Lipase-mediated synthesis of the enantiomeric forms of 4,5-epoxy4,5-dihydro-α-ionone, and 5,6-epoxy-5,6-dihydro-β-ionone. A new direct access to enantiopure (R)-, and (5)-α-ionone

Article abstract of DOI:10.1039/a808780f

Stereoselective lipase-mediated esterifications of epoxy-a-ionpl 5, and epoxy-ionol 9 afTorded suitable precursors of the enantiomers of the corresponding oxidised derivatives epoxy-u-ionone 3, and epoxy-ionone 4. An interesting development of this work is the easy conversion of enantiopure 3a, and 3b into highly valuable enantiopure (5)-, and (R)-ionone (1a, and Ib) via a mild deoxygenation reaction.

Full text of DOI:10.1039/a808780f

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Lipase-mediated synthesis of the enantiomeric forms of 4,5-epoxy-
4,5-dihydro-á-ionone and 5,6-epoxy-5,6-dihydro-â-ionone. A new
direct access to enantiopure (R)- and (S)-á-ionone
Josefina Aleu,† Elisabetta Brenna,* Claudio Fuganti and Stefano Serra
Dipartimento di Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy
Received (in Cambridge) 10th November 1998, Accepted 7th December 1998
Stereoselective lipase-mediated esterifications of epoxy-α-ionol 5 and epoxy-β-ionol 9 afforded suitable precursors of
the enantiomers of the corresponding oxidised derivatives epoxy-α-ionone 3 and epoxy-β-ionone 4. An interesting
development of this work is the easy conversion of enantiopure 3a and 3b into highly valuable enantiopure (S)- and
(R)-ionone (1a and 1b) via a mild deoxygenation reaction.
Amongst the naturally occurring and synthetic polyoxygenated
compounds possessing the C13 ionone skeleton reported in
recent years,1 epoxy ionones 3 and 4, directly accessible from
α- and β-ionone 1 and 2, respectively, upon peracid treatment,2
the major drawback of the twenty crystallisations of the (Ϫ)-
menthyl hydrazone needed to obtain optically pure (R)-α-
ionone, and the ten crystallisations to prepare the (S)-enantio-
mer.13 Since the work of Eugster, apparently no improvements
in the methods of synthesis of enantiomerically pure 3 and 4
have been reported, apart from the preparation of enantio-
merically enriched (ϩ)-4a and (Ϫ)-4b through a solid state
kinetic resolution of the racemic material,14 and the prepar-
ation of the precursors of (R)- and (S)-α-ionone from the
enantiomers of α-damascone.15
Recently, we described a new access to the enantiomeric
forms of α-ionone based on the preparation of the enantiopure
diastereoisomers of α-ionol via lipase-mediated selective acyl-
ation of the racemic mixture, followed by MnO2 oxidation.16
The relative simplicity of this procedure prompted us to study
an extension of this method to the preparation of enantio-
merically pure 3a,b and 4a,b starting from the racemic
materials. We report herein on the stereoselective enzyme-
mediated esterification of cis-epoxy-α-ionol 5 and epoxy-β-
ionol 9, affording suitable precursors of the enantiomers of the
corresponding oxidised derivatives 3 and 4. A further develop-
ment of this work is the easy conversion of 3a and 3b into
highly valuable enantiopure (S)- and (R)-ionone (1a and 1b) via
a mild deoxygenation reaction.17
Results and discussion
4,5-Epoxy-4,5-dihydro-á-ionone
It was known in the literature11 that peracid epoxidation of
α-ionone afforded predominantly the cis-epoxide. Both 1H
NMR and GC data showed that the mixture we obtained upon
m-chloroperbenzoic acid treatment of α-ionone at 0 ЊC con-
tained racemic cis-epoxy-α-ionone and racemic trans-epoxy-α-
ionone in a 5:1 ratio.
are particularly important. Whereas epoxy-β-ionone 4 has been
identified as a flavour component in many foods, including,
among others, carrots3 and black tea,4 epoxy-α-ionone 3 was
used as a starting material for one of the first syntheses of
γ-ionone.5 Subsequently, enantiomerically pure 3a and 3b were
used by Eugster et al. as starting materials in the synthesis of
a variety of naturally occurring hydroxylated derivatives of 1
and 2 and of oxidised carotenoids such as isozeaxanthine and
diepoxy-β,β-carotene.6–11 The enantiomers of 3 needed for this
synthesis were prepared by peracid treatment of (S)- and (R)-α-
ionone 1.12 Enantiomerically pure (Ϫ)-4b was obtained from
(Ϫ)-3a in a lengthy five step sequence.8 The aforementioned
methods to enantiomerically pure 3a,b and 4b suffered from
Preliminary studies of lipase-mediated acetylation in tert-
butyl methyl ether in the presence of vinyl acetate as an acyl
donor were performed on the 1:1 mixture of the two racemic
diastereoisomers of cis-4,5-epoxy-α-ionol 5a,c and 5b,d ob-
tained upon reduction of the epoxidation mixture with sodium
borohydride. The trans-stereoisomers made up an estimated
1
17% of the total content, on the basis of the H NMR spectra
(δH 3.07 C(4)Hcis, 2.98 C(4)Htrans). The enzyme-catalysed
experiments were followed by means of chiral GC analysis, as
under suitable conditions the acetate derivatives 6a–d of the
four stereoisomers 5a–d gave rise to four baseline-separated
peaks on a permethylated β-cyclodextrin column. In order to
† Present address: Departamento Quimica Organica, Facultad de
Ciencias, Apdo. 40, Poligono Rio, S. Pedro, 11510-Puerto Real (Cadiz),
Spain.
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Table 1 Results of enzyme-mediated acetylation of (i) 4,5-epoxy-4,5-
dihydro-α-ionol 5 (5:1 mixture of racemic cis- and racemic trans-
epoxides), (ii) racemic 5,6-epoxy-5,6-dihydro-β-ionol 9, (iii) α-ionol
(1:1 mixture of two racemic diastereoisomers)16
.
