A general and concise enantioselective divergent approach to 13-alkyl-substituted ionones

Article abstract of DOI:10.1002/cbdv.201400030

A novel enantioselective divergent route to 13-alkyl derivatives of a- and g-ionone, important components of perfumes and fragrances, is reported. This relatively short and convenient methodology takes advantage of the use of a common intermediate, easily obtained from highly enantiomerically enriched (S)-a-ionone, which avoids the separate installation of the butenone side chain at C(6) for each analog. Olfactory evaluation of synthesized compounds reconfirmed the influence of the hydrophobic interactions of alkyl substituents at C(5) with olfactory receptors (ORs) in the chemoreception of ionones, and suggested that a synperiplanar orientation of C(13) and the lateral chain is the better geometry fitting OR's cavity.

Full text of DOI:10.1002/cbdv.201400030

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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
A General and Concise Enantioselective Divergent Approach to 13-Alkyl-
Substituted Ionones
by Serena Bugoni, Valentina Merlini, Alessio Porta, Giuseppe Zanoni, and Giovanni Vidari*
Dipartimento di Chimica, Universit a` di Pavia, Via Taramelli 12, I-27100 Pavia (phone: þ39-0382-
987322; fax: þ39-0382-987323; e-mail: vidari@unipv.it)
A novel enantioselective divergent route to 13-alkyl derivatives of a- and g-ionone, important
components of perfumes and fragrances, is reported. This relatively short and convenient methodology
takes advantage of the use of a common intermediate, easily obtained from highly enantiomerically
enriched (S)-a-ionone, which avoids the separate installation of the butenone side chain at C(6) for each
analog. Olfactory evaluation of synthesized compounds reconfirmed the influence of the hydrophobic
interactions of alkyl substituents at C(5) with olfactory receptors (ORs) in the chemoreception of
ionones, and suggested that a synperiplanar orientation of C(13) and the lateral chain is the better
geometry fitting ORꢀs cavity.
Introduction. – Discovered at the end of the 19th century by Tiemann and Krꢀger
[
1], the regioisomeric a-, b- and g-ionones, 1–3, respectively, occurring in the
headspace of violets and other flowers in bloom, soon became central to perfurmery
and fragrance chemistry for the creation of violet and other odor notes [2][3].
Moreover, inspired by the ionones, many synthetic odorants have been developed in
the last decades. These generally share the woody-floral, violet scent characteristics of
the natural compounds, as well as individual odor facets and tonalities. They include,
among others, dihydro and tetrahydro ionone analogs, the bicyclo[6.4.0]dodecyl ketone
4
[4], the seven-membered ring compound 5 [5], Georgywood 6 [6], and even acyclic
ꢁ
compounds such as the seco-ionone derivatives Koavone (7) [6] and dienone 8 [7].
Such a large variety of different structures makes it difficult to define an ꢂionone
olfactophoreꢀ, based on molecular parameters common to the entire group; however,
excellent superposition found for modeled conformations of different compounds
showing similar odor profiles shed some light on the relationship between structure and
the violet-orris scent. Indeed, thanks to our and other investigations on synthetic
ionone derivatives [7–9], we have shown that the minimum-energy conformers of
modeled compounds can roughly be represented by a general molecular model
comprising two domains of opposite polarity, namely a polar acyl group and a
hydrophobic moiety, separated from each other by a C chain and laying in almost
2
orthogonal planes [9].
Moreover, considering the two alkyl groups flanking, either side, of C(6) carrying
the carbonyl-containing chain of ionones, we have demonstrated the importance of the
steric hindrance around C(5) in modulating the olfactory properties of ionones [8]. In
fact, the olfactory comparison of synthetic 13-alkyl-substituted homologs 9–11 with
parent (S)-a-ionone (1; odor threshold 2.7 ng/l air) [10] showed that a predominant
ꢃ 2014 Verlag Helvetica Chimica Acta AG, Zꢄrich

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1541
violet tonality persisted for all the three compounds, although accompanied by distinct
odor facets. The potency notably increased for the ethyl derivative 9 (0.085 ng/l air) [8],
while it dramatically decreased for longer alkyl chain-substituted analogs, i.e., 10 and 11
[
8]. Incorporation of the Et substituent at C(5) in 9 in conformationally constrained
cyclic structures, such as in compounds 12–14, led to the discovery of ionone odorants
possessing an even lower odor threshold than the parent ionone [9]. Thus, the bicyclic
compound 12 showed an odor threshold of 0.076 ng/l air, while its regioisomer 13, with
an odor threshold of 0.010 ng/l air, was the most potent member of the ionone family so
far in terms of threshold [9].
In the light of these results, we considered it interesting to further model the steric
hindrance around C(13) of a- and g-ionones, by considering the disubstituted isopropyl
and isopropylidene derivatives 15 and 16, respectively.
In this article, we describe a divergent synthetic path to the molecular target
structures 15 and 16 from a common intermediate, namely the allylic phosphate 42,
which already contained the oxygenated side chain of ionones. Moreover, we
demonstrate the possibility to use this same compound for the synthesis of different
C(13)-alkyl-substituted derivatives, i.e., 9–11, via S 2’-type reactions of the corre-
N
sponding organocuprates.
For the comparison of olfactory properties, compounds 15 and 16 were prepared in
the same (6S)-enantiomeric series as the other ionone derivatives 9–14 [8][9].

