3-en-2-yloxy]benzene (6; 1.65 g, 9.36 mmol) in N,N-
diethylaniline (1.6 mL) was heated at 190 °C for 4 h. The mixture
was then diluted with Et2O, washed with 1 n HCl and water. The
organic layer was dried with Na2SO4, filtered, and the solvent was
removed under reduced pressure. Initial flash chromatography
(hexane/AcOEt = 99:1) allowed 5 (0.875 g, mixture of E/Z isomers)
to be separated from 7 (0.22 g, 13%) and 8 (0.18 g, 11%). A second
purification, using hexane as the eluent, on silica gel 60 (230–
400 mesh), previously impregnated with a solution of 10 wt./vol.-
% AgNO3 in water and dried in an oven at 70 °C, afforded pure
(E)-5 (0.53 g, 32%) and (Z)-5 (0.06 g, 3.5%). Data for (E)-5: 1H
NMR (400.5 MHz, [D6]DMSO, 28 °C): δ = 1.17 (d, J = 7.0 Hz, 3
H, CH3CH), 1.59–1.64 (m, 3 H, CH3CH=), 2.16 (s, 3 H, CH3Ar),
3.64–3.71 (m, 1 H, CHCH3), 5.33–5.41 (m, 1 H, CH=CHCH3),
5.57–5.65 (m, 1 H, CH=CHCH3), 6.53 (dd, J = 7.7, 1.6 Hz, 1 H,
ArCH), 6.57 (d, J = 1.6 Hz, 1 H, ArCH), 6.89 (d, J = 7.7 Hz, 1 H,
ArCH), 9.07 (s, 1 H, OH) ppm. 13C NMR (125.7 MHz, [D6]-
DMSO, 25 °C): δ = 17.6 (CH3CH=), 20.3 (CH3CH), 20.6 (CH3Ar),
34.1 (CHCH3), 115.4 (ArCH), 119.3 (ArCH), 122.5 (CH=CHCH3),
127.0 (ArCH), 130.0 (ArCCH), 135.5 (ArCCH3), 136.0
(CH=CHCH3), 154.2 (ArCOH) ppm. HRMS (ESI+): calcd for
1-Methyl-3-[(3E)-pent-3-en-2-yloxy]benzene [(؎)-6]: To a solution
of (3E)-pent-3-en-2-ol (5 g, 0.058 mol), m-cresol (12.4 g,
0.115 mol), and PPh3 (30.45 g, 0.116 mol) in THF (70 mL), cooled
to 0 °C, DEAD (18 mL, 0.116 mol) in THF (15 mL), was added
dropwise. The reaction, which was monitored by TLC (hexane/Ac-
OEt = 98:2), was stirred at room temperature overnight. The pre-
cipitate was filtered off and thoroughly washed with ethyl acetate.
Purification by flash chromatography (hexane/AcOEt = 98:2) af-
forded (Ϯ)-6 (6.64 g, 65%) as a colorless oil. IR (film): ν = 963 cm–1
˜
(absence of signals at 720, 953, 1006 cm–1 indicated that no Z iso-
mer was present).[11] 1H NMR (400.5 MHz, [D6]DMSO, 28 °C): δ
= 1.30 (d, J = 6.2 Hz, 3 H, CH3CH), 1.63 (ddd, J = 6.5, 1.5, 0.7 Hz,
3 H, CH3CH=), 2.24 (s, 3 H, CH3Ar), 4.81–4.88 (m, 1 H, CHCH3),
5.46–5.53 (m,
1
H, CH=CHCH3), 5.65–5.76 (m,
1
H,
CH=CHCH3), 6.63–6.74 (m, 3 H, ArH), 7.11 (m, 1 H, ArH) ppm.
13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ = 16.8 (CH3CH=),
20.5 (CH3Ar), 20.9 (CH3CH), 72.0 (CHCH3), 112.8 (ArCH), 116.2
(ArCH), 120.7 (ArCH), 126.4 (CH=CHCH3), 129.1 (ArCH), 131.3
(CH=CHCH3), 139.0 (ArCCH3), 158.0 (ArCO) ppm. HRMS
(ESI+): calcd for C12H17O [M + H]+ 177.1274; found 177.1280.