(i) Epoxy-α-ionol 5
Products
cis:trans 6b:6c
6b
6c
Enzyme
(GC)
(GC)
ee (%) (GC) ee (%) (GC)
PPL
CCL
4.4:1
3.4:1
1.6:1
86
64
99
79
78
99
1
1
:1.8
:1.4
Lipase PS 4.4:1
(ii) Epoxy-β-ionol 9
Enzyme
10c:10d
(GC)
10c
10d
ee (%) (GC) ee (%) (GC)
PPL
CCL
Lipase PS
1:3.7
1:1
1:2.3
99
99
99
99
99
99
(iii) α-Ionol
(6S,9R):(6R,9R) (6S,9R)
(6R,9R)
Enzyme
(GC)
ee (%) (GC) ee (%) (GC)
PPL
CCL
Lipase PS
3:1
1:1.15
1:1
90
72
99
64
79
99
assign the correct stereochemistry to 6a–d a sample of optically
pure (S)-α-ionone 1a16 was treated with m-chloroperbenzoic
acid, reduced with sodium borohydride, and acetylated in acetic
anhydride and pyridine: the first two peaks of the chiral GC
chromatogram were thus found to be the two cis-stereoisomers
having the (S)-configuration at C6. We then assumed that the
two diastereoisomers preferentially acetylated by the lipase
(second and third peak) had the (R)-configuration at C9, as we
had already verified this by means of chemical correlation for
the enzyme-mediated esterification of α-ionol in some previous
work.16 As we shall see later on in this work, this assumption was
subsequently confirmed at the end of the synthetic sequence.
The results of the bio-catalysed esterifications of 5a–d are
reported in Table 1. PPL mediated acetylation afforded enan-
tiomerically enriched acetate derivatives 6b (second GC peak,
ee 86%) and 6c (third GC peak, ee 79%) in a 1.6:1 ratio,
the overall content of the trans stereoisomers of the starting
material being maintained. Lower enantiomeric excesses were
shown by the same two diastereoisomers produced in CCL-
catalysed reactions, with a slight preference for diastereoisomer
6c. The use of Lipase PS (from Pseudomonas cepacia) as a
catalyst assured enantiospecific acetylation of substrates 5b
and 5c, with very low diastereoselectivity. These results clearly
showed that an efficient method for the separation of the two
diastereoisomers of epoxy α-ionol 5a,c and 5b,d was to be
found, in order to prepare suitable precursors of enantiopure
cis-epoxy-α-ionone taking advantage of the enantiospecificity
shown by Lipase PS.
Table 2 Results of Lipase PS mediated acetylations of the two separ-
ate diastereoisomers 5a,c and 5b,d
Recovered alcohol:
ee (%), de (%)a
Acetylated product:
ee (%), de (%)a
Substrate
Eb,c (%)
5a,c
5b,d
5a: 47, 84
5d: 91, 65
6c: 99, 84
6b: 99, 67
316, 32
635, 48
a Ees and des were measured by GC. b Enantiomeric ratio. c Conversion.
unreacted alcohol 5a, having ee = 47% (GC) and de = 84%
(GC) (E = 316, c = 32).19 Saponification of substrate 6c with
methanolic potassium hydroxide afforded enantiopure deriv-
ative 5c {de = 84%, 1H NMR; [α]D20 = 141 (c 0.49, CHCl3)}, which
was oxidised with MnO2 to give (ϩ)-4,5-epoxy-α-ionone 3b
{ee > 99%, GC; de = 64%, GC and 1H NMR; [α]D20 = 141 (c 1.3,
EtOH); lit.,11 [α]D20 = 210 (c 1, EtOH)}, thus confirming the
assumption of the (R)-configuration at C9 made at the begin-
ning of the work. (ϩ)-4,5-Epoxy-α-ionone 3b was brought to
diastereoisomeric purity {[α]2D0 = 207 (c 1.2, EtOH)} by means of
a careful chromatographic purification on a silica gel column.
Treatment of enantiopure 5c (de = 84%) with a saturated
solution of HCl in methanol20 (Scheme 1) allowed us to isolate
for the first time an enantiomerically pure sample of chloro-
hydrin derivative 7a (de = 98%, 1H NMR) showing [α]D20 = Ϫ30,
(c 0.51, CHCl3), which was soon converted into the corre-
sponding oxidised product 8a {ee > 99%, GC; de > 99%, GC;
[α]2D0 = Ϫ23 (c 0.66, CHCl3)}. To the best of our knowledge, no
previous resolution of racemic chlorohydrin 8 has ever been
reported in the literature.
Fortunately, the two racemic diastereoisomers of cis-epoxy-
α-ionol could be separated by column chromatography and
submitted to Lipase PS-mediated esterification separately
(Scheme 1 and Table 2).
The first eluted racemic stereoisomer 5a,c (first and third
peak in the GC analysis of the corresponding acetate deriv-
atives) was found to contain 6% of racemic trans-epoxy-α-ionol
(de18 = 88%, GC and 1H NMR). Enzyme-mediated acetylation
gave enantiopure (GC) acetate derivative 6c {third peak, GC;
A useful development of the work was then the conversion
of the optically active dextrorotatory isomer of cis-epoxy-α-
ionone ([α]2D0 = 141) into (R)-α-ionone by means of reaction with
trimethylchlorosilane and sodium iodide in acetonitrile17
(Scheme 1). The sample of (R)-1b was found to be enantio-
merically pure by chiral GC analysis, thus showing that the
1
de = 84%, GC and H NMR; [α]2D0 = 179 (c 1.00, CHCl3)}, and
272
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Scheme 1
trans-epoxide by-product lowering the diastereoisomeric purity
merically enriched alcohol 5d (ee = 91%, GC, de = 65%, GC;
of 3b had the same configuration at C6.
E = 635, c = 48). Treatment of substrate 6b with potassium
hydroxide in methanol afforded cis-epoxy-α-ionol 5b {ee >
The second eluted diastereoisomer 5b,d (second and fourth
peaks in the GC analysis of the corresponding acetate deriv-
atives) was found to contain the corresponding trans-epoxide
stereoisomer (de = 66%, GC and 1H NMR). Lipase PS-
mediated acetylation of 5b,d allowed us to obtain enantiopure
acetate derivative 6b (second peak, GC) showing de = 67% (GC
1
99%, GC; de = 88%, H NMR; [α]2D0 = Ϫ142 (c 0.57, CHCl3)},
which was converted into enantiopure 3a (de = 89%, GC and
1H NMR) showing [α]D20 = Ϫ199 (c 0.61, CHCl3) {lit.,6 [α]2D0
=
Ϫ210 (c 0.59, CHCl3)}, upon oxidation with MnO2 in methyl-
ene chloride. The oxirane ring of derivative 5b (ee > 99%,
de > 88%) was opened by means of gaseous HCl in methanol to
1
and H NMR) and [α]2D0 = Ϫ56 (c 1.04, CHCl3), and enantio-
J. Chem. Soc., Perkin Trans. 1, 1999, 271–278
273

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give enantiopure chlorohydrin 7b {ee > 99%, GC; de = 98%, 1H
NMR; [α]2D0 = 46 (c 0.72, CHCl3)} which was oxidised to 8b by
reaction with MnO2 in methylene chloride. The other enantio-
mer of chlorohydrin 8 was thus obtained in enantiopure form
{ee > 99%, GC; de > 99%; [α]2D0 = 24 (c 0.52, CHCl3)}.
