Synthesis, olfactory evaluation and determination of the absolute configuration of the β- and γ-Iralia isomers

Article abstract of DOI:10.1016/j.tetasy.2008.09.028

The regioselective synthesis of the methyl-ionone isomers 6-9 is described. The enantiomers of the γ-isomers 8 and 9 are prepared by enzyme-mediated resolution of the corresponding 4-hydroxy derivatives followed by reductive elimination of the hydroxy group. The absolute configuration of the latter compound is determined by chemical correlation with the known α-isomers. Since all the isomers obtained are components of the artificial violet odourants sold under the trade name of Iralia, their odour properties are evaluated by professional perfumers.

Full text of DOI:10.1016/j.tetasy.2008.09.028

Tetrahedron: Asymmetry 19 (2008) 2316–2322
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis, olfactory evaluation and determination of the absolute
configuration of the b- and c
-Iraliaâ isomers
*
Assem Barakat, Elisabetta Brenna, Claudio Fuganti, Stefano Serra
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Presso Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective synthesis of the methyl-ionone isomers 6–9 is described. The enantiomers of the c-iso-
mers 8 and 9 are prepared by enzyme-mediated resolution of the corresponding 4-hydroxy derivatives
followed by reductive elimination of the hydroxy group. The absolute configuration of the latter com-
Received 29 August 2008
Accepted 30 September 2008
Available online 22 October 2008
pound is determined by chemical correlation with the known a-isomers. Since all the isomers obtained
are components of the artificial violet odourants sold under the trade name of IraliaÒ, their odour prop-
erties are evaluated by professional perfumers.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
been reported till now. Therefore, a comprehensive olfactory eval-
uation of each isomeric forms of IraliaÒ is still lacking (Fig. 1).
The industrial creation of new perfumes1 requires two essential
lines of research: the discovery of new odourous molecules and the
reinvestigation or chemical modification of older commercial
products. Due to the unpredictable relationship between chemical
structure and odour,2 the latter approach is particularly interesting
from a chemical point of view. Indeed, many fragrances are sold as
a mixture of isomers, whose specific contribution to the perceived
odour may be very different. Moreover, enantiomer composition of
a single chemical compound greatly affects the fragrance proper-
ties, either in terms of features or as odour thresholds.3
O
9
7
Δ4,5
α
-ionone 1
6
5
1
4
2
Δ5,6 β−ionone 2
Δ5,13 γ−ionone 3
(carotenoid
numbering )
10
8
3
13
O
O
O
As part of a programme on the synthesis of enantioenriched
( )-4
O
6
( )-8
odourants, we have previously prepared
a large number of
enantiomerically pure isomers of commercial fragrances and
natural flavours by enzyme-mediated methods.3,4 In this context,
we have focused our attention on the odourants with the ionone
framework5 that are of pivotal relevance in industrial perfumery.
Methyl-ionone isomers 4–9 (Fig. 1) are relevant artificial violet
odourants sold as a mixture of isomers under the trade name of Ira-
liaÒ.1a The latter commercial product is prepared by condensation
of citral with ethyl methyl ketone followed by acid-catalyzed cycli-
zation. The first step proceeds without selectivity, whereas the sec-
ond one shows a regioselectivity that depends on the kind of acid
O
O
( )-5
7
( )-9
Figure 1.
Recently,5f we have described the preparation and odour evalu-
ation of the enantiomeric forms of
a-isomers 4 and 5, which are
the main components of commercial IraliaÒ. Otherwise, the impact
of the minor components on the final odour could be relevant and
their specific evaluation is highly desired. This aspect is particu-
used. Concentrated phosphoric acid affords
a-isomers with high
selectivity, whereas sulfuric acid or Lewis acids afforded b- or
c-iso-
mers, respectively, with low selectivity. As a consequence of this
fact, the overall quality of the product is affected by the synthetic
larly evident for
have shown fragrance performances superior to those described
for the corresponding -isomers.
Herein we report on the stereoselective preparation of b- and
isomers 6, 7 and 8, 9, respectively. In addition, we prepared the
four enantiomeric forms of the latter -isomers and determined
their absolute configuration by chemical correlation. All the
c
-isomers of ionone6 and methyl ionone7 which
method used. Moreover,
a- and
c-isomers are a mixture of enanti-
a
omers and the specific preparation of b- and
c-isomers has not yet
c
-
c
* Corresponding author. Tel.: +39 02 2399 3076; fax: +39 02 2399 3180.
E-mail address: stefano.serra@polimit.it (S. Serra).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.028

A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
2317
isomers obtained were evaluated by professional perfumers to
achieve a complete description of each component of IraliaÒ.
cial product was described many years ago.9 Indeed, the synthesis
of -ionone derivatives by cyclization invariably afforded an insep-
arable mixture of regioisomers. Otherwise, -isomers 4 and 5 are
prepared on a large scale and in good isomeric purity by cyclization
of 3,6,10-trimethyl-undeca-3,5,9-trien-2-one and from -ionone 1,
respectively (Section 4.1). We have previously developed a stereo-
selective procedure that allows the conversion of -ionone deriva-
tives into
-ionone derivatives.5c,10 The regioselective base-
mediated isomerization of 4,5-epoxy-4,5-dihydro- -ionone fol-
lowed by reductive elimination of the obtained allylic alcohols
were the key steps of our syntheses. Therefore, we decided to apply
the latter synthetic pathway for the conversion of compounds 4
and 5 into 8 and 9, respectively (Scheme 2).
c
a
2. Results and discussion
a
2.1. Preparation of b-isomers 6 and 7
a
c
As mentioned above, only compounds with high isomeric purity
are suitable for a correct olfactory evaluation. This aspect is espe-
cially relevant for methyl-ionone isomers which are inseparable
by the usual methodologies. We found that cyclization of
methyl-pseudoionone isomers (3,6,10-trimethylundeca-3,5,9-tri-
en-2-one and 7,11-dimethyldodeca-4,6,10-trien-3-one) affords
b-isomers 6 or 7 contaminated with a substantial amount of the
a
corresponding a-isomers. Therefore, we studied two different reg-
iospecific pathways to these compounds (Scheme 1). 8-Methyl b-
ionone 6 was prepared starting from citral. The Horner–Emmons
reaction of the latter aldehyde with triethyl 2-phosphonopropio-
nate afforded ester 10 that was cyclized using H2SO4 as an acid cat-
alyst. The ester 11 obtained was reduced with LiAlH4 to give the
corresponding alcohol, which was converted into ester 12 by treat-
ment with 3,5-dinitrobenzoyl chloride and pyridine.
