Enzyme-Mediated Preparation of (+)- and (-)-β-Irone and (+)- and (-)-cis-γ-Irone from Irone alpha

Article abstract of DOI:10.1002/1522-2675(20010131)84:1<69::AID-HLCA69>3.0.CO;2-U

The (-)- and (+)-β-irones ((-)- and (+)-2, resp.), contaminated with ca. 7-9 percent of the (+)- and (-)-trans-α-isomer, respectively, were obtained from racemic α-irone via the 2,6-trans-epoxide (+/-)-4 (Scheme 2). Relevant steps in the sequence were the LiAlH4 reduction of the latter, to provide the diastereoisomeric-4,5-dihydro-5-hydroxy-trans-α-irols (+/-)-6 and (+/-)-7, resolved into the enantiomers by lipase-PS-mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)- and (-)-8 and (+)- and (-)-9, upon treatment with POCl3/pyridine, were converted to the β-irol acetate derivatives (+)- and (-)-10, and (+)- and (-)-11, respectively, eventually providing the desired ketones (+)- and (-)-2 by base hydrolysis and MnO2 oxidation. The 2,6-cis-epoxide (+/-)-5 provided the 4,5-dihydro-4-hydroxy-cis-α-irols (+/-)-13 and (+/-)14 in a 3:1 mixture with the isomeric 5-hydroxy derivatives (+/-)-15 and (+/-)-16 on hydride treatment (Scheme 1). The POCl3/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (+/-)-13 and (+/-)-14, provided enantiomerically pure cis-α-irol acetate esters, from which ketones (+)- and (-)-22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)-13 and (-)-14, treated first with MnO2, then with POCl3/pyridine (Scheme 4). Conversely, the dehydration with POCl3/pyridine of the enantiomerically pure 2,6-cis-5-hydroxy derivatives obtained from (+/-)-15 and (+/-)-16 gave rise to a mixture in which the γ-irol acetates 25a and 25b and 26a and 26b prevailed over the α- and β-isomers (Scheme 5). The (+)- and (-)-cis-γ-irones ((+)- and (-)-3, resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α-double bond to the γ-double bond. External panel olfactory evaluation assigned to (+)-β-irone ((+)-2) and to (-)-cis-γ-irone ((-)-3) the strongest character and the possibility to be used as dry-down note.

Full text of DOI:10.1002/1522-2675(20010131)84:1<69::AID-HLCA69>3.0.CO;2-U

Helvetica Chimica Acta ± Vol. 84 (2001)
69
Enzyme-Mediated Preparation of (‡)- and ( )-b-Irone and (‡)- and
( )-cis-g-Irone from Irone alphaꢀ
by Elisabetta Brenna*, Marco Delmonte, Claudio Fuganti, and Stefano Serra
Dipartimento di Chimica del Politecnico di Milano, Centro CNR per lo Studio delle Sostanze Organiche
Naturali, Via Mancinelli, 7, I-20131 Milano
The ( )- and (‡)-b-irones (( )- and (‡)-2, resp.), contaminated with ca. 7 ± 9% of the (‡)- and ( )-trans-
a-isomer, respectively, were obtained from racemic a-irone via the 2,6-trans-epoxide (Æ)-4 (Scheme 2).
Relevant steps in the sequence were the LiAlH4 reduction of the latter, to provide the diastereoisomeric-4,5-
dihydro-5-hydroxy-trans-a-irols (Æ)-6 and (Æ)-7, resolved into the enantiomers by lipase-PS-mediated
acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (‡)- and ( )-8 and (‡)- and
(
)-9, upon treatment with POCl3/pyridine, were converted to the b-irol acetate derivatives (‡)- and ( )-10,
and (‡)- and ( )-11, respectively, eventually providing the desired ketones (‡)- and ( )-2 by base hydrolysis
and MnO2 oxidation. The 2,6-cis-epoxide (Æ)-5 provided the 4,5-dihydro-4-hydroxy-cis-a-irols (Æ)-13 and (Æ)-
14 in a 3 :1 mixture with the isomeric 5-hydroxy derivatives (Æ)-15 and (Æ)-16 on hydride treatment (Scheme 1).
The POCl3/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic
resolution of (Æ)-13 and (Æ)-14, provided enantiomerically pure cis-a-irol acetate esters, from which ketones
(‡)- and ( )-22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (‡)-13
and ( )-14, treated first with MnO2, then with POCl3/pyridine (Scheme 4). Conversely, the dehydration with
POCl3/pyridine of the enantiomerically pure 2,6-cis-5-hydroxy derivatives obtained from (Æ)-15 and (Æ)-16
gave rise to a mixture in which the g-irol acetates 25a and 25b and 26a and 26b prevailed over the a- and b-
isomers (Scheme 5). The (‡)- and ( )-cis-g-irones ((‡)- and ( )-3, resp.) were obtained from the latter mixture
by a sequence involving as the key step the photochemical isomerization of the a-double bond to the g-double
bond. External panel olfactory evaluation assigned to (‡)-b-irone ((‡)-2) and to ( )-cis-g-irone (( )-3) the
strongest character and the possibility to be used as dry-down note.
Introduction. ± The synthesis of the enantiomerically pure isomers of irones (the C14
nor-terpenoid ketone components of the essential oil of Iris rhizomes [1]) starting from
the components of the ꢀpool of chiralityꢁ [2] is still attracting a great deal of attention
[3]. Recently, Monti et al. [4] obtained (‡)-cis-g-irone from naturally occurring (‡)-
(2R,5R)-trans-dihydrocarvone. Prompted by this report, we refer now on the synthesis
of (‡)- and ( )-b-irone ((‡)- and ( )-2, resp.) and of (‡)- and ( )-cis-g-irone ((‡)-
and ( )-3, resp.) from Irone alphaꢂ, the commercially available 55 :45 mixture of
racemic trans- and cis-a-irone 1, containing 5% of the b-isomer. This is part of a wider
study designed to obtain the olfactory active enantiomeric forms of potent odorants
from readily available racemic materials [5][6] by enzymic procedures.
Relevant intermediates in the preparation of (‡)- and ( )-2 and (‡)- and ( )-3
were the 2,6-trans- and 2,6-cis-epoxides (Æ)-4 and (Æ)-5, which we had already
exploited in a previous synthesis of (‡)- and ( )-trans-a-irone and (‡)- and ( )-cis-a-
irone from Irone alpha ꢂ (1) [6]. Indeed, direct peracid treatment of the trans/cis
mixture 1 led to a mixture of (Æ)-4 and (Æ)-5, which were separated by column
chromatography (CC; SiO2). The single enantiomers of the diastereoisomerically pure
species (Æ)-4 and (Æ)-5 were prepared in a sequence starting with the acetylation by

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Helvetica Chimica Acta ± Vol. 84 (2001)
vinyl acetate, in the presence of lipase PS, of the single diastereoisomeric alcohols
obtained upon NaBH4 reduction. The (9R)-allyl alcohols, obtained by hydrolysis of the
enzymically generated esters, and the (9S)-enantiomers, recovered unreacted after
acetylation, were oxidized with MnO2, to afford (‡)- and ( )-4 and (‡)- and ( )-5.
These latter derivatives provided (‡)- and ( )-trans-a-irone and (‡)- and ( )-cis-a-
irone, respectively, by a deoxygenation reaction.
The access to (Æ)-4 and (Æ)-5 from trans/cis-a-irone 1 became much simpler thanks
to the observation that (Æ)-5 crystallized nicely from the crude oily epoxidation
mixture by seeding at low temperature. Its recovery was then possible by filtration of
the mixture taken up with cold pentane. This additional feature of a practical nature
induced us to attempt the synthesis of some other naturally occurring irone isomers [7],
i.e., of trans- and cis-g-irone and b-irone, starting from racemic trans- and cis-a-irone
epoxide (Æ)-4 and (Æ)-5. We report now the results of this study.
Results and Discussion. ± To convert a-irone epoxides (Æ)-4 and (Æ)-5 to
derivatives of the other skeletal series, i.e., to trans- and cis-g-irone and b-irone, which
differ by the position of the CˆC bond in the cyclohexane ring, we considered useful
the reductive opening of the 4,5-oxirane moiety to the corresponding alcohols at
position 5, followed by dehydration under conditions leading either to the exocyclic or
to the more-substituted endocyclic 5,6-double bond.
Enantiomeric b-Irones (‡)- and ( )-2 from Racemic Epoxy-trans-a-irone (Æ)-4.
Racemic (Æ)-4 was refluxed in tetrahydrofuran (THF) in the presence of LiAlH4
(5 mol-equiv.) for 48 h, affording diols (Æ)-6 and (Æ)-7 in a ca. 1:1 ratio (Scheme 1,a).
These products crystallized nicely from hexane, once separated by CC (SiO2). The

Helvetica Chimica Acta ± Vol. 84 (2001)
71
relative configuration at the stereocenters characterizing derivatives (Æ)-6 and (Æ)-7
was first assigned on the basis of the following considerations: a) Hydride attack at the
less-substituted C-atom should afford the tertiary alcohol with the OH group on the
same side as the side chain, through the highly favored trans-diaxial opening [8] of the
oxirane ring (Scheme 1,a). This is in accordance with what was reported for the
reduction of 4,5-epoxy-4,5-dihydro-a-ionone showing the same relative configuration
at C(5) and C(6) [9]. b) The relative configuration at C(9) and C(6) was assigned by
comparison of derivatives (Æ)-6 and (Æ)-7 with the same diols obtained by LiAlH4
reduction of the known (2RS,4RS,5SR,6SR,9SR)-4,5-epoxy-4,5-dihydro-trans-a-irol
and of its (9RS)-diastereoisomer [6].
Scheme 1
This configurational assignment was confirmed by NOE experiments performed on
(Æ)-7. The following strong and useful NOEs were observed: i) between Me C(2) and
H
C(6) (2,6-trans-configuration); ii) between Me C(5) and Hax C(4) and H C(6)
(anti relation between Me C(5) and the side chain at C(6)).
In enzymic acetylation experiments, diols (Æ)-6 and (Æ)-7 showed a behavior very
similar to that of their 4,5-epoxy precursors [6]. As a matter of fact, they were
converted to the corresponding (9R)-acetate esters (‡)-8 and (‡)-9, respectively, upon
treatment with vinyl acetate in the presence of lipase PS in t-butyl methyl ether
(tBuOMe) solution (Scheme 2). On the contrary, they did not react when Candida
cylindracea lipase (CCL) or Porcine pancreatic lipase (PPL) were employed as
catalysts.

