Chemoenzymatic resolution of cis- and trans-3,6-dihydroxy-α-ionone. Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-dehydrotheaspirone

Article abstract of DOI:10.1016/j.tetasy.2007.10.014

A straightforward synthesis of both enantiomers of cis- and trans-3-acetoxy-6-hydroxy-α-ionone is described. The title compounds are prepared by resolution of the diastereoisomerically pure racemic 3,6-dihydroxy-α-ionone isomers. The latter process is bas

Full text of DOI:10.1016/j.tetasy.2007.10.014

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2573–2580
Chemoenzymatic resolution of cis- and trans-3,6-dihydroxy-a-ionone.
Synthesis of the enantiomeric forms of dehydrovomifoliol
and 8,9-dehydrotheaspirone
Stefano Serra,* Assem Barakat and Claudio Fuganti
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
Received 20 September 2007; accepted 10 October 2007
Available online 5 November 2007
Abstract—A straightforward synthesis of both enantiomers of cis- and trans-3-acetoxy-6-hydroxy-a-ionone is described. The title com-
pounds are prepared by resolution of the diastereoisomerically pure racemic 3,6-dihydroxy-a-ionone isomers. The latter process is based
on two steps. The first is the enantio- and regioselective lipase-mediated acetylation of diols to afford the corresponding 3-acetoxy-deriv-
atives. The second is the fractional crystallization of the latter compounds that increase their enantiomeric purity. These building blocks
were used for the synthesis of both enantiomeric forms of the natural norterpenoids dehydrovomifoliol 3 and 8,9-dehydrotheaspirone 5.
The latter compound is a natural flavor and its odor properties were evaluated by professional perfumers.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
10
7
OH
Ionone isomers and their hydroxylated derivatives are
1
4
2
R'
(carotenoid
numbering )
9
R= OH, H or O
R'= carotenoids or
apocarotenoid chain
6
8
important starting materials for the synthesis of several
natural products. Since many of the latter compounds
show biological activity, which is strictly related to their
absolute configuration, their synthesis requires optically
active starting materials.1 Therefore the enantioselective
preparation of these chiral building blocks has become an
important research topic. In this context, we have been
working on the enantioselective synthesis of different nor-
terpenoid compounds, such as ionone,2 irone,3 damas-
cone,4 and 7,11-epoxymegastigma-5(6)-en-9-one5 isomers.
Our general approach consists of the preparation of diaste-
reoisomerically pure racemic ionol isomers and then their
resolution by means of lipase-mediated enantioselective
acetylation. Recently,2b,4,5 we found that different hydrox-
ylated ionone derivatives are good substrates in this resolu-
tion protocol. In order to exploit the synthetic significance
of the method, we herein report a study on the resolution
of 3,6-dihydroxy-a-ionone isomers. The latter derivatives
are potential building blocks for the stereospecific synthesis
of compounds of the general structures 1, 4, and 5 (Fig. 1).
1
R
3
5
O
OH
OH
COOH
2
4
3
O
O
O
O
5
O
O
Figure 1.
Carotenoids and apocarotenoids of type 1 have been iso-
lated6 from different natural sources; the most well known
is (+)-abscisic acid 2, which is well established as an impor-
tant growth regulator in most plants.7 (+)-Dehydrovomi-
foliol 3 occurs in Nature8 but its relevance is due to its
use as penultimate precursor in the well established synthe-
sis of 2.9
*
Corresponding author. Tel.: +39 02 2399 3076; fax: +39 02 2399 3080;
e-mail: stefano.serra@polimi.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.014

2574
S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
O
( )-8
O
Moreover, spiroderivatives 4 and 5 are important flavors.
Theaspirone 4 is a component of the thea scent10 whereas
the less well known dehydrotheaspirone 5 has received
increasing attention after its isolation from tobacco,11 Ries-
ling wine,12 nectarines,13 honey,8c and Reseda odorata flow-
ers.14 All of the above-mentioned compounds share the
same difficult accessibility by chemical synthesis, particu-
larly in their enantiomerically pure forms. Within this
topic, the known procedures are based essentially on three
approaches: resolution of the enantiomers, the asymmetric
synthesis, and the use of two easily available C-9 chiral
building blocks. The first method13,15 proved to be unsuit-
able for preparative purposes and is applied in only a few
analytical studies dedicated to the evaluation of the physi-
cal15a,b or organoleptic13,15c properties of compounds 2 and
5, respectively. Concerning the second pathway,16 some
leading methods exploited the Sharpless epoxidation16a
and chiral bicyclic lactam16b or ketal16c alkylation proce-
dure as a key step in the formation of the quaternary asym-
metric center. The chiral intermediates obtained were then
manipulated in order to obtain derivatives 2 and 3. On the
other hand, the third pathway is based on the use of
(4R,6R)- and (4R,6S)-isomers of 4-hydroxy-2,2,6-trimeth-
ylcyclohexanone1,17 that are in turn obtained in high enan-
tiomeric excess by microbial reduction of oxoisophorone
and by fractional crystallization of its diastereoisomeric
esters, respectively. The latter two compounds were used
as starting materials in a number of carotenoid syntheses
involving the preparation of compounds of type 1–3. As
described above, we propose a different approach to the
synthesis of enantioenriched derivatives 1–5 based on the
lipase-mediated resolution of diastereoisomerically pure
3,6-dihydroxy-a-ionone isomers. Herein, we report the
accomplishment of our plan by the stereoselective prepara-
tion of the four isomers of 3-acetoxy-6-hydroxy-a-ionone.