( )-4
i
85%
O
O
+
+
15b
15a
O
O
15a /15b 4:1
O
ii
83%
O
ii
OEt
O
O
O
i
OEt
β/α
Citral
78%
4:1
10
11
iii, iv
86%
( )-8
16a
16b
OH
OH
NO
2
vi, vii, viii, vii
iii, iv, v
61%
O
6
63%
12
O
O
NO
2
iii, iv
80%
( )-9
+
18a
18b
CO H
OH
OH
ii 78%
2
ix
x, iii
90%
vii, xi, vii
69%
OH
2
7
14
13
O
O
Scheme 1. Regioselective preparation of b-iralia isomers 6 and 7. Reagents and
conditions: (i) NaH, triethyl 2-phosphonopropionate, THF, reflux; (ii) H2SO4/AcOH,
ꢀ5 °C; (iii) LiAlH4, Et2O, 0 °C; (iv) 3,5-dinitrobenzoyl chloride, Py/CH2Cl2; (v) two
crystallizations from MeOH; (vi) NaOH, MeOH; (vii) MnO2, CHCl3, reflux; (viii)
MeMgI, Et2O; (ix) Br2, NaOH/H2O, dioxane; (x) MeOH/H2SO4; (xi) EtMgBr, Et2O.
+
17b
17a
O
O
17 a/ 17b 4:1
i
88%
The latter compound was then purified by crystallization from
methanol in order to remove all of the unwanted isomers. The pure
ester was saponified and the alcohol oxidized by MnO2. The lacking
carbon atom was then introduced by treatment of the obtained
aldehyde with methyl magnesium iodide, and the resulting ionol
was converted into pure 6 by MnO2 oxidation.
( )-5
Scheme 2. Regioselective preparation of racemic c-iralia isomers 8 and 9. Reagents
and conditions: (i) MCPBA, CH2Cl2, 0 °C; (ii) LDA, THF, ꢀ78 °C then reflux; (iii) Ac2O/
Py; (iv) HCOOH, Et3N, PPh3, PdCl2(PPh3)2 cat., THF, reflux.
A different pathway was used for the preparation of isomer 7. b-
Ionone 2 is commercially available in good isomeric purity (up to
96%) and was used as a starting material. The haloform reaction
(Br2/NaOH) afforded acid 13,8 which was converted into alcohol
14 by esterification to the corresponding methyl ester followed
by reduction with LiAlH4. The latter allylic alcohol was oxidized
and the aldehyde obtained was treated with ethyl magnesium bro-
mide. The resulting ionol was then converted into pure 7 by MnO2
oxidation.
Accordingly, we submitted methyl ionones 4 and 5 to an epox-
idation procedure with m-chloroperbenzoic acid to afford the cis/
trans mixtures of epoxides 15a/15b and 17a/17b, respectively.
The latter compounds were added to an excess (2.5–3 equiv,
ꢀ78 °C) of LDA in THF and then warmed at reflux. After quenching,
we obtained the cis/trans mixtures of alcohols 16a/16b and 18a/
18b, respectively, showing the same diastereoisomeric ratio of
the starting epoxides (cis/trans 4:1). The allylic alcohols obtained
were acetylated, and then the acetate group was reductively
removed by treatment with triethylammonium formate and a
2.2. Preparation of
c-isomers 8 and 9
palladium catalyst to give 8-methyl
ionone 9, respectively. As previously reported in the synthesis of
-ionone, the latter reduction proceeds with good regioselectivity
although with some slight differences among the isomers. The
c-ionone 8 and 10-methyl c-
As mentioned in the introduction, the specific preparation of
isomers 8 and 9 has not previously been reported although some
studies on their isolation and characterization from the commer-
c
-
c

2318
A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
above mentioned
c-ionones were obtained with the following
O
O
isomeric purity: 3 (97%), 8 (96–97%) and 9 (94%).
i
83:17
78:22
+
6
α/β
α/β
71%
( )-8
−
(S)-( )-4
2.3. Synthesis of enantioenriched
and (+) and (–)-9
c-iralia isomers (+) and (–)-8
−
O
O
The aforementioned allylic alcohols 16 and 18 are suitable
starting materials for the preparation of enantioenriched isomers
8 and 9, respectively. Indeed, we have established5c that lipase-
i
+
7
(−)-9
(R)-(+)-5
65%
mediated acetylation of 4-hydroxy
c-ionone yielded enantiopure
Scheme 4. Chemical correlation of enantioenriched
c-iralia isomers 8 and 9 with
(4R,6S)-4-acetoxy- -ionone. The reaction proceeds with high
c
enantioenriched -iralia isomers 4 and 5. Reagent and condition: (i) 85% H3PO4.
a
enantioselectivity and with complete diastereoselectivity allowing
the exclusive transformation of the cis isomers. Preliminary acety-
lation experiments confirmed that alcohols 16 and 18 showed the
same behaviour.
As a result, we performed the enzyme-mediated resolution of
the above mentioned alcohols (Scheme 3). The described reductive
elimination of the acetate group (Section 2.2) proceeds without
racemization thus allowing the preparation of enantioenriched
ble mixture of unreacted alcohols (4S,6R)-18a and racemic 18b
(50% de, 85% ee). As described above, the reductive removal of
the acetoxy group converted the latter compounds into (+)-10-
methyl
c
-ionone (99% ee) and (ꢀ)-10-methyl
c-ionone (65% ee),
respectively.
methyl-
c
-ionone isomers. This is noteworthy, since the diastereo-
2.4. Determination of the absolute configuration of
isomers
c-iralia
isomeric allylic alcohols 16a/16b and 18a/18b are not separable by
chromatography, while the resolution procedure gives the corre-
sponding acetylated compounds with high ee and de leaving unre-
acted alcohols with low de. Luckily, epoxide 15a is separable from
its diastereoisomer 15b, and the following base-mediated isomer-
ization afforded 16a as the sole isomers. Accordingly, racemic alco-
hol 16a was acetylated with vinyl acetate in the presence of lipase
PS as catalyst. The reaction was interrupted at 50% of conversion to
give unreacted alcohol (+)-16a (99% de, 87% ee) and acetate (ꢀ)-19
(99% de, 99% ee). The reductive removal of the acetoxy group con-
The absolute configurations of the enantiomeric forms of 8 and
9 were unknown. In order to associate odour descriptions with the
configuration of the c-ionone isomers, we needed to assign these
data. Since the absolute configuration of the enantiomers of a-iso-
mers 4 and 5 was determined unambiguously,5f we decided to cor-
relate the enantiomeric forms of 8 and 9 with the aforementioned
a
-isomers. Indeed, it is known5c that treatment of
c-ionone iso-
mers with concentrated phosphoric acid gave isomerization of
the exocyclic double bond without any racemization. Therefore,
we treated a sample of compound (ꢀ)-8 and of compound (ꢀ)-9
with H3PO4 (Scheme 4). By this means we achieved complete isom-
verted the latter compounds into (+)-8-methyl
c-ionone (87% ee)
and (ꢀ)-8-methyl -ionone (99% ee), respectively. Otherwise,
c
epoxides 17a and 17b are not separable; the 4:1 mixture of alco-
hols 18a and 18b was used in the resolution step. The latter race-
mic compounds were treated with vinyl acetate in the presence of
lipase PS as a catalyst. The reaction was interrupted at 40%
conversion to give acetate (+)-20 (99% de, 99% ee) and an insepara-
erization of the starting
Methyl
-ionone (ꢀ)-8 afforded a mixture of (S)-(ꢀ)-8-methyl
ionone 4 and 8-methyl b-ionone 6, whereas 10-methyl -ionone
-ionone 5 and
c-isomers to the a- and b-isomers. 8-
c
a-
c
(ꢀ)-9 afforded a mixture of (R)-(+)-10-methyl
a
10-methyl b-ionone 7. In conclusion, the absolute configuration
of (ꢀ)-8 and (ꢀ)-9 was assigned unambiguously as (S) and (R),
respectively.