1
C12H17O [M + H]+ 177.1274; found 177.1271. Data for (Z)-5: H
NMR (400.5 MHz, [D6]DMSO, 28 °C): δ = 1.16 (d, J = 7.0 Hz, 3
H, CH3CH), 1.58 (dd, J = 6.7, 1.7 Hz, 3 H, CH3CH=), 2.16 (s,
3 H, CH3Ar), 3.97–4.04 (m, 1 H, CHCH3), 5.26–5.37 (m, 1 H,
CH=CHCH3), 5.56 (m, 1 H, CH=CHCH3), 6.53 (dd, J = 7.7,
Methyl (3E)-Pent-3-en-2-yl Carbonate (9): (3E)-Pent-3-en-2-ol (5 g, 1.6 Hz, 1 H, ArCH), 6.56 (d, J = 1.6 Hz, 1 H, ArCH), 6.97 (d, J
0.058 mol) was dissolved in anhydrous Et2O (130 mL) under an
inert atmosphere and cooled to –78 °C. LiHMDS (1 m in THF,
70 mL, 0.07 mol) and, after 30 min, methylchloroformate (6.7 mL,
0.087 mol) were added. The disappearance of the starting material
was monitored by TLC (hexane/AcOEt = 95:5). After 40 min, the
reaction was quenched with water (130 mL) and then washed with
1 n HCl and water. The organic layer was dried with Na2SO4, fil-
tered, and concentrated in vacuo. Crude 9 was purified on silica
gel (CH2Cl2) and isolated as a colorless oil (6.37 g, 76%). 1H NMR
(400.5 MHz, [D6]DMSO, 28 °C): δ = 1.27 (d, J = 6.5 Hz, 3 H,
= 7.7 Hz, 1 H, ArCH), 9.08 (s, 1 H, OH) ppm. 13C NMR
(125.7 MHz, [D6]DMSO, 25 °C): 17.4 (CH3CH=), 20.5
δ
=
(CH3Ar), 21.6 (CH3CH), 29.4 (CHCH3), 115.3 (ArCH), 119.2
(ArCH), 121.4 (CH3CH=CH), 126.5 (ArCH), 129.4 (ArCCH),
135.4 (CH3CH=CH), 135.4 (ArCCH3), 150.1 (ArCOH) ppm. Data
1
for (E)-7: H NMR (400.5 MHz, [D6]DMSO, 28 °C): δ = 1.30 (d,
J = 7.1 Hz, 3 H, CH3CH), 1.59 (ddd, J = 6.5, 1.3, 1.0 Hz, 3 H,
CH3CH=), 2.22 (s, 3 H, CH3Ar), 3.74–3.82 (m, 1 H, CHCH3),
5.33–5.42 (m,
1
H, CH=CHCH3), 5.87–5.93 (m,
1
H,
CH=CHCH3), 6.54 (d, J = 7.8 Hz, 1 H, ArCH), 6.60 (d, J =
CH3CH), 1.66 (ddd, J = 6.5, 1.6, 0.7 Hz, 3 H, CH3CH=), 3.67 7.6 Hz, 1 H, ArCH), 6.83 (dd, J = 7.8, 7.6 Hz, 1 H, ArCH), 9.03
(s, 3 H, OCH3), 5.04–5.10 (m, 1 H, CHCH3), 5.46–5.56 (m, 1 H,
(s, 1 H, OH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ =
17.5 (CH3CH=), 18.6 (CH3CH), 20.3 (CH3Ar), 35.6 (CHCH3),
CH=CHCH3), 5.67–5.79 (m, 1 H, CH=CHCH3) ppm. 13C NMR
6798
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6794–6801

Synthesis of (+)-7,11-Helianane and (+)-5-Chloro-7,11-helianane
113.5 (ArCH), 120.6 (ArCH), 121.8 (CH3CH=CH), 125.8 (ArCH),
130.0 (ArCCH), 135.1 (CH3CH=CH), 136.3 (ArCCH3), 155.5 (Ar-
COH) ppm. Data for Compound 8: 1H NMR (400.5 MHz, [D6]-
DMSO, 28 °C): δ = 1.19 (d, J = 7.1 Hz, 3 H, CH3CH), 1.61 (dt, J
= 6.3, 1.2 Hz, 3 H, CH3CH=), 2.17 (s, 3 H, CH3Ar), 3.45–3.51 (m,
1 H, CHCH3), 5.22–5.39 (m, 1 H, CH=CHCH3), 5.42–5.56 (m, 1
(s, 3 H, CH3Ar), 3.76–3.84 (m, 1 H, CHCH3), 4.93–5.04 (m, 2 H,
CH2=), 5.98 (ddd, J = 17.1, 10.4, 6.3 Hz, 1 H, CH=CH2), 6.51 (br.