The synthetic relevance of the latter compounds is demon-
strated by their transformation in the enantiomeric forms
of dehydrovomifoliol 3 and dehydrotheaspirone 5.
O
OH
OH
i
ii
O
O
7
O
HO
HO
6
O
iii, iv
O
9
( )-10
Scheme 1. Preparation of racemic diols 8 and 10. Reagents and condi-
tions: (i) Rose Bengal, O2, MeOH; (ii) thiourea, MeOH, rt, 56% (two
steps); (iii) MCPBA, Et2O, 0 ꢁC; (iv) NaHCO3, H2O, rt, then crystalli-
zation from hexane/AcOEt, 59% (two steps).
derivative 7, which was reduced with thiourea20 to give
the cis-3,6-dihydroxy-a-ionone 8. Conversely, the oxida-
tion of 6 with MCPBA afforded the epoxy-derivative 9,
which is not stable in the reaction environment and rear-
ranged to give a 5:1 mixture of diols 10 and 8, respec-
tively.21 Due to the different crystal properties of the
latter compounds, the crystallization of the crude reaction
mixture afforded pure diol 10.
2.2. Lipase-mediated resolution of diols 8 and 10
Each of the two diastereoisomerically pure diols 8 and 10
was treated with vinyl acetate in t-BuOMe solution in the
presence of lipases (PS, CRL, and PPL). The reactivity of
each substrate toward the irreversible acetylation was
tested by monitoring at regular time intervals the product
distribution by GC analysis. After interruption of the reac-
tion, the products were isolated and their ee and absolute
configuration determined by specific rotation values mea-
surements and chemical correlation with the known dehy-
drovomifoliol 3, respectively (see Section 2.3). The results
of this study are collected in Table 1 and allow some inter-
esting considerations.
Table 1. Results of the enzyme-mediated acetylation of diols ( )-8 and
(
)-10
2. Results and discussion
Diol
Enzyme
Conversion (%)
ee (%) and absolute
configurationa
Eb
2.1. Preparation of racemic diols 8 and 10
8
PPL
CRL
Lipase PS
3
42
50
9 (3S,6R)
3 (3S,6R)
60 (3S,6R)
1.2
1.1
7.2
As part of a program aimed at the preparation of enantio-
pure odorants,18 we have previously shown the efficiency of
lipase-mediated kinetic resolutions of racemic materials.19
Accordingly, we extended this flexible enzymic methodol-
ogy to the resolution of 3,6-dihydroxy-a-ionone deriva-
tives. Our study first needed a valuable amount of
racemic starting materials. Preliminary experiments dem-
onstrated that different lipases catalyze the irreversible ki-
netic acetylation of the 3-hydroxy group of the above-
mentioned isomers with complete regioselectivity and with
very low diastereoselectivity. Therefore, we selected two
diastereoselective preparations of racemic cis- and trans-
3,6-dihydroxy-a-ionone 8 and 10, respectively (Scheme 1).
In accordance with previously reported methods, both
diols were prepared by starting from the easily available
3,4-dehydroxy-b-ionone 6. Treatment of the latter com-
pound with oxygen and visible light in the presence of rose
bengal as a photosensitizer15a provided the stable peroxy-
10
PPL
CRL
Lipase PS
15
30
13
3 (3S,6S)
8 (3R,6R)
36 (3S,6S)
1.1
1.2
2.3
a The ee and absolute configuration were determined on the isolated 3-
acetoxy-derivative 11 and 12 according with Section 2.3.
b E = ln[1 ꢀ c · (1 + eep)]/ln[1 ꢀ c · (1 ꢀ eep)].
All the lipases tested, regioselectively catalyzed the acetyla-
tion of the secondary alcohol function. Transformation of
cis-diol 8 afforded (3S,6R)-3-acetoxy-derivative with an
enantioselectivity that ranged from very low for PPL and
CRL to moderate for lipase PS. Similarly, PPL and lipase
PS mediated the conversion of trans-diol 10 in the (3S,6S)-
3-acetoxy-derivative with very low and modest enantio-
selectivity, respectively. Conversely, CRL catalyzed the acet-
ylation of the same diol with opposite enantioselectivity

S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
2575
showing a preference for the (3R)-configuration and thus
affording the (3R,6R)-3-acetoxy-derivative. Also in the
latter case, the enantioselectivity was very low. Overall,
the enantiomeric ratio did not exceed the value of 1.2 for
PPL and CRL whereas values of 7.2 and 2.3 were seen
when lipase PS catalyzed the acetylation of 8 and 10,
respectively. Even though by the employment of the latter
enzyme, an efficient resolution process of 8 and 10 was not
easily achieved. Providentially, we observed that both cis-
and trans-3-acetoxy-derivatives were nice crystalline com-
pounds and for an ee inferior to 60–70%, racemic crystals
were much less soluble than enantiomeric enriched ones.
The combined application of the enzyme-mediated acetyl-
ation and of fractional crystallization was a successful path
to enantiopure 3-acetoxy-derivatives.
very low ee values. Thus, the liquid phases were submitted
again to the crystallization process, which was repeated
using the mother liquors till the crystals showed a specific
rotation value superior of that measured for the liquid.