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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Initial Steps. – Initially, the synthesis of 15 and 16 was pursued following our
traditional approach to C(13)-alkyl-substituted ionone derivatives [8]; accordingly, we
planned to introduce first the desired C(13)-alkyl substituent(s) on a cyclogeraniol-like
structure, and then to install the enone side chain on the cyclohexene ring via the
MeyerꢀSchuster rearrangement of a propargylic alcohol of type 27 [11]. To this end,
C(13)-homocyclogeraniol 17 [8] was converted to allylic alcohol 20a (mixture of
diastereoisomers) via syn-epoxidation to 18 [8][12], followed by epoxideꢀallylic
i
alcohol rearrangement upon exposure of silyl ether 19 to excess ( PrO) Al in refluxing
3
xylene [8][13] (Scheme 1).
Scheme 1. Initial Unsuccessful Approach to the Synthesis of 15
i) 3-Chloroperbenzoic acid (mCPBA), CH Cl , 08. ii) (tert-Butyl)(diphenyl)silyl chloride (TBDPSCl),
2
2
i
1
H-imidazole (ImH), 4-(dimethylamino)pyridine (DMAP), 08!r.t. iii) ( PrO) Al, xylene, 1408. iv)
3
NaH or BuLi, (EtO) P(O)Cl, pyridine, CH Cl , 08!r.t.
2
2
2
Subsequently, we tried to activate the allylic OH group of 20a as a phosphate to
introduce the other Me group of the C(13)-isopropyl derivative 15 via an S 2’-type
N
t
reaction with a methyl organocuprate to give the TBDPS ( BuPh Si) ether of alcohol
2
24 (Scheme 2). However, under the standard phosphorylation conditions ((EtO)2-
P(O)Cl, Py, CH Cl ) [8], compound 20a was recovered unaltered, while, under forced
2
2
conditions i) NaH or BuLi; ii) (EtO) P(O)Cl, Py, CH Cl ), 3,5(13)-diene was the main
2
2
2
product. Also unsuccessful were our attempts to prepare 16 via the MeyerꢀSchuster
rearrangement [11] of propargylic alcohol 27, in principle obtainable by the addition of
a propylide anion to aldehyde 25. The latter was prepared from known sulfone 21 [9]
via dimethylation to 22, followed by desulfonylation (Scheme 2) and oxidation of the
free alcohol 23. In fact, neither CeCl [14] nor the THF-soluble LaCl ·2 LiCl [15]
3
3
promoted the reaction of 25 with the Grignard reagent 26 in a satisfactory yield
(
Scheme 2).
Having thus realized that the severe steric hindrance around synthetically strategic
C-atoms of cyclogeraniol-like structures could frustrate other routes to 15 and 16 based
on our traditional approach [8], we explored a new synthetic pathway to the target
compounds, based on chemical modifications around the cyclohexene C¼C bond of an
(
S)-a-ionone derivative. (S)-a-Ionone was recently prepared by us with high ee (98%)
by an efficient catalytic Au-mediated methodology [11]. We envisaged the feasibility to
introduce different alkyl substituents at C(13) through synthetic routes diverging from
a common advanced intermediate with the characteristic unsaturated side chain of
ionones already installed at C(6). Thus, we anticipated that this strategy would have

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1543
Scheme 2. Initial Unsuccessful Approach to the Synthesis of 16
i) BuLi, MeI, THF, ꢀ788. ii) Bu NF, THF, r.t. iii) Mg, MeOH, r.t. iv) DessꢀMartin periodinane (DMP),
4
CH Cl , r.t. v) CeCl , THF or LaCl ·2 LiCl, THF, ꢀ788 (25), followed by the addition of (propyn-1-
2
2
3
3
yl)magnesium bromide (26), ꢀ788!r.t.
been a significant advancement with respect to our traditional approach in which the
side chain was separately constructed for each compound [8][9]. The successful
synthesis of compounds 9, 15, and 16, reported herein, exemplifies, in our opinion, this
new strategy.
Retrosynthetic Analysis of Compounds 9, 15, and 16. – Retrosynthetically
(
Scheme 3), allylic alcohol 32 was envisioned to be the key intermediate for the
conversion of (S)-a-ionone 1 to the target compounds 9, 15, and 16. Compound 32
could lead to the ethyl derivative 9 via an S 2’ reaction on an activated allylic alcohol
N
29. Compounds 15 and 16 might be obtained from desulfonylation of compound 30,
ultimately prepared via a MislowꢀEvans rearrangement of alcohol 32 and subsequent
oxidation of sulfoxide 31. Two key steps, namely the epoxide 33/allylic alcohol 32
rearrangement and the S 2’ reaction on 29, were, however, of our great concern as
N
possible end-points of this synthetic project. In fact, we were well aware of a precedent,
reported by Kaiser [16], in which epoxides 34 and 35 rearranged to megastimadiene-
i
oxide 36 and 7-oxabicyclo[3.3.0]octane 37, respectively, upon treatment with ( PrO) Al
3
i
in boiling PrOH or xylene, respectively (Scheme 4). In addition, with the conversion of
29 to 28, we were faced with the regioselective differentiation of two allylic alcohol
moieties, in principle both suitable to undergo an S 2’ reaction. We envisioned that
N
decreasing the electrophilicity of the C¼C bond in the side chain through reduction of
the conjugated C¼O group and a proper choice of groups R and R’ in 33 and 29 would
t
remove these two obstacles. As to R, the TBDPS ( BuPh Si) protecting group was
2
i
selected to hamper the coordination of the O-atom with ( PrO) Al by steric hindrance,
3
minimizing formation of 36 and 37. Electronic and steric factors should also favor the
regioselective S 2’ reaction on the allylic alcohol moiety in 29 activated as a phosphate
N
ester (R’¼PO(OEt) ) [17] with respect to the allylic silyl-ether unit (R¼TBDPS) in
2
the side chain.

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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Scheme 3. Retrosyntheses of 9, 15, and 16
Scheme 4. Rearrangement of 34 and 35
i
i
i
3 3
i) ( PrO) Al, PrOH, 1308. ii) ( PrO) Al, refluxing xylene.
Synthesis of the Enantiomerically Enriched a-Ionones (S)-9, (S)-15, and (S)-16. –
S)-a-Ionone 1 [11] was quantitatively reduced under Luche conditions [18] to the
(
allylic alcohol 38 as a mixture of C(9)-diastereoisomers which was protected as O-
TBDPS mixture 39 (Scheme 5). Subsequently, regioselective epoxidation of the more
electron-rich cyclohexene C¼C bond in 39 with a stoichiometric amount of 3-
chloroperbenzoic acid (mCPBA) in CH Cl at 08 afforded epoxide 40 in 73% yield, as a
2
2
mixture of diastereoisomers with unassigned configuration. This mixture was carried
through to the final product. Isomerization of 40 to allylic alcohols 41 proceeded
i
smoothly in the presence of ( PrO) Al in refluxing xylene. Though an excess of
3

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1545
Scheme 5. Synthesis of 9
i) NaBH , CeCl ·7 H O, MeOH, 08. ii) TBDPSCl, ImH, DMAP, CH Cl , r.t. iii) mCPBA, CH Cl , 08. iv)
4
3
2
2
2
2
2
i
(
PrO) Al, xylene, 1408. v) (EtO) P(O)Cl, pyridine, CH Cl , 08!r.t. vi) MeMgBr, CuBr-Me S, Me S/
3
2
2
2
2
2
THF 2 :1, ꢀ458!r.t. vii) Bu NF, THF, r.t. viii) SIBX, DMSO, r.t.
4
(iPrO) Al was required to complete the reaction [8][13], no rearrangement products of
3
types 36 and 37 were observed. After the easy conversion of alcohol 41 to the
corresponding phosphate 42 under standard conditions [8], the subsequent key S 2’
N
displacement was achieved in good yield (73%) and with complete regioselectivity by
employing an excess of methylmagnesium bromocuprate (3 equiv.) as described by
Curran et al. [19]. Finally, deprotection of 43, and oxidation of the allylic alcohol 44
with stabilized 2-iodoxybenzoic acid (SIBX) [20] readily afforded (S)-9, identical to a
sample prepared using our original procedure [8]. Compound (S)-9 displayed an ee
value of 97%, indicating that the stereochemical integrity at C(6) of starting (S)-a-
ionone 1 (ee 98%) was maintained throughout the synthesis.
The synthesis of compounds 15 and 16 commenced with a transposition of reactivity
from C(4) of allylic alcohol 41 to C(11) of sulfoxide 45 via a MislowꢀEvans [2,3]-
sigmatropic rearrangement [21] of the corresponding sulfenate (Scheme 6). Sulfoxide
45, obtained in 89% yield, was smoothly oxidized to sulfone 46 with mCPBA, with no
appreciable oxidation of the two C¼C bonds. As expected, the subsequent dimethy-
lation at C(13) of 46 via generation of the a-carbanion, followed by alkylation, proved
rather difficult because of the severe steric hindrance around the anion. While the
monomethyl derivative was obtained in good yield, generating the anion with BuLi and
quenching it with MeI (2 equiv.), the introduction of the second alkyl substituent
required more forcing conditions. After some experimentation, we found that
regeneration of the anion with (Me Si) NK (2 equiv.), followed by the addition of a
3
2
strong excess of MeI (10 equiv.) and a mild heating, led to the desired product 47 in
77% overall yield from 46 (Scheme 6).
After removal of the OH-protecting group under standard conditions, treatment of
alcohol 30 with granular Mg in MeOH, afforded a chromatographically inseparable