s, 1 H, ArCH), 6.73 (br. d, J = 7.8 Hz, 1 H, ArCH), 7.00 (d, J =
7.8 Hz, 1 H, ArCH), 12.99 (br. s, 1 H, COOH) ppm. 13C NMR
(125.7 MHz, [D6]DMSO, 25 °C): δ = 19.4 (CH3CH), 21.0 (CH3Ar),
25.3 [(CH3)2C], 35.5 (CHCH3), 78.5 [(CH3)2C], 113.1 (CH2=),
H, CH=CHCH3), 6.49–6.56 (m, 2 H, ArCH), 6.92 (m, 1 H, ArCH), 117.2 (ArCH), 121.6 (ArCH), 127.4 (ArCH), 132.7 (ArCCH),
8.99 (s, 1 H, OH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C): 135.6 (ArCCH3), 143.3 (CH=CH2), 152.9 (ArCO), 176.0
δ = 17.9 (CH3CH=), 19.5 (CH3Ar), 20.7 (CH3CH), 36.4 (CHCH3), (COOH) ppm. HRMS (ESI+): calcd. for C15H21O3 [M + H]+
112.4 (ArCH), 116.5 (ArCH), 121.7 (CH3CH=CH), 126.1 (ArCH),
134.1 (ArCCH), 136.0 (ArCCH3), 136.4 (CH3CH=CH), 155.0 (Ar-
COH) ppm.
249.1485; found 249.1480.
(3S)-3-{2-[(1-Hydroxy-2-methylpropan-2-yl)oxy]-4-methylphenyl}-
butan-1-ol (12): To a solution of 11 (570 mg, 2.29 mmol) in anhy-
drous THF (20 mL), cooled to –78 °C, BH3·THF (14 mL,
14 mmol) was slowly added dropwise. The mixture was allowed to
reach room temperature, and stirred overnight. The reaction mix-
ture was then cooled to 0 °C, and water (7 mL), H2O2 (2.1 mL, 30
wt.-% in water), and 0.1 n NaOH (1.4 mL) were subsequently
added. The mixture was then allowed to reach room temperature
and stirred for 2.5 h, then diluted with AcOEt and washed with an
aqueous saturated solution of Na2S2O3 and water. The organic
phase was dried with Na2SO4, filtered, and the solvents evaporated
to dryness. Diol 12 was isolated by flash chromatography (hexane/
Lewis Acid Catalyzed Claisen Rearrangement: A solution of 6
(100 mg, 0.567 mmol) and Eu(fod)3 (13.3 mg, 0.013 mmol) in DCE
(0.1 mL) was heated at 80 °C under an inert atmosphere for 48 h.
After removal of the solvent under reduced pressure, the crude ma-
terial was dissolved in Et2O and washed with water. The organic
layer was then dried with Na2SO4, filtered, and taken to dryness
under vacuum. Initial flash chromatography (hexane/AcOEt =
99:1) allowed 5 (48 mg) to be isolated as a mixture of E/Z isomers.
A second purification, using hexane as the eluent, on silica gel 60
(230–400 mesh), previously impregnated with a solution of 10 wt./
vol.-% AgNO3 in water and dried in an oven at 70 °C, afforded
pure (E)-5 (14 mg, 14%).