At this point a further crystallization of the solid afforded
enantiomerically pure acetate whose optical rotation value
did not increase by recrystallization. All the crystal crops
showing low ee were collected and then converted again
into the starting diols 8 and 10 by means of treatment with
methanolic KOH. Although a number of simple chemical
manipulations are necessary, the recycling of compounds
with low ee increase the significance of the method and
overall the process gives access to the enantiomeric forms
of acetate 11 and 12 in high ee.
2.3. Determination of the absolute configuration of acetates
(ꢀ)-11 and (+)-12; synthesis of dehydrovomifoliol
Taking advantage of the aforementioned results, we de-
vised a large-scale method for the resolution of the title
compounds. Following Scheme 2, diols 8 and 10 were sub-
mitted to lipase PS-mediated acetylation to afford acetates
(ꢀ)-11 and (+)-12, respectively, and unreacted diols (+)-8
and (ꢀ)-10, respectively. After chromatographic separa-
tion, the latter diols were converted into the corresponding
acetates (+)-11 and (ꢀ)-12, respectively, by treatment with
pyridine and acetic anhydride. The enantiomeric purity of
the four acetates obtained was increased by crystallization
from hexane/ethyl acetate. The crystals obtained showed
The absolute configuration of the enantiomeric forms of 11
and 12 was unknown. Therefore, we decided to assign these
data by chemical correlation. Since we were unable to accu-
rately determine the ee of the above-mentioned compounds
by GC or HPLC analysis, we converted these acetates in
(ꢀ)- and (+)-enantiomers of dehydrovomifoliol 3 of known
absolute configuration, which display high and easily mea-
surable specific rotation values.16a,b,17
Following Scheme 3, enantiomerically pure (ꢀ)-11 and (+)-
12 were treated with methanolic KOH and the diols
obtained were oxidized with MnO2 in CH2Cl2 to afford
(ꢀ)-(R) and (+)-(S) dehydrovomifoliol 3, respectively.
Judging from the comparison of the measured specific rota-
(–)-11
O
iv
OH
(low ee)
ii
+
(–)-11
20
20
tion value, ½aꢁD ¼ ꢀ219:5 (c 0.5, CH2Cl2) and ½aꢁD ¼ þ222
AcO
(–)-11
(97% ee)
(c 0.5, CH2Cl2), with that reported in the lit.16b
i
20
½aꢁD ¼ ꢀ219 (c 0.4, CH2Cl2) for (ꢀ)-3 of ee >95%, we
( )-8
(+)-11
O
assigned the absolute configurations of (ꢀ)-11 and (+)-
12, as (3S,6R) and (3S,6S), respectively. Concerning the
enantiomeric purity of the latter two compounds we assert
that both show an ee >95%. This assumption has been
confirmed by chiral GC analysis of dehydrotheaspirones
(ꢀ)-5 and (+)-5 (see Section 2.4).
OH
(96% ee)
ii
iii
AcO
+
(+)-8
(+)-11
(+)-11
(low ee)
iv
O
OH
i, ii
(–)-11
(–)-3
(R)-dehydrovomifoliol
(S)-dehydrovomifoliol
69%
(+)-12
O
O
iv
OH
(low ee)
ii
+
(+)-12
O
AcO
(+)-12
(98% ee)
OH
i, ii
i
( )-10
(+)-12
(+)-3
(–)-12
O
72%
O
OH
(97% ee)
ii
iii
AcO
Scheme 3. Chemical correlation of acetates 11 and 12 with dehydrovomi-
foliol 3. Reagents and conditions: (i) KOH, MeOH; (ii) MnO2, CH2Cl2, rt.
+
(-)-10
(-)-12
(–)-12
(low ee)
iv
2.4. Synthesis of the enantiomeric forms of 8,9-dehydro-
theaspirone 5
Scheme 2. Preparation of the enantiomeric forms of acetates 11 and 12 by
a chemoenzymatic resolution procedure. Reagents and conditions: (i)
lipase PS, t-BuOMe, vinyl acetate, column chromatography; (ii) fractional
crystallization procedure; (iii) Ac2O, Py; (iv) KOH, MeOH.
As mentioned in Section 1, enantioenriched 3,6-dihydroxy-
a-ionone derivatives are important synthetic intermediates.
Since we are involved in a research program devoted to the

2576
S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
preparation of enantiopure odorants, we decided to exploit
the use of compounds 11 and 12 for the synthesis of flavors
of type 4 and 5. Herein, we report the transformation of the
enantioenriched acetates (ꢀ)-11 and (+)-12 in the 8,9-dehy-
drotheaspirone enantiomers (ꢀ)-5 and (+)-5, respectively.
(ꢀ)-(R)-5: woody, dry, cedarwood odor with a green,
earthy, tobacco and olibanum inflection and floral-fruity
nuances. Odor threshold (5 panellists): 13.7 ng/L air.
(+)-(S)-5: floral, woody-ambery, powdery, reminiscent of
Cetonal with natural fruity, orris-like facets. Odor thresh-
old (5 panellists): 9.8 ng/L air.