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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Scheme 6. Synthesis of 15 and 16
i) PhSCl, Et N, toluene, r.t. ii) mCPBA, Et O, ꢀ208. iii) BuLi, MeI, THF, ꢀ788!r.t., (Me Si) NK, MeI,
3
2
3
2
ꢀ
208!408. iv) Bu NF, THF, r.t. v) Mg, MeOH, r.t. vi) SIBX, DMSO, r.t. vii) Chromatographic
4
separation.
mixture (ca. 1:1 by NMR) of regioisomeric olefines 48 and 49 in 84% yield. Oxidation
of the mixture with SIBX, followed by a careful chromatographic separation of the
mixture of enones on a column of silica gel, finally afforded the target optically active
products 15 and 16 in 23 and 41% yields, respectively (Scheme 6). Although the ee
values of 15 and 16 were not determined, we presumed that no loss of the
stereochemical integrity at C(6) occurred in the transformations from allylic alcohol
41 to the final products.
Olfactory Evaluation of the Homologs 15 and 16. – Compounds 15 and 16 were
submitted to olfactory evaluation (Givaudan Schweiz AG, Fragrance Research). The 5-
isopropyl-a-ionone homolog (S)-15 was described as a sweet-powdery, floral, violet
odor with slightly green and floral facets; its odor threshold was determined as 1.44 ng/l
air, which is almost halfway between (ꢀ)-(S)-a-ionone (1; 2.7 ng/l of air) [10] and 5-
ethyl-a-ionone (0.085 ng/l air) [8]. In sharp contrast, the odor of the g-ionone
derivative 16 was found to be very weak, fruity-floral, rosy, citrus, slightly fatty, with an
odor threshold of 121 ng/l air. This is much higher than the threshold of the parent (þ)-
(
S)-g-ionone (3; 0.07 ng/l of air) which is the most powerful of naturally occurring
ionones [10].
Modelling Studies. – To have some hints on the relationships between structures
and olfactory properties, compounds 15 and 16 were subjected to B3LYP/6-31þG(d,p)
modeling studies (Fig.). They indicated that the most populated conformations 15Aa

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1547
and 15Ac, representing almost 86% conformational space of 15, are not very different
from those identified as the most populated for the previously modeled compound 9
[
22]. Actually, a predominant 2HC1 half-chair geometry was found for the six-
membered ring of 15Aa and 15Ac, carrying a pseudoaxially oriented lateral chain at
i
C(1). Furthermore, the modelling suggested that the allylic strain between the Pr
group and the side chain in 15 is alleviated to some extent by rotation around the C(5)–
C(13) bond, greatly favoring the geometries in which the HꢀC(13) is oriented towards
the chain, while the Me groups are pointing to other directions. However, this spatial
arrangement inevitably results in an increased steric hindrance around the cyclohexene
C¼C bond of ionone 15 in comparison with 9 and, possibly, in an unfavorable
interaction of at least one Me group with ionone olfactory receptors (ORs). In the
isopropylidene derivative 16, the rotation around the C(5)–C(13) bond is blocked, and
the olefinic endo-Me group causes an increased allylic strain with the side chain. As a
result, the most populated conformation of 16 is by far 16Aa (87%), showing an almost
perfect chair conformation and an axially oriented butenone chain. This geometry is in
sharp contrast to the minimum-energy conformations calculated for (S)-g-ionone 3
[
22] and its bicyclic homolog 13 [9], for which the equatorial orientation of the
butenone moiety is preferred. Accordingly, the two torsional angles
w [C(7)ꢀC(6)ꢀC(5)ꢀC(13)] and w [C(12)ꢀC(1)ꢀC(6)ꢀC(7)] change dramatically
1
2
from ca. ꢁ38 and þ608, respectively, for 3 and 13 to þ1068 and ꢀ498, respectively,
for 16. These striking geometrical changes are accompanied by a significant decrease of
the odor threshold in the order 13 (0.01 ng/l air)>3 (0.07 ng/l air)>16 (1.44 ng/l air).
Actually, the odor threshold of compound 16 is the lowest among those determined so
far for our synthetic 13-alkyl-substituted ionones [8][9].
Figure. 3D Plot of the most populated members of 15 and 16 computed at B3LYP/6-31þG(d,p) level of
theory
Conclusions. – A novel highly enantioselective and regioselectivity route to C(13)-
monoalkyl-substituted a-ionone homologs has been described. This strategy has been
exemplified by the synthesis of the 5-Et derivative (S)-9 starting from (S)-a-ionone (1);
however, the introduction of other alkyl substituents on the cyclohexene C¼C bond of
synthetic ionones appears to be easily feasible by analogous S 2’ displacements of
N
allylic phosphate 42 with the corresponding organocuprates. Noteworthily, compared