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Scheme 2
i) LiAlH4, THF. ii) Lipase PS, tBuOMe, vinyl acetate; column chromatography. iii) Ac2O, pyridine. iv) POCl3,
pyridine. v) KOH, MeOH. vi) MnO2, CH2Cl2.

Helvetica Chimica Acta ± Vol. 84 (2001)
73
The (9R)-configuration was assigned to (‡)-8 and (‡)-9 on the basis of the
preference shown by lipase PS for the acetylation of (R)-alcohols of this structural
series [5][6]. The enantiomer excesses (ee) of acetyl derivatives (‡)-8 and (‡)-9 and of
the surviving alcohols ( )-6 and (‡)-7 were inferred from those of their transformation
products, i.e. the b-irol acetates (‡)-10, (‡)-11, ( )-10, and ( )-11, respectively.
Products structurally similar to (‡)-8 and (‡)-9, showing a C(Me)OH moiety at
C(5) of a 1,1-dimethyl-6-alkyl-substituted cyclohexane ring, had been previously
converted to exo-cyclic-methylene derivatives, for example, by Ohloff and Mignat [10]
on thermal treatment of the corresponding tertiary acetate ester in the synthesis of
dihydro-g-ionone. We first investigated the dehydration of the tertiary-alcohol moiety
of allylic monoacetates (‡)-8 and (‡)-9 by reaction with POCl3 in pyridine, as it was
reported to proceed with high stereo- and regioselectivity [11]. In the synthesis of
isotheaspirane [12], by means of this reagent, Weyerstahl and co-workers converted an
intermediate resembling (‡)-8 and (‡)-9 into a mixture of unsaturated products in
which the ratio of the isomer with the exo-cyclic-methylene group to that possessing the
4,5-double bond was ca. 95 :5.
At room temperature, monoacetate (‡)-8 reacted slowly with POCl3, the
conversion being complete after one week. b-Irol acetate (‡)-10 (ee ˆ 99% by chiral
GC) was obtained in 90% yield, contaminated by 9% of the ( )-trans-a-isomer. The g-
isomer was not detected by GC/MS among the reaction products. The components of
the oily mixture could not be separated by chromatography and the same was true
for the alcohols obtained by basic hydrolysis. A purification of b-irol from the
contaminating trans-a-isomer was attempted by fractional crystallization of the 4-
nitrobenzoate ester, obtained as low melting crystals from cold hexane. However, the
ratio of the isomers in the mixture recovered from the base hydrolysis of the ester (50%
recovery from the crystallization solvent) was substantially unaltered with respect to
that of the starting material.
The sequence described for (‡)-8 was extended (Scheme 2) to (‡)-9 and to the
acetyl derivatives of ( )-6 and (‡)-7, which yielded a similar distribution of isomers.
The (2R)-diastereoisomeric b-irol acetate esters ( )-10 and (‡)-11 were then pooled,
hydrolyzed, and oxidized with MnO2 to provide (‡)-(2R)-b-irone ((‡)-2) in high yield.
Similarly, from (‡)-10 and ( )-11, the ( )-(2S)-enantiomer ( )-2 was obtained. Thus
far, (‡)-2 and ( )-2 prepared by this synthetic sequence were contaminated by ( )-
trans-a-irone (9%, by GC/MS) and (‡)-trans-a-irone (7%, by GC/MS), respectively.
This made the definition of the enantiomer purity by optical measurements very
difficult.
Reports on the characterization of the enantiomers of b-irone were scarce, despite
of the fact that this compound is present in Iris extracts [7]. This is really a minor
component. Mixtures highly enriched in b-irone could be obtained upon equilibration
of the a- and g-isomers [13] in basic medium. Thus, product (‡)-2, containing a minute
but definite amount of (‡)-cis-g-irone ((‡)-3), obtained via base isomerization of the
natural extract originally used by Ruzicka for the structure-elucidation studies, was
assigned a specific optical rotation of ‡ 33 in CH2Cl2 (calculated value ‡ 59) as
deduced by Rautenstrauch and Ohloff [13]. Chapuis and Brauchli [3d] found [a]D20
65.0 for the ( )-enantiomer ( )-3 (86% ee), prepared by synthesis and purified by
prep. GC. Unfortunately, our samples of (‡)-2 and ( )-2 were contaminated with ( )-
ˆ

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and (‡)-trans-a-irone, whose specific optical rotations ([a]D20
ˆ
420 (c ˆ 0.98, CH2Cl2)
and [a]2D0 ˆ ‡427 (c ˆ 0.95, CH2Cl2) [6]) were opposite in sign and of much higher
numerical value than those of the b-irone enantiomers1).
The enantiomer purity of the two b-irone samples (‡)- and ( )-2 was then assessed
by a spectroscopic NMR method based on the use of chiral shift reagents. In the
1H-NMR spectrum of racemic b-irone, on progressive addition of [Eu(hfc)3] (hfc ˆ 3-
[(heptafluoropropyl)hydroxymethylene]camphorate), the two s corresponding to
Me C(5) (d(H) 1.73) and to one of the geminal Me C(1) (d(H) 1.06), were shifted
downfield (d(H) 2 and 1.8, resp.) and split into two lines each (Dd ˆ 0.01 ppm for both
signals, with chiral shift reagent/substrate 4.6 :1). By this method, the two b-irone
samples (‡)- and ( )-2 were found to be enantiomerically pure (see Exper. Part for
details).
To verify whether a different regiochemical course of dehydration could be
achieved, we experimented with reaction conditions other than the concerted
elimination of phosphate ester promoted by POCl3 and affording b-irone. Thus, the
tertiary alcohol (Æ)-9 did not react at room temperature by treatment either with
pyridinium 4-toluenesulfonate in EtOH, or with 4-toluenesulfonic acid in toluene, or
with thionyl chloride/pyridine in CHCl3. However, it was soon converted to a complex
mixture of decomposition products, by forcing the reaction conditions. Catalytic 85%
perchloric acid in THF at 08 rapidly converted (Æ)-9 to (7E,9E)-5,6,6-trimethylundeca-
7,9-dien-2-one ((Æ)-12) (Scheme 3). The C-skeleton fragmentation thus described was
likely initiated by the protonation of the allylic acetate at position 9.
Scheme 3
i) Cat. 85% HClO4 in THF.
Enantiomeric cis-a-Irones (‡)- and ( )-22 and Enantiomeric cis-g-Irones (‡)- and
( )-3 from Racemic Epoxy-cis-a-irone (Æ)-5. When the sequence of chemo-enzymatic
reactions was applied to epoxy-cis-a-irone (Æ)-5, a different synthetic course was
observed: the final products were the enantiomerically enriched forms of cis-a-irone
and cis-g-irone.
The first difference between (Æ)-4 and (Æ)-5 was the mode of reaction with LiAlH4.
The reduction of (Æ)-5 was much slower than that of (Æ)-4, and it afforded a ca. 3 :1
1
)
Taking into account the chemical composition of the two samples of b-irone ((‡)-2: 91% of b-irone and 9%
of ( )-trans-a-irone, by GC/MS; ( )-2: 93% of b-irone and 7% of (‡)-trans-a-irone, by GC/MS), we
determined an extrapolated value of specific optical rotation for enantiomerically pure b-irone of ca. Æ 60
from the measured values of [a]2D0 ˆ ‡17.1 (c ˆ 1.45, CH2Cl2) and [a]2D0
ˆ
20.2 (c ˆ 2.30, CH2Cl2).

Helvetica Chimica Acta ± Vol. 84 (2001)
75
mixture of 4,5-dihydro-4-hydroxy-cis-a-irols (Æ)-13 and (Æ)-14 and 4,5-dihydro-5-
hydroxy-cis-a-irols (Æ)-15 and (Æ)-16 (Scheme 1,b). Each component of the mixture
was separated by column chromatography (SiO2), the 4-hydroxy isomers (Æ)-13 and
(Æ)-14 being eluted first.
In a previous work [6], we had shown by X-ray analysis that, in the derivative (Æ)-5,
the oxirane ring was in ꢀantiꢁ relation to the side chain at C(6). Thus, this course of
epoxide opening could be tentatively explained on the basis of a competition between
the hydride attack at the most-hindered C-atom C(5), leading to a highly favored trans-
diaxial opening in a chair-like transition state [8], and the reaction at the less
substituted C-atom C(4) (Scheme 1,b). The resulting configurations of the favored (Æ)-
1
13 and (Æ)-14 were confirmed by H-NMR analysis.
In derivatives (Æ)-13 and (Æ)-14, the H-atom at C(4) gave rise to a q at ca. 3.80 ppm with J ˆ 3 Hz, in
accordance with its equatorial arrangement and its coupling with Hax C(3), Heq C(3), and Hax C(5) with low
coupling constants. Moreover, H C(6) gave a dd with J ˆ 10 and 11.3 Hz at 1.83 ppm, thus sustaining the axial
position of H C(5).
Derivatives (Æ)-13 to (Æ)-16 were submitted to enzymic acetylation with vinyl
acetate and lipase PS in tBuOMe solution, to provide (9R)-acetate esters (‡)-17, (‡)-
18, (‡)-23, (‡)-24, respectively, and the (9S)-allylic alcohols (‡)-13, ( )-14, (‡)-15,
and (‡)-16, respectively (see below, Schemes 4 and 5). Interestingly enough, the
enzyme-mediated transesterification of 4,9-diols (Æ)-13 and (Æ)-14 afforded only the
allylic (9R)-acetate esters under these conditions. The assignment of the relative
configuration and of the enantiomer purity of this set of materials was based on the
direct comparison with the products of LiAlH4 treatment of enantiomerically pure
(9R)- and (9S)-diastereoisomeric epoxy-cis-a-irols [6].
The (9R)-4,5-dihydro-4-hydroxy-cis-a-irol acetate esters (‡)-17 and (‡)-18 and the
corresponding (9S)-alcohols (‡)-13 and ( )-14 were converted to cis-a-irones ( )- and
(‡)-22 by the convergent sequences outlined in Scheme 4. Treatment of the acetate
esters (‡)-17 and (‡)-18 with POCl3 in pyridine at room temperature [14] provided,
within a few minutes, the diastereoisomeric a-irol acetate esters ( )-19 (ee ˆ 98%, by
chiral GC) and (‡)-20 (ee ˆ 97%, by chiral GC) [6][15], respectively. These latter
compounds were found to contain 13% (by GC/MS) and 28% (by GC/MS),
respectively, of the corresponding 4-chloro derivatives, obtained by Cl-substitution of
the intermediate phosphate ester (Scheme 1,c). Acetates ( )-19 and (‡)-20 afforded
the cis-a-irones (‡)- and ( )-22 by basic hydrolysis and MnO2 oxidation, the
purification of the a-irones being possible by CC (removal of the contaminating 4-
chloro-4,5-dihydro ketone analogue). The conversion of the diastereoisomeric 4,9-diols
(‡)-13 and ( )-14 into ( )- and (‡)-22, respectively, by the same route required the

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Helvetica Chimica Acta ± Vol. 84 (2001)
regioselective chemical acetylation of the allylic alcohol. The attempt based on the use
of Ac2O and pyridine in CH2Cl2 failed: ca. 1:1 mixtures of 4- and 9-monoacetate esters
were invariably obtained. However, by inverting the order of application of the
reactions of Scheme 4, (‡)-13 and ( )-14 were straightforwardly converted to ( )- and
(‡)-22, respectively. To this end, (‡)-13 and ( )-14 were first oxidized with MnO2 to
the enantiomeric 4,5-dihydro-4-hydroxy-cis-a-irones (‡)-21 and ( )-21 and then
treated with POCl3 in pyridine.
Scheme 4
t
i) Lipase PS, BuOMe, vinyl acetate. ii) POCl3, pyridine. iii) MnO2, CH2Cl2. iv) KOH, MeOH.