AcOEt = 65:35) as a white solid (380 mg, 66%). M.p. 90–93 °C. IR
1
(film): ν = 3303 cm–1. H NMR (400.5 MHz, [D ]DMSO, 28 °C):
˜
6
δ = 1.08 (d, J = 7.0 Hz, 3 H, CH3CH), 1.20 and 1.23 [2 s, 6 H,
(CH3)2C], 1.59 (q, J = 7.0 Hz, 2 H, CHCH2), 2.23 (s, 3 H, CH3Ar),
3.25–3.36 (m overlapped by water signal, 3 H, CHCH2CH2OH),
3.43–3.49 (m, 2 H, CCH2 OH), 4.32 (t, J = 5.2 Hz, 1 H,
CH2CH2OH), 4.92 (t, J = 5.9 Hz, 1 H, CCH2OH), 6.78 (br. d, J =
7.8 Hz, 1 H, ArCH), 6.85 (br. s, 1 H, ArCH), 7.05 (d, J = 7.8 Hz,
1 H, ArCH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ =
20.6 (CH3Ar), 21.0 (CH3CH), 23.2 [(CH3)2C], 27.2 (CHCH3), 40.5
(CHCH2), 59.2 (CH2CH2OH), 68.7 (CCH2OH), 80.2 [(CH3)2C],
122.2 (ArCH), 123.3 (ArCH), 126.4 (ArCH), 135.0 (ArCCH3),
137.1 (ArCCH), 152.5 (ArCO) ppm. HRMS (ESI+): calcd. for
C15H25O3 [M + H]+ 253.1798; found 253.1798.
2-[(2S)-But-3-en-2-yl]-5-methylphenol (10): Gaseous ethylene was
bubbled for 15 min through a solution of 5 (420 mg, 2.38 mmol) in
degassed anhydrous CH2Cl2 (40 mL). In a separate flask, a solution
of second generation Grubbs catalyst (B; 222 mg, 0.261 mmol) in
the same solvent (26 mL), was bubbled with ethylene for 15 min.
The contents of the first flask was then added via cannula to the
catalyst solution, and the reaction was aged at room temperature
under an ethylene atmosphere overnight. Disappearance of starting
material was judged by TLC (hexane/AcOEt = 95:5). Volatiles were
removed under vacuum, the crude material was dissolved in Et2O,
and the suspension was filtered through a pad of Celite. Compound
10 was finally purified by flash chromatography (hexane/AcOEt =
(3S)-3-{4-Methyl-2-[(2-methyl-1-oxopropan-2-yl)oxy]phenyl}butanal
(4): To a solution of oxalyl chloride (0.5 mL, 5.9 mmol) in anhy-
drous CH2Cl2 (11 mL), cooled to –78 °C, a solution of DMSO
(0.8 mL, 11.3 mmol) in anhydrous CH2Cl2 (3 mL) was carefully
added under an argon atmosphere. After 25 min, a solution of 12
(363 mg, 1.44 mmol) in CH2Cl2 (7 mL) was added and the mixture
was stirred at –78 °C for 1 h, then treated dropwise with Et3N
(2 mL, 14.3 mmol). After 2 h, the mixture was allowed to reach
room temperature and stirred for an additional 2 h. Disappearance
of the starting material was judged by TLC (hexane/AcOEt =
80:20). The mixture was then washed with an aqueous saturated
solution of Na2CO3 and water. The organic layer was dried with
99:1) and isolated as a colorless oil (244 mg, 63%). IR (neat): ν =
˜
3457, 1634, 911 cm–1. 1H NMR (400.5 MHz, [D6]DMSO, 28 °C):
δ = 1.20 (d, J = 7.1 Hz, 3 H, CH3CH), 2.17 (s, 3 H, CH3Ar), 3.69–
3.76 (m, 1 H, CHCH3), 4.92–5.03 (m, 2 H, CH2=), 6.00 (ddd, J =
17.2, 10.2, 6.2 Hz, 1 H, CH=CH2), 6.54 (br. d, J = 7.7 Hz, 1 H,
ArCH), 6.59 (br. s, 1 H, ArCH), 6.88 (d, J = 7.7 Hz, 1 H, ArCH),
9.14 (s, 1 H, OH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C):
δ = 19.7 (CH3CH), 20.9 (CH3Ar), 35.5 (CHCH3), 113.0 (CH2=),
116.1 (ArCH), 120.3 (ArCH), 127.8 (ArCH), 128.6 (ArCCH),
135.9 (ArCCH3), 143.7 (CH=CH2), 154.7 (ArCOH) ppm. HRMS
(ESI+): calcd. for C11H15O [M + H]+ 163.1117; found 163.1120.