Following Scheme 4, regioselective hydrogenation of (ꢀ)-
11 and (+)-12 using Ni Raney as a catalyst afforded hemi-
acetals 13 and 14, respectively; each of them were obtained
as an inseparable mixture of diastereoisomers. The latter
compounds were not characterized and were used in the
next step. Thus, dehydratation of 13 and 14 with POCl3
and Et3N afforded compounds (ꢀ)-15 and (ꢀ)-16, respec-
tively. The removal of the acetyl protecting group by the
reaction with methanolic KOH and the following oxida-
tion of the obtained allyl alcohols by MnO2 treatment,
afforded dehydrotheaspirone isomers (ꢀ)-5 and (+)-5,
respectively. The enantiomeric excesses of the latter com-
pounds were easily measured by chiral GC analysis as
97% and 98%, respectively. These values also indicate the
ee of the starting materials (ꢀ)-11 and (+)-12 and the ee
of the synthesized (ꢀ)-(R) and (+)-(S) dehydrovomifoliol
3. All these data (absolute configuration and enantiomeric
purity) are in good agreement with those described above
(see Section 2.3) and those reported by other authors.15c,16b
3. Conclusions
A number of results have been achieved. We have reported
a new chemoenzymatic approach to all isomeric forms of
the 3-acetoxy-6-hydroxy-a-ionone. Our synthetic pathways
consist of the preparation of the diastereoisomerically pure
racemic 3,6-dihydroxy-a-ionone isomers and then in their
resolution by means of the combination of the lipase-med-
iated enantioselective acetylation and of the fractional crys-
tallization of the acetates obtained. The proposed process
is operationally simple, does not require demanding reac-
tion conditions or reagents, and the starting material is
the inexpensive 3,4-dehydro-b-ionone. The chiral building
blocks obtained were used for the synthesis of the enantio-
meric forms of the natural norterpenoid dehydrovomifoliol
3 and 8,9-dehydrotheaspirone 5. Finally, the odor proper-
ties of the latter compound were evaluated by professional
perfumers.
(–)-11
(+)-12
i
i
4. Experimental
4.1. General experimental
OH
13
OH
14
O
O
O
All moisture-sensitive reactions were carried out under a
static atmosphere of nitrogen. All reagents were of com-
mercial quality. Lipase from Porcine pancreas (PPL) type
II, Sigma, 147 units/mg; lipase from Candida rugosa
(CRL) type VII, Sigma, 1150 units/mg and Lipase from
Pseudomonas cepacia (PS), Amano Pharmaceuticals Co.,
Japan, 30 units/mg were employed in this work. TLC:
Merk Silica Gel 60F254 plates. Column chromatography
(CC): silica gel. GC–MS analyses: HP-6890 gas chromato-
graph equipped with a 5973 mass detector, using a HP-
5MS column (30 m · 0.25 mm, 0.25 lm film thickness;
Hewlett Packard) with the following temperature 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 (3) 22.2, tR (5) 18.0, tR (7)
21.6, tR (8) 24.8, tR (10) 22.4, tR (11) 23.4, tR (12) 23.2,
tR (15) 19.9, tR (16) 19.5; mass spectra: m/z (rel %). Chiral
GC analyses: DANI-HT-86.10 gas chromatograph; enan-
tiomeric excesses determined on a CHIRASIL DEX
CB-Column with the following temperature program
80 ꢁC (0 min)–2 ꢁC/min–100 ꢁC (0 min)–1 ꢁC/min–110 ꢁC
(0 min)–25 ꢁC/min–180 ꢁC (2 min); tR given in min:
tR((+)-5) 16.8, tR((ꢀ)-5) 15.3. Optical rotations: Jasco-
AcO
AcO
AcO
AcO
ii
ii
55%
57%
O
(–)-16
(–)-15
iii, iv
iii, iv
87%
87%
O
O
(–)-5
(+)-5
O
(R)-8,9-dehydrotheaspirone
O
(S)-8,9-dehydrotheaspirone
Scheme 4. Preparation of the enantiomeric forms of 8,9-dehydrotheaspi-
rone 5 starting from acetates 11 and 12. Reagents and conditions: (i) H2,
AcOEt, Ni Raney cat.; (ii) POCl3, Et3N, 0 ꢁC; (iii) KOH, MeOH; (iv)
MnO2, CH2Cl2, rt.
2.5. Olfactory evaluation of the enantiomeric forms of
dehydrotheaspirone 5
1
DIP-181 digital polarimeter. H and 13C Spectra: CDCl3
soln at rt; Bruker-AC-400 spectrometer at 400 and
100 MHz, respectively; chemical shifts in ppm rel to inter-
nal SiMe4 (=0 ppm), J values in Hz. IR spectra were
recorded on a Perkin–Elmer 2000 FT-IR spectrometer;
films; m in cmꢀ1. Melting points were measured on a Reic-
The enantiomerically enriched forms of 8,9-dehydrotheas-
pirone were evaluated by qualified perfumers (Givaudan
Schweiz AG, Fragrance Research). The following results
were obtained:

S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
2577
hert apparatus, equipped with a Reichert microscope, and
are uncorrected. Microanalyses were determined on an
analyzer 1106 from Carlo Erba.
acetate (1:1) to give pure trans-3,6-dihydroxy-a-ionone 10
(20.9 g, 59% yield, 98% chemical purity (GC)) as colorless
1
crystals: mp 114–115 ꢁC (lit.20a mp 116–117 ꢁC); H NMR
(400 MHz, CDCl3) d 6.83 (d, J = 15.8 Hz, 1H), 6.34 (d,
J = 15.8 Hz, 1H), 5.64–5.60 (m, 1H), 4.30 (br s, 1H), 2.28
(s, 3H), 1.91 (br s, 1H), 1.87 (ddd, J = 13.4, 6.5, 1.4 Hz,
1H), 1.79 (s, 1H), 1.67–1.57 (m, 1H), 1.63 (t, J = 1.7 Hz,
3H), 1.04 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz) d
198.3, 148.6, 136.8, 129.4, 128.8, 78.9, 65.4, 44.0, 39.8,
27.8, 25.0, 22.4, 17.3. IR (Nujul, cmꢀ1) 3360, 3315, 1684,
1619, 1454, 1109, 990. GC–MS m/z (rel intensity) 224
(M+, 1), 206 (M+ꢀH2O, 17), 191 (8), 164 (30), 150 (31),
135 (31), 125 (49), 111 (32), 108 (100), 97 (23), 91 (11), 77
(15), 71 (15), 55 (15). Anal. Calcd for C13H20O3: C,
69.61; H, 8.99. Found: C, 69.55; H, 9.03.