Helvetica Chimica Acta ± Vol. 84 (2001)
77
This sequence would represent a new simple entry to enantiomerically pure forms
of cis-a-irone from Irone alpha ꢂ via crystalline epoxy derivative (Æ)-5 [6]. However,
there is a drawback in the process. As a matter of fact, the POCl3/pyridine treatment of
the 4-hydroxy derivatives (‡)-17, (‡)-18, (‡)-21, and ( )-21 produced also the
corresponding 4-chloro-4,5-dihydro analogues in small amounts by nucleophilic
substitution, together with the desired dehydration products with the cis-a-irone
skeleton. The chlorinated compounds were separated by CC and completely
characterized as ketone derivatives (‡)-27 (from (‡)-17 and ( )-21) and ( )-27
(from (‡)-18 and (‡)-21). The configurations of (‡)- and ( )-27 were in accordance
with the inversion of the configuration at C(4) promoted by the nucleophilic
substitution of the phosphate ester by the Cl-ion (Scheme 1,c) and was confirmed by
1H-NMR analysis.
The H-atom at C(4) of ( )- or (‡)-27 gave rise to a ddd with J ˆ 4.6, 10.7, 12.1 Hz at ca. 3.5 ppm. This was in
accordance with an axial arrangement of this H-atom, involved in two axial-axial couplings (with Hax C(3) and
Hax C(5)), and one axial-equatorial coupling (with Heq C(3)).
The equatorially located Cl-atom could not be eliminated. Various reaction
t
conditions were attempted: BuOH/THF, DBU/CHCl3, and 35% KOH/EtOH. Thus,
the rapid dehydration of (‡)-17, (‡)-18, (‡)-21, and ( )-21 occurring by POCl3/
pyridine treatment was the result of the anti-periplanar elimination of the axially
located phosphate ester, together with the axial H C(5). The competing substitution
of the phosphate ester by the Cl ion occurred with inversion of configuration at C(4),
and the desired 4,5-dehydrohalogenation became very difficult for stereochemical
reasons.
The (9R)-acetate esters (‡)-23 and (‡)-24 (see below, Scheme 5) and their (9S)-
enantiomers (obtained upon treatment with Ac2O/pyridine of the alcohols (‡)-15 and
(‡)-16) were also treated with POCl3/pyridine. These materials reacted immediately
with POCl3, even at 08, affording almost quantitatively mixtures of cis-g-, cis-a-, and b-
irol acetate diastereoisomers in a ca. 45 :35 :20 ratio. Chiral GC analysis of the reaction
mixtures showed conservation of the enantiomer purity during the dehydration process.
The different regiochemistry of the POCl3/pyridine-induced dehydration of the
tertiary alcohols of the trans-series (derived from (Æ)-6 and (Æ)-7; see Scheme 2) and of
the cis-series (derived from (Æ)-15 and (Æ)-16; see below, Scheme 5) could be
tentatively explained, taking into account the precise stereochemical requisites of E2
elimination. Anti-periplanar arrangement of the H-atom and of the other leaving group
is required. In such cyclohexane derivatives, this steric condition is best satisfied when
the H-atom and, in this case, the phosphate ester are in a trans-diaxial relation. The
analysis of the chair conformations reported in Scheme 1 allowed us to draw the
following conclusions: a) In derivatives (Æ)-6 and (Æ)-7, H C(6) and OH C(5) are in

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Helvetica Chimica Acta ± Vol. 84 (2001)
trans-diaxial relation. Thus, dehydration of the corresponding allylic acetates to b-
derivatives is highly favored. Traces of trans-a-irol acetate are due to a competing anti-
periplanar elimination with the axial H C(4). b) In derivatives (Æ)-15 and (Æ)-16,
OH C(5) is equatorial and is eliminated to give cis-g- and cis-a-derivatives
preferentially. The distribution of the dehydration products might suggest an E1
mechanism [16]. The elucidation of the mechanism of this kind of reaction far exceeds
the purpose of this work.
The mixture of cis-g-, cis-a-, and b-irol acetate diastereoisomers, prepared from
(‡)- and ( )-23 and (‡)- and ( )-24, as well as the alcohols obtained by base
hydrolysis, were unseparable by CC (SiO2). Thus, the amount of the g-isomers present
in the various mixtures was increased by photoisomerization, under conditions similar
to those described in the synthesis of presiccanochromene A by Nozoe and Hirai [17]
from an intermediate similar to our products. The irol acetate mixtures were thus
irradiated with UV lamps, in iPrOH solution containing 10% xylene, while the course
of the reaction was followed by GC/MS. Within 24 h, the cis-a-irol acetate was
completely converted into the corresponding cis-g analogue, while the b-isomer almost
immediately disappeared, giving rise to various minor products, which were not
characterized. As irradiation proceeded, before the conversion of the a-isomer could
be completed, we noticed also the formation of the (7Z)-isomer of cis-g-irol acetate. At
the end of the photoisomerization, CC (SiO2) allowed us to separate the mixture of
(7Z)- and (7E) cis-g-irol acetate from the more polar products of transformation of the
b-isomer. No further purification of the irol mixture obtained by base hydrolysis of the
latter acetate esters was possible by CC. During MnO2 oxidation, (7Z)-cis-g-irone [18]
was formed together with the (E)-isomer, but it was the first to be eluted on CC (SiO2,
3 ± 4% AcOEt/hexane), thus a final complete separation was possible.
All the mixtures originated from the POCl3/pyridine treatment of (‡)- and ( )-23
and (‡)- and ( )-24 were UV-irradiated ( ! 25 and 26, resp.), pooled according to the
configuration at C(2) and C(6), hydrolyzed in alcoholic KOH solution, and then
submitted to MnO2 oxidation and CC purification (Scheme 5). The following samples
of cis-g-irone were obtained (Scheme 5): a) (‡)-cis-g-irone ((‡)-3; 96% ee, by chiral
GC), containing 5% of (‡)-cis-a-irone ((‡)-22) and 3% of (‡)-b-irone ((‡)-2), with
[a]2D0 ˆ ‡9.5 (c ˆ 2.15, CH2Cl2), and b) ( )-cis-g-irone (( )-3; 97% ee by chiral GC),
containing 4.5% of ( )-cis-a-irone (( )-22) and 1.5% of ( )-b-irone (( )-2), with
[a]D20
ˆ
6.3 (c ˆ 1.05, CH2Cl2). Some discrepancies could be observed in the
magnitude of the specific rotations of cis-g-irone reported2). It was only possible to
conclude that optically pure cis-g-irone was characterized by a very low specific
rotation. Our values, however, were altered by the presence of traces of cis-a-irone and
b-irone showing specific rotations of the same sign. Enantiomer purity was then
determined by chiral GC analysis.
2
)
The following solution data for [a] were available: i) [19]: ( )-cis-g-irone, chemical purity (GC) 99%,
20
20
[a]
ˆ
1 (c ˆ 0.5, CH2Cl2); (‡)-cis-g-irone, chemical purity (GC) 99%, [a] ˆ ‡2 (c ˆ 0.5, CH2Cl2); ii)
578
578
[13a]: (‡)-cis-g-irone, [a]2D0 ˆ (‡)-2 (c ˆ 0.443, CH2Cl2); iii) [3d]: ( )-cis-g-irone, purified from ( )-trans-g-
irone by prep. GC, ee 76%, [a]D20
ˆ
5.3 (c ˆ 1.66, CH2Cl2); iv) [20]: ( )-cis-g-irone [a]D20
ˆ
5.3 (c ˆ 0.75,
CHCl3); v) [4]: (‡)-cis-g-irone, de 99%, ee 99%, [a]2D0 ˆ ‡0.4 (c ˆ 3, CHCl3).

Helvetica Chimica Acta ± Vol. 84 (2001)
79
Scheme 5
t
i) Lipase PS, BuOMe, vinyl acetate. ii) POCl3, pyridine. iii) hv, xylene/iPrOH. iv) Ac2O, pyridine. v) KOH,
MeOH. vi) MnO2, CH2Cl2.
Olfactory Evaluation. ± The odor descriptions of samples (‡)- and ( )-2 and (‡)-
and ( )-3 were performed at Givaudan-Roure Research Ltd. (Dübendorf, Switzer-
land):
(‡)-b-Irone ((‡)-2) (91% chemical purity) possesses a b-ionone-type odor of warm
floral-woody tonality with green and anisic aspects. The odor is linear, and the tenacity