2-{2-[(2S)-But-3-en-2-yl]-5-methylphenoxy}-2-methylpropanoic Acid Na2SO4, filtered, and taken to dryness under reduced pressure.
(11): Under an inert atmosphere, 10 (193 mg, 1.19 mmol) was dis- Compound 4 was finally purified on silica gel by flash chromatog-
solved in 2-butanone (4 mL) and NaOH (261 mg, 6.52 mmol) was raphy (hexane/AcOEt = 98:2), and isolated as a yellow oil (260 mg,
added. The mixture was stirred at 55 °C for 70 min, then a solution
of 2-bromo-2-methylpropanoic acid (302 mg, 1.81 mmol) in 2-but-
anone (1 mL) was added dropwise, and the mixture was kept at
55 °C for a further 3 h (TLC: hexane/AcOEt = 90:10 + 2 vol.-% of
4 m HCl in dioxane). After removal of the volatiles, the crude mate-
rial was treated with AcOEt and washed with 0.5 m HCl and water.
The organic layer was dried with Na2SO4, filtered, and taken to
dryness under reduced pressure. Flash chromatography (hexane/
AcOEt = 95:5 + 2 vol.-% of 4 m HCl in dioxane) yielded 11 as a
73%). IR (film): ν = 1722 cm–1. 1H NMR (400.5 MHz, [D ]DMSO,
˜
6
28 °C): δ = 1.19 (d, J = 7.0 Hz, 1 H, CH3CH), 1.40 [s, 6 H,
(CH3)2C], 2.20 (s, 3 H, CH3Ar), 2.64–2.67 (m, 2 H, CHCH2), 3.60–
3.72 (m, 1 H, CHCH3), 6.44 (br. s, 1 H, ArCH), 6.78 (d, J = 7.6,
1 Hz, ArCH), 7.12 (d, J = 7.6 Hz, 1 H, ArCH), 9.62 (t, J = 2.1 Hz,
1 H, CHOCH2), 9.82 (s, 1 H, CHOC) ppm. 13C NMR (125.7 MHz,
[D6]DMSO, 25 °C): δ = 20.5 (CH3Ar), 20.7 (CH3CH), 21.3
[(CH3)2C], 26.4 (CHCH3), 50.2 (CHCH2), 82.6 [(CH3)2C], 117.6
(ArCH), 123.3 (ArCH), 127.3 (ArCH), 133.0 (ArCCH), 136.5
yellow oil (274 mg, 93%). IR (film): ν = 2966, 1711, 1411, 1254, (ArCCH3), 152.2 (ArCO), 203.3 (CHOCH2), 204.3 (CHOC) ppm.
˜
1
909 cm–1. H NMR (400.5 MHz, [D6]DMSO, 28 °C): δ = 1.22 (d,
HRMS (ESI+): calcd. for C15H21O3 [M + H]+ 249.1485; found
J = 7.0 Hz, 3 H, CH3CH), 1.49 and 1.51 [2 s, 6 H, (CH3)2C], 2.20 249.1483.
Eur. J. Org. Chem. 2011, 6794–6801
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6799

G. Papeo et al.
(5S)-2,2,8-Trimethyl-2,5-dihydro-1-benzoxepine-5-carbaldehyde 33.7 (CH2CH), 39.3 (CH3CH), 80.2 [(CH3)2C], 125.0 (ArCH),
FULL PAPER
(14): TiCl3 (57.5 mg, 0.373 mmol) was dissolved in DME (2.5 mL)
under an inert atmosphere, LiAlH4 (7 mg, 0.184 mmol) was added
and the suspension was heated to reflux for 20 min. A solution of
4 (20 mg, 0.081 mmol) in DME (3 mL) was then added by syringe-
pump (flow: 0.009 mL/ min) under reflux. The reaction was moni-
tored by TLC (hexane/AcOEt = 95:5). When the addition of 4 was
complete, the reaction mixture was heated to reflux for a further
17 h before being filtered through a pad of Celite and concentrated
to dryness. Flash chromatography (hexane/AcOEt = 98:2) allowed
126.6 (ArCH), 129.8 (CCH=CHCH2), 130.5 (ArCH), 134.8
(ArCCH3), 134.9 (CCH=CHCH2), 136.5 (ArCCH), 152.3
(ArCO) ppm. HRMS (ESI+): calcd. for C15H21O [M + H]+
217.1587; found 217.1580.