An enantiopure sample of (S)-ionone 1a was prepared by
treatment of laevorotatory 3a ([α]2D0 = Ϫ199) with trimethyl-
chlorosilane and sodium iodide in acetonitrile, thus showing the
efficiency of this resolution procedure for the synthesis of both
the enantiomers of the precious fragrance α-ionone.
NMR) in 22% yield. Higher conversion and worse diastereo-
selection were observed in Lipase PS-catalysed acetylation: the
acetate derivative was found to be a 2.3:1 mixture of enantio-
pure 10d and 10c (45% yield). On the contrary, the use of CCL
led to a complete loss of diastereoselectivity, as a 1:1 mixture
of enantiopure 10c and 10d was obtained.
As the diastereoselectivity of these enzymic reactions was
poor, the preparation of the enantiomers of epoxy-β-ionone
required the complete separation of the two diastereoisomers
of epoxy-β-ionol. No separation could be achieved by column
chromatography, so we decided to rely upon the fractional crys-
tallisation of some crystalline derivatives. As a matter of fact,
in some previous work16 the crystallisation of 4-nitrobenzoate
esters of α-ionol had allowed us to obtain diastereoisomeric
enrichment.
5,6-Epoxy-5,6-dihydro-â-ionone
For the sake of completeness the same preliminary studies
(Table 1) of enzyme-mediated acetylation in tert-butyl methyl
ether solution, in the presence of vinyl acetate, were performed
on the 1:1 mixture of the two racemic diastereoisomers of 5,6-
epoxy-5,6-dihydro-β-ionol 9a–d, prepared upon reaction of
Enantiopure acetate derivative 10d, prepared by PPL-
mediated acetylation of 9a–d and containing 20% of diastereo-
isomer 10b, was hydrolysed in methanolic potassium hydroxide
and transformed into the corresponding 4-nitrobenzoate ester
1
(de = 60%, H NMR: δH = 0.93 C(1)Me in 11d, δH = 0.90 C(1)-
Me in 11b) (Scheme 2). This latter derivative was brought to
racemic epoxy-β-ionone 4 with sodium borohydride. These
enzymic reactions were followed by means of chiral GC analy-
sis, in spite of the fact that it was not possible to find suitable
conditions for a complete gas chromatographic separation of
the corresponding four acetate derivatives 10a–d: a partial over-
lapping of the two central peaks was observed. The assignment
of the right configuration to the GC peaks was performed on
the basis of these considerations: (i) the enantiopure acetate
derivative 10d (fourth GC peak), prepared by enzyme-mediated
esterification, afforded at the end of the synthetic sequence (ϩ)-
(5S,6R)-4a; (ii) the diastereoisomers preferentially acetylated by
lipases (third and fourth GC peaks) were assumed to have the
(R) configuration at C9; (iii) 9a and 9c are the two enantiomers
of epoxy-β-ionol (first and third peaks in the GC analysis of
the corresponding acetate derivatives) affording the 4-nitro-
benzoate derivative which was found to be less soluble in
hexane.
Scheme 2
diastereoisomeric purity (1H NMR) by crystallisation from
methanol, converted into the corresponding alcohol derivative
9d by saponification, and oxidised with MnO2 to afford a
sample of enantiopure dextrorotatory epoxy-β-ionone 4a
{[α]2D0 = 99 (c 0.66, CHCl3); lit.,21 [α]D20 = 104 (c 0.70, CHCl3)}.
In order to devise a convenient access to a suitable precursor
of laevorotatory epoxy-β-ionone 4b, the 1:1 mixture of the two
PPL-Mediated acetylation afforded enantiomerically pure
diastereoisomers 10c and 10d in a nearly 1:4 ratio (GC and 1H
274
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racemic diastereoisomers of epoxy-β-ionol 9a–d was treated
with 4-nitrobenzoyl chloride and pyridine in methylene chlor-
ide, to give the corresponding ester derivatives 11a–d. Five crys-
tallisations from hexane afforded racemic diastereoisomer 11a,c
(first and third peaks of the GC analysis of the corresponding
acetate derivatives) in 19% yield from epoxy-β-ionol. It is very
likely that PPL-mediated acetylation of alcohol derivative 9a,c,
recovered from 4-nitrobenzoate ester 11a,c, affords enantiopure
acetate 10c as a single diastereoisomer, to be used as a precursor
of laevorotatory epoxy-β-ionone 4b.
by chiral GC analysis on a Chirasil DEX CB, 25 m × 0.25 mm
(Chrompack), column using a DANI HT 86.10 gas chromato-
graph; 70 ЊC (1 min)—3.5 ЊC minϪ1—140 ЊC (6 min)—8 ЊC
minϪ1 180 ЊC (1 min): tR/min; 1a, 19.08; 1b, 19.63; 3a, 23.25;
3b, 23.98; 6a, 24.15; 6b, 24.66; 6c, 24.92; 6d, 25.08; 10a, 23.18;
10b, 23.27; 10c, 23.32; 8d, 23.61; 8a, 24.55; 8b, 23.81. 1H
NMR spectra were recorded in CDCl3 solutions at room
temperature unless otherwise stated, on a Bruker AC-250
spectrometer (250 MHz). The chemical shift scale was based on
internal tetramethylsilane. J Values are in Hz. Optical rotations
were measured on a JASCO DIP 181 digital polarimeter, and
are given in 10Ϫ1 deg cm2 gϪ1. TLC analyses were performed
on Merck Kieselgel 60 F254 plates. All the chromatographic
separations were carried out on silica gel columns.
Conclusions
The experimental work described in this paper can fulfil two
different purposes: the study of the effect of substrate structure
on the steric course of lipase-mediated acetylations within a
certain class of compounds and the application of these
enzymic techniques to the preparation of enantiopure deriv-
atives, showing intrinsic interest or as precursors to relevant
chiral products.
The data for the diastereoselectivity and enantioselectivity
of lipase-mediated acetylations of epoxy derivatives of α- and
β-ionol can be usefully compared with those of α-ionol col-
lected during previous work16 and repeated in Table 1 for the
sake of clarity. The steric course of the biocatalysed acetylation
of these substrates clearly appears to be unpredictable; how-
ever, some general conclusions can be made.
The three kinds of lipase we employed on α-ionol, epoxy-α-
ionol and epoxy-β-ionol always showed a clear preference for
the acetylation of (9R)-alcohol diastereoisomers. The highest
enantiomeric excesses were always obtained using Lipase PS
(from Pseudomonas cepacia), while PPL generally assured the
best diastereoselection. The presence of the oxirane ring at C4
and C5 in epoxy-α-ionol was found to be deleterious to the
diastereoselectivity.