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Helvetica Chimica Acta ± Vol. 84 (2001)
of the note is good. It can be considered a dry-down note. This compound is the
strongest of the series.
( )-b-Irone (( )-2) (93% chemical purity) has a woody odor with a distinct honey
note, that is quite sweet. Besides, it shows floral ionone-type facets, and a fruity tonality,
but also an unpleasant smokey character. It belongs to the ionone-type family, without
being very close to b-ionone.
( )-cis-g-Irone (( )-3) (94% chemical purity) exhibits a b-ionone-type odor of
warm floral-woody tonality, and green aspects are present, too. Instead of anisic
attributes, the compound shows some fruity nuances, reminiscent of pineapples. The
odor is linear; it is the second strongest compound of this series, and it can also be
considered a dry-down note. Odor threshold (chiral GC olfactometry): 0.75 ng/l.
(‡)-cis-g-Irone ((‡)-3) shows a floral, fatty, sweet, and woody odor character, an
ionone-type odor with slightly sweet aspects. Odor threshhold (chiral GC olfactom-
etry): >100 ng/l.
Conclusions. ± The chemo-enzymatic sequence described here allowed us to
prepare enantiomerically enriched samples of six of the ten stereoisomers of irone,
starting from the commercial 55 :45 mixture of racemic trans- and cis-a-irone 1. The
(‡)- and ( )-b-irone, (‡)- and ( )-cis-a-irone, and (‡)- and ( )-cis-g-irone were
obtained and fully characterized. The two samples of (‡)-b-irone ((‡)-2) and ( )-cis-g-
irone (( )-3) were found to be the strongest of the series, to be eventually used as a dry-
down note.
The key intermediates were the two epoxide derivatives (Æ)-4 and (Æ)-5, readily
prepared from Irone alphaꢂ. The different arrangement of the oxirane moiety in
relation to the side chain at C(6) was responsible for the different regiochemical course
of LiAlH4 reduction of the two epoxides. Thus, (Æ)-4 afforded almost exclusively the
diastereoisomeric tertiary alcohols (Æ)-6 and (Æ)-7, while (Æ)-5 provided both the
secondary alcohols (Æ)-13 and (Æ)-14 and the tertiary derivatives (Æ)-15 and (Æ)-16.
The axial OH group at C(5) of (Æ)-6 and (Æ)-7 was lost in the dehydration process
affording b-analogues. A completely different and unexpected regiochemical course
was observed when the dehydration process involved the equatorial OH group at C(5)
of (Æ)-15 and (Æ)-16: a mixture of cis-a-, cis-g-, and b-irol acetates was obtained, and
then enriched in the cis-g-derivative by photoisomerization. Access to the cis-g-
analogues was thus found.
POCl3 Treatment of secondary alcohols (Æ)-13 and (Æ)-14 allowed us to find a route
to the cis-a-irones alternative to that described in [6].
Work is now in progress to prepare both the enantiomers of trans-g-irone by
enzymatic resolution of a suitable derivative obtained from Irone alphaꢂ.
The authors are indebted to Dr. Philip Kraft, Dr. Caroline Denis, and Dr. Heinz Koch (Givaudan-Roure
Research Ltd., Switzerland) for the odour descriptions and thresholds evaluation of the irone samples. The
authors would like to thank CNR-Progetto Finalizzato Biotecnologie for financial support.
Experimental Part
General. Irone alpha ꢂ was purchased from IES (Allauch, France). Lipase PS from Pseudomonas cepacia
(Amano Pharmaceuticals Co., Japan), Candida cylindracea lipase (CCL; Sigma, type VII, 900 U mg 1), and
porcine pancreatic lipase (PPL, Sigma, type II) were employed in this work. Chiral GC analysis: Chirasil-

Helvetica Chimica Acta ± Vol. 84 (2001)
81
DEX-CB (Chrompack) column (25 m  0.25 mm), DANI-HT-86.10 gas chromatograph; temp. program: 708
(3 min), then 3.58/min ! 1408, then 88/min ! 1808 (1 min). Anal. GC: mass-detection limit ca. 10 ng for an
injected volume of 1 ml; tR in min. TLC: Merck silica-gel 60 F254 plates. Column chromatography (CC): silica gel.
Optical rotations: Jasco DIP-181 digital polarimeter. 1H-NMR Spectra: CDCl3 solns. at r.t. unless otherwise
stated; Bruker ARX-400 spectrometer (400 MHz 1H); d in ppm rel. to SiMe4, J in Hz, chx ˆ cyclohexane moiety.
GC/MS: HP 6890 gas chromatography, 5773 mass detector, HP 5MS column (30 m  0.25 mm  0.25 mm);
temp. program: 608 (1 min), then 68/min ! 1508 (1 min), then 128/min ! 2808 (5 min); m/z (rel. %).
Microanalyses were determined on an analyzer 1106 from Carlo Erba.
1. Lithium Aluminium Hydride Reduction of Epoxy-a-irones. 1.1. General Procedure 1 (GP 1). A mixture
of the suitable epoxy-a-irone (30 g, 0.135 mol) and LiAlH4 (25.7 g, 0.676 mol) in THF (500 ml) was refluxed.
The mixture was treated with AcOEt and MeOH and then diluted with H2O. After concentration under reduced
pressure, the aq. layer was extracted with AcOEt, the org. phase dried and evaporated, and the residue
submitted to CC (hexane/AcOEt 7 :3).
1.2. (Æ)-(2RS,5RS,6SR,9SR)-4,5-Dihydro-5-hydroxy-trans-a-irol (ˆ(1RS,2SR,4RS)-2-[(1E,3SR)-3-Hy-
droxybut-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (Æ)-6) and (Æ)-(2RS,5RS,6SR,9RS)-4,5-Dihydro-5-hy-
droxy-trans-a-irol (ˆ(1RS,2SR,4RS)-2-[(1E,3RS)-3-Hydroxybut-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (Æ)-
7). According to GP 1, (Æ)-(2RS,4RS,5SR,6SR)-4,5-epoxy-trans-a-irone ((Æ)-4; 30 g, 0.135 mol) gave, after
48 h, the less polar (Æ)-6 (12.5 g, 41%) and the more polar (Æ)-7 (13.1 g, 43%).
Data of (Æ)-6: 1H-NMR: 5.76 (ddd, J ˆ 0.9, 10.3, 15.7, H C(7)); 5.53 (dd, J ˆ 6.4, 15.7, H C(8)); 4.35
(quint. d, J ˆ 0.9, 6.4, H C(9)); 2.09 (tt, J ˆ 4, 13.4, Hax C(3)); 1.81 (d, J ˆ 10.3, H C(6)); 1.64 (td, J ˆ 4, 13.4,
13.4, Hax C(4)); 1.55 (m, H C(2)); 1.45 (dt, J ˆ 4, 4, 13.4, Heq C(4)); 1.29 (d, J ˆ 6.4, Me C(9)); 1.24 (dq, J ˆ
4, 4, 4, 13.4, Heq C(3)); 1.10 (s, Me C(5)); 1.09 (s, Meax C(1)); 0.92 (d, J ˆ 7, Me C(2)); 0.78 (s, Meeq C(1)).
Anal. calc. for C14H26O2: C 74.29, H 11.58; found: C 74.25, H 11.62.
Data of (Æ)-7: 1H-NMR: 5.75 (dd, J ˆ 10.2, 15.2, H C(7)); 5.50 (dd, J ˆ 6.4, 15.2, H C(8)); 4.33
(quint. J ˆ 6.4, H C(9)); 2.07 (tt, J ˆ 4.3, 13.8, Hax C(3)); 1.80 (d, J ˆ 10.2, H C(6)); 1.62 (td, J ˆ 4.3, 13.8,
13.8, Hax C(4)); 1.54 (m, H C(2)); 1.48 (dt, J ˆ 4.3, 4.3, 13.8, Heq C(4)); 1.28 (d, J ˆ 6.4, Me C(9)); 1.24
(dq, J ˆ 4.3, 4.3, 4.3, 13.8, Heq C(3)); 1.14 (s, Me C(5)); 1.07 (s, Meax C(1)); 0.91 (d, J ˆ 7, Me C(2)); 0.75
(s, Meeq C(1)). Anal. calc. for C14H26O2: C 74.29, H 11.58; found: C 74.33, H 11.54.
1.3. (Æ)-(2RS,5RS,6RS,9RS)-4,5-Dihydro-5-hydroxy-cis-a-irol (ˆ(1RS,2RS,4RS)-2-[(1E,3RS)-3-Hydroxy-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (Æ)-15), (Æ)-(2RS,5RS,6RS,9SR)-4,5-Dihydro-5-hydroxy-cis-a-
irol (ˆ(1RS,2RS,4RS)-2-[(1E,3SR)-3-Hydroxybut-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (Æ)-16), (Æ)-
(2RS,4RS,5SR,6SR,9RS)-4,5-Dihydro-4-hydroxy-cis-a-irol (ˆ(1RS,2SR,3SR,5RS)-3-[(1E,3RS)-3-Hydroxy-
but-1-enyl]-2,4,4,5-tetramethylcyclohexanol; (Æ)-13), (Æ)-(2RS,4RS,5SR,6SR,9SR)-4,5-Dihydro-4-hydroxy-
cis-a-irol (ˆ(1RS,2SR,3SR,5RS)-3-[(1E,3SR)-3-Hydroxybut-1-enyl]-2,4,4,5-tetramethylcyclohexanol; (Æ)-
14). According to GP 1, (Æ)-(2RS,4RS,5SR,6RS)-4,5-epoxy-cis-a-irone ((Æ)-5; 40 g, 0.180 mol) gave, after
96 h, the less polar (Æ)-13 (13.4 g, 33%), then in this elution order (Æ)-14 (11.80 g, 29%), (Æ)-15 (4.07 g, 10%),
and (Æ)-16 (4.48 g, 11%).
Data of (Æ)-13: 1H-NMR: 5.50 (dd, J ˆ 6.4, 15.2, H C(8)); 5.34 (dd, J ˆ 10, 15.2, H C(7)); 4.30
(quint., J ˆ 6.4, H C(9)); 3.80 (q, J ˆ 3, H C(4)); 1.83 (dd, J ˆ 10, 11.5, H C(6)); 1.68 (m, 1 H); 1.65 ± 1.45
(m, 3 H); 1.27 (d, J ˆ 6.4, (Me C(9)); 0.87 (s, Me C(1)); 0.83 (d, J ˆ 7, Me C(2), Me C(5)); 0.69
(s, Meeq C(1)). Anal. calc. for C14H26O2: C 74.29, H 11.58; found: C 74.32, H 11.56.
Data of (Æ)-14. 1H-NMR: 5.50 (dd, J ˆ 6.4, 15.7, H C(7)); 5.34 (dd, J ˆ 10, 15.7, H C(7)); 4.30 (quint. J ˆ
6.4, H C(9)); 3.81 (q, J ˆ 3, H C(4)); 1.83 (dd, J ˆ 10, 11.8, H C(6)); 1.68 (m, 1 H); 1.65 ± 1.45 (m, 3 H); 1.28
(d, J ˆ 6.4, Me C(9)); 0.88 ± 0.80 (2d, s, J ˆ 7, Me C(5), Me C(2), Me C(1)); 0.67 (s, Me C(1)). Anal. calc.
for C14H26O2: C 74.29, H 11.58; found: C 74.27, H 11.65%.
1
Data of (Æ)-15: H-NMR: 5.69 (m, H C(7), H C(8)); 4.35 (m, H C(9)); 1.77 (m, 2 H); 1.45 (m, 2 H);
1.30 (d, J ˆ 6.4, Me C(9)); 1.22 (m, 2 H); 1.15 (s, Me C(5)); 0.84 (s, d, J ˆ 7, Me C(1), Me C(2)); 0.75
(s, Me C(1)). Anal. calc. for C14H26O2: C 74.29, H 11.58; found: C 74.34, H 11.61.
1
Data of (Æ)-16: H-NMR: 5.69 (m, H C(7), H C(8)); 4.35 (m, H C(9)); 1.77 (m, 2 H); 1.46 (m, 2 H);
1.30 (d, J ˆ 6.4, Me C(9)); 1.23 (m, 2 H); 1.15 (s, Me C(5)); 0.84 (s, d, J ˆ 7, Me C(1), Me C(2)); 0.75
(s, Me C(1)). Anal. calc. for C14H26O2: C 74.29, H 11.58; found: C 74.30, H 11.53.
2. Lipase PS-Mediated Acetylation. 2.1. General Procedure (GP 2). A mixture of the suitable allyl alcohol
t
(10 g, 0.044 mol), lipase PS (Pseudomonas cepacia; 10 g) and vinyl acetate (10 ml) in BuOMe (80 ml) was
stirred at r.t. for 24 h. The residue obtained upon evaporation of the filtered mixture was chromatographed
(hexane/AcOEt 7:3).