(S)-(+)-7,11-Helianane (1): Alkene 13 (16 mg, 0.074 mmol), dis-
solved in MeOH (11 mL), was hydrogenated in the presence of 5
wt.-% Pd/C (10 mg) at 30 psi for 5 h. The catalyst was filtered
through a pad of Celite, and (S)-(+)-7,11-helianane (1; 14 mg, 87%)
was recovered as a colorless oil after flash chromatography (hexane/
AcOEt = 100:1). [α]D = +18.9 (c = 0.59, CH2Cl2). 80%ee (Chiral
HPLC; column: Phenomenex Lux Amylose-2, 4.6ϫ250 mm, 5 μm;
eluent: H2O/CH3CN = 60:40 isocratic; flow: 0.8 mL/min; detector:
1
the isolation of pure 14 as a colorless oil (11 mg, 63%). H NMR
(400.5 MHz, [D6]DMSO, 28 °C): δ = 1.23 (s, 3 H, CH3CCH3), 1.30
(d, J = 7.1 Hz, 3 H, CH3CH), 1.59 (s, 3 H, CH3CCH3), 2.24 (s, 3
H, ArCH3), 3.72 (q, J = 7.1 Hz, 1 H, CHCH3), 6.63 (s, 1 H, CH=),
6.80 (br. s, 1 H, ArCH), 6.83 (br. d, J = 7.9 Hz, 1 H, ArCH), 7.03
(d, J = 7.9 Hz, 1 H, ArCH), 9.34 (s, 1 H, CHO) ppm. 13C NMR
(125.7 MHz, [D6]DMSO, 25 °C): δ = 19.8 (CH3Ar), 21.1 (CH3CH),
24.6 (CH3CCH3), 28.6 (CH3CCH3), 33.0 (CHCH3), 77.8
[(CH3)2C], 124.1 (ArCH), 124.1 (ArCH), 128.5 (ArCH), 135.3
(ArCCH), 136.8 (ArCCH3), 141.3, (CH=C), 152.9 (ArCO), 157.3
(CH=), 193.7 (CHO) ppm. HRMS (ESI+): calcd. for C14H17O2 [M
+ H]+ 217.1223; found 217.1218.
1
UV 220 nm). H NMR (499.7 MHz, CDCl3, 50 °C): δ = 1.25 (d, J
= 7.1 Hz, 3 H, CH3CH), 1.28 (s, 3 H, CH3CCH3), 1.40 (s, 3 H,
CH3CCH3), 1.35–1.39 (m, 1 H, CHCH2CH2CHHC), 1.40–1.46 (m,
2 H , C H C H H C H H C H 2 C ) , 1 . 5 0 – 1 . 5 5 ( m , 1 H ,
CHCH2CH2CHHC), 1.56–1.63 (m, 1 H, CHCH2CHHCH2C),
1.70–1.78 (m, 1 H, CHCHHCH2CH2C), 2.27 (s, 3 H, ArCH3),
3.14–3.21 (m, 1 H, CHCH3), 6.70 (br. s, 1 H, ArCH), 6.87 (d, J =
7.0 Hz, 1 H, ArCH), 7.05 (d, J = 7.0 Hz, 1 H, ArCH) ppm. 13C
NMR (125.7 MHz, [D6]DMSO, 50 °C): δ = 21.0 (CH3Ar), 21.3
(CH3CH), 21.9 (CHCH2CH2CH2C), 26.9 (CH3CCH3), 29.3
(CH3CCH3), 31.7 (CHCH3), 38.2 (CHCH2CH2CH2C), 39.5
(CHCH2CH2CH2C), 80.8 [(CH3)2C], 124.7 (ArCH), 126.1 (ArCH),
126.1 (ArCH), 134.9 (ArCCH3 ), 138.5 (ArCCH), 152.7
(ArCO) ppm. HRMS (ESI+): calcd. for C15H22ONa [M + Na]+
241.1568; found 241.1571.