4,5-Epoxy-4,5-dihydro-á-ionone 3
m-Chloroperbenzoic acid (67 g, 0.39 mol) was added to a solu-
tion of racemic α-ionone 1 (50 g, 0.26 mol) in methylene chlor-
ide (450 cm3) at 0 ЊC. The reaction mixture was stirred at 0 ЊC
for 2 h, then poured into water. The organic phase was washed
with a saturated solution of sodium hydrogen carbonate, dried
on sodium sulfate and concentrated under reduced pressure.
The residue was chromatographed on a silica gel column
eluting with hexane→hexane–ethyl acetate 8:2. The first eluted
fractions gave 4,5-epoxy-4,5-dihydro-α-ionone (38 g, 71%),
which was found to be (1H NMR) a 5:1 mixture of cis (δH 3.11
C(4)H) and trans (δH 3.02 C(4)H) diastereoisomeric epoxides
(Found: C, 74.91; H, 9.62; C13H20O2 requires: C, 74.96;
H, 9.68%); νmax/cmϪ1 (neat) 1700, 1680, 1620, 1250; δH major
diastereoisomer (cis-4,5-epoxy-4,5-dihydro-α-ionone) 6.73 (1H,
dd, J 10 and 16, C(7)H), 6.09 (1H, d, J 16, C(8)H), 3.11 (1H,
m, C(4)H), 2.30 (3H, s, MeCO), 2.09 (1H, d, J 10, C(6)H),
2.00–1.80 (2H, m, C(3)H2), 1.40 (1H, m, C(2)H), 1.26 (3H, s,
C(5)Me), 1.01 (1H, m, C(2)H), 0.94 (3H, s, C(1)Me), 0.76
C(1)Me); m/z 208 (Mϩ, 5%), 165 (30), 109 (62), 95 (48).
However, the combination of physical (column chroma-
tography) or chemical (fractional crystallisation of 4-nitro-
benzoate esters) methods for diastereoisomer separation with
enantioselective lipase-catalysed acetylation reactions allowed
us to obtain enantiopure epoxy derivatives of α- and β-ionone.
We thus devised a synthetic access to these substrates which did
not suffer from the drawbacks of the known routes, starting
from enantiopure α-ionone. Indeed, we have shown that (S)-
and (R)-α-ionone can be prepared from enantiopure 3a and 3b
through a mild deoxygenation reaction. The great improvement
is that because the two racemic diastereoisomers of epoxy-α-
ionol are separable by column chromatography, laborious
crystallisations of (Ϫ)-menthyl hydrazone derivatives13 or 4-
nitrobenzoate esters16 are readily avoided.
The search for new and efficient synthetic methods affording
enantiopure (R)- and (S)-α-ionone is of much current interest.
As a matter of fact, α-ionone is itself a well known floral odor-
ant22 and careful studies have shown that the (R)-enantiomer
shows the finest and most powerful organoleptic properties.23
Moreover, α-ionone has been used as a precursor of new syn-
thetic woody odorants, such as dehydro-nor-Ambrox,24 display-
ing an ambergris aspect with a wood-tobacco tonality, and
the derivative responsible for the intense woody odour of
ISO E Super.25 Work is now in progress to exploit this synthetic
sequence to enantiopure α-ionone, via enzymatic acetylation
of epoxy-α-ionol derivatives, in order to prepare optically active
γ-ionone.
4,5-Epoxy-4,5-dihydro-á-ionol 5
Reduction of 4,5-epoxy-4,5-dihydro-α-ionone 3 (38 g, 0.18 mol)
with sodium borohydride (9.0 g, 0.24 mol) in methylene
chloride–methanol 2:1 (350 cm3) at 0 ЊC gave 4,5-epoxy-4,5-
dihydro-α-ionol 5 (33 g, 91%) (Found: C, 74.31; H, 10.49;
C13H22O2 requires: C, 74.24; H, 10.54%); νmax/cmϪ1 (neat)
3423, 1601, 1451, 1365; m/z 210 (Mϩ, 1%), 195 (10), 165 (15),
123 (21), 109 (17), 95 (32), 43 (100). This reduction mixture
was chromatographed on a silica gel column eluting with
hexane→hexane–ethyl acetate 7:3. The first eluted fractions
gave racemic cis-epoxy-α-ionol 5a,c (14.4 g, 42%) which was
found to contain 6% of the corresponding racemic trans-epoxy-
1
α-ionol diastereoisomer (δH 2.98 C(4)H); de = 88% (from H
NMR and GC analysis of the corresponding acetate deriv-
atives); δH: 5.61 (2H, m, vinylic H), 4.36 (1H, m, C(9)H), 3.06
(1H, m, C(4)H), 2.0–1.7 (3H, m, C(3)H2 ϩ C(6)H), 1.5–1.2
(7H, m ϩ d ϩ s, J 6, C(2)H ϩ CH3CHOH ϩ C(5)Me), 0.95
(1H, m, C(2)H), 0.88 (3H, s, C(1)Me), 0.75 (3H, s, C(1)Me).
The last eluted fractions gave racemic cis-epoxy-α-ionol 5b,d
(15.4 g, 45%) which was found to contain 17% of the corre-
sponding racemic trans-epoxy-α-ionol diastereoisomer (δH 3.00
1
C(4)H); de = 66% (by H NMR and GC analysis of the corre-
sponding acetate derivatives); δH 5.61 (2H, m, vinylic H), 4.36
(1H, m, C(9)H), 3.09 (1H, m, C(4)H), 2.0–1.6 (3H, m, C(6)H ϩ
C(3)H2), 1.4–1.1 (7H, m ϩ d ϩ s, J 6, C(2)H ϩ CH3CHOH ϩ
C(5)Me), 0.95 (1H, m, C(2)H), 0.88 (3H, s, C(1)Me), 0.71 (3H,
s, C(1)Me).
Experimental
The following enzymes were employed in this work: Candida
Cylindracea Lipase (CCL) (Sigma, Type VII, 900 U mgϪ1), Por-
cine Pancreas Lipase (PPL) (Sigma, Type II), and Lipase PS
Pseudomonas cepacia (Amano Pharmaceuticals Co., Japan).