O
O
2.5. Olfactory evaluation of the iralia isomers
(R)-( )-8
(S)-( )-8
+
−
The regioisomers of b-iralia and the enantiomerically enriched
forms of c- iralia were evaluated by qualified perfumers (Givaudan
Schweiz AG, Fragrance Research). The following results were
ii, iii
iii
obtained:
O
O
8-Methyl b-ionone 6—Floral-woody and powdery violet note
with a more pronounced woody, powdery cedarwood character
and fatty-buttery aspects. Weaker than 7 and b-ionone on the blot-
ter, less dry than b-ionone. Dry down weak powdery-woody, and
less substantive than 7.
10-Methyl b-ionone 7—Strong and typical floral-woody b-io-
none note with a more pronounced floral violet side, less woody-
powdery and stronger than 6 on blotter. Dry down floral-woody,
typical b-ionone like, more substantive than 6.
i
i
( )-16a
+
(+)-16a
( )-19
−
(49%)
(45%)
OH
OAc
O
O
( )-
18a/18b
+
(4S,6R)-18a + ( )-18b
(+)-20
(35%)
(60%)
(S)-(ꢀ)-8-Methyl-
tween methyl ionone and Iso E Super of dry character.
(R)-(+)-8-Methyl -ionone 8—Rich and interesting woody-amb-
c-ionone 8—Woody-ambery mix odour be-
OH
OAc
ii, iii
iii
c
O
O
ery leather odour with fruity-floral facets in the direction of irone
and methyl ionone and additional green accents.
(S)-(+)-10-Methyl-c-ionone 9—Woody-floral odour in the direc-
tion of methyl ionone, with a fruity-floral violet inclination and
(S)-( )-9
(R)-( )-9
+
−
facets of orris, but also an oily background.
Scheme 3. Preparation of enantioenriched c-iralia isomers 8 and 9. Reagents and
conditions: (i) vinyl acetate, t-BuOMe, lipase PS; (ii) Ac2O/Py; (iii) HCOOH, Et3N,
PPh3, PdCl2(PPh3)2 cat., THF, reflux.
(R)-(ꢀ)-10-Methyl
c-ionone 9—Woody odour in the direction of
methyl ionone with additional dry, leathery aspects.

A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
2319
4.2. Synthesis of b-iralia isomers 6 and 7
3. Conclusions
4.2.1. 8-Methyl b-ionone = (E)-3-methyl-4-(2,6,6-trimethyl-
A number of results have been achieved. We have reported a
cyclohex-1-enyl)-but-3-en-2-one 6
new regioselective synthesis of the methyl-ionones isomers 6–9.
Triethyl 2-phosphonopropionate (38.1 g, 160 mmol) was added
dropwise under nitrogen over a period of 1 h to a stirred suspen-
sion of NaH (7 g, 60% in mineral oil, 175 mmol) in dry THF
(200 mL) at rt. To the resulting mixture citral (23 g, 151 mmol) in
dry THF (100 mL) was added slowly and the reaction mixture
was heated at reflux for 2 h. After cooling, the mixture was poured
onto ice-water and extracted with diethyl ether (3 ꢁ 200 mL). The
organic phase was washed with brine (2 ꢁ 100 mL), dried over
Na2SO4 and concentrated under reduced pressure. The residue
was diluted with hexane (30 mL) and, while stirring at ꢀ5 °C, a
mixture of 120 g of concentrated sulfuric acid and 35 g of glacial
acetic acid was added dropwise. After 1 h the reaction was
quenched by addition of ice and extracted with hexane
(2 ꢁ 200 mL). The combined organic phases were washed in turn
with saturated NaHCO3 solution (100 mL) and brine (100 mL),
dried (Na2SO4) and concentrated under reduced pressure. The res-
idue was purified by distillation to give pure ester 11 (27.9 g, 78%
The enantiomers of the
mo-enzymatic approach, and their absolute configuration deter-
mined by chemical correlation with the known -isomers.
Finally, the odour properties of all the aforementioned compounds
were evaluated by professional perfumers. In previous work, we
c-isomers 8 and 9 were prepared by a che-
a
reported the odour descriptions of the enantiomers of
a-isomers
4 and 5. Therefore, we have now achieved a complete description
of each component of the commercial odourants IraliaÒ. The fol-
lowing considerations are noteworthy:
(a) All the isomeric forms show distinct olfactory features.
(b) For the methyl-ionone isomers, the difference between the
a
-isomers and the
nounced than those reported for the ionone series.5a
(c) The difference between the enantiomers of -methyl-ionone
c-isomers, although evident, is less pro-
c
isomers are much less pronounced than those reported for
the ionone series.
yield) as a 4:1 mixture of b/a-isomers.
(d) Overall, these data show that any structural modification to
the ionone framework (methyl group introduction and posi-
tion, double bond position absolute configuration) gives a
definite and unpredictable modification to the odour.
Data for (E)-2-methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-ac-
rylic acid ethyl ester 11 (b-isomer): colourless oil; 1H NMR
(400 MHz, CDCl3) d 7.22 (br s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.99
(br t, J = 6.0 Hz, 2H), 1.71 (d, J = 1.3 Hz, 3H), 1.68–1.60 (m, 2H),
1.55–1.45 (m, 2H), 1.47 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 0.98 (s,
6H). IR (film, cm–1) 1711, 1635, 1366, 1245, 1112, 1033, 975,
743. GC–MS m/z (rel intensity) 236 (M+, 68), 221 (100), 193 (35),
175 (51), 163 (29), 147 (91), 133 (18), 119 (24), 107 (59), 91
(31), 77 (17), 69 (10), 55 (9).
4. Experimental
4.1. General experimental
The above mentioned ester was added dropwise to a stirred and
cooled (0 °C) suspension of LiAlH4 (4.5 g, 119 mmol) in dry ether
(200 mL). After work-up procedure, the crude alcohol was dis-
solved in pyridine (30 mL) and treated with a solution of 3,5-
dinitrobenzoyl chloride (29 g, 126 mmol) in dry CH2Cl2 (100 mL).
After complete conversion of the starting alcohol, the mixture
was diluted with water (200 mL) and extracted with CH2Cl2
(2 ꢁ 250 mL). The combined organic phases were washed with
saturated NaHCO3 solution, brine and then dried over Na2SO4.
Concentration at reduced pressure gave an oil that was purified
by CC (hexane/Et2O 9:1) and crystallized twice from methanol to
afford pure 12 (28.2 g, 61% yield).
All moisture-sensitive reactions were carried out under a static
atmosphere of nitrogen. All reagents were of commercial quality.