4.2. Synthesis of racemic (3RS,6SR)-3,6-dihydroxy-a-ionone
and of (3SR,6SR)-3,6-dihydroxy-a-ionone
4.2.1. (3RS,6SR)-3,6-Dihydroxy-a-ionone ( )-8. A solu-
tion of 3,4-dehydro-b-ionone 6 (25 g, 132 mmol) and Rose
Bengal (0.3 g, 0.3 mmol) in methanol (600 mL) was irradi-
ated with 12 8-W visible light lamps with continuous purg-
ing of dry oxygen until starting compound 6 was less than
5% of the mixture (2 days, GC analysis). The reaction was
then flushed with nitrogen and a sample of the solution
(10 mL) was concentrated in vacuo and purified by CC
(hexane/Et2O from 95:5 to 7:3) to allow the isolation of
the stable peroxy-derivative 7. 1H NMR (400 MHz,
CDCl3) d 6.97 (d, J = 16.1 Hz, 1H), 6.42 (d, J = 16.1 Hz,
1H), 6.32 (dq, J = 6.2, 1.7 Hz, 1H), 4.61–4.55 (m, 1H),
2.27 (s, 3H), 2.01 (dd, J = 13.0, 3.8 Hz, 1H), 1.87 (d,
J = 1.7 Hz, 3H), 1.36 (dd, J = 13.0, 2.0 Hz, 1H), 1.13 (s,
3H), 0.98 (s, 3H); 13C NMR (100 MHz) d 196.6, 142.3,
138.8, 130.6, 124.7, 84.2, 72.4, 40.1, 35.1, 28.9, 27.9, 25.0,
19.4. IR (film, cmꢀ1) 1701, 1679, 1629, 1441, 1363, 1256,
986. GC–MS m/z (rel intensity) 222 (M+, 10), 179 (54),
166 (9), 151 (4), 137 (11), 125 (50), 107 (22), 95 (100), 83
(24), 67 (15), 55 (20). The remaining solution was treated
with thiourea (12 g, 158 mmol) stirring at room tempera-
ture for 12 h and then concentrated at reduced pressure.
The residue obtained was chromatographed (hexane/Et2O
from 9:1 to 1:1) to afford starting 6 (1.1 g, 5.7 mmol) and
cis-3,6-dihydroxy-a-ionone 8 (15.3 g, 68.3 mmol, 56% yield
based on reacted 6, 96% chemical purity (GC)) as a color-
less oil that crystallized on standing: mp 71–73 ꢁC; 1H
NMR (400 MHz, CDCl3) d 6.74 (d, J = 16.4 Hz, 1H),
6.47 (d, J = 16.4 Hz, 1H), 5.65 (s, 1H), 4.26 (br s, 1H),
2.63 (br s, 1H), 2.55 (s, 1H), 2.28 (s, 3H), 1.79 (dd,
J = 13.4, 6.0 Hz, 1H), 1.71 (dd, J = 13.4, 8.0 Hz, 1H),
1.65 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H); 13C NMR
(100 MHz) d 198.2, 148.0, 136.8, 130.3, 128.3, 77.2, 64.9,
41.9, 38.4, 27.9, 24.4, 24.2, 19.1. IR (film, cmꢀ1) 3364,
3317, 1683, 1459, 1250, 1022, 988. GC–MS m/z (rel inten-
sity) 191 (<1), 164 (1), 155 (5), 137 (1), 121 (1), 111 (1), 105
(43), 104 (100), 91 (6), 85 (2), 79 (5), 77 (5), 71 (4). Anal.
Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.75;
H, 9.00.
4.3. General procedure for lipase-mediated resolution of
racemic substrates ( )-8 and ( )-10
A mixture of the racemic diol (15 g, 67 mmol), lipase PS
(15 g), vinyl acetate (50 mL), and t-BuOMe (180 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 by filtration of the enzyme and evaporation
of the solvent at reduced pressure. The residue was purified
by chromatography using hexane-diethyl ether as eluent to
give the enantiomeric enriched (3S)-acetate and (3R)-diol.
The latter compound was converted into the corresponding
(3R)-acetate by treatment with pyridine (20 mL) and acetic
anhydride (30 mL) and left at rt until no more starting diol
was detected by TLC analysis (4 h) after which the solvents
were removed at reduced pressure. The enantiomeric purity
of both acetates was increased by crystallization from hex-
ane/ethyl acetate (3:1). The recrystallization procedure was
identical for all the acetates and the number of the steps
depend upon the ee of the starting compounds. A general
protocol is the following.
The crystals were filtered and washed with a minimum
amount of cold solvent. The liquid was concentrated in
vacuo and the specific rotation values were measured for
both phases. Usually, for ee of the starting acetates inferior
to 60–70%, racemic crystals were less soluble than the
enantiomeric enriched ones. The corresponding solid crop
showed specific rotation values inferior to those measured
for the liquid. Thus the latter phase was submitted again
to the crystallization process, which was repeated using
the mother liquors until the crystals showed an optical
rotation value superior to that measured for the liquid.