Enantiomeric and diastereoisomeric excesses were determined
General procedure for enzyme-mediated acetylations of
4,5-epoxy-4,5-dihydro-á-ionol 5
A mixture of 4,5-epoxy-4,5-dihydro-α-ionol 5 (10 g, 0.04 mol),
lipase (10 g), and vinyl acetate (40 cm3) in tert-butyl methyl ether
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(150 cm3) was stirred at room temperature for 24 h. The residue
obtained upon evaporation of the filtered reaction mixture
was chromatographed on a silica gel column, eluting with
hexane→hexane–ethyl acetate 1:1. The first eluted fractions
provided the acetate derivative to be analysed on a chiral GC
column. The last eluted fractions afforded the unreacted
starting material, a sample of which was acetylated by treat-
ment with acetic anhydride and pyridine to perform chiral GC
analysis. This procedure was employed both for the preliminary
studies performed on the 1:1 mixture of the two diastereoiso-
meric cis-epoxides, containing the corresponding trans-stereo-
isomers, and for Lipase PS mediated acetylation of the two
separate diastereoisomers 5a,c and 5b,d. Detailed results of the
enzyme-mediated acetylations are reported in Tables 1 and 2.
(4S,5R,6R)-4,5-epoxy-4,5-dihydro-α-ionone 3b {[α]2D0 = 141 (c
1.3, EtOH)} (1.5 g, 7.2 mmol) in acetonitrile was added. After
stirring at room temperature for 30 minutes, the reaction mix-
ture was poured into a 4 M solution of sodium thiosulfate, and
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate and concentrated under reduced pressure, to
give a residue which was chromatographed on a silica gel
column, eluting with hexane. The first eluted fractions gave (R)-
α-ionone (0.88 g, 64%, ee 98% GC) showing, after bulb to bulb
distillation, [α]D20 = 418 [c 1, CHCl3; lit.,15 [α]2D0 = 407 (c 0.04,
CHCl3)].
(؊)-(4R,5R,6R,9R)-4-Chloro-5-hydroxy-1,1,5-trimethyl-6-(3-
hydroxybut-1-en-1-yl)cyclohexane 7a
Treatment of (4S,5R,6R,9R)-4,5-epoxy-4,5-dihydro-α-ionol
5c {[α]2D0 = 141 (c 0.57, CHCl3)} (1.5 g, 7.1 mmol) with a
saturated solution of hydrogen chloride in methylene chloride
afforded, after purification on a silica gel column eluting with
hexane→hexane–ethyl acetate 7:3 and crystallisation from
hexane, enantiopure chlorohydrin 7a {1.06 g, 61%, de > 99%
(؉)-(4S,5R,6R,9R)-4,5-Epoxy-4,5-dihydro-á-ionol O-acetate
6c. Lipase PS-mediated acetylation of racemic cis-epoxy-α-
ionol 5a,c (first and third peaks in the GC analysis of the corre-
sponding acetate derivatives) (10 g, 0.048 mol) gave, after
purification on a silica gel column eluting with hexane and bulb
to bulb distillation (bp 130 ЊC, 0.2 mmHg), enantiopure acetate
derivative (4S,5R,6R,9R)-6c (3.1 g, 26%) (third GC peak;
ee > 99%, GC; de = 84%, GC; [α]2D0 = 179 (c 1.00, CHCl3)
(Found: C, 71.31; H, 9.52; C15H24O3 requires: C, 71.39; H,
9.59%); νmax/cmϪ1 (neat) 1736, 1458, 1369; m/z 252 (Mϩ, 1%),
210 (5), 192 (10), 165 (15), 123 (18), 95 (54), 43 (100); δH 5.69
(1H, dd, J 15 and 10, C(7)H), 5.50 (1H, dd, J 15 and 6, C(8)H),
5.36 (1H, quintet, J 6, C(9)H), 3.06 (1H, m, C(4)H), 2.03 (3H, s,
CH3OCO), 2.0–1.75 (3H, m ϩ d, J 10, C(3)H2 ϩ C(6)H), 1.5–
1.3 (4H, m ϩ d, J 6, C(2)H ϩ C(9)Me), 1.23 (3H, s, C(5)Me),
0.92 (1H, m, C(2)H), 0.87 (3H, s, C(1)Me), 0.72 (3H, s, C(1)-
Me). This compound was found to contain 8% of a single
(ee > 99%, GC) trans-epoxy diastereoisomer (δH = 2.98 C(4)H).
The recovered unreacted alcohol derivative 5a (5.9 g, 58%)
showed ee = 47% and de = 84% (by GC of the corresponding
acetate derivative) (E = 316, c = 32).
by H NMR, [α]2D0 = Ϫ30 (c 0.51, CHCl3)} (Found: C, 63.17;
1
H, 9.29; C13H23ClO2 requires: C, 63.27; H, 9.39%); mp 85 ЊC;
νmax/cmϪ1 (Nujol) 3310, 1142, 737; δH 5.66 (2H, m, 2 vinylic H),
4.37 (1H, quintet, J 6, CHOH), 3.98 (1H, m, CHCl), 2.42 (1H,
m, C(3)H), 2.07 (1H, d, J 10, C(6)H), 1.78 (2H, m, C(3)H and
C(2)H), 1.4–1.2 (m ϩ d ϩ s,
J 6, C(2)H ϩ CH3CHOH ϩ
C(5)Me), 1.02 (3H, s, C(1)Me), 0.87 (3H, s, C(1)Me); m/z 248
(Mϩ ϩ 2, 1%), 246 (Mϩ, 4), 195 (15), 123 (30).
(؊)-(4R,5R,6R)-4-Chloro-5-hydroxy-1,1,5-trimethyl-6-(3-oxo-
but-1-en-1-yl)cyclohexane 8a
Oxidation of chlorohydrin 7a {1.0 g, 4.1 mmol, [α]2D0 = Ϫ30 (c
0.51, CHCl3)} with manganese() oxide (1.5 equiv.) in methyl-
ene chloride (20 cm3) gave, after purification on a silica gel
column eluting with hexane and bulb to bulb distillation (bp
200 ЊC, 0.6 mmHg), enantiopure derivative 8a (0.63 g, 63%;
ee > 99%, GC; de > 99%, GC) showing [α]D20 = Ϫ23 (c 0.66,
CHCl3) (Found: C, 63.72; H, 8.70; Cl, 14.53; C13H21ClO2
requires: C, 63.79; H, 8.65; Cl, 14.48%); νmax/cmϪ1 (CCl4) 3470,
1660, 1640; δH 6.93 (1H, dd, J 16 and 10, C(7)H), 6.11 (1H,
d, J 16, C(8)H), 3.98 (1H, m, CHCl), 2.48 (1H, m, C(3)H),
2.30 (3H, s, CH3CO), 2.24 (1H, d, J 10, C(6)H), 1.82 (2H, m,
C(2)H ϩ C(3)H), 1.35–1.2 (4H, m ϩ s, C(2)H ϩ C(5)Me), 1.06
(3H, s, C(1)H), 0.86 (3H, s, C(1)H); m/z 246 (M ϩ 2, 1%), 244
(M, 5), 193 (30), 125 (100).