Racemic
tion of 3,6,10-trimethyl-undeca-3,5,9-trien-2-one in accord to the
well-known procedure used in the synthesis of -ionone from
pseudoionone. Racemic -iralia isomer 5 was prepared from -io-
a-iralia isomer 4 was prepared by acid-catalyzed cycliza-
a
a
a
none in accord to our previously reported procedure.5f Lipase from
Pseudomonas cepacia (PS), Amano Pharmaceuticals Co., Japan,
30 units/mg was employed in this work. TLC: Merk Silica Gel 60
F254 plates. Column chromatography (CC): silica gel. GC–MS analy-
ses: HP-6890 gas chromatograph equipped with a 5973 mass
detector, using a HP-5MS column (30 m ꢁ 0.25 mm, 0.25
thickness; Hewlett Packard) with the following temp program:
60 °C (1 min)—6 °C/min—150 °C (1 min)—12 °C/min—280 °C
(5 min); carrier gas, He; constant flow 1 mL/min; split ratio, 1/
30; tR given in min: tR(4) 17.50, tR(5) 18.28, tR(6) 18.07, tR(7)
lm firm
Data for 3,5-dinitrobenzoic acid (E)-2-methyl-3-(2,6,6-tri-
methyl-cyclohex-1-enyl)-allyl ester 12: colourless crystals, mp
69–70 °C; 1H NMR (400 MHz, CDCl3) d 9.22 (m, 1H), 9.16 (m, 2H),
6.13 (s, 1H), 4.94 (s, 2H), 1.99 (br t, J = 6.0 Hz, 2H), 1.69–1.59 (m,
2H), 1.65 (d, J = 1.1 Hz, 3H), 1.52 (s, 3H), 1.51–1.45 (m, 2H), 0.97
(s, 6H). 13C NMR (100 MHz) d 162.3, 148.8, 134.6, 134.2, 131.5,
129.5, 129.3, 129.1, 122.2, 72.2, 39.1, 34.6, 31.9, 28.2, 20.9, 19.3,
15.5. IR (Nujol, cm–1) 1716, 1630, 1551, 1294, 1167, 952, 727.
GC–MS m/z (rel intensity) 388 (M+, 9), 373 (23), 207 (7), 195
(25), 176 (16), 161 (100), 149 (17), 133 (30), 119 (52), 105 (59),
91 (29), 75 (14), 55 (13).
A sample of 12 (25 g, 64.4 mmol) was treated with a solution of
NaOH (5 g, 125 mmol) in methanol (150 mL) and stirring at rt until
no more starting acetate was detected by TLC analysis. The mixture
was diluted with water (300 mL) and extracted with diethyl ether
(2 ꢁ 150 mL). The combined organic phases were washed with
brine, dried (Na2SO4) and concentrated. The residue was dissolved
in CHCl3 (200 mL) and treated with MnO2 (30 g, 345 mmol) under
stirring at reflux for 6 h. The mixture was then cooled, filtered and
the organic phase concentrated under reduced pressure to afford
an oil (13 g). The latter was dissolved in dry diethyl ether
(150 mL) and treated under stirring with an excess of methylmag-
nesium iodide (100 mL of a 1 M solution in ether) keeping the
19.39, tR(8) 17.64, tR(9) 18.59, tR(11a) 19.23, tR(11b) 19.55, tR(12)
30.76, tR(14) 15.88, tR(15a) 19.31, tR(15b) 19.73, tR(16a) 21.16,
tR(16b) 20.80, tR(17a) 20.19, tR(17b) 20.27, tR(18a) 21.73, tR(18b)
21.45 tR(19) 22.27, tR(20) 22.61; mass spectra: m/z (rel.%). Chiral
GC analyses: DANI-HT-86.10 gas chromatograph; enantiomer
excesses determined on a CHIRASIL DEX CB-Column with the
following temp program: compound 19: 70 °C (1 min)—2 °C/
min—150 °C (0 min)—30 °C/min—180 °C (0 min); tR given in min:
tR((ꢀ)-19) 33.7, tR((+)-19) 34.0; compound 20: 70 °C (0 min)—
2 °C/min—130 °C (0 min)—1 °C/min—140 °C (0 min)—30°/min—
180 °C (0 min); tR given in min: tR((+)-20) 35.4, tR((ꢀ)-20) 35.6.
Optical rotations: Jasco-DIP-181 digital polarimeter. 1H and 13C
Spectra: CDCl3 solns at rt; Bruker-AC-400 spectrometer at 400
and 100 MHz, respectively; chemical shifts in ppm rel to internal
SiMe4 (=0 ppm), J values in Hertz. IR spectra were recorded on a
Perkin–Elmer 2000 FT-IR spectrometer;
m
in cm–1. Melting points
were measured on a Reichert apparatus, equipped with a Reichert
microscope, and are uncorrected.

2320
A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
reaction temperature under 5 °C by external cooling (ice bath). The
usual work-up afforded crude carbinol that was dissolved in CHCl3
(200 mL) and treated with MnO2 (30 g, 345 mmol) under stirring at
reflux for 12 h. After filtration and concentration, the crude ketone
was purified by chromatography (hexane/Et2O 95:5) and bulb to
bulb distillation (oven temperature 105 °C, 0.4 mmHg) to afford
pure 6 (8.4 g, 63% yield).
4.3. Synthesis of racemic c-iralia isomers 8 and 9
4.3.1. General procedure for epoxidation of
m-Chloroperbenzoic acid (12 g, of 75% wet acid, 52.1 mmol)
was added to a solution of racemic -iralia isomer 4 or 5 (10 g,
a-iralia isomers
a
48.5 mmol) in methylene chloride (100 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 2 h and then filtered in order to re-
move the m-chlorobenzoic acid precipitate. The organic phase was
washed in turn with saturated Na2SO3 solution and saturated NaH-
CO3 solution, dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was chromatographed on a silica gel column
(hexane/Et2O 9:1) to give the corresponding a-epoxy-derivatives.
Epoxide 15 (85% yield) 15a:15b = 4:1 separable by chromatog-
raphy. Both colourless oils.
Data for 8-methyl b-ionone 6: colourless oil; 1H NMR (400 MHz,
CDCl3) d 7.09 (s, 1H), 2.36 (s, 3H), 2.01 (t, J = 6.2 Hz, 2H), 1.70–
1.61 (m, 2H), 1.66 (d, J = 1.2 Hz, 3H), 1.53–1.48 (m, 2H), 1.46
(s, 3H), 0.99 (s, 6H); 13C NMR (100 MHz) d 199.9, 140.6, 139.5,
134.8, 129.7, 39.0, 34.7, 31.8, 28.3, 25.6, 21.1, 19.1, 12.9. IR
(film, cm–1) 1670, 1625, 1431, 1384, 1363, 1251, 1101, 1034,
997, 897. GC–MS m/z (rel intensity) 206 (M+, 2), 191 (100), 176
(5), 163 (4), 149 (12), 136 (7), 123 (8), 105 (5), 91 (9), 77 (5), 69
(2), 55 (3).
Epoxide 17 (88% yield) 17a:17b = 4:1; inseparable mixture. Col-
ourless oil.