At this point, a further crystallization of the solid afforded
enantiomerically pure acetate whose specific rotation value
does not increase by recrystallization.
4.2.2. (3SR,6SR)-3,6-Dihydroxy-a-ionone ( )-10. A solu-
tion of 3,4-dehydro-b-ionone 6 (30 g, 158 mmol) in diethyl
ether (250 mL) was treated with MCPBA (29.4 g,
170 mmol) stirring at 0 ꢁC until no more starting com-
pound 6 was detected by TLC analysis (3 h). The reaction
was then treated with a 5% solution of Na2S2O5 aq
(100 mL) and stirred at rt for 2 h. Powdered NaHCO3
(20 g, 238 mmol) was then added portionwise and the mix-
ture was diluted with water (80 mL). The aqueous phase
was separated and extracted with ether (2 · 100 mL). The
organic layer was washed in turn with saturated NaHCO3
solution (100 mL) and brine (100 mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by chromatography (hexane/Et2O from 7:3 to 1:2)
and the obtained oil was crystallized from hexane/ethyl
4.3.1. Resolution of (3RS,6SR)-3,6-dihydroxy-a-ionone ( )-
8. According to the general procedure, ( )-8 was con-
verted into acetate (ꢀ)-11 and diol (+)-8. The latter com-
pound was acetylated to give (+)-11 and both esters were
submitted to the fractional crystallization procedure to
afford enantiopure (ꢀ)-11 (3.6 g, 20% yield after 3 crystal-
lizations) and (+)-11 (2.8 g, 16% yield after 4 crystalli-
zations) showing the following spectral data:

2578
S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
(3S,6R)-3-Acetoxy-6-hydroxy-a-ionone (ꢀ)-11: 98% chem-
tected by TLC analysis. The mixture was diluted with water
(50 mL) and extracted with CH2Cl2 (3 · 50 mL). The com-
bined organic phases were washed with brine, dried over
Na2SO4, and concentrated. The residue was dissolved in
CH2Cl2 (20 mL) and treated with MnO2 (1.5 g, 17.2 mmol)
while stirring at rt for 4 h. The mixture was then filtered.
The organic phase was concentrated under reduced
pressure and the residue purified by chromatography
(hexane/Et2O from 9:1 to 2:1) to afford pure dehydrovomi-
foliol 3.
20
ical purity (GC), ½aꢁD ¼ ꢀ198:8 (c 1, CHCl3), mp 69–
72 ꢁC. 1H NMR (400 MHz, CDCl3) d 6.71 (d, J =
15.8 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.61 (s, 1H),
5.34–5.26 (m, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 1.88 (dd,
J = 14.2, 6.4 Hz, 1H), 1.78 (s, 1H), 1.75 (dd, J = 14.2,
6.1 Hz, 1H), 1.67 (t, J = 1.5 Hz, 3H), 1.02 (s, 3H), 0.98
(s, 3H); 13C NMR (100 MHz) d 197.6, 170.5, 147.0,
139.5, 130.2, 123.9, 77.6, 67.5, 38.4, 37.7, 28.1, 24.3, 23.8,
21.2, 18.7. IR (film, cmꢀ1) 3492, 1734, 1675, 1624, 1361,
1245, 1120, 1021, 991, 948. GC–MS m/z (rel intensity)
248 (M+ꢀH2O, <1), 233 (2), 224 (5), 206 (33), 191 (32),
163 (82), 150 (74), 135 (42), 123 (95), 108 (100), 93 (22),
91 (22), 77 (21), 69 (14), 55 (20). Anal. Calcd for
C15H22O4: C, 67.64; H, 8.33. Found: C, 67.80; H, 8.35.
4.4.1. (ꢀ)-Dehydrovomifoliol (ꢀ)-3. According to the gen-
eral procedure (ꢀ)-11 was converted into (6R)-3-oxy-6-hy-
droxy-a-ionone (ꢀ)-3 (230 mg, 69%) as a colorless oil that
crystallized on standing: 97% chemical purity (GC), mp
20
68–70 ꢁC; ½aꢁD ¼ ꢀ219:5 (c 0.5, CH2Cl2). 1H NMR
(3R,6S)-3-Acetoxy-6-hydroxy-a-ionone (+)-11: 98% chem-
(400 MHz, CDCl3) d 6.84 (d, J = 15.7 Hz, 1H), 6.47 (d,
J = 15.7 Hz, 1H), 5.97–5.94 (m, 1H), 2.49 (d,
J = 17.1 Hz, 1H), 2.37 (s, 1H), 2.34 (dd, J = 17.1, 1.1 Hz,
1H), 2.30 (s, 3H), 1.89 (d, J = 1.5 Hz, 3H), 1.11 (s, 3H),
1.03 (s, 3H); 13C NMR (100 MHz) d 197.4, 197.0, 160.5,
145.1, 130.4, 127.7, 79.2, 49.6, 41.4, 28.2, 24.3, 22.9, 18.6.
IR (film, cmꢀ1) 3438, 1698, 1651, 1629, 1266, 1076, 987.
GC–MS m/z (rel intensity) 222 (M+, 1), 204 (M+ꢀH2O,
1), 189 (1), 180 (3), 166 (16), 149 (7), 124 (100), 109 (3),
95 (8), 77 (4), 69 (6), 55 (5). Anal. Calcd for C13H18O3:
C, 70.24; H, 8.16. Found: C, 70.35; H, 8.15.