1
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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
to our previous protocol [8], this new route has the great synthetic advantage of
avoiding the separate construction of the enone side chain for each alkyl homolog.
Olfactory evaluation of new compounds 15 and 16, obtained via the same
intermediate 41 used for the synthesis of 9, confirmed our previous results showing that
the odor strength and tonalities of ionones are subtly modulated by the bulkiness of the
substituent at C(5). They provided further evidences that hydrophobic interactions of
this group with ORs and the spatial orientation of the C¼O side chain with respect to
the apolar moieties near C(6) play a significant role in the chemoreception of ionones.
Thus, while the smell of the ethyl derivative 9 was significantly stronger than that of the
parent (S)-a-ionone (1), introduction of another Me substituent at the same C(13)
reduced the odor potency, as the lower threshold values of ionones 15 and 16 clearly
indicated. These data, along with the results of modelling studies, reconfirm that the
spatial orientation of the C¼O side chain with respect to the apolar moieties near C(6)
play a significant role in the chemoreception of ionones and suggest that a
conformation of ionone derivatives in which the C(6)ꢀC(7) and the C(5)ꢀC(13)
bonds are almost synperiplanar is better accommodated by the ORs cavity. Accord-
ingly, though a receptor protein can induce a conformational change in the odorant, the
increasing allylic strain from compound 9 to 15 and 16 significantly hampers the two
dimethyl derivatives to attain such optimal geometry, resulting in a low odor potency
and, in the case of 16, even a change in the odor profile.
The authors are deeply grateful to Dr. Philip Kraft, Givaudan Schweiz AG, Fragrance Research,
CH-Dꢄbendorf, for the olfactory description and the threshold determinations. We thank the Italian
MIUR for partial financial support (PRIN funds).
Experimental Part
General. All reagents were of commercial quality. THF was distilled over Na/benzophenone, and
CH Cl and hexanes were distilled from CaH . All moisture-sensitive reactions were carried out under a
2
2
2
positive static atmosphere of Ar in glassware that had been dried in an oven at 1408 for at least 3 h prior
to use, and allowed to cool in a desiccator over self-indicating silica-gel pellets. Syringes and needles for
the transfer of reagents were dried at 1408 and allowed to cool in a desiccator over P O before use.
2
5
Routine monitoring of reactions was performed using silica gel 60 GF254 (SiO ; 0.25 mm, Merck), Al-
2
supported TLC plates. Compounds were visualized by UV irradiation at a wavelength of 254 nm, or
stained by exposure to a 0.5% soln. of vanillin in H SO /EtOH, followed by charring. Flash column
2
4
chromatography (FC): Kieselgel 60 (40–63 mm, Merck). Purifications by MPLC: Isolera One Biotage
Flash Chromatography. Yields are reported for isolated compounds with 96% purity established by
NMR; HP-5890 II gas chromatograph. Enantiomeric excess (ee) values were determined by GC on a
Mega DEX column (20 mꢂ0.25 mm; 0.18 mm f.t.; stationary phase, DAC-n-pentilSilBETACDX) with
the following temp. program: 808 (1 min)–28/min–2008 (5 min). Optical rotations: PerkinElmer 241
digital polarimeter; in (degml)/(gdm); c in g/ml. IR Spectra: PerkinElmer Paragon 100 PC-FT-IR
ꢀ
1
1
13
spectrometer; films; ˜n in cm . H- and C-NMR spectra: Bruker AV-300 spectrometer at 300 MHz; d in
ppm rel. to CHCl (d(H) 7.26, d(C) (central line of t) 77.0) if not indicated otherwise; J values in Hz. The
3
number of H-atoms attached to each C-atom was determined by DEPT experiments.
(
2RS,3E)-4-[(1S)-2,6,6-Trimethylcyclohex-2-en-1-yl]but-3-en-2-ol (38). CeCl ·7 H O (20 mg,
3 2
0
0
.055 mmol) was added to a soln. of (S)-1 (106 mg, 0.55 mmol) in MeOH (5.5 ml). After cooling to
8, NaBH (26 mg, 0.66 mmol) was slowly added. After 40 min, the reaction was quenched by adding
4
acetone (1 ml). After removing the solvent at reduced pressure, the residue was diluted with Et O
2
(
10 ml), and a sat. aq. NH Cl soln. (10 ml) was added. The aq. phase was extracted with Et O (2ꢂ10 ml),
4
2