Data for (4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-8-methyl
a-io-
none 15a: 1H NMR (400 MHz, CDCl3) d 6.65 (dd, J = 10.8, 1.3 Hz,
1H), 3.08 (s, 1H), 2.50 (d, J = 10.8 Hz, 1H), 2.36 (s, 3H), 2.05–1.88
(m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.45 (ddd, J = 13.7, 9.8, 5.7 Hz,
1H), 1.23 (s, 3H), 1.02 (dt, J = 13.7, 5.1 Hz, 1H), 0.96 (s, 3H), 0.76
(s, 3H). 13C NMR (100 MHz) d 199.8, 141.6, 138.8, 59.6, 59.2,
4.2.2. 10-Methyl b-ionone = (E)-1-(2,6,6-trimethyl-cyclohex-1-
enyl)-pent-1-en-3-one 7
A
solution of (E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-acrylic
acid 13 (20 g, 103 mmol) in methanol (100 mL) was treated with
concentrated sulfuric acid (25 mL) and then heated under reflux
for 1 h. The reaction mixture was then cooled, poured in ice and ex-
tracted with ether (2 ꢁ 150 mL). The organic phase was washed in
turn with saturated NaHCO3 solution (100 mL) and brine (100 mL),
then dried over Na2SO4 and concentrated under reduced pressure.
The obtained ester was added dropwise to a stirred and cooled
(0 °C) suspension of LiAlH4 (2.95 g, 78 mmol) in dry ether
(150 mL). After work-up procedure, the crude alcohol was purified
by chromatography (hexane/AcOEt 95:5) to afford pure 14 (16.8 g,
90% yield).
47.6, 31.8, 29.0, 28.3, 26.4, 25.5, 24.1, 21.7, 11.8. IR (film, cm–1
)
1670, 1368, 1253, 1177, 1095, 910. GC–MS m/z (rel intensity)
222 (M+, 2), 207 (5), 193 (10), 179 (16), 165 (9), 153 (12), 137
(30), 123 (100), 109 (53), 95 (17), 81 (16), 69 (15), 55 (16).
Data for (4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-8-methyl
a-io-
none 15b: 1H NMR (400 MHz, CDCl3) d 6.54 (dd, J = 11.6, 1.4 Hz,
1H), 3.00 (s, 1H), 2.69 (d, J = 11.6 Hz, 1H), 2.35 (s, 3H), 2.05 (dm,
J = 15.5 Hz, 1H), 1.97–1.87 (m, 1H), 1.86 (d, J = 1.4 Hz, 3H), 1.50–
1.36 (m, 1H), 1.20–1.12 (m, 1H), 1.17 (s, 3H), 0.89 (s, 3H), 0.79 (s,
3H). 13C NMR (100 MHz) d 199.4, 140.8, 139.7, 59.7, 58.1, 49.5,
32.8, 32.5, 29.4, 25.7, 23.3, 21.5, 21.4, 11.8. IR (film, cm–1) 1672,
1368, 1250, 1154, 1067, 908. GC–MS m/z (rel intensity) 222 (M+,
2), 207 (5), 189 (3), 179 (14), 165 (15), 153 (10), 137 (15), 123
(100), 109 (55), 95 (14), 79 (13), 69 (14), 55 (16).
Data for (E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-prop-2-en-1-
ol 14: colourless oil; 1H NMR (400 MHz, CDCl3)
d 6.11 (d,
J = 16.0 Hz, 1H), 5.61 (dt, J = 16.0, 6.0 Hz, 1H), 4.19 (br s, 2H), 1.98
(br t, J = 6.2 Hz, 2H), 1.67 (s, 3H), 1.65–1.53 (m, 2H), 1.49–1.41
(m, 2H), 1.31 (br s, 1H), 1.00 (s, 6H). 13C NMR (100 MHz) d 136.8,
132.4, 129.8, 129.1, 64.2, 39.7, 34.0, 32.8, 28.7, 21.3, 19.3. IR (film,
cm–1) 3351, 1360, 1094, 1011, 972. GC–MS m/z (rel intensity) 180
(M+, 79), 165 (86), 147 (100), 137 (14), 121 (65), 105 (81), 91 (75),
81 (50) 67 (25), 55 (39), 41 (42).
A solution of alcohol 14 (12.5 g, 69.3 mmol) in CHCl3 (200 mL)
was treated with MnO2 (25 g, 287 mmol) with stirring at reflux
for 5 h. The mixture was then cooled, filtered and the organic
phase concentrated under reduced pressure to afford an oil
(12 g). The latter was dissolved in dry diethyl ether (150 mL)
and treated under stirring with an excess amount of ethylmagne-
sium bromide (100 mL of a 0.9 M solution in ether) keeping the
reaction temperature under 5 °C by external cooling (ice bath).
After the usual work-up, the crude carbinol obtained was dis-
solved in CHCl3 (200 mL) and was treated with MnO2 (30 g,
345 mmol) under stirring at reflux for 12 h. Filtration and con-
centration afforded the crude ketone that was purified by chro-
matography (hexane/Et2O 95:5) and bulb to bulb distillation
(oven temperature 115 °C, 0.9 mmHg) to give pure 7 (9.9 g,
69% yield).
Data for (E)-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-3-
one 7: colourless oil; 1H NMR (400 MHz, CDCl3) d 7.29 (dd,
J = 0.7, 16.4 Hz, 1H), 6.12 (d, J = 16.4 Hz, 1H), 2.57 (q, J = 7.4 Hz,
2H), 2.06 (t, J = 6.2 Hz, 2H), 1.75 (d, J = 0.7 Hz, 3H), 1.67–1.58 (m,
2H), 1.52–1.46 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H), 1.07 (s, 6H); 13C
NMR (100 MHz) d 200.8, 141.8, 136.3, 135.2, 130.5, 39.9, 34.1,
33.7, 33.5, 28.8, 21.6, 19.0, 8.3. IR (film, cm–1) 1694, 1673, 1607,
1459, 1376, 1361, 1195, 1114, 1037, 980. GC–MS m/z (rel intensity)
206 (M+, 7), 191 (100), 177 (7), 163 (4), 149 (15), 135 (6), 121 (10),
107 (9), 91 (11), 77 (7), 57 (13).
Data for (4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-10-methyl
a-io-
none 17a: 1H NMR (400 MHz, CDCl3) d 6.68 (dd, J = 16.1, 10.3 Hz,
1H), 6.04 (d, J = 16.1 Hz, 1H), 3.01 (s, 1H), 2.68–2.48 (m, 2H), 2.01
(d, J = 10.3 Hz, 1H), 1.98–1.78 (m, 2H), 1.43–1.26 (m, 1H), 1.18 (s,
3H), 1.05 (t, J = 7.3 Hz, 3H), 0.94 (dt, J = 13.6, 4.9 Hz, 1H), 0.86 (s,
3H), 0.69 (s, 3H). GC–MS m/z (rel intensity) 222 (M+, 3), 207 (4),
193 (72), 179 (8), 165 (54), 147 (19), 137 (20), 123 (100), 109
(72), 95 (60), 81 (28), 69 (35), 57 (69).