(؉)-(4S,5R,6R,9R)-4,5-Epoxy-4,5-dihydro-á-ionol 5c
Treatment of acetate derivative 6c (3.1 g, 0.012 mol) with potas-
sium hydroxide (0.90 g, 0.016 mol) in methanol solution (35
cm3) at room temperature afforded, after bulb to bulb distil-
lation (bp 120 ЊC, 0.8 mmHg), enantiopure alcohol derivative
(4S,5R,6R,9R)-5c (2.9 g, 83%) showing [α]2D0 = 141 (c 0.49,
CHCl3). This product was found to contain 8% of a trans-
epoxy diastereoisomer (δH = 2.98 C(4)H). The 1H NMR of this
enantiopure stereoisomer was in accordance with that of the
racemic mixture 5a,c.
(؊)-(4R,5S,6S,9R)-4,5-Epoxy-4,5-dihydro-á-ionol O-acetate 6b
(؉)-(4S,5R,6R)-4,5-Epoxy-4,5-dihydro-á-ionone 3b
Lipase PS-mediated acetylation of racemic cis-epoxy-α-ionol
5b,d (second and fourth peaks in the GC analysis of the corre-
sponding acetate derivatives) (10 g, 0.048 mol) gave, after puri-
fication on a silica gel column eluting with hexane and bulb to
bulb distillation (bp 130 ЊC, 0.2 mmHg), enantiopure acetate
derivative (4R,5S,6S,9R)-6b (3.7 g, 31%) {second GC peak;
ee > 99%, GC; de = 67%, GC; [α]D20 = Ϫ56 (c 1.04, CHCl3)}. This
compound was found to contain 17% of a single (ee > 99%,
GC) trans-epoxy diastereoisomer (δH = 2.98 C(4)H): δH 5.61
(2H, m, vinylic H), 5.37 (1H, m, C(9)H), 3.06 (1H, m, C(4)H),
2.05 (3H, s, CH3OCO), 2.0–1.75 (3H, m, C(3)H2 ϩ C(6)H),
1.4–1.3 (4H, m ϩ d, J 6, C(2)H ϩ C(9)Me), 1.24 (3H, s, C(5)-
Me), 0.95 (1H, m, C(2)H), 0.87 (3H, s, C(1)Me), 0.71 (3H, s,
C(1)Me). The recovered unreacted alcohol (3.9 g, 39%) showed
ee = 91% and de = 65% (GC of the corresponding acetate
derivative) (E = 635, c = 48).
Oxidation of enantiopure ionol derivative 5c (2.10 g, 10 mmol)
with manganese() oxide (1.5 equiv.) in methylene chloride (20
cm3) at room temperature afforded, after purification on a silica
gel column eluting with hexane and bulb to bulb distillation (bp
130 ЊC, 0.2 mmHg) cis-epoxy-α-ionone (4S,5R,6R)-3b (1.49 g,
72%) showing ee > 99% (GC), de = 84% (GC) and [α]2D0 = 141 [c
1.3, EtOH; lit.,11 [α]D20 = 210 (c 1, EtOH)]. This derivative was
found to contain 8% of a single (ee > 99%, GC) trans-epoxy
diastereoisomer (δH = 3.02 C(4)H). Careful chromatographic
purification on a silica gel column, using hexane→hexane–ethyl
acetate 9:1 as eluents, afforded a sample of (4S,5R,6R)-3b
showing both enantiomeric and diastereoisomeric purity (GC)
1
([α]2D0 = 207, c 1.2, EtOH). The H NMR spectrum of enantio-
pure 3b was in accordance with that of racemic cis-epoxy-α-
ionone 3.
(؉)-(6R)-á-Ionone 1b
(؊)-(4R,5S,6S,9R)-4,5-Epoxy-4,5-dihydro-á-ionol 5b
Trimethylchlorosilane (2.39 g, 22 mmol) was added dropwise to
a solution of sodium iodide (1.62 g, 11 mmol) in dry aceto-
nitrile under nitrogen. After a few minutes, a solution of
Treatment of acetate derivative 6b (3.7 g, 0.015 mol) with potas-
sium hydroxide (1.06 g, 0.019 mol) in methanol (30 cm3) at
room temperature afforded, after bulb to bulb distillation (bp
276
J. Chem. Soc., Perkin Trans. 1, 1999, 271–278

View Article Online
115 ЊC, 0.8 mmHg), enantiopure alcohol derivative (4R,5S,6S,
9R)-5b (2.68 g, 85%) showing [α]D20 = Ϫ142 (c 0.57, CHCl3). This
substrate was found to contain 6% of a trans-epoxy diastereo-
isomer (δH = 3.00 C(4)H). The H NMR of this enantiopure
stereoisomer was in accordance with that of the racemic mix-
cm3) at 0 ЊC. The reaction mixture was stirred at 0 ЊC for 2 h,
then poured into water. The organic phase was washed with
a saturated solution of sodium hydrogen carbonate, dried on
sodium sulfate and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column eluting
with hexane→hexane–ethyl acetate 8:2, to give racemic 5,6-
epoxy-5,6-dihydro-β-ionone (40 g, 74%) (Found: C, 74.91; H,
9.61; C13H20O2 requires: C, 74.96; H, 9.68%); νmax/cmϪ1 (neat)
1700, 1680, 1630; δH 7.03 (1H, d, J 16, C(7)H), 6.09 (1H, d, J 16,
C(8)H), 2.28 (3H, s, MeCO), 2.0–1.3 (6H, 2 m, C(2)H2 ϩ
C(3)H2 ϩ C(4)H2), 1.17 (6H, s, C(5)Me ϩ C(1)Me), 0.96 (3H, s,
C(1)Me); m/z 193 (Mϩ Ϫ 15, 1%), 135 (10), 123 (100), 95 (8), 43
(34).
1
ture 5b,d.