20
ical purity (GC), ½aꢁD ¼ ꢀ194:3 (c 1, CHCl3), mp 70–
1
73 ꢁC. IR, H NMR, MS: in accordance with that of (ꢀ)-
11.
4.3.2. Resolution of (3SR,6SR)-3,6-dihydroxy-a-ionone ( )-
10. According to the general procedure, ( )-10 was con-
verted in the acetate (+)-12 and diol (ꢀ)-10. The latter
compound was acetylated to give (ꢀ)-12 and both esters
were submitted to the fractional crystallization procedure
to afford enantiopure (+)-12 (2.1 g, 12% yield after 3 crys-
tallizations) and (ꢀ)-12 (1.75 g, 10% yield after 4 crystalli-
zations) showing the following spectral data:
4.4.2. (+)-Dehydrovomifoliol (+)-3. According to the gen-
eral procedure (+)-12 was converted into (6S)-3-oxy-6-hy-
droxy-a-ionone (+)-3 (240 mg, 72%) as a colorless oil that
(3S,6S)-3-Acetoxy-6-hydroxy-a-ionone (+)-12: 98% chemi-
20
cal purity (GC), mpà 132–133 ꢁC; ½aꢁD ¼ þ164 (c 1,
crystallized on standing: 96% chemical purity (GC), mp
20
68–69 ꢁC; lit.16a 69–70 ꢁC, ½aꢁD ¼ þ222 (c 0.5, CH2Cl2).
CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.82 (d,
1
IR, H NMR, MS: in accordance with that of (ꢀ)-3.
J = 15.8 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 5.57–5.52
(m, 1H), 5.41–5.32 (m, 1H), 2.29 (s, 3H), 2.06 (s, 3H),
1.90 (ddd, J = 13.4, 6.5, 1.4 Hz, 1H), 1.77 (s, 1H), 1.78–
1.68 (m, 1H), 1.64 (t, J = 1.5 Hz, 3H), 1.08 (s, 3H), 0.94
(s, 3H); 13C NMR (100 MHz) d 198.0, 170.7, 148.0,
139.0, 129.6, 124.3, 78.6, 68.5, 39.7, 39.6, 27.9, 24.8, 22.3,
21.2, 17.5. IR (film, cmꢀ1) 3502, 1732, 1675, 1651, 1362,
1251, 1113, 1021, 973. GC–MS m/z (rel intensity) 248
(M+ꢀH2O, <1), 233 (1), 224 (7), 206 (53), 191 (33), 163
(100), 150 (56), 135 (33), 121 (40), 108 (85), 93 (21), 91
(20), 77 (17), 69 (15), 55 (20). Anal. Calcd for C15H22O4:
C, 67.64; H, 8.33. Found: C, 67.70; H, 8.35.
4.5. General procedure for conversion of 3-acetoxy-6-
hydroxy-a-ionone isomers in the 8,9-dehydrotheaspirone
enantiomers
A solution of acetates 11 or 12 (1 g, 3.8 mmol) in AcOEt
(50 mL) was hydrogenated at atmospheric pressure using
Ni Raney as a catalyst. After complete consumption of
the starting materials (TLC monitoring, 1 h), the organic
phases were filtered, and concentrated in vacuo. The resi-
dues were dissolved in triethylamine (10 mL) and cooled
to 0 ꢁC. POCl3 (1 mL, 10.7 mmol) was added dropwise to
the resulting solutions and the reactions were vigorously
stirred for 30 min. The mixtures were then poured onto
an ice cooled satd solution of NaHCO3 (100 mL) and then
extracted with diethyl ether (2 · 50 mL). The combined
organic phases were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residues were purified by
chromatography (eluting with hexane/ether/triethylamine
94:5:1) to afford pure compounds 15 and 16, respectively,
as a colorless oil. The latter spiro derivatives were treated
with a solution of KOH (1 g, 17.8 mmol) in methanol
(10 mL) stirring at rt until no more starting acetates were
detected by TLC analysis. The mixtures were diluted with
water (50 mL) and extracted with CH2Cl2 (3 · 50 mL).
The combined organic phases were washed with brine,
dried over Na2SO4, and concentrated. The residues were
dissolved in CH2Cl2 (20 mL) and treated with MnO2 (2 g,
(3R,6R)-3-Acetoxy-6-hydroxy-a-ionone (ꢀ)-12: 98% chem-
20
ical purity (GC), mp 129–130 ꢁC; ½aꢁD ¼ ꢀ162:6 (c 1,
1
CHCl3). IR, H NMR, MS: in accordance with that of
(+)-12.
4.4. General procedure for conversion of 3-acetoxy-6-
hydroxy-a-ionone isomers in the dehydrovomifoliol
enantiomers
A sample of acetate 11 or 12 (400 mg, 1.5 mmol) was trea-
ted with a solution of KOH (1 g, 17.8 mmol) in methanol
(10 mL) stirring at rt until no more starting acetate was de-
For racemic 11 mp is 88–90 ꢁC.
à For racemic 12 mp is 118–119 ꢁC.

S. Serra et al. / Tetrahedron: Asymmetry 18 (2007) 2573–2580
2579
20
23 mmol) stirring at rt for 2 h. The mixtures were then fil-
(S)-8,9-Dehydrotheaspirone (+)-5: mp 79–81 ꢁC; ½aꢁD
¼
1
tered, the organic phases concentrated under reduced pres-
sure and the residues were purified by chromatography
(hexane/Et2O from 95:5 to 9:1) to afford pure dehydrothe-
aspirone 5 as a colorless oil that crystallized on standing.