2-Methylbut-3-en-2-yl 5-Methyl-2-[(2S)-pent-4-en-2-yl]phenyl Ether
(15): A solution of 4 (91 mg, 0.367 mmol) and Petasis reagent
(Cp2TiMe2; 10.7 wt.-% in THF/toluene, 4.26 g, 2.19 mmol) in an-
hydrous THF (1.5 mL) was irradiated in a microwave reactor at
100 °C for 15 min. Hexane was then added and the mixture was
stirred for 1 h. The resulting white precipitate was filtered off and
the mother liquor was taken to dryness under reduce pressure.
Diene 15 was purified by flash chromatography (hexane/AcOEt =
100:1) and isolated as a colorless oil (44 mg, 50 %). 1H NMR
(499.7 MHz, [D6]DMSO, 25 °C): δ = 1.10 (d, J = 6.9 Hz, 3 H,
CH3CH), 1.41 [s, 6 H, (CH3)2C], 2.18 (s, 3 H, ArCH3), 2.16–2.31
(m, 2 H, CH2CH), 3.12–3.20 (m, 1 H, CHCH3), 4.90–4.93 (m, 1
H, CH2CH=CHcis), 4.94–5.00 (m, 1 H, CH2CH=CHtrans), 5.15 (dd,
J = 10.8, 1.1 Hz, 1 H, CCH=CHcis), 5.22 (dd, J = 17.6, 1.1 Hz, 1
H, CCH=CHtrans), 5.62–5.75 (m, 1 H, CH2CH=CH), 6.12 (dd, J
= 17.66, 10.8 Hz, 1 H, CCH=CH), 6.71 (br. d, J = 7.6 Hz, 1 H,
ArCH), 6.80 (s, 1 H, ArCH), 7.03 (d, J = 7.6 Hz, 1 H, ArCH) ppm.
13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ = 20.1 (CH3CH),
20.7 (CH3Ar), 27.1 [(CH3)2C], 31.3 (CHCH3), 40.9 (CH2CH), 79.0
[(CH3)2C], 112.7 (CCH=CH2), 115.6 (CH2CH=CH2), 119.1
(ArCH), 121.7 (ArCH), 126.2 (ArCH), 134.9 (ArCCH), 135.3
(ArCCH3), 137.4 (CH2CH=CH2), 144.2 (CCH=CH2), 153.2
(ArCO) ppm. HRMS (ESI+): calcd. for C17H25O [M + H]+
245.1900; found 245.1896.
(S)-(+)-5-Chloro-7,11-helianane (3): A solution of (S)-(+)-7,11-heli-
anane (1; 8 mg, 0.0366 mmol) and NCS (5.7 mg, 0.0366 mmol) in
anhydrous CH3CN (1 mL) was heated at 50 °C for 3.5 h [the reac-
tion was monitored by TLC (hexane)]. After removal of the solvent
under reduced pressure, purification by flash chromatography (hex-
ane/AcOEt = 100:1) afforded 3 as a colorless oil (7.9 mg, 85%).
[α]D = +33.4 (c = 0.36, CHCl3). 80%ee (Chiral HPLC; column:
Phenomenex Lux Amylose-2, 4.6ϫ250 mm, 5 μm; eluent: H2O/
CH3CN = 50:50 isocratic; flow: 1 mL/min; detector: UV 220 nm).