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Helvetica Chimica Acta ± Vol. 84 (2001)
2.2. ( )-(2R,5R,6S,9S)-4,5-Dihydro-5-hydroxy-trans-a-irol (ˆ(1R,2S,4R)-2-[(1E,3S)-3-hydroxybut-1-en-
yl]-1,3,3,4-tetramethylcyclohexanol; ( )-6) and (‡)-(2S,5S,6R,9R)-4,5-Dihydro-5-hydroxy-trans-a-irol Acetate
(ˆ(1S,2R,4S)-2-[(1E,3R)-3-(Acetyloxy)but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (‡)-8). According to
GP 2, (Æ)-6 (12.5 g, 0.055 mol) gave the less polar (‡)-8 (6.08 g, 41%) and the more polar ( )-6 (4.75 g, 38%).
Data of (‡)-8: [a]D20 ˆ ‡102.6 (c ˆ 0.62, CH2Cl2). 1H-NMR: 5.83 (ddd, J ˆ 0.9, 10.3, 15.2, H C(7)); 5.45
(dd, J ˆ 6.4, 15.2, H C(8)); 5.35 (quint. d, J ˆ 0.9, 6.4, H C(9)); 2.09 (tt, J ˆ 4, 13.2, Hax C(3)); 2.03
(s, MeCOO); 1.79 (d, J ˆ 10.3, H C(6)); 1.63 (td, J ˆ 4, 13.2, 13.2, Hax C(4)); 1.54 (m, H C(2)); 1.44
(dt, J ˆ 4, 4, 14.2, Heq C(4)); 1.32 (d, J ˆ 6.4, Me C(9)); 1.24 (dq, J ˆ 4, 4, 4, 14.2, Heq C(3)); 1.10
(s, Me C(5)); 1.08 (s, Me C(1)); 0.91 (d, J ˆ 7, Me C(2)); 0.75 (s, Me C(1)). Anal. calc. for C16H28O3:
C 71.60, H 10.52; found: C 71.55, H 10.54%.
Data of ( )-6: [a]2D0
ˆ
66.8 (c ˆ 0.75, CH2Cl2). 1H-NMR: in accordance with that of (Æ)-6.
2.3. (‡)-(2S,5S,6R,9S)-4,5-Dihydro-5-hydroxy-trans-a-irol (ˆ(1S,2R,4S)-2-[(1E,3S)-3-Hydroxybut-1-en-
yl]-1,3,3,4-tetramethylcyclohexanol; (‡)-7) and (‡)-(2R,5R,6S,9R)-4,5-Dihydro-5-hydroxy-trans-a-irol Acetate
(ˆ(1R,2S,4R)-2-[(1E,3R)-3-(Acetyloxy)but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (‡)-9). According to
GP 2, (Æ)-7 (13.1 g, 0.058 mol) gave the less polar (‡)-9 (6.52 g, 42%) and the more polar (‡)-7 (5.37 g, 41%).
Data of (‡)-9: [a]D20 ˆ ‡25.5 (c ˆ 0.38, CH2Cl2). 1H-NMR: 5.82 (ddd, J ˆ 0.9, 10.3, 15.2, H C(7)); 5.44
(dd, J ˆ 6.4, 15.2, H C(8)); 5.32 (quint. d, J ˆ 0.9, 6.4, H C(9)); 2.07 (tt, J ˆ 4.4, 13.3, Hax C(3)); 2.03
(s, MeCOO); 1.79 (d, J ˆ 10.3, H C(6)); 1.70 ± 1.40 (m, 3 H); 1.32 (d, J ˆ 6.4, Me C(9)); 1.23 (m, 1 H); 1.10
(s, Me C(5)); 1.05 (s, Me C(1)); 0.90 (d, J ˆ 7, Me C(2)); 0.75 (s, Me C(1)). Anal. calc. for C16H28O3:
C 71.60, H 10.52; found: C 71.64, H 10.48.
Data of (‡)-7: [a]D20 ˆ ‡48.6 (c ˆ 0.90, CH2Cl2). 1H-NMR: in accordance with that of (Æ)-7.
2.4. (‡)-(2S,4S,5R,6R,9S)-4,5-Dihydro-4-hydroxy-cis-a-irol (ˆ(1S,2R,3R,5S)-3-[(1E,3S)-3-Hydroxybut-1-
enyl]-2,4,4,5-tetramethylcyclohexanol; (‡)-13) and (‡)-(2R,4R,5S,6S,9R)-4,5-Dihydro-4-hydroxy-cis-a-irol
Acetate (ˆ(1R,2S,3S,5R)-3-[(1E,3R)-3-(Acetyloxy)but-1-enyl]-2,4,4,5-tetramethylcyclohexanol; (‡)-17). Ac-
cording to GP 2 (Æ)-13 (13.4 g, 0.059 mol) gave the less polar (‡)-17 (6.19 g, 39%) and the more polar (‡)-13
(4.96 g, 37%).
Data of (‡)-17: [a]D20 ˆ ‡42.8 (c ˆ 0.90, CH2Cl2). 1H-NMR: 5.40 (m, H C(7),
H C(8)); 5.32
(m, H C(9)); 3.80 (q, J ˆ 3, H C(4)); 2.02 (m, s, MeCOO, 1 H of chx); 1.81 (m, 1 H); 1.70 ± 1.40 (m, 3 H);
1.29 (d, J ˆ 6.4, Me C(9)); 0.84 ± 0.80 (2d, s, Me C(5), Me C(2), Me C(1)); 0.67 (s, Me C(1)). Anal. calc.
for C16H28O3: C 71.60, H 10.52; found: C 71.63, H 10.47.
Data of (‡)-13: [a]D20 ˆ ‡26.7 (c ˆ 0.40, CH2Cl2). 1H-NMR: in accordance with that of (Æ)-13.
2.5. (‡)-(2R,4R,5S,6S,9S)-4,5-Dihydro-4-hydroxy-cis-a-irol (ˆ(1R,2S,3S,5R)-3-[(1E,3S)-3-Hydroxybut-1-
enyl]-2,4,4,5-tetramethylcyclohexanol; ( )-14) and (‡)-(2S,4S,5R,6R,9R)-4,5-Dihydro-4-hydroxy-cis-a-irol
Acetate (ˆ(1S,2R,3R,5S)-3-[(1E,3R)-3-(Acetyloxy)but-1-enyl]-2,4,4,5-tetramethylcyclohexanol; (‡)-18). Ac-
cording to GP 2, (Æ)-14 (11.80 g, 0.052 mol) gave the less polar (‡)-18 (5.18 g, 37%) and the more polar ( )-14
(5.07 g, 43%).
Data of (‡)-18: [a]D20 ˆ ‡93.8 (c ˆ 1.35, CH2Cl2). 1H-NMR: 5.40 (m, H C(7),
H C(8)); 5.33
(m, H C(9)); 3.80 (q, J ˆ 3, H C(4)); 2.02 (m, s, MeCOO, 1 H of chx); 1.80 (m, 1 H); 1.75 ± 1.40 (m, 3 H);
1.31 (d, J ˆ 6.4, Me C(9)); 0.82 (2d, s, Me C(5), Me C(2), Me C(1)); 0.66 (s, Me C(1)). Anal. calc. for
C16H28O3: C 71.60, H 10.52; found: C 71.61, H 10.57.
1
Data of ( )-14: [a]2D0
ˆ
37.9 (c ˆ 0.50, CH2Cl2). H-NMR: in accordance with that of (Æ)-14.
2.6. (‡)-(2R,5R,6R,9R)-4,5-Dihydro-5-hydroxy-cis-a-irol Acetate (ˆ(1R,2R,4R)-2-[(1E,3R)-3-(Acetyloxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (‡)-23) and (‡)-(2S,5S,6S,9S)-4,5-Dihydro-5-hydroxy-cis-a-irol
(ˆ(1S,2S,4S)-2-[(1E,3S)-3-Hydroxybut-1-enyl]-1,3,3,4-tetramethylcyclohexanol (‡)-15). According to GP 2
(Æ)-15 (4.07 g, 0.018 mol) gave the less polar (‡)-23 (1.93 g, 40%) and the more polar (‡)-15 (1.75 g, 43%).
Data of (‡)-23: [a]D20 ˆ ‡33.7 (c ˆ 0.55, CH2Cl2). 1H-NMR: 5.74 (dd, J ˆ 10.3, 15.2, H C(7)); 5.61 (dd, J ˆ
6.4, 15.2, H C(8)); 5.36 (quint. J ˆ 6.4, H C(9)); 2.04 (s, MeCOO); 1.82 ± 1.74 (m, d, J ˆ 10.3, H C(6), 1 H of
chx); 1.47 (m, 2 H); 1.35 (d, J ˆ 6.4, Me C(9)); 1.26 (m, 2 H); 1.14 (s, Me C(5)); 0.85 (d, J ˆ 6, Me C(2));
0.82 (s, Me C(1)); 0.75 (s, Me C(1)). Anal. calc. for C16H28O3: C 71.60, H 10.52; found: C 71.61, H 10.48.
1
Data of (‡)-15: [a]D20 ˆ ‡9.8 (c ˆ 1.50, CH2Cl2). H-NMR: in accordance with that of (Æ)-15.
2.7. (‡)-(2S,5S,6S,9R)-4,5-Dihydro-5-hydroxy-cis-a-irol Acetate (ˆ(1S,2S,4S)-2-[(1E,3R)-3-(Acetyloxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (‡)-24) and (‡)-(2R,5R,6R,9S)-4,5-Dihydro-5-hydroxy-cis-a-irol
(ˆ(1R,2R,4R)-2-[(1E,3S)-3-Hydroxybut-1-enyl]-1,3,3,4-tetramethylcyclohexanol; (‡)-16. According to GP 2,
(Æ)-16 (4.48 g, 0.020 mol) gave the less polar (‡)-24 (2.28 g, 43%) and the more polar (‡)-16 (1.75 g, 39%).
Data of (‡)-24: [a]D20 ˆ ‡47 (c ˆ 0.18, CH2Cl2). 1H-NMR: 5.73 (dd, J ˆ 10.3, 15.3, H C(7)); 5.61 (dd, J ˆ
6.4, 15.3, H C(8)); 5.36 (quint., J ˆ 6.4, H C(9)); 2.04 (s, MeCOO); 1.81 ± 1.75 (m, d, J ˆ 10.3, H C(6), 1 H of