þ35 (c 1, CHCl3). IR, H NMR, MS: in accordance with
that of (ꢀ)-5.
Acknowledgment
4.5.1. (R)-8,9-Dehydrotheaspirone (ꢀ)-5. According to the
general procedure, (ꢀ)-11 afforded acetate (ꢀ)-15 (0.54 g,
57% yield), which was transformed into (R)-dehydrotheas-
pirone (ꢀ)-5 (0.39 g, 87% yield). The latter compounds
showed the following analytical data:
The authors would like to thank Dr. Philip Kraft (Givau-
dan Schweiz AG) for the odor evaluation of the dehydro-
theaspirone enantiomers.
(5R,8S)-2,6,10,10-Tetramethyl-1-oxa-spiro[4.5]deca-2,6-
References
dien-8-yl acetate (ꢀ)-15: 99% chemical purity (GC),
20
1
½aꢁD ¼ ꢀ17:4 (c 1, CHCl3). H NMR (400 MHz, CDCl3)
d 5.37 (s, 1H), 5.27–5.20 (m, 1H), 4.44–4.40 (m, 1H), 2.69
(dm, J = 15.7 Hz, 1H), 2.40 (dm, J = 15.7 Hz, 1H), 2.03
(s, 3H), 1.79–1.74 (m, 8H), 1.02 (s, 3H), 0.93 (s, 3H); 13C
NMR (100 MHz) d 170.8, 154.7, 141.6, 121.1, 94.2, 90.1,
68.1, 38.4, 37.1, 35.0, 23.5, 22.5, 21.3, 17.9, 13.3. IR (film,
cmꢀ1) 1737, 1683, 1380, 1246, 1189, 1016, 973, 951. GC–
MS m/z (rel intensity) 251 (M++1, 3), 250 (M+, 23), 208
(2), 194 (37), 190 (36), 175 (100), 152 (48), 147 (37), 131
(29), 120 (64), 109 (36), 105 (51), 91 (23), 79 (12), 77 (13),
55 (7). Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found:
C, 71.80; H, 8.90.
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20
(R)-8,9-Dehydrotheaspirone (ꢀ)-5: mp 80–82 ꢁC; ½aꢁD
¼
1
ꢀ34:2 (c 1, CHCl3). H NMR (400 MHz, CDCl3) d 5.69
(br s, 1H), 4.52–4.48 (m, 1H), 3.02 (dm, J = 15.7 Hz,
1H), 2.46 (dm, J = 15.7 Hz, 1H), 2.41 (d, J = 16.8 Hz,
1H), 2.23 (d, J = 16.8 Hz, 1H), 1.97 (d, J = 1.5 Hz, 3H),
1.82–1.79 (m, 3H), 1.09 (s, 3H), 1.01 (s, 3H); 13C NMR
(100 MHz) d 198.0, 164.7, 155.2, 123.9, 93.7, 90.7, 48.8,
40.6, 37.1, 22.8, 22.7, 18.2, 13.1. IR (film, cmꢀ1) 1675,
1628, 1382, 1262, 1188, 935. GC–MS m/z (rel intensity)
206 (M+, 68), 191 (16), 173 (6), 163 (7), 150 (53), 136
(35), 121 (28), 108 (100), 93 (50), 91 (21), 79 (15), 77 (22),
53 (9). Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found:
C, 75.55; H, 8.82.
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general procedure, (+)-12 afforded acetate (ꢀ)-16 (0.52 g,
55% yield), which was transformed into (S)-dehydrotheas-
pirone (+)-5 (0.37 g, 87% yield). The latter compounds
showed the following analytical data:
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(5S,8S)-2,6,10,10-Tetramethyl-1-oxa-spiro[4.5]deca-2,6-
20
dien-8-yl acetate (ꢀ)-16: ½aꢁ ¼ ꢀ48:7 (c 1, CHCl3). 1H
NMR (400 MHz, CDCl3) dD5.38–5.30 (m, 1H), 5.27–5.23
(m, 1H), 4.45–4.40 (m, 1H), 2.78 (dm, J = 15.7 Hz, 1H),
2.44 (dm, J = 15.7 Hz, 1H), 2.03 (s, 3H), 1.83 (ddd,
J = 13.2, 6.5, 1.4 Hz, 1H), 1.75–1.78 (m, 3H), 1.73 (t,
J = 1.5 Hz, 3H), 1.57 (dd, J = 13.2, 9.1 Hz, 1H), 1.06 (s,
3H), 0.94 (s, 3H); 13C NMR (100 MHz) d 170.6, 155.1,
143.8, 119.4, 94.0, 90.8, 69.1, 39.3, 39.0, 38.7, 23.6, 22.2,
21.3, 17.1, 13.2. IR (film, cmꢀ1) 1735, 1713, 1376, 1256,
1101, 1053, 1011, 972, 936. GC–MS m/z (rel intensity)
251 (M++1, 2), 250 (M+, 17), 208 (2), 194 (31), 190 (32),
175 (100), 152 (42), 147 (38), 131 (36), 120 (73), 109 (35),
105 (58), 91 (24), 79 (13), 77 (14), 55 (8). Anal. Calcd for
C15H22O3: C, 71.97; H, 8.86. Found: C, 71.85; H, 8.90.
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