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1549
and the combined org. layers were dried (Na SO ) and evaporated at reduced pressure. The crude
2
4
product was purified by CC (pentane/Et O 9 :1) to yield 38 (105 mg, 98%). Pale-yellow oil. IR: 3654,
2
1
3
1
136, 3104, 2976, 1416, 1304, 1136, 1128, 648. H-NMR: 5.54 (dd, J¼15.3, 6.5, 1 H); 5.44 (dd, J¼15.3, 8.4,
H); 4.31 (quint., J¼6.5, 1 H); 5.42 (m, 1 H); 2.48 (br. s, OH); 2.10 (d, J¼8.4, 1 H); 1.96–2.06 (m, 2 H);
1
.58 (br. s, 3 H); 1.35–1.52 (m, 1 H); 1.28 (d, J¼6.5, 3 H); 1.12–1.25 (m, 1 H); 0.91 (s, 3 H); 0.84 (s, 3 H).
13
C-NMR: 135.8 (d); 133.9 (s); 131.3 (d); 121.0 (d); 69.0 (d); 53.8 (d); 31.9 (s); 31.4 (t); 27.6 (q); 26.9 (q);
þ
þ
2
8
3.5 (q); 23.0 (q); 22.8 (t). HR-MS: 194.1673 (M , C H O ; calc. 194.1671). Anal. calc. for C H O: C
13 22 13 22
0.35, H 11.41; found C 80.41, H 11.48.
tert-Butyl)(diphenyl)({(2RS,3E)-4-[(1S)-2,6,6-trimethylcyclohex-2-en-1-yl]but-3-en-2-yl}oxy)silane
39). 1H-Imidazole (463 mg, 5.1 mmol), 4-(dimethylamino)pyridine (DMAP; 83 mg, 0.68 mmol), and
TBDPS-Cl (1.3 ml, 4.4 mmol) were added to a soln. of 38 (661 mg, 3.4 mmol) in anh. CH Cl (16 ml).
(
(
2
2
After stirring 3 h at r.t., the reaction was quenched with H O (25 ml) and CH Cl (9 ml). The aq. phase
2
2
2
was extracted with CH Cl (2ꢂ25 ml), and the combined org. layers were dried (Na SO ) and
2
2
2
4
concentrated at reduced pressure. The crude was purified by FC on SiO (MPLC hexane) to yield 39
2
(
1.1 g, 75%). Colorless dense oil. IR: 2962, 1590, 1472, 1428, 1364, 1146, 1112, 1077, 998, 823, 739, 701, 614.
1
H-NMR: 7.82–7.68 (m, 4 H); 7.52–7.33 (m, 6 H); 5.56 (dd, J¼15.1, 6.4, 1 H); 5.43–5.35 (m, 1 H); 5.34–
5
1
1
1
.21 (m, 1 H); 4.36 (qd, J¼6.2, 0.7, 1 H); 2.15–1.94 (m, 3 H); 1.65 (d, J¼1.7, 3 H); 1.51–1.27 (m, 2 H);
13
.24 (d, J¼6.2, 3 H); 1.18 (s, 9 H); 0.85 (s, 3 H); 0.78 (s, 3 H). C-NMR: 137.1 (d); 137.0 (d); 136.0 (d);
35.9 (d); 134.4 (s); 134.4 (s); 134.2 (s); 132.8 (s); 129.7 (d); 129.6 (d); 129.5 (d); 129.4 (d); 127.4 (d);
20.8 (d); 120.6 (d); 72.0 (d); 70.4 (d); 70.3 (d); 53.9 (d); 52.7(d); 40.0 (t); 38.2 (t); 36.0 (t); 32.0 (q); 32.0
(
q); 31.9 (q); 31.7 (t); 31.6 (t); 31.0 (q); 27.4 (q); 27.3 (q); 27.2 (q); 27.0 (q); 25.7 (q); 24.9 (q); 23.1 (q); 22.9
þ
þ
(t); 22.8 (q); 19.5 (q); 19.2 (s). HR-MS: 432.2851 (M , C H OSi ; calc. 432.2848). Anal. calc. for
29 40
C H OSi: C 80.49, H 9.32; found C 80.55, H 9.41.
29
40
(
tert-Butyl)(diphenyl)({(2RS,3E)-4-[(1RS,2S,6SR)-1,3,3-trimethyl-7-oxabicyclo[4.1.0]hept-2-yl]but-
3
0
-en-2-yl}oxy)silane (40). mCPBA (50 mg, 0.25 mmol) was added to a cooled soln. of 39 (100 mg,
.23 mmol) in anh. CH Cl (2.3 ml) at 08. After stirring for 2 h at 08, the mixture was diluted with CH Cl
2
2
2
2
(
2.7 ml), and the reaction was quenched by adding a 1:1 mixture of a sat. aq. NaHCO soln. (2.5 ml) and
3
a sat. aq. Na S O soln. (2.5 ml). The aq. phase was extracted with CH Cl (2ꢂ5 ml), and the combined
2
2
3
2
2
org. layers were dried (Na SO ) and evaporated at reduced pressure. The residue was purified by CC
2
4
(
1
hexane/ Et O 98 :2) to yield 40 (76 g, 73%) as a mixture of four diastereoisomers. IR: 2962, 1428, 1364,
2
1
112, 739, 701. H-NMR (CD Cl ): 7.83–7.72 (m, 4 H); 7.50–7.36 (m, 6 H); 5.70–5.60 (m, 1 H); 5.54–5.39
2
2
(
0
m, 1 H); 4.48–4.37 (m, 1 H); 3.04–2.93 (m, 1 H); 2.15 (d, J¼10.1, 0.5 H); 2.00–1.82 (m, 1.5 H); 1.62–
13
.50 (m, 24 H). C-NMR (CD Cl ): 139.5 (d); 138.4 (d); 138.2 (d); 136.7 (d); 135.4 (s); 135.2 (s); 135.1
2 2
(s); 130.3 (d); 130.3 (d); 130.2 (d); 128.3 (d); 127.9 (d); 127.8 (d); 127.4 (d); 127.2 (d); 71.3 (d); 71.2 (d);
7
3
1.0 (d); 70.8 (d); 60.7 (d); 60.2 (d); 60.0 (s); 59.9 (s); 59.1 (s); 54.6 (d); 52.7 (d); 33.7 (t); 32.0 (s); 31.9 (s);
1.6 (s); 30.1 (t); 30.0 (q); 29.8 (t); 28.8 (q); 28.7 (q); 27.7 (q); 27.6 (q); 25.4 (q); 24.6 (q); 24.4 (q); 24.3
þ
þ
(q); 24.2 (q); 22.8 (t); 22.5 (t); 21.7 (q); 19.9 (s). HR-MS: 448.2795 (M , C H O Si ; calc. 448.2798).
29 40 2
Anal. calc. for C H O Si: C 77.62, H 8.99; found C 77.52, H 8.91.
29
40
2
(
1RS,3S)-3-[(3RS,1E)-3-{[(tert-Butyl)(diphenyl)silyl]oxy}but-1-en-1-yl]-4,4-dimethyl-2-methylide-
i
necyclohexanol (41). ( PrO) Al (1.0 g, 4.9 mmol) was added to a soln. of 40 (551 mg, 1.2 mmol) in anh.
3
xylene (12 ml). After heating at 1508 for 10 h, the mixture was diluted with Et O (12 ml), and the
2
reaction was quenched with 0.6m HCl (24 ml). The aq. phase was extracted with Et O (2ꢂ24 ml), and
2
the combined org. layers were washed with a sat. aq. NaHCO soln. (72 ml), dried (Na SO ), and
3
2
4
evaporated at reduced pressure. The crude was purified by CC (hexane/Et O 8 :2) to yield 41 (468 mg,
2
1
8
5%). Sticky colorless oil. IR: 3340, 2931, 1648, 1472, 1428, 1366, 1112, 998, 903, 823, 739, 702. H-NMR:
7.73 (m, 4 H); 7.47–7.28 (m, 6 H); 5.68–5.31 (m, 2 H); 5.13–4.96 (m, 1 H); 4.72–4.62 (m, 1 H); 4.43–
4
.36 (m, 1 H); 4.26–4.15 (m, 0.3 H); 4.04–3.99 (m, 0.7 H); 2.78 (t, J¼6.6, 0.3 H); 2.37 (d, J¼9.2, 0.7 H);
13
1.97–0.71 (m, 23 H). C-NMR: 152.3 (s); 151.9 (s); 137.7 (d); 137.4 (d); 137.2 (d); 137.0 (d); 135.8 (d);
1
34.6 (s); 134.3 (s); 129.5 (d); 129.4 (d); 127.4 (d); 127.1 (d); 126.6 (d); 126.4 (d); 109.3 (t); 105.5 (t); 105.1
(t); 72.9 (d); 71.7 (d); 71.6 (d); 70.2 (d); 69.9 (d); 55.2 (d); 55.1 (d); 53.8 (s); 38.8 (t); 38.5 (t); 35.3 (s); 35.0
(
s); 34.4 (t); 32.6 (t); 32.5 (t); 30.7 (t); 30.0 (q); 29.8 (q); 29.0 (q); 28.9 (q); 26.9 (q); 24.9 (q); 24.8 (q); 23.0
þ
þ
(d); 20.7 (q); 20.5 (q); 19.2 (s). HR-MS: 448.2794 (M , C H O Si ; calc. 448.2798). Anal. calc. for
29 40 2
C H O Si: C 77.62, H 8.99; found C 77.68, H 9.04.
29
40
2