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chx); 1.47 (m, 2 H); 1.35 (d, J ˆ 6.4, Me C(9)); 1.26 (m, 2 H); 1.14 (s, Me C(5)); 0.85 (d, J ˆ 6, Me C(2));
0.82 (s, Me C(1)); 0.76 (s, Me C(1)). Anal. calc. for C16H28O3: C 71.60, H 10.52; found: C 71.64, H 10.49.
1
Data of (‡)-16: [a]D20 ˆ ‡9.5 (c ˆ 0.81, CH2Cl2). H-NMR: in accordance with that of (Æ)-16.
2.8. ( )-(2R,5R,6S,9S)-4,5-Dihydro-5-hydroxy-trans-a-irol Acetate (ˆ(1R,2S,4R)-2-[(1E,3S)-3-(Acetoxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; ( )-8). Treatment of ( )-6 (4.65 g, 0.021 mol) with Ac2O in
pyridine gave ( )-8 (5.40 g, 98%). [a]2D0
(‡)-8.
ˆ
100.1 (c ˆ 0.74, CH2Cl2). 1H-NMR: in accordance with that of
2.9. ( )-(2S,5S,6R,9S)-4,5-Dihydro-5-hydroxy-trans-a-irol Acetate (ˆ(1S,2R,4S)-2-[(1E,3S)-3-(Acetoxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; ( )-9). Treatment of (‡)-7 (5.25 g, 0.023 mol) with Ac2O in
pyridine gave ( )-9 (6.04 g, 97%). [a]2D0
ˆ
24.3 (c ˆ 0.41, CH2Cl2). 1H-NMR: in accordance with that of (‡)-9.
2.10. ( )-(2S,5S,6S,9S)-4,5-Dihydro-5-hydroxy-cis-a-irol Acetate (ˆ(1S,2S,4S)-2-[(1E,3S)-3-(Acetyloxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; ( )-23). Treatment of (‡)-15 (1.68 g, 7.43 mmol) with Ac2O in
pyridine gave ( )-23 (1.91 g, 96%). [a]2D0
(‡)-23.
ˆ
31.6 (c ˆ 0.42, CH2Cl2). 1H-NMR: in accordance with that of
2.11. ( )-(2R,5R,6R,9S)-4,5-Dihydro-5-hydroxy-cis-a-irol Acetate (ˆ(1R,2R,4R)-2-[(1E,3S)-3-(Acetoxy)-
but-1-enyl]-1,3,3,4-tetramethylcyclohexanol; ( )-24). Treatment of (‡)-16 (2.15 g, 9.51 mmol) with Ac2O in
pyridine gave ( )-24 (2.50 g, 98%). [a]2D0
(‡)-24.
ˆ
45.8 (c ˆ 0.32, CH2Cl2). 1H-NMR: in accordance with that of
2.12. (‡)-(2S,4S,5R,6S)-4,5-Dihydro-4-hydroxy-cis-a-irone (ˆ(3E)-4-[(1S,3S,5S,6R)-5-Hydroxy-2,2,3,6-
tetramethylcyclohexyl]but-3-en-2-one; (‡)-21). A mixture of (‡)-13 (4.84 g, 0.021 mol) and MnO2 (1.5 equiv.)
in CH2Cl2 (30 ml) was stirred at r.t. for 3 h. The mixture was filtered, the filtrate evaporated, and the residue
purified by CC (hexane/AcOEt 8 :2): (‡)-21 (4.31 g, 90%). [a]D20 ˆ ‡57 (c ˆ 0.61, CH2Cl2). 1H-NMR: 6.58
(dd, J ˆ 10.3, 15.7, H C(7)); 6.08 (d, J ˆ 15.7, H C(8)); 3.83 (q, J ˆ 2.5, H C(4)); 2.25 (s, MeCO); 2.08 (t, J ˆ
10.3, H C(6)); 1.79 ± 1.67 (m, H C(2), H C(5)); 1.64 (dt, J ˆ 3.4, 3.4, 14.2, Heq C(3)); 1.52 (ddd, J ˆ 3.4, 13.1,
14.2, Hax C(3)); 0.88 ± 0.81 (s, 2 d, J ˆ 7, Me C(1), Me C(2), Me C(5)); 0.76 (s, Me C(1)). Anal. calc. for
C14H24O2: C 74.95, H 10.78; found: C 74.90, H 10.82.
2.13. ( )-(2R,4S,5S,6R)-4,5-Dihydro-4-hydroxy-cis-a-irone (ˆ(3E)-4-[(1R,3R,5R,6)-5-Hydroxy-2,2,3,6-
tetramethylcyclohexyl]but-3-en-2-one; ( )-21). As described in 2.12, with ( )-14 (4.90 g, 0.022 mol) and
MnO2 (1.5 equiv.). ( )-21 (4.32 g, 89%). [a]2D0
(‡)-21.
ˆ
54.3 (c ˆ 0.84, CH2Cl2). 1H-NMR: in accordance with that of
3. Dehydration with Phosphorous Oxychloride in Pyridine. 3.1. General Procedure 3 (GP 3). A mixture of
the suitable alcohol derivative (3 g, 0.011 mol), POCl3 (2.57 g, 0.017 mol), and pyridine (15 ml) was stirred at r.t.
The mixture was treated with H2O and then extracted with AcOEt. After evaporation, the residue was purified
by CC (hexane/AcOEt 9 :1).
3.2. (‡)-(2S,9R)-b-Irol Acetate (ˆ(2R,3E)-4-[(5S)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-ol
Acetate; (‡)-10). According to GP 3, (‡)-8 (5.90 g, 0.022 mol) gave, at r.t. after 7 days, (‡)-10 (4.29 g, 78%).
[a]D20 ˆ ‡57 (c ˆ 0.95, CH2Cl2); ee 99% by chiral GC (tR 22.74); 91% chemical purity, 9% trans-a-irol acetate.
1H-NMR: 6.10 (d, J ˆ 15, H C(7)); 5.38 (m, H C(8), H C(9)); 2.03 (s, m, MeCOO, 2 H of chx); 1.63
(s, Me C(5)); 1.55 ± 1.20 (d, m, J ˆ 6.1, Me C(9), 3 H of chx); 0.98 (s, Me C(1)); 0.88 (d, J ˆ 6, Me C(2));
0.82 (s, Me C(1)). GC/MS: tR 19.44; 250 (4.9), 208 (6.1), 190 (46.5), 175 (100), 133 (78.9), 119 (77.0). Anal.
calc. for C16H26O2: C 76.75, H 10.47; found: C 76.70, H 10.52.
3.3. (‡)-(2R,9S)-b-Irol Acetate (ˆ(2S,3E)-4-[(5R)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-ol
Acetate; ( )-10. As described in 3.2, with ( )-8 (5.30 g, 0.020 mol): ( )-10 (3.86 g, 78%). [a]2D0
ˆ
54 (c ˆ
1.5, CH2Cl2); ee 99% by chiral GC (tR 22.57); 92% chemical purity, 8% trans-a-irol acetate. GC/MS: tR 19.44.
1H-NMR: in accordance with that of (‡)-10.
3.4. (‡)-(2R,9R)-b-Irol Acetate (ˆ(2R,3E)-4-[(5R)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-ol
Acetate (‡)-11). As described in 3.2 with (‡)-9 (6.40 g, 0.024 mol): (‡)-11 (4.48 g, 75%). [a]D20 ˆ ‡111.7 (c ˆ
1
0.69, CH2Cl2); ee 90% by chiral GC (tR 21.47); 95% chemical purity, 5% trans-a-irol acetate. H-NMR: 6.10
(d, J ˆ 15, H C(7)); 5.38 (m, H C(8), H C(9)); 2.03 (s, m, MeCOO, 2 H of chx); 1.63 (s, Me C(5)); 1.55 ±
1.20 (d, m, J ˆ 6.1, Me C(9), 3 H of chx); 0.97 (s, Me C(1)); 0.88 (d, J ˆ 6, Me C(2)); 0.83 (s, Me C(1)). GC/
MS: tR 19.44; 250 (5.0), 208 (6.5), 190 (55.0), 175 (100), 133 (66), 119 (65). Anal. calc. for C16H26O2: C 76.75,
H 10.47; found: C 76.80, H 10.42.
3.5. (‡)-(2S,9S)-b-Irol Acetate (ˆ(2S,3E)-4-[(5S)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-ol Ace-
tate; ( )-11). As described in 3.2, with ( )-9 (5.90 g, 0.022 mol): ( )-11 (4.18 g, 76%). [a]2D0
CH2Cl2); ee 90% by chiral GC (tR 21.27); 93% chemical purity, 7% trans-a-irol acetate. GC/MS: tR 19.44.
1H-NMR: in accordance with that of (‡)-11.
ˆ
108.2 (c ˆ 0.75,