Data for (4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-10-methyl
a-io-
none 17b: 1H NMR (400 MHz, CDCl3) d 6.63 (dd, J = 15.7, 11.2 Hz,
1H), 6.10 (d, J = 15.7 Hz, 1H), 2.93 (s, 1H), 2.68–2.48 (m, 2), 2.25
(d, J = 11.2 Hz, 1H), 1.98–1.78 (m, 2H), 1.43–1.26 (m, 1H), 1.14–
1.00 (m, 1H), 1.12 (s, 3H), 1.06 (t, J = 7.3 Hz, 3H), 0.79 (s, 3H),
0.74 (s, 3H). GC–MS m/z (rel intensity) 222 (M+, 8), 207 (9), 193
(19), 179 (13), 165 (60), 147 (21), 137 (22), 123 (100), 109 (77),
95 (49), 81 (23), 69 (32), 57 (85).
IR (for 17a/17b mixture, film, cm–1) 1699, 1675, 1627, 1379,
1367, 1204, 991.
4.3.2. General procedure for conversion of epoxides 15 and 17
into allylic alcohols 16 and 18, respectively
BuLi (5.5 mL of a 10 M solution in hexane) was added dropwise
to a cooled (ꢀ78 °C) solution of iPr2NH (5.8 g, 57.3 mmol) in dry
THF (90 mL) under nitrogen. The mixture was stirred at this tem-
perature for 30 min then a solution of the epoxide 15 or 17
(4.5 g, 20.2 mmol) in dry THF (20 mL) was added dropwise. The
reaction mixture was gradually warmed to rt (1 h) and then was
heated at reflux until no more starting epoxide was detected by
TLC analysis (3 h). After cooling to rt, the mixture was poured into
a mixture of crushed ice and 5% HCl soln (80 mL) and extracted

A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
2321
with Et2O (3 ꢁ 200 mL). The organic phase was successively
washed with satd aq NH4Cl soln (100 mL), brine, dried over Na2SO4
and concentrated under reduced pressure. The residue was puri-
fied by chromatography (eluting from hexane/AcOEt 9:1 to hex-
ane/AcOEt 1:1) to give allylic alcohol 16 (16a:16b = 4:1, 83%
yield) or allylic alcohol 18 (18a:18b = 4:1, 78% yield).
(s, 1H), 4.51 (s, 1H), 2.88 (d, J = 10.1 Hz, 1H), 2.36–2.25 (m, 1H),
2.35 (s, 3H), 2.12–2.02 (m, 1H), 1.77 (d, J = 1.3 Hz, 3H), 1.68–1.52
(m, 3H), 1.45–1.35 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H). 13C NMR
(100 MHz) d 199.6, 147.6, 142.2, 138.7, 109.0, 53.1, 39.1, 35.9,
34.5, 29.2, 25.5, 23.2, 22.9, 11.4. IR (film, cm–1) 1670, 1645, 1439,
1386, 1367, 1262, 1233, 889. GC–MS m/z (rel intensity) 206 (M+,
17), 191 (25), 178 (15), 163 (100), 149 (16), 135 (93), 123 (70),
107 (22), 95 (36), 77 (17), 69 (26), 55 (9).
Data for (4SR,6RS)-4-hydroxy-8-methyl
c-ionone 16a: colour-
less oil; 1H NMR (400 MHz, CDCl3) d 6.76 (dd, J = 9.9, 1.3 Hz, 1H),
5.15 (s, 1H), 4.65 (s, 1H), 4.10 (m, 1H), 2.86 (d, J = 9.9 Hz, 1H),
2.37 (s, 3H), 2.04–1.93 (m, 1H), 1.74 (d, J = 1.3 Hz, 3H), 1.66–1.45
(m, 3H), 0.90 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz) d 199.7,
149.5, 141.4, 139.0, 106.6, 72.6, 51.3, 38.0, 36.0, 32.2, 29.4, 25.6,
21.2, 11.4. GC–MS m/z (rel intensity) 222 (M+, 2), 204 (11), 189
(13), 179 (100), 161 (53), 148 (13), 135 (18), 123 (33), 109 (30),
91 (24), 79 (19), 69 (15), 55 (16).
Data for 10-methyl
c-ionone = (E)-1-(2,2-dimethyl-6-methy-
lene-cyclohexyl)-pent-1-en-3-one ( )-9: colourless oil; 1H NMR
(400 MHz, CDCl3) d 6.97 (dd, J = 9.9, 15.7 Hz, 1H), 6.11 (dd,
J = 15.7, 0.6 Hz, 1H), 4.78 (s, 1H), 4.55 (s, 1H), 2.62–2.53 (m, 1H),
2.58 (q, J = 7.4 Hz, 2H), 2.27 (dt, J = 13.5, 5.8 Hz, 1H), 2.06 (dt,
J = 13.5, 6.7 Hz, 1H), 1.65–1.55 (m, 2H), 1.55–1.47 (m, 1H), 1.40–
1.30 (m, 1H), 1.11 (t, J = 7.4 Hz, 3H), 0.91 (s, 3H), 0.86 (s, 3H). 13C
NMR (100 MHz) d 200.6, 148.5, 145.7, 131.5, 109.5, 57.6, 38.6,
35.5, 34.1, 33.6, 29.1, 23.9, 23.1, 8.1. IR (film, cm–1) 1695, 1677,
1626, 1460, 1366, 1207, 1187, 990, 891. GC–MS m/z (rel intensity)
206 (M+, 25), 191 (26), 178 (38), 163 (99), 149 (92), 135 (100), 123
(47), 109 (57), 93 (41), 81 (59), 69 (63), 57 (47).
Data for (4SR,6SR)-4-hydroxy-8-methyl
c-ionone 16b: colour-
less oil; 1H NMR (400 MHz, CDCl3) d 6.71 (dd, J = 10.0, 1.3 Hz,
1H), 5.03 (s, 1H), 4.67 (s, 1H), 4.31 (br t, J = 4.6 Hz, 1H), 3.33 (d,
J = 10.0 Hz, 1H), 2.34 (s, 3H), 2.08–1.80 (m, 3H), 1.80–1.67 (m,
1H), 1.78 (d, J = 1.3 Hz, 3H), 0.95 (s, 3H), 0.85 (s, 3H). 13C NMR
(100 MHz) d 199.6, 149.4, 141.4, 139.2, 110.1, 71.6, 49.6, 35.7,
34.5, 30.5, 29.0, 25.7, 22.4, 11.4. GC–MS m/z (rel intensity) 222
(M+, 2), 204 (8), 189 (13), 179 (100), 161 (55), 148 (14), 135 (19),
123 (32), 109 (28), 96 (26), 81 (18), 69 (15), 55 (17).
4.4. Synthesis of enantioenriched
and (+) and (ꢀ)-9
c-iralia isomers (+) and (ꢀ)-8
IR (for 16a/16b mixture, film, cm–1) 3424, 1666, 1387, 1368,
1250, 1071, 1049, 993, 900.