1
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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
(
1RS,3S)-3-[(3RS,1E)-3-{[(tert-Butyl)(diphenyl)silyl]oxy}but-1-en-1-yl]-4,4-dimethyl-2-methylide-
necyclohexyl Diethyl Phosphate (42). Pyridine (0.12 ml, 1.4 mmol) was added to a soln. of 41 (91 mg,
.2 mmol) in anh. CH Cl (2.2 ml). The mixture was stirred at r.t. for 3 d, then diluted with Et O (7.8 ml),
0
2
2
2
and the reaction was quenched with 1.2m HCl (10 ml). The aq. phase was extracted with Et O (2ꢂ
2
1
0 ml), and the combined org. layers were washed with a sat. aq. NaHCO soln. (30 ml), dried (Na SO ),
3 2 4
and evaporated at reduced pressure. The crude was purified by CC (hexane/AcOEt 75 :25) to yield 42
(
8
6
79 mg, 67%). Sticky colorless oil. IR: 2963, 2857, 1473, 1428, 1389, 1366, 1264, 1150, 1112, 1034, 981, 903,
22, 740, 703, 611. HR-MS: 584.3082 (M , C H O PSi ; calc. 584.3087). Anal. calc. for C H O PSi: C
33 49 5 33 49 5
þ
þ
7.78, H 8.45; found C 67.89, H 8.53.
tert-Butyl)({(2RS,3E)-4-[(1S)-2-ethyl-6,6-dimethylcyclohex-2-en-1-yl]but-3-en-2-yl}oxy)diphenyl-
silane (43). Carefully dried CuBr-Me S (83 mg, 0.4 mmol) was dissolved in anh. THF (1.0 ml)/Me S
(
2
2
(
(
ꢀ
0.5 ml). After adding a soln. of 3m MeMgBr in Et O (0.14 ml, 0.4 mmol), the formation of MeCuMgBr2
2
intense yellow color) was observed. To the generated cuprate, cooled at ꢀ208 for 10 min and then at
458, was cannulated a soln. of 42 (79 mg, 0.14 mmol) in anh. THF (1.5 ml). The mixture was allowed to
warm to r.t. over 1.5 h, then it was diluted with Et O (10 ml), and the reaction was quenched by adding a
2
sat. aq. NH Cl soln. (5 ml) and then NH ·H O (2 ml). The aq. phase was extracted with Et O (2ꢂ15 ml),
4
3
2
2
and the combined org. layers were dried (Na SO ) and evaporated at reduced pressure. The crude was
2
4
purified by CC (hexane) to yield 43 (44 mg, 73%). IR: 2973, 1599, 1468, 1431, 1360, 1141, 1111, 1071, 999,
1
8
5
9
1
1
26, 739, 704, 618. H-NMR: 7.74–7.67 (m, 4 H); 7.44–7.28 (m, 6 H); 5.51 (dd, J¼15.3, 6.4, 1 H); 5.38–
.30 (m, 2 H); 4.33–4.31 (m, 1 H); 2.15–1.89 (m, 5 H); 1.57–1.32 (m, 2 H); 1.16 (d, J¼6.3, 3 H); 1.07 (s,
13
H); 0.95 (td, J¼7.4, 2.5, 3 H); 0.89–0.76 (m, 6 H). C-NMR: 140.0 (s); 139.9 (s); 136.1 (d); 136.0 (d);
35.9 (d); 134.7 (s); 134.4 (s); 130.0 (d); 129.9 (d); 129.4 (d); 129.3 (d); 127.4 (d); 127.4 (d); 119.0 (d);
18.7 (d); 70.4 (d); 52.1 (d); 52.0 (d); 31.9 (s); 31.7 (t); 31.6 (t); 28.3 (t); 27.6 (q); 27.6 (q); 27.0 (q); 26.8
þ
þ
(
q); 24.9 (q); 23.0 (t); 19.2 (s); 12.6 (q). HR-MS: 446.3009 (M , C H OSi ; calc. 446.3005). Anal. calc.
30 42
for C H OSi: C 80.66, H 9.48; found C 80.71, H 9.42.
30
42
(
2RS,3E)-4-[(1S)-2-Ethyl-6,6-dimethylcyclohex-2-en-1-yl]but-3-en-2-ol (44). A soln. of 1m Bu NF in
4
THF (0.25 ml, 0.25 mmol) was added to a soln. of 43 (44 mg, 0.1 mmol) in anh. THF (1.0 ml). After
stirring at r.t. for 12 h, the solvent was removed at reduced pressure, and the crude was purified by CC
(
hexane/Et O 8 :2) to yield 44 (20 mg, 98%). Spectroscopic data were in accordance with those reported
2
in [8].
(
ꢀ)-(S)-13-Methyl-a-ionone (¼(3E)-4-[(1S)-2-Ethyl-6,6-dimethylcyclohex-2-en-1-yl]but-3-en-2-
one; 9). SIBX (45% (w/w); 90 mg, 0.14 mmol) was added to a soln. of 44 (20 mg, 0.1 mmol) in anh.
DMSO (1 ml). After stirring for 2 h at r.t., the mixture was diluted with pentane (3 ml), and the reaction
was quenched by addition of a 1:1 mixture of sat. aq. NaHCO soln. (1 ml) and sat. aq. Na S O soln.
3
2
2
3
(
(
1 ml). The aq. phase was extracted with pentane (2ꢂ3 ml), and the combined org. layers were dried
Na SO ) and evaporated at reduced pressure (>100 mmHg). The crude was purified by CC (pentane/
2
4
2
Et O 99 :1) to yield 9 (14 mg, 71%). Spectroscopic data were identical with those reported in [8]; ee 97%
(
determined by chiral GC chromatography [8]).
tert-Butyl){[(2RS,3E)-4-{(1S)-6,6-dimethyl-2-[(phenylsulfinyl)methyl]cyclohex-2-en-1-yl}but-3-
(
en-2-yl]oxy}diphenylsilane (45). PhSH (0.39 g, 3.4 mmol) was added dropwise to a soln. of N-
chlorosuccinimide (NCS; 0.51 g, 3.4 mmol) in anh. toluene (19 ml) cooled to 08. After stirring at r.t. for
1
h, the formation of PhSCl was observed by the appearance of an orange color. The soln. of PhSCl in
toluene (19 ml) was added dropwise to a soln. of 41 (566 mg, 1.3 mmol) in Et N (1.8 ml). After adding
DMAP (31 mg, 0.2 mmol) and stirring at r.t. for 1.5 h, the reaction was quenched by addition of Et O
3
2
(
20 ml) and H O (40 ml). The aq. phase was extracted with Et O (2ꢂ40 ml), and the combined org.
2
2
layers were dried (Na SO ) and evaporated at reduced pressure. The crude was purified by CC (hexane/
2
4
AcOEt 85 :15) to yield 45 (622 mg, 89%). Sticky yellow oil. IR: 2962, 2858, 1590, 1473, 1444, 1428, 1365,
1
1
5
1
143, 1112, 1086, 1047, 998, 909, 738, 703. H-NMR: 7.71–7.25 (m, 15 H); 5.72–5.24 (m, 3 H); 4.36 (q, J¼
.5, 1 H); 3.49 (d, J¼12.5, 0.5 H); 3.37–3.19 (m, 1.5 H); 2.35 (d, J¼9.4, 0.5 H); 2.23–1.90 (m, 2.5 H);
13
.49–0.74 (m, 20 H). C-NMR: 144.4 (s); 144.3 (s); 144.2 (s); 137.7 (d); 137.6 (d); 137.4 (d); 135.7 (d);
134.4 (s); 134.3 (s); 134.2 (s); 130.9 (d); 130.7 (d); 130.5 (d); 130.3 (d); 130.2 (d); 129.5 (d); 129.4 (d);
129.0 (d); 128.8 (d); 128.6 (d); 128.4 (d); 128.4 (d); 128.2 (d); 128.0 (d); 127.4 (d); 124.5 (d); 124.4 (d);
124.0 (d); 69.9 (d); 69.8 (d); 69.7 (d); 65.8 (t); 64.6 (t); 64.1 (t); 53.3 (s); 52.6 (d); 51.8 (d); 51.6 (d); 32.0