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Helvetica Chimica Acta ± Vol. 84 (2001)
3.6. (2R,6S,9R)-g-Irol Acetate (ˆ(2R,3E)-4-[(1S,3R)-2,2,3-Trimethyl-6-methylidenecyclohexyl]but-3-en-2-
ol Acetate; 25a), (2R,6S,9R)-a-Irol Acetate (( )-19), and (2R,9R)-b-Irol Acetate ((‡)-11). According to GP 3,
(‡)-23 (1.85 g, 6.90 mmol) gave, at 08, 25a/( )-19/(‡)-11 (1.52 g, 88%). GC/MS: ( )-19 (tR 19.19, 35%): 190
(25.7), 180 (84.5), 138 (65.2), 120 (73.5), 105 (100), 95 (75.5); 25a (tR 19.37, 46%): 250 (3.6), 232 (2.5), 217 (4.6),
207 (30.8), 190 (40.5), 175 (43.3), 43 (100); (‡)-11: tR 19.44, 19%.
3.7. (2S,6R,9S)-g-Irol Acetate (ˆ(2S,3E)-4-[(1R,3S)-2,2,3-Trimethyl-6-methylidenecyclohexylbut-3-en-2-ol
Acetate; 25b), (2S,6R,9S)-a-Irol Acetate ((‡)-19), and (2S,9S)-b-Irol Acetate (( )-11). As described in 3.6, with
(
(
)-23 (1.80 g, 6.71 mmol): 25b/(‡)-19/( )-11 (1.49 g, 89%). GC/MS: (‡)-19: tR 19.19, 35%; 25b: tR 19.37, 46%;
)-11: tR 19.44, 19%.
3.8. (2S,6R,9R)-g-Irol Acetate (ˆ(2R,3E)-4-[(1R,3S)-2,2,3-Trimethyl-6-methylidenecyclohexyl]but-3-en-2-ol
Acetate; 26b), (2S,6R,9R)-a-Irol Acetate ((‡)-20), and (2S,9R)-b-Irol Acetate ((‡)-10). As described in 3.6,
with (‡)-24 (1.62 g, 6.05 mmol): 26b/(‡)-20/(‡)-10 (1.34 g, 89%). GC/MS: (‡)-20 (tR 19.28, 36%): 190 (28), 180
(82.5), 138 (67.9), 120 (72.3), 105 (100), 95 (78.9); 26b/(‡)-10: tR 19.44, 64%.
3.9. (2R,6S,9S)-g-Irol Acetate (ˆ(2S,3E)-4-[(1S,3R)-2,2,3-Trimethyl-6-methylidenecyclohexyl]but-3-en-2-ol
Acetate; 26a), (2R,6S,9S)-a-Irol Acetate (( )-20), and (2R,9S)-b-Irol Acetate (( )-10). As described in 3.6, with
(
)-24 (2.40 g, 8.95 mmol): 26a/( )-20/( )-24 (1.92 g, 86%). GC/MS: ( )-20: tR 19.28, 34%; 26a/(‡)-10: tR
19.44, 66%.
3.10. (2R,6S,9R)-a-Irol Acetate (ˆ(2R,3E)-4-[(1S,5R)-2,5,6,6-Tetramethylcyclohex-2-en-1-yl]but-3-en-2-ol
Acetate; ( )-19). According to GP 3, (‡)-17 (6.00 g, 0.022 mol) gave, at r.t. after 15 min, ( )-19 (4.42 g, 79%).
[a]D20
ˆ
73 (c ˆ 1.5, CH2Cl2); ee 98% by chiral GC (tR 20.56). 1H-NMR: 5.50 (m, H C(7)); 5.38 (m, H C(8),
H
C(9), H C(4)); 2.33 (m, 1 H); 2.05 (s, MeCOO); 1.90 (m, 1 H); 1.65 (m, 1 H); 1.49 (m, Me C(5)); 1.40
(m, 1 H); 1.32 (d, J ˆ 6.4, Me C(9)); 0.84 (s, d, J ˆ 7, Me C(1), Me C(2)); 0.64 (s, Me C(1)). GC/MS: ( )-
19 (tR ˆ 19.19, 87%); 4-chloro-4,5-dihydro-cis-a-irol acetate (tR 21.85 min, 13%): 286 (0.5), 246 (4.1), 244 (12.6),
228 (6.0), 226 (16.9, 124 (57.0), 107 (74.1), 95 (86.0), 43 (100).
3.11. (2S,6R,9R)-a-Irol Acetate (ˆ(2R,3E)-4-[(1R,5S)-2,5,6,6-Tetramethylcyclohex-2-en-1-yl]but-3-en-2-ol
Acetate (‡)-20). According to GP 3, (‡)-18 (5.00 g, 0.018 mol) gave, at r.t. after 15 min, (‡)-20 (3.59 g, 77%).
[a]D20 ˆ ‡9.5 (c ˆ 0.21, CH2Cl2); ee 97% by chiral GC (tR 20.78). 1H-NMR: 5.49 (m, H C(7)); 5.38
(m, H C(8), H C(9), H C(4)); 2.32 (m, 1 H); 2.05 (s, MeCOO); 1.90 (m, 1 H); 1.70 (m, 1 H); 1.51
(m, Me C(5)); 1.42 (m, 1 H); 1.33 (d, J ˆ 6.4, Me C(9)); 0.84 (s, d, J ˆ 7, Me C(1), Me C(2)); 0.62
(s, Me C(1)). GC/MS: (‡)-20 (tR 19.28, 72%); 4-chloro-4,5-dihydro-cis-a-irol acetate (tR 21.95, 28%): 246
(3.1), 244 (10.7), 226 (15.6), 211 (22.8), 191 (24.1), 124 (51.1), 107 (70.6), 95 (79.1), 43 (100).
3.12. (2S,6R)-cis-a-Irone (ˆ(3E)-4-[(1R,5S)-2,5,6,6-Tetramethylcyclohex-2-en-1-yl]but-3-en-2-one ( )-22)
and (2S,4R,5R,6R)-4-Chloro-4,5-dihydro-a-irone (ˆ(3E)-4-[(1R,3S,5R,6R)-5-Chloro-2,2,3,6-tetramethylcyclo-
hexyl]but-3-en-2-one; ( )-27). According to GP 3, (‡)-21 (4.20 g, 0.019 mol) gave ( )-22 (2.24 g, 58%) and
(
)-27 (0.68 g, 15%).
Data of ( )-22: [a]2D0
ˆ
121 (c ˆ 1.55, CH2Cl2). 1H-NMR: 6.65 (dd, J ˆ 15.7, 11, H C(7)); 6.12 (d, J ˆ 15.7,
H
C(8)); 5.52 (m, H C(5)); 2.55 (m, 1 H); 2.28 (s, MeCO); 2.10 (m, 1 H); 1.80 ± 1.50 (m, 2 H); 1.53
(m, Me C(5)); 1.46 (m, 1 H); 0.88 (d, J ˆ 7, Me C(2)); 0.86 (s, Me C(1)); 0.71 (s, Me C(1)). GC-MS: tR
17.87, 95% pure; 206 (14.4), 191 (20.3), 136 (52.4), 121 (100), 93 (56.7).
Data of ( )-27: [a]2D0
ˆ
53.8 (c ˆ 0.41, CH2Cl2). 1H-NMR: 6.53 (dd, J ˆ 10.4, 16, H C(7)); 6.03 (d, J ˆ 16,
H
C(8)); 3.50 (ddd, J ˆ 4.6, 10.7, 12.4, H C(4)); 2.26 (s, MeCO); 2.00 (ddd, J ˆ 3.9, 4.9, 13.4, Heq C(3)); 1.78
(m, 1 H); 1.74 (q, J ˆ 12.4, Heq C(3)); 1.63 (t, J ˆ 10.4, H C(6)); 1.38 (m, 1 H); 0.98 (d, J ˆ 6.4, 3 H); 0.90
(d, J ˆ 7, 3 H); 0.83 (s, Me C(1)); 0.81 (s, Me C(1)). GC/MS: tR 21.00, 97% pure; 244 (1.0), 242 (3.1), 227
(1.9), 206 (14.2), 191 (24.5), 121 (97.6), 111 (100). Anal. calc. for C14H23ClO: C 69.26, H 9.55, Cl 14.60; found:
C 69.21, H 9.49, Cl 14.65.
3.13. (2R,6S)-cis-a-Irone (ˆ(3E)-4-[(1S,5R)-2,5.6,6-Tetramethylcyclohex-2-en-1-yl]but-3-3-en-2-one (‡)-
22) and (2R,4S,5S,6S)-4-Chloro-4,5-dihydro-a-irone (ˆ(3E)-4-[(1S,3R,5S,6S)-5-chloro-2,2,3,6-tetramethylcy-
clohexyl]but-3-en-2-one (‡)-27). According to GP 3 ( )-21 (4.20 g, 0.019 mol) gave (‡)-22 (2.12 g, 55%) and
(‡)-27 (0.82 g, 18%).
Data of (‡)-22: [a]D20 ˆ ‡118 (c ˆ 1.45, CH2Cl2). 1H-NMR: in accordance with that of ( )-22. GC/MS: 93%
pure, tR 17.87.
Data of (‡)-27: [a]D20 ˆ ‡57 (c ˆ 0.41, CH2Cl2). 1H-NMR: in accordance with that of ( )-27. GC/MS: 96%
pure, tR 21.00.
4. Photoisomerization of Irol Acetate Derivatives. 4.1. General Procedure 4 (GP 4). A soln. of the suitable
irol acetate (2 g, 8 mmol) in iPrOH (150 ml) and xylene (15 ml) was irradiated for 24 h in a Rayonet