(؊)-(4R,5S,6S)-4,5-Epoxy-4,5-dihydro-á-ionone 3a
Oxidation of enantiopure ionol derivative 5c (2.60 g, 0.02 mol)
with manganese() oxide (1.5 equiv.) in methylene chloride (20
cm3) at room temperature afforded, after purification on a silica
gel column eluting with hexane and bulb to bulb distillation (bp
130 ЊC, 0.2 mmHg), cis-epoxy-α-ionone (4R,5S,6S)-3a (1.72 g,
69%) showing ee > 99% (GC), de = 89% (GC), and [α]D20 = Ϫ199
{c 0.61, CHCl3; lit.,6 [α]D20 = Ϫ210 (c 0.59, CHCl3)}. This deriv-
ative was found to contain 5% of a single (ee > 99%, GC)
5,6-Epoxy-5,6-dihydro-â-ionol 9
Reduction of ( )-5,6-epoxy-5,6-dihydro-β-ionone 4 (40 g, 0.19
mol) with sodium borohydride (9.4 g, 0.25 mol) in methylene
chloride–methanol 2:1 (350 cm3) at 0 ЊC gave, after purification
on a silica gel column eluting with hexane→hexane–ethyl acetate
7:3, 5,6-epoxy-5,6-dihydro-β-ionol 7 (34.7 g, 87%) (Found: C,
74.29; H, 10.61; C13H22O2 requires: C, 74.24; H, 10.54%) as a
1:1 mixture of the two racemic diastereoisomers 9a,c and 9b,d;
νmax/cmϪ1 (neat) 3422, 1458, 1363; δH 5.89 (1H, d, J 15.5,
C(7)H), 5.73 (1H, dd, J 15.5 and 5.5, C(8)H), 4.38 (1H, m,
CHOH), 2.0–1.3 (6H, m, C(2)H2 ϩ C(3)H2 ϩ C(4)H2), 1.28
(3H, d, J 6, C(9)Me), 1.17 and 1.15 (3H, 2 s, C(5)Me of the two
diastereoisomers), 1.07 and 1.05 (3H, 2 s, C(1)Me of the two
diastereoisomers), 0.94 and 0.92 (3H, 2 s, C(1)Me of the two
diastereoisomers); m/z 195 (Mϩ Ϫ 15, 3%), 123 (100), 95 (14).
1
trans-epoxy diastereoisomer (δH = 2.98 C(4)H). The H NMR
spectrum of enantiopure 3a was in accordance with that of
racemic cis-epoxy-α-ionone 3.
(؊)-(6S)-á-Ionone 1a
Trimethylchlorosilane (2.39 g, 22 mmol) was added dropwise to
a solution of sodium iodide (1.62 g, 11 mmol) in dry aceto-
nitrile (20 cm3) under nitrogen. After a few minutes, a solution
of (4R,5S,6S)-4,5-epoxy-4,5-dihydro-α-ionone 3a, [α]D20 = Ϫ199
(c 0.59, CHCl3) (1.50 g, 7.2 mmol) in acetonitrile (5 cm3) was
added. After stirring at room temperature for 30 minutes, the
reaction mixture was poured into a 4 M solution of sodium
thiosulfate, and extracted with ethyl acetate. The organic phase
was dried over sodium sulfate and concentrated under reduced
pressure, to give a residue which was chromatographed on a
silica gel column, eluting with hexane. The first eluted fractions
gave (S)-α-ionone (0.83 g, 60%, ee 97%, GC) showing, after
4-Nitrobenzoate ester derivatives of epoxy-â-ionol (1:1 mixture
of two racemic diastereoisomers) 11a–d
A solution of epoxy-β-ionol 9 (40 g, 0.19 mol), 4-nitrobenzoyl
chloride (46 g, 0.25 mol) and pyridine (40 cm3) in methylene
chloride (300 cm3) was stirred at room temperature for 2 h. The
reaction mixture was poured into ice, and treated with 10%
aqueous HCl; the organic layer was separated, washed first with
a saturated solution of sodium hydrogen carbonate, then with
water, and dried over sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by column
chromatography eluting with hexane. The first eluted fractions
gave a 1:1 mixture of 4-nitrobenzoate esters (50.4 g, 74%) 11a,c
and 11b,d (Found: C, 66.92; H, 7.08; N, 3.96; C20H25NO5
requires: C, 66.84; H, 7.01; N, 3.90%); νmax/cmϪ1 (Nujol) 1721,
1523; δH 8.26 (4H, m, aromatic H), 6.05 (1H, d, J 15, C(7)H),
5.8–5.6 (2H, m, C(8)H ϩ C(9)H), 1.6–1.2 (2H, m, cyclohexane
H), 1.48 and 1.49 (3H, 2 overlapping d, J 6, C(9)Me of the two
diastereoisomers), 1.40 (4H, m, cyclohexane H), 1.16 and 1.12
(3H, 2 s, C(5)Me of the two diastereoisomers), 1.08 and 1.05
(3H, 2 s, C(1)Me of the two diastereoisomers), 0.93 and 0.90
(3H, 2 s, C(1)Me of the two diastereoisomers). Six crystallis-
ations from hexane afforded diastereoisomer 11a,b (12.9 g,
26%; de > 99%, 1H NMR): mp 72 ЊC; δH 8.26 (4H, m, aromatic
H), 6.05 (1H, d, J 15, C(7)H), 5.77 (1H, dd, J 15 and 6, C(8)H),
5.66 (1H, quintet, J 6, C(9)H), 1.6–1.2 (3H, m, cyclohexane H),
1.48 (3H, d, J 6, C(9)Me), 1.40 (3H, m, cyclohexane H), 1.16
(3H, s, C(5)Me), 1.08 (3H, s, C(1)Me), 0.90 (3H, s, C(1)Me).
bulb to bulb distillation, [α]2D0 = Ϫ418 {c 1, CHCl3; lit.,15 [α]2D0
Ϫ431 (c 0.035, CHCl3)}.
=
(؉)-(4S,5S,6S,9R)-4-Chloro-5-hydroxy-1,1,5-trimethyl-6-(3-
hydroxybut-1-en-1-yl)cyclohexane 7b
Treatment of (4R,5S,6S,9R)-4,5-epoxy-4,5-dihydro-α-ionol
5b {[α]D20 = Ϫ142 (c 0.57, CHCl3)} (1.5 g, 7.1 mmol) with a
saturated solution of hydrogen chloride in methylene chloride
afforded, after purification on a silica gel column eluting with
hexane→hexane–ethyl acetate 7:3 and crystallisation from
hexane, enantiopure chlorohydrin 7b (0.99 g, 57 %) {de > 99%,
1H NMR, [α]D20 = 46 (c 0.72, CHCl3)} (Found: C, 63.18; H, 9.32;
Cl, 14.29; C13H23ClO2 requires: C, 63.27; H, 9.39; Cl, 14.37%);
mp 85 ЊC; νmax/cmϪ1 (Nujol) 3315, 1140, 730; δH 5.70 (1H, dd,
J 15.5 and 9, C(7)H), 5.57 (1H, dd, J 15.5 and 6, C(8)H), 4.36
(1H, quintet, J 6, CHOH), 3.98 (1H, m, CHCl), 2.43 (1H, m,
C(3)H), 2.06 (1H, d, J 9, C(6)H), 1.78 (2H, m, C(3)H and
C(2)H), 1.4–1.2 (7H, m ϩ d ϩ s, J 6, C(2)H ϩ CH3CHOH ϩ
C(5)Me), 1.00 (3H, s, C(1)Me), 0.84 (3H, s, C(1)Me); m/z 248
(Mϩ ϩ 2, 2%), 246 (Mϩ, 7), 195 (18), 123 (35).