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1551
(
5
s); 31.3 (t); 31.2 (t); 31.1 (t); 27.1 (q); 26.9 (q); 26.8 (q); 24.7 (q); 24.7 (q); 23.3 (q); 19.1 (s). HR-MS:
56.2837 (M , C H O SSi ; calc. 556.2831). Anal. calc. for C H O SSi: C 75.49, H 7.96; found C 75.58,
35 44 2 35 44 2
þ
þ
H 7.90.
(
tert-Butyl){[(2RS,3E)-4-{(1S)-6,6-dimethyl-2-[(phenylsulfonyl)methyl]cyclohex-2-en-1-yl}but-3-
en-2-yl]oxy}diphenylsilane (46). mCPBA (212 mg, 1.2 mmol) was added to a soln. of 45 (622 mg,
1
.12 mmol) in Et O (11 ml) precooled to ꢀ208. After stirring to ꢀ208 for 1.5 h, the mixture was diluted
2
with CH Cl (20 ml), and the reaction was quenched by addition of a 1:1 mixture of sat. aq. NaHCO
2
2
3
soln. (15 ml) and sat. aq. Na
the combined org. layers were dried (Na SO ) and evaporated at reduced pressure. The crude was
2
S
2
O
3
soln. (15 ml). The aq. phase was extracted with CH
2
Cl
2
(2ꢂ30 ml), and
2
4
purified by CC (hexane/Et O 9 :1) to yield 46 (572 mg, 90%). Sticky colorless oil. IR: 2927, 1446, 1428,
2
1
1
5
1
318, 1147, 1086, 822, 740, 702. H-NMR: 7.88–7.85 (m, 2 H); 7.70–7.52 (m, 7 H); 7.44–7.28 (m, 6 H);
.51–5.41 (m, 2 H); 5.31–5.17 (m, 1 H); 4.33 (quint., J¼6.1, 1 H); 3.69–3.45 (m, 2 H); 2.45 (t, J¼9.5,
13
H); 1.96–1.63 (m, 2 H); 1.32–0.76 (m, 20 H). C-NMR: 139.0 (s); 139.0 (s); 137.5 (d); 135.7 (d); 135.7
(d); 134.3 (s); 134.2 (s); 133.3 (d); 132.3 (d); 132.2 (d); 129.5 (d); 128.8 (d); 128.3 (d); 128.2 (d); 127.4 (d);
1
26.7 (s); 126.4 (s); 69.8 (d); 61.7 (t); 51.0 (d); 50.8 (d); 31.9 (s); 30.3 (t); 27.6 (q); 27.4 (q); 26.8 (q); 26.6
þ
þ
(q); 24.8 (q); 24.7 (q); 23.3 (t); 19.1 (s). HR-MS: 572.2773 (M , C H O SSi ; calc. 572.2780). Anal.
35 44 3
calc. for C H O SSi: C 73.38, H 7.74; found C 73.47, H 7.82.
35
44
3
(
tert-Butyl){[(2RS,3E)-4-{(1S)-6,6-dimethyl-2-[2-(phenylsulfonyl)propan-2-yl]cyclohex-2-en-1-yl}-
but-3-en-2-yl]oxy}diphenylsilane (47). BuLi (2.5m in hexane, 0.24 ml, 0.61 mmol) was added dropwise to
a soln. of 46 (179 mg, 0.31 mmol) in anh. THF (3 ml), precooled to ꢀ788. After stirring for 30 min at ꢀ
7
88, MeI (0.04 ml, 0.61 mmol) was added. After 1 h, the formation of the monomethyl derivative was
observed (TLC); the mixture was then warmed to ꢀ208, and (Me Si) NK (0.5m in toluene, 1.22 ml,
3
2
0
.61 mmol) was added. After stirring for 30 min at ꢀ208, MeI (0.19 ml, 3.05 mmol) was added, and the
mixture was warmed at 408 for 1 h. The reaction was quenched by adding CH Cl (7 ml) and a sat. aq.
2
2
NH Cl soln. (10 ml). The aq. phase was extracted with CH Cl (2ꢂ10 ml), and the combined org. layers
4
2
2
were washed with a sat. aq. Na S O soln. (30 ml), dried (Na SO ), and evaporated at reduced pressure.
2
2
3
2
4
The crude was purified by CC (hexane/AcOEt 95 :5) to yield 47 (140 mg, 77%). IR: 2930, 1482, 1301,
1
1
1
(
272, 1131, 1080, 1032, 1000, 992, 768, 728, 720, 616, 608. H-NMR: 7.88–7.28 (m, 15 H); 5.93 (t, J¼3.7,
H); 5.63–5.19 (m, 2 H); 4.36 (quint., J¼6.1, 1 H); 2.82–2.78 (m, 1 H); 2.23–1.97 (m, 3 H); 1.60–0.84
13
m, 25 H). C-NMR: 136.7 (d); 136.0 (d); 134.6 (s); 134.3 (s); 133.2 (d); 132.9 (s); 131.5 (d); 130.6 (d);
1
2
6
29.5 (d); 129.4 (s); 128.7 (s); 128.4 (d); 127.4 (d); 70.2 (d); 70.1 (d); 67.2 (s); 48.4 (d); 33.5 (s); 28.9 (q);
8.7 (t); 26.9 (q); 26.2 (q); 25.5 (q); 25.4 (q); 24.5 (q); 24.0 (t); 21.4 (q); 21.3 (q); 19.2 (s). HR-MS:
00.3099 (M , C H O SSi ; calc. 600.3093). Anal. calc. for C H O SSi: C 73.95, H 8.05; found C 74.06,
37 48 3 37 48 3
þ
þ
H 8.14.
(
2RS,3E)-4-{(1S)-6,6-Dimethyl-2-[2-(phenylsulfonyl)propan-2-yl]cyclohex-2-en-1-yl}but-3-en-2-ol
(
30). Bu NF (1m in THF, 0.17 ml, 0.13 mmol) was added to a soln. of 47 (39.4 mg, 0.07 mmol) in anh.
4
THF (0.7 ml). After stirring at r.t. for 12 h, the solvent was removed at reduced pressure. The crude was
purified by CC (hexane/Et O 1:1) to yield 30 (20.6 mg, 87%). IR: 3501, 2926, 1447, 1387, 1366, 1289, 1152,
2
1
1
5
2
123, 1075, 984, 917, 760, 726, 692. H-NMR: 7.91–7.78 (m, 2 H); 7.66–7.48 (m, 3 H); 5.94 (q, J¼3.7, 1 H);
.73–5.48 (m, 1 H); 5.42–5.27 (m, 1 H); 4.36–4.21 (m, 1 H); 2.79 (dd, J¼19.8; 8.2, 1 H); 2.39–2.00 (m,
13
H); 1.79–0.75 (m, 18 H). C-NMR: 136.5 (s); 136.3 (d); 133.4 (d); 133.2 (d); 132.9 (d); 131.9 (d); 131.7
(
(
(
8
d); 130.6 (d); 129.3 (s); 129.0 (s); 128.7 (s); 128.4 (d); 68.9 (d); 68.8 (d); 67.4 (s); 48.9 (d); 48.6 (d); 33.3
s); 33.2 (s); 29.3 (q); 29.1 (q); 28.9 (t); 28.8 (t); 26.1 (q); 24.9 (q); 24.4 (q); 24.0 (t); 23.4 (q); 23.2 (q); 23.0
þ
þ
q); 22.3 (q). HR-MS: 362.1913 (M , C H O S ; calc. 362.1916). Anal. calc. for C H O S: C 69.57, H
21
30
3
21 30
3
.34; found C 69.68, H 8.28.
2RS,3E)-4-[(1S)-6,6-Dimethyl-2-(1-methylethyl)cyclohex-2-en-1-yl]but-3-en-2-ol (48) and
(
(
2RS,3E)-4-[(1S)-2,2-Dimethyl-6-(1-methylethylidene)cyclohexyl]but-3-en-2-ol (49). Granular Mg
(
188 mg, 7.73 mmol) was added to a soln. of 30 (140 mg, 0.39 mmol) in MeOH (3.9 ml). After vigorous
ꢁ
stirring at r.t. for 6 h, the mixture was filtered on Celite , the solvent was removed at reduced pressure,
and Et O (2 ml) and a sat. aq. NH Cl soln. (2 ml) were added. The aq. phase was extracted with Et O (2ꢂ
2
4
2
2
ml), and the combined org. layers were dried (Na SO ) and evaporated at reduced pressure. The crude
2 4
was purified by CC (pentane/Et O 9 :1) to yield 48 and 49 (72.2 mg, 84%) as a chromatographically
2
1
inseparable mixture. H-NMR: 5.88–5.72 (m, 0.5 H); 5.55–5.34 (m, 2.5 H); 4.37–4.21 (m, 1 H); 2.93