1H NMR (499.7 MHz, CDCl3, 25 °C):
(d, J = 7.1 Hz, 3 H, CH3CH), 1.27 (s, 3 H, CH3CCH3), 1.39 (s, 3
H, CH3CCH3), 1.35–1.39 (m, H, CHCH2CH2CHHC),
δ
=
1.24
1
1.40–1.46 (m, 2 H, CHCHHCHHCH2C), 1.50–1.55 (m, 1 H,
CHCH2CH2CHHC), 1.56–1.63 (m, 1 H, CHCH2CHHCH2C),
1.72–1.77 (m, 1 H, CHCHHCH2CH2C), 2.28 (s, 3 H, ArCH3),
3.11–3.17 (m, 1 H, CHCH3), 6.74 (br. s, 1 H, ArCH), 7.11 (s, 1 H,
ArCH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ = 19.3
(CH3Ar), 20.8 (CH3CH), 21.6 (CHCH2CH2CH2C), 26.3
(CH3CCH3),
29.2
(CH3CCH3),
31.9
(CHCH3),
37.9
(3Z,6S)-2,2,6,9-Tetramethyl-5,6-dihydro-2H-1-benzoxocine (13):
The second generation Grubbs catalyst (B; 8.8 mg, 0.01 mmol) was
charged in a two-necked round-bottomed flask under an inert at-
mosphere. A solution of 15 (24 mg, 0.098 mmol) in anhydrous de-
gassed CH2Cl2 (8 mL) was then added and the mixture was stirred
for 6 h [reaction monitored by TLC (hexane)]. After the disappear-
ance of the starting material, the solvent was removed in vacuo
and 13 was isolated by flash chromatography on silica gel (hexane/
AcOEt = 100:1) as a light-yellow oil (17 mg, 80 %). 1H NMR
(499.7 MHz, [D6]DMSO, 25 °C): δ = 1.13 (d, J = 6.7 Hz, 3 H,
CH3CH), 1.31 (s, 3 H, CH3CCH3), 1.51 (s, 3 H, CH3CCH3), 2.09
(br. s, 1 H, CHHCH), 2.21 (s, 3 H, ArCH3), 2.89 (br. s, 1 H,
CHCH3), 3.13 (br. s, 1 H, CHHCH), 5.22 (d, J = 10.8 Hz, 1 H,
CCH=CHCH2), 5.57–5.66 (m, 1 H, CCH=CHCH2), 6.68 (s, 1 H,
ArCH), 6.83 (br. d, J = 7.3 Hz, 1 H, ArCH), 6.96 (d, J = 7.3 Hz,
(CHCH2CH2CH2C), 39.2 (CHCH2CH2CH2C), 81.5 [(CH3)2C],
126.6 (ArCH), 127.1 (ArCH), 129.5 (ArCCl), 132.9 (ArCCH3),
141.3 (ArCCH), 151.7 (ArCO) ppm. HRMS (ESI+): calcd. for
C15H21ClONa [M + Na]+ 275.1173; found 275.1790.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra (1H, COSY, TROESY, gradient-
enhanced HSQC, and HMBC experiments) for compounds 1, 3, 5,
6, 11, 12, 13, and 14 described in this paper. Copies of chiral HPLC
spectra of compounds 1, 3, and 6. Experimental procedures for the
synthesis of Mosher’s esters of 5, diastereomeric amides of 11 (21),
and compound 20.
Acknowledgments
1 H, ArCH) ppm. 13C NMR (125.7 MHz, [D6]DMSO, 25 °C): δ = The authors like to thank Dr. Eduard Felder (Chemical Core Tech-
20.6 (CH3Ar), 25.2 (CH3CH), 28.2 (CH3CCH3), 29.3 (CH3CCH3), nologies, Department Head) and Dr. Daniele Donati (Medicinal
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Eur. J. Org. Chem. 2011, 6794–6801

Synthesis of (+)-7,11-Helianane and (+)-5-Chloro-7,11-helianane
amounts of the domino Claisen–Cope rearrangement product
19 in the Lewis acid-catalyzed aromatic Claisen rearrangement
has been already documented (see ref.[15]).
Chemistry, Department Head) for support, encouragement, and
valuable suggestions. F. Q. is profoundly indebted to Dr. Maurizio
Pulici for helpful suggestions.
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ˇ
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1-position of the allylic chain. In fact, by exposing the simpler
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1
ment occurred (Scheme 6). However, H NMR analysis of the
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crude reaction mixture (17: 40%, 18: 23%, and 19: 37%)
showed profound discrepancies with the published data (80%
isolated yield of 17, see ref.[5e]). The formation of competitive
Received: May 19, 2011
Published Online: September 1, 2011
Eur. J. Org. Chem. 2011, 6794–6801
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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