4.4.1. Lipase-mediated resolution of alcohols 16 and 18
Data for (4SR,6RS)-4-hydroxy-10-methyl-ionone 18a: 1H NMR
(400 MHz, CDCl3) d 6.95 (dd, J = 15.8, 10.3 Hz, 1H), 6.09 (d,
J = 15.8 Hz, 1H), 5.16 (s, 1H), 4.69 (s, 1H), 4.05 (m, 1H), 2.58 (q,
J = 7.4 Hz, 2H), 2.55 (d, J = 10.3 Hz, 1H), 2.00–1.91 (m, 1H), 1.75–
1.35 (m, 4H), 1.12 (t, J = 7.4 Hz, 3H), 0.89 (s, 3H), 0.87 (s, 3H). 13C
NMR (100 MHz) d 200.8, 150.4, 144.8, 132.0, 107.0, 72.4, 55.7,
37.9, 35.6, 33.5, 32.1, 29.6, 21.5, 8.1. GC–MS m/z (rel intensity)
222 (M+, 6), 207 (8), 189 (7), 175 (13), 165 (99), 147 (71), 135
(29), 122 (36), 107 (55), 91 (43), 81 (30), 69 (31), 57 (100).
Diastereoisomerically pure alcohol 16a (obtained from epoxide
15a) and the cis/trans 4:1 mixture of 18a/18b were employed in
the resolution procedure. A sample of the above mentioned race-
mic material (5 g, 22.5 mmol), lipase PS (5 g), vinyl acetate
(25 mL) and tBuOMe (100 mL) was stirred at rt, and the formation
of the acetate was monitored by TLC analysis. The reaction was
stopped at about 50% of conversion when the substrate was 16a
and at 40% of conversion when the substrate was the 18a/18b mix-
ture. The enzyme was then filtered, and the solvent was evapo-
rated at reduced pressure after which the residue was purified by
chromatography (eluting from hexane/AcOEt 9:1 to hexane/AcOEt
1:1). The first-eluted fractions afforded derivatives (ꢀ)-19 (45%
yield) and (+)-20 (35% yield), respectively. The last eluted fractions
afforded derivatives (+)-16a (49% yield) and a mixture of (4S,6R)-
18a and racemic 18b (60% yield), respectively.
Data for (4SR,6SR)-4-hydroxy-10-methyl
c
-ionone 18b: 1H
NMR (400 MHz, CDCl3) d 6.91 (dd, J = 15.9, 9.9 Hz, 1H), 6.15 (d,
J = 15.9 Hz, 1H), 5.06 (s, 1H), 4.72 (s, 1H), 4.28 (br s, 1H), 2.96 (d,
J = 9.9 Hz, 1H), 2.58 (q, J = 7.4 Hz, 2H), 1.90–1.80 (m, 1H), 1.75–
1.35 (m, 4H), 1.11 (t, J = 7.4 Hz, 3H), 0.94 (s, 3H), 0.87 (s, 3H).
GC–MS m/z (rel intensity) 222 (M+, 5), 207 (6), 189 (7), 175 (12),
165 (99), 147 (100), 135 (23), 123 (27), 105 (36), 91 (41), 81
(28), 69 (30), 57 (87).
Data for (4R,6S)-4-acetoxy-8-methyl
c
-ionone (ꢀ)-19: colour-
less oil; 98% chemical purity, 99% de (GC); 99% ee (chiral GC);
½
a 2D0
ꢂ
¼ ꢀ17:1 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 6.72 (dd,
IR (for 18a/18b mixture, film, cm–1) 3408, 1715, 1675, 1627,
1206, 1049, 989, 902.
J = 10.0, 1.4 Hz, 1H), 5.28–5.19 (m, 1H), 5.01 (s, 1H), 4.67 (s, 1H),
2.93 (d, J = 10.0 Hz, 1H), 2.36 (s, 3H), 2.10 (s, 3H), 2.00–1.90 (m,
1H), 1.76 (d, J = 1.4 Hz, 3H), 1.73–1.61 (m, 2H), 1.59–1.47 (m,
1H), 0.92 (s, 3H), 0.91 (s, 3H). 13C NMR (100 MHz) d 199.3, 169.7,
144.4, 140.5, 139.1, 108.3, 73.6, 51.4, 37.3, 35.7, 29.1, 28.8, 25.6,
21.6, 21.1, 11.5. IR (film, cm–1) 1743, 1674, 1652, 1369, 1240,
1041, 998, 900. GC–MS m/z (rel intensity) 264 (M+, 1), 249 (9),
222 (19), 204 (55), 189 (34), 179 (59), 161 (100), 148 (50), 135
(35), 123 (36), 105 (34), 91 (29), 77 (17), 69 (12), 55 (13).
4.3.3. General procedure for the reduction of allylic alcohols 16
and 18 to c-iralia isomers 8 and 9, respectively
A sample of compound 16 or 18 (3 g, 13.5 mmol) was converted
in the corresponding acetate by treatment with pyridine (20 mL)
and Ac2O (20 mL) at rt for 24 h. The crude product was added to
a solution of formic acid (1.2 g, 26 mmol), Et3N (2.7 g, 26.7 mmol),
(PPh3)2PdCl2 (280 mg, 0.4 mmol) and triphenylphosphine (0.5 g,
1.9 mmol) in dry THF (60 mL). The mixture was refluxed under a
static nitrogen atmosphere until reduction was complete (2 h,
TLC analysis). The reaction mixture was then diluted with ether
(150 mL) and washed with water (50 mL), 5% HCl soln (50 mL),
satd aq NaHCO3 soln (50 mL), and brine. The organic phase was
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography (hexane/Et2O 95:5) and
Data for (4R,6S)-4-acetoxy-10-methyl c-ionone (+)-20: colour-
less oil; 98% chemical purity, 99% de (GC); 99% ee (chiral GC);
½
a 2D0
ꢂ
¼ þ27:1 (c 1.7, CHCl3); 1H NMR (400 MHz, CDCl3) d 6.94 (dd,
J = 15.7, 10.3 Hz, 1H), 6.12 (d, J = 15.7 Hz, 1H), 5.22–5.16 (m, 1),
5.02 (s, 1H), 4.71 (s, 1H), 2.61 (d, J = 10.3 Hz, 1H), 2.57 (q,
J = 7.4 Hz, 2H), 2.10 (s, 3H), 1.96–1.85 (m, 1H), 1.78–1.58 (m, 2H),
1.52–1.38 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.90 (s, 3H), 0.89 (s,
3H). 13C NMR (100 MHz) d 200.3, 169.8, 145.3, 144.0, 131.7,
109.1, 73.5, 55.9, 36.8, 35.3, 34.0, 29.2, 28.7, 22.2, 21.1, 8.0. IR (film,
cm–1) 1743, 1677, 1630, 1369, 1264, 1125, 1040, 996, 898. GC–MS
m/z (rel intensity) 264 (M+, 1), 249 (6), 222 (24), 204 (36), 189 (14),
175 (30), 163 (63), 147 (100), 135 (29), 119 (25), 105 (35), 91 (37),
79 (15), 69 (16), 57 (52).
bulb-to-bulb distillation to give c-iralia isomers 8 (86% yield, 97%
isomeric purity (GC)) or 9 (80% yield, 94% isomeric purity (GC)),
respectively.