Helvetica Chimica Acta ± Vol. 84 (2001)
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photochemical reactor with a 120-W high-pressure Hg lamp. The soln. was evaporated, and the residue purified
by CC (hexane/AcOEt 9 :1).
4.2. (2R,6S9R)-g-Irol Acetate (25a). According to GP 4, 25a ( )-19/(‡)-11 (1.70 g, 6.8 mmol) was
converted to 25a (1.45 g, 85%), containing 20% (1H-NMR) of the (7Z)-diastereoisomer (CˆCH2 at d 4.73 and
4.50); ee 98% by chiral GC (tR 20.97). 1H-NMR: 5.81 (dd, J ˆ 10, 15, H C(7)); 5.45 (dd, J ˆ 6.5, 10, H C(8));
5.38 (quint., J ˆ 6.5, H C(9)); 4.73 (m, CˆCH); 4.45 (m, CˆCH); 2.32 (m, 2 H); 2.03 (s ‡ m, MeCOO, 1 H of
chx); 1.67 ± 1.15 (d, m, J ˆ 6.5, Me C(9), 3 H of chx); 0.86 (d, s, J ˆ 7, Me C(2), Me C(1)); 0.63
(s, Me C(1)).
4.3. (2S,6R,9S)-g-Irol Acetate (25b). According to GP 4, 25b/(‡)-19/( )-11 (1.35 g, 5.4 mmol) was
converted to 25b (1.16 g, 86%), containing 18% (1H-NMR) of the (7Z) diastereoisomer; ee 98% by chiral GC
(tR 21.25). 1H-NMR: in accordance with that of 25a.
4.4. (2S,6R,9R)-g-Irol Acetate (26b). According to GP 4 26b/(‡)-20/(‡)-10 (1.25 g, 5.0 mmol) was
converted into 26b (1.05 g, 84%), containing 22% (1H-NMR) of the (7Z) diastereoisomer (CˆCH2 at d 4.73 and
4.50); ee 98% by chiral GC (tR 21.62). 1H-NMR: 5.82 (dd, J ˆ 10, 15, H C(7)); 5.45 (dd, J ˆ 6.5, 10, H C(8));
5.38 (quint., J ˆ 6.5, H C(9)); 4.73 (m, CˆCH); 4.46 (m, CˆCH); 2.32 (m, 2 H); 2.04 (s, m, MeCOO, 1 H of
chx); 1.67 ± 1.15 (d, m, J ˆ 6.5, Me C(9), 3 H of chx); 0.86 (d, s, J ˆ 7, Me C(2), Me C(1)); 0.64
(s, Me C(1)).
4.5. (2R,6S,9S)-g-Irol Acetate (26a). According to GP 4, 26a/( )-20/( )-10 (1.85 g, 7.4 mmol) was
converted into 26a (1.61 g, 87%), containing 19% (1H-NMR) of the (7Z) diastereoisomer; ee 98% by chiral
GC (tR 20.98). 1H-NMR: in accordance with that of 26b.
5. Manganese(IV) Oxide Oxidation. 5.1. General Procedure 5 (GP 5). The suitable irol acetate derivatives
were pooled, saponified by reaction with KOH in MeOH, and then directly submitted to oxidation in CH2Cl2
soln. in the presence of MnO2 (1.5 equiv.) at r.t. The mixture was filtered, the filtrate evaporated, and the residue
purified by CC (hexane/AcOEt 97:3). All the samples of irone isomers were distilled bulb-to-bulb before
analysis and optical-rotation measurement.
5.2. (‡)-(R)-b-Irone (ˆ(3E)-4-[(5R)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-one; (‡)-2). Ac-
cording to GP 5, ( )-10 (3.70 g, 0.015 mol) and (‡)-11 (4.30 g, 0.018 mol) gave (‡)-2 (6.07 g, 88%). [a]2D0
ˆ
‡17.1 (c ˆ 1.45, CH2Cl2); ee 98% by 1H-NMR (chiral shift reagents). 1H-NMR: 7.25 (dm, J ˆ 16, H C(7)); 6.08
(d, J ˆ 16, H C(8)); 2.30 (s, MeCO); 2.07 (m, 2 H); 1.73 (s, Me C(5)); 1.65 ± 1.34 (m, 3 H); 1.06 (s, Me C(1));
0.91 (s, d, J ˆ 7, Me C(1), Me C(2)). GC/MS: (‡)-2: tR 18.55, 91%; 206 (4.0), 191 (100), 149 (12.4), 121 (15.4);
(
)-trans-a-irone: tR 17.37, 9%; 206 (17.0), 191 (6.5), 136 (54.2), 121 (100), 93 (60.2).
5.3. ( )-(S)-b-Irone (ˆ(3E)-4-[(5S)-2,5,6,6-Tetramethylcyclohex-1-en-1-yl]but-3-en-2-one; ( )-2). Ac-
cording to GP 5, (‡)-10 (4.10 g, 0.016 mol) and ( )-11 (4.00 g, 0.016 mol) gave ( )-2 (5.27 g, 80%). [a]2D0
ˆ
20.2 (c ˆ 2.30, CH2Cl2); ee 98% by 1H-NMR (chiral shift reagents). 1H-NMR: in accordance with that of (‡)-
2. GC/MS: ( )-2: tR 18.55, 93%; (‡)-trans-a-irone: tR 17.37, 7%.
5.4. (‡)-(2R,6S)-g-Irone (ˆ(3E)-4-[(1S,3R)-2,2,3-Trimethyl-6-methylidenecyclohexyl]but-3-en-2-one;
(‡)-3). According to GP 5, 25a (1.30 g, 5.2 mmol) and 26a (1.50 g, 6.0 mmol) gave (‡)-3 (1.24 g, 54%):
1
[a]D20 ˆ ‡9.5 (c ˆ 2.15, CH2Cl2): ee 96% by chiral GC (tR 19.70). H-NMR: 6.93 (dd, J ˆ 15.8, 10.3, H C(7));
6.09 (d, J ˆ 15.8, H C(8)); 4.80 (m, CˆCH); 4.43 (m, CˆCH); 2.55 (d, J ˆ 10.3, H C(6)); 2.35 (ddd, J ˆ 2.5,
4.4, 13.3, Hax C(4)); 2.28 (s, MeCO); 2.10 (m, 1 H); 1.60 ± 1.20 (m, 3 H); 0.87 (s, d, J ˆ 7, Me C(1), Me C(2));
0.73 (s, Me C(1)). GC/MS: (‡)-3: 92%, tR 18.08; 206 (2.9), 191 (8.9), 173 (5.4), 163 (31.2), 149 (41.9), 121
(100), 83 (23.8)); (‡)-(2R,6S)-cis-a-irone ((‡)-22): 5%, tR 17.89; (‡)-(2R)-b-irone ((‡)-2): 3%, tR 18.59.
An anal. sample of (2R,6S,7Z)-g-irone was recovered: 1H-NMR: 6.30 (d, J ˆ 11.8, H C(8)); 6.21 (dd, J ˆ
11.8, 10.3, H C(7)); 4.73 (m, CˆCH); 4.42 (m, CˆCH); 3.86 (d, J ˆ 10.3, H C(6)); 2.19 (s, m, MeCO, 1 H of
chx); 1.60 ± 1.20 (m, 3 H); 0.89 (s, Me C(1)); 0.84 (d, J ˆ 7, Me C(2)); 0.68 (s, Me C(1)). Anal. calc. for
C14H22O: C 81.50, H 10.75; found: C 81.46, H 10.71.
5.5.
(
)-(2S,6R)-g-Irone (ˆ(3E)-4-[(1R,3S)-2,2,3-Trimethyl-6-methylidenecyclohexyl]but-3-en-2-one;
(
)-3). According to GP 5, 25b (1.00 g, 4.0 mmol) and 26b (0.90 g, 3.6 mmol) gave ( )-3 (0.892 g, 57%).
[a]D20
ˆ
6.3 (c ˆ 1.05, CH2Cl2); ee 97% by chiral GC (tR 20.08). GC/MS: ( )-3: 94%, tR ˆ 18.08; ( )-(2S,6R)-
cis-a-irone (( )-22): tR 17.89, 4.9%; ( )-(2S)-b-irone (( )-2): 1.5%, tR 18.59. 1H-NMR: in accordance with that
of (‡)-3.
5.6. (‡)-(2R,6S)-a-Irone ((‡)-22). According to GP 5, ( )-19 (4.30 g, 0.017 mol) gave (‡)-22 (2.41 g,
68%). [a]D20 ˆ ‡108 (c ˆ 1.5, CH2Cl2); optical purity 97%. 1H-NMR: 6.65 (dd, J ˆ 15.7, 11, H C(7)); 6.12
(d, J ˆ 15.7, H C(8)); 5.52 (m, H C(5)); 2.55 (m, 1 H); 2.28 (s, MeCO); 2.10 (m, 1 H); 1.80 ± 1.50 (m, 2 H);
1.53 (m, Me C(5)); 1.46 (m, 1 H); 0.88 (d, J ˆ 7, Me C(2)); 0.86 (s, Me C(1)); 0.71 (s, Me C(1)). GC/MS:
97% pure, tR 17.87. Anal. calc. for C14H22O: C 81.50, H 10.75; found: C 81.53, H 10.82.

86
Helvetica Chimica Acta ± Vol. 84 (2001)
5.7. ( )-(2S,6R)-a-Irone (( )-22). According to GP 5, (‡)-20 (3.40 g, 0.014 mol) gave ( )-22 (1.71 g,
1
61%). [a]D20
MS: 96% pure tR 17.87.
ˆ
115 (c ˆ 1.05, CH2Cl2); optical purity 97%. H-NMR: in accordance with that of (‡)-22. GC/
5.8. (7E,9E)-5,6,6-Trimethylundeca-7,9-dien-2-one ((Æ)-12). Treatment of (Æ)-9 (2 g, 7.46 mmol) with cat.
85% perchloric acid in THF (20 ml) at 08 afforded, after evaporation and purification of the residue by CC
(hexane/AcOEt 9 :1), (Æ)-12 (0.85 g, 55%). 1H-NMR: 6.03 (ddq, J ˆ 1.4, 15, 10.3, H C(9)); 5.92 (dd, J ˆ 15, 10,
H
C(8)); 5.60 (dq, J ˆ 15, 7, H C(10)); 5.50 (d, J ˆ 15, H C(7)); 2.48 (ddd, J ˆ 5, 10, 16.7, CHCO); 2.31
(ddd, J ˆ 6.4, 8, 15.7), 2.12 (s, MeCO); 1.73 (dd, J ˆ 1.4, 7, Me C(10)); 1.20 ± 1.10 (m, 2 H); 0.97 (s, Me C(6));
0.96 (s, Me C(6)); 0.80 (d, J ˆ 6.4, Me C(5)). GC/MS: tR 17.68; 208 (5.1), 109 (100), 99 (14.1), 67 (20.9). Anal.
calc. for C14H24O: C 80.71, H 11.61; found: C 80.76, H 11.57.
6. Determination of the Optical Purity of b-Irone Samples. The 1H-NMR spectrum of (Æ)-b-irone was
recorded in CDCl3 soln. at r.t. On progressive addition of [Eu(hfc)3], the two s corresponding to Me C(5)
(d(H) 1.73) and to one of the geminal Me C(1) (d(H) 1.06) were shifted downfield (d(H) 2 and 1.8, resp.), and
splitted into two lines each (Dd ˆ 0.01 ppm for both signals; chiral shift reagent/substrate 4.6 :1). The same
chiral shift reagent/sample ratio was used to record 1H-NMR spectra of (‡)-2, ( )-2, and of two mixtures of the
single enantiomer with the racemate in a 2 :1 ratio: (R)-b-irone gave rise to the lines at d(H) 2.080 and 1.86, (S)-
b-irone to those at d(H) 2.070 and 1.87.
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Received August 3, 2000