1
552
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
(
(
d, J¼6.9, 0.5 H); 2.55 (d, J¼13.8, 0.5 H); 2.20–1.98 (m, 1 H); 2.38–0.76 (m, 20 H). HR-MS: 220.1825
þ
þ
M , C H O ; calc. 220.1827). Anal. calc. for C H O: C 81.76, H 10.98; found C 81.83, H 11.04.
15
24
15 24
(
3E)-4-[(1S)-6,6-Dimethyl-2-(1-methylethyl)cyclohex-2-en-1-yl]but-3-en-2-one (15) and (3E)-4-
(1S)-2,2-Dimethyl-6-(1-methylethylidene)cyclohexyl]but-3-en-2-one (16). SIBX (45% w/w, 274 mg,
.44 mmol) was added to a soln. of a mixture 48/49 (65.3 mg, 0.29 mmol) in anh. DMSO (3 ml). After
[
0
stirring at r.t. for 2 h, the mixture was diluted with pentane (5 ml), and the reaction was quenched by
addition of a 1:1 mixture of sat. aq. NaHCO soln. (1 ml) and sat. aq. Na S O soln. (1 ml). The aq. phase
3
2
2
3
was extracted with pentane (2ꢂ5 ml), and the combined org. layers were dried (Na SO ) and evaporated
2
4
at reduced pressure (>100 mmHg). The residue was separated by CC (pentane/Et O 98 :2; crude
2
mixture/silica 1:500) to yield 15 (14.8 mg, 23%) and 16 (26.4 mg, 41%), resp.
2
0
(
ꢀ)-(S)-13,13-Dimethyl-a-ionone (15). [a] ¼ ꢀ321.25 (c¼0.1, CH Cl ) IR: 2961, 2959, 2947, 1680,
D
2
2
1
1
1
1
(
2
674, 1666, 1414, 1364, 1252, 875, 707. H-NMR (CD Cl ): 6.65 (dd, J¼15.9, 9.6, 1 H); 6.02 (d, J¼15.9,
2
2
H); 5.55 (t, J¼3.2, 1 H); 2.47 (d, J¼9.6, 1 H); 2.24 (s, 3 H); 2.20–1.95 (m, 3 H); 1.55–1.45 (m, 1 H);
13
.30–1.15 (m, 1 H); 1.03 (d, J¼6.5, 3 H); 0.97 (d, J¼6.5, 3 H); 0.95 (s, 3 H); 0.90 (s, 3 H). C-NMR
CD Cl ): 198.8 (s); 150.3 (d); 143.2 (s); 133.0 (d); 119.7 (d); 53.0 (d); 33.2 (s); 32.9 (d); 31.6 (t); 29.0 (q);
2
2
þ
þ
7.4 (q); 26.9 (q); 23.7 (t); 23.3 (q); 21.7 (q). HR-MS: 220.1829 (M , C H O ; calc. 220.1827).
15 24
2
0
(
þ)-(S)-13,13-Dimethyl-g-ionone (16). [a] ¼ þ68.97 (c¼0.14, CH Cl ). IR: 2928, 1687, 1674, 1618,
D
2
2
1
1
450, 1364, 1252, 1197, 982. H-NMR (CD Cl ): 7.02 (dd, J¼15.8, 9.3, 1 H); 6.03 (d, J¼15.8, 1 H); 3.14 (d,
2
2
J¼9.3, 1 H); 2.62 (dd, J¼14.1, 1.3, 1 H); 2.24 (s, 3 H); 2.90–2.75 (m, 1 H); 1.75 (br. s, 3 H); 1.70 (br. s,
13
3
1
H); 1.70–1.25 (m, 4 H); 0.94 (s, 3 H); 0.92 (s, 3 H). C-NMR (CD Cl ): 199.1 (s); 148.8 (d); 132.0 (d);
2 2
28.2 (s); 126.0 (s); 53.2 (d); 35.8 (t); 30.4 (q); 27.5 (q); 27.1 (q); 26.1 (t); 23.5 (t); 21.0 (q); 20.5 (q). HR-
þ
þ
MS: 220.1830 (M , C H O ; calc. 220.1827).
15
24
Computationals. Calculations were carried out by using the GAUSSIAN09 program package [23].
The conformational space of compounds 15 and 16 was explored through optimization of all the possible
starting geometries, which were optimized by the DFT approach at the B3LYP level with the 6-31þ
G(d,p) basis set. All the degrees of conformational freedom were considered. Vibrational frequencies
were computed at the same level of theory to verify that the optimized structures were minima.
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Received January 17, 2014