Data for 8-methyl
c-ionone = (E)-4-(2,2-dimethyl-6-methy-
lene-cyclohexyl)-3-methyl-but-3-en-2-one ( )-8: colourless oil;
1H NMR (400 MHz, CDCl3) d 6.76 (dd, J = 10.1, 1.3 Hz, 1H), 4.77

2322
A. Barakat et al. / Tetrahedron: Asymmetry 19 (2008) 2316–2322
Data for (4S,6R)-4-hydroxy-8-methyl
c
-ionone (+)-16a: 96%
and brine. The organic phase was dried (Na2SO4), concentrated
under reduced pressure and the residue was purified by CC
(hexane/Et2O 9:1) and bulb-to-bulb distillation to give a /b-iralia
chemical purity, 99% de (GC); 87% ee (chiral GC); ½a D20
¼ þ32:6 (c
ꢂ
2, CHCl3); IR, 1H NMR, MS: in accordance with that of ( )-16a.
a
Data for (4S,6R)-4-hydroxy-10-methyl
c-ionone (4S,6R)-18a:
isomers mixture. According to the above described procedure com-
96% chemical purity, 50% de (GC); 85% ee (chiral GC). IR, 1H
NMR, MS: in accordance with that of ( )-18a. Optical rotation
power of this compound is near to 0. Therefore we describe the
optical rotation value of the corresponding acetylated (Ac2O/Py)
pound (ꢀ)-8 (½a 2D0
¼ ꢀ19:8 (c 1, CHCl3)) afforded a mixture of (ꢀ)-4
ꢂ
and 6 (71% yield, 98% chemical purity,
a
/b 83:17, ½a 2D0
¼ ꢀ401:8 (c
ꢂ
1, CHCl3)), whereas compound (ꢀ)-9 (½a D20
¼ ꢀ8:2 (c 1, CHCl3))
ꢂ
afforded a mixture of (+)-5 and 7 (65% yield, 98% chemical purity,
derivative: ½a 2D0
ꢂ
¼ ꢀ12:6 (c 1.5, CHCl3).
a
/b 78:22, ½a 2D0
¼ þ97:2 (c 1, CHCl3)).
ꢂ
4.4.2. Preparation of enantioenriched
c
-iralia isomers
Acknowledgement
The above obtained compounds (ꢀ)-19, (+)-20, (+)-16 and
(4S,6R)-18a were submitted to the reductive deoxygenation proce-
The authors would like to thank Dr. Philip Kraft (Givaudan
Schweiz AG) for the odour evaluation of the Iralia isomers.
dure described in Section 4.4.3 to afford
c
-iralia isomers (ꢀ)-8, (+)-
9, (+)-8 and (ꢀ)-9, respectively. The latter compounds showed the
following analytical data:
References
(S)-(ꢀ)-8-Methyl- -ionone (ꢀ)-8: 99% chemical purity, 96% reg-
c
ioisomeric purity (GC); ½a D20
ꢂ
¼ ꢀ19:8 (c 1, CHCl3); IR, 1H NMR, MS:
1. (a) Ohloff, G. Scent and Fragrances: The Fascination of Fragrances and their
Chemical Perspectives; Springer: Berlin, 1994; (b) Kraft, P.; Bajgrowicz, J. A.;
Denis, C.; Fráter, G. Angew. Chem., Int. Ed. 2000, 39, 2980–3010.
in accordance with that of ( )-8.
(S)-(+)-10-Methyl-c-ionone (+)-9: 99% chemical purity, 94%
regioisomeric purity (GC); ½a D20
ꢂ
¼ þ18:7 (c 1, CHCl3); IR, 1H NMR,
2. Sell, C. S. Angew. Chem., Int. Ed. 2006, 45, 6254–6261.
3. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 1–42.
4. (a) Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Chem. Biodiv. 2004, 1,
1888–1898; (b) Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. J. Mol.
Catal. B: Enzym. 2004, 32, 33–51; (c) Brenna, E.; Fuganti, C.; Serra, S.
Tetrahedron: Asymmetry 2005, 16, 1699–1704; (d) Brenna, E.; Fuganti, C.;
Gatti, F. G.; Malpezzi, L.; Serra, S. Tetrahedron: Asymmetry 2008, 19, 800–807.
5. (a) Brenna, E.; Fuganti, C.; Serra, S.; Kraft, P. Eur. J. Org. Chem. 2002, 967–978;
(b) Brenna, E.; Fuganti, C.; Serra, S. C. R. Chim. 2003, 6, 529–546; (c) Serra, S.;
Fuganti, C.; Brenna, E. Helv. Chim. Acta 2006, 89, 1110–1122; (d) Serra, S.;
Fuganti, C. Tetrahedron: Asymmetry 2006, 17, 1573–1580; (e) Serra, S.; Barakat,
A.; Fuganti, C. Tetrahedron: Asymmetry 2007, 18, 2573–2580; (f) Abate, A.;
Brenna, E.; Fuganti, C.; Malpezzi, L.; Serra, S. Tetrahedron: Asymmetry 2007, 18,
1145–1153.
6. Fuganti, C.; Serra, S.; Zenoni, A. Helv. Chim. Acta 2000, 83, 2761–2768.
7. Matsui, M.; Kawanobe, T.; Kurihara, T. Japanese Patent No. JP03188062, 1991.
8. He, J.-F.; Wu, Y.-L. Tetrahedron 1988, 44, 1933–1940.
9. (a) Theimer, E. T.; Somerville, W. T.; Mitzner, B.; Lemberg, S. J. Org. Chem. 1962,
27, 635–637; (b) Theimer, E. T.; Somerville, W. T.; Mitzner, B.; Lemberg, S. J. Org.
Chem. 1962, 27, 2934–2935.
MS: in accordance with that of ( )-9.
(R)-(+)-8-Methyl-c-ionone (+)-8: 98% chemical purity, 96% reg-
ioisomeric purity (GC); ½a D20
ꢂ
¼ þ16:4 (c 2, CHCl3); IR, 1H NMR, MS:
in accordance with that of ( )-8.
(R)-(ꢀ)-10-Methyl- -ionone (ꢀ)-9: 98% chemical purity, 94%
c
regioisomeric purity (GC); ½a D20
ꢂ
¼ ꢀ13:8 (c 1, CHCl3); IR, 1H NMR,
MS: in accordance with that of ( )-9.
4.4.3. General procedure for isomerization of c-iralia isomers
to
a
c
and b-iralia isomers
-Iralia isomers (0.25 g, 1.2 mmol) were stirred in 85% H3PO4
-isomer was detected by GC
(2 mL) at rt until no more starting
c
analysis (2 h). The reaction mixture was poured onto crushed ice
and the products were extracted with ether (2 ꢁ 40 mL). The
organic phase was washed with satd aq NaHCO3 soln (60 mL),
10. Serra, S.; Fuganti, C.; Brenna, E. Flavour Fragr. J. 2007, 22, 505–511.