(؉)-(4S,5S,6S)-4-Chloro-5-hydroxy-1,1,5-trimethyl-6-(3-oxo-
but-1-en-1-yl)cyclohexane 8b
Oxidation of chlorohydrin 7b {0.90 g, 3.68 mol, [α]2D0 = 46
(c 0.72, CHCl3)} with manganese() oxide (1.5 equiv.) in
methylene chloride (20 cm3) gave, after purification on a silica
gel column eluting with hexane and bulb to bulb distillation (bp
180 ЊC, 0.2 mmHg), enantiopure derivative 10b (0.494 g, 55%;
ee > 99%, GC; de > 99%, GC) showing [α]2D0 = 23 (c 0.66,
CHCl3). The 1H NMR was in accordance with that of the
corresponding enantiomer 8a.
General procedure for enzyme-mediated acetylations of 5,6-
epoxy-5,6-dihydro-â-ionol 9
A mixture of 5,6-epoxy-5,6-dihydro-β-ionol 9 (10 g, 0.048 mol),
lipase (10 g), and vinyl acetate (40 cm3) in tert-butyl methyl
ether (150 cm3) was stirred at room temperature for 24 h. The
residue obtained upon evaporation of the filtered reaction
mixture was chromatographed on a silica gel column, eluting
with hexane→hexane–ethyl acetate 1:1. The first eluted frac-
tions provided the acetate derivative to be analysed on a chiral
GC column. The last eluted fractions afforded the unreacted
( )-5,6-Epoxy-5,6-dihydro-â-ionone 4
m-Chloroperbenzoic acid (67 g, 0.39 mol) was added to a solu-
tion of β-ionone 2 (50 g, 0.26 mol) in methylene chloride (450
J. Chem. Soc., Perkin Trans. 1, 1999, 271–278
277

View Article Online
1
starting material, a sample of which was acetylated by treat-
ment with acetic anhydride and pyridine to perform chiral GC
analysis. Detailed results of the enzyme-mediated acetylations
are reported in Table 1.
71%) showing [α]2D0 = 99Њ (c 0.66, CHCl3). The H NMR spec-
trum was in accordance with that of the racemic mixture.
Acknowledgements
We thank Amano Pharmaceuticals Co. for a generous gift of
Lipase PS and CNR Progetto Finalizzato Biotecnologie for
partial financial support.
(5S,6R,9R)-5,6-Epoxy-5,6-dihydro-â-ionol O-acetate 10d
Lipase PS-mediated acetylation of epoxy-β-ionol 9 (1:1 mix-
ture of two racemic diastereoisomers) (10 g, 0.048 mol) gave,
after purification on a silica gel column eluting with hexane,
enantiopure acetate derivative 10d (fourth GC peak, 2.66 g,
References
1
22%; de = 60%, GC and H NMR) (Found: C, 71.43; H, 9.52;
1 G. Ohloff, in Fortschritte der Chemie der organische Naturstoffe,
ed. W. Herz, H. Grisebach and G. W. Kirby, Springer, 1978, vol. 35,
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2 P. Karrer and H. Stuerzinger, Helv. Chim. Acta, 1946, 29, 1829.
3 J. E. Ayers, M. J. Fishwick, D. G. Land and T. Swain, Nature, 1964,
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4 F. Mueggler-Chavan, R. Viani, J. Bricout, J. P. Marion, H. Mechtler,
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1980, 63, 10.
C15H24O3 requires: C, 71.39; H, 9.59%) contaminated with
enantiopure (third GC peak) diastereoisomer 10c (δH = 2.09
OAc); νmax/cmϪ1 (neat) 1730, 1450, 1371; δH (major diastereo-
isomer) 5.90 (1H, d, J 15.5, C(7)H), 5.64 (1H, dd, J 15.5 and
6.5, C(8)H), 5.38 (1H, quintet, J 6.5, C(9)H), 2.03 (3H, s, OAc),
1.4–2.2 (9H, m ϩ d, J 6.5, cyclohexane H ϩ C(9)Me), 1.13 (3H,
s, C(5)Me), 1.05 (3H, s, C(1)Me), 0.91 (3H, s, C(1)Me); m/z 237
(Mϩ Ϫ 15%), 192 (15), 123 (20).
7 W. Eschenmoser, P. Uebelhart and C. H. Eugster, Helv. Chim. Acta,
1981, 64, 2681.
8 M. Acemoglu, W. Eschenmoser and C. H. Eugster, Helv. Chim.
Acta, 1981, 64, 2691.
9 A. Haag and C. H. Eugster, Helv. Chim. Acta, 1982, 65, 1975.
10 M. Acemoglu and C. H. Eugster, Helv. Chim. Acta, 1984, 67, 184.
11 P. Uebelhart, A. Baumeler, H. Haag, R. Prewo, J. H. Bieri and
C. H. Eugster, Helv. Chim. Acta, 1986, 69, 816.
12 H. Sobotka, E. Bloch, H. Chanmann and E. Feldbau, J. Am. Chem.
Soc., 1943, 65, 2061.
13 W. Eschenmoser, P. Ueberhalt and C. H. Eugster, Helv. Chim. Acta,
1979, 62, 2534.
14 F. Toda, K. Mori, Y. Matsuura and H. Akai, J. Chem. Soc., Chem.
Commun., 1990, 1591.
15 C. Fehr and O. Guntern, Helv. Chim. Acta, 1992, 75, 1023.
16 E. Brenna, C. Fuganti, P. Grasselli, M. Redaelli and S. Serra,
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Lett., 1981, 22, 3551.
(5S,6R,9R)-5,6-Epoxy-5,6-dihydro-â-ionol O-p-nitrobenzoate
11d
Epoxy-β-ionol O-acetate 10d (3.0 g, 0.012 mol), prepared by
lipase-mediated acetylation of 9, was hydrolysed with potas-
sium hydroxide in methanol (85%) and converted into the
corresponding 4-nitrobenzoate ester derivative 11d (de = 60%,
1H NMR; 2.60 g, 71%) by reaction with 4-nitrobenzoyl chloride
and pyridine in methylene chloride. The ester was crystallised
thrice from methanol to give 11d as a single diastereoisomer
(1H NMR) {1.25 g, 48%; [α]D20 = 11 (c 0.42, CHCl3)}: mp 79 ЊC;
δH 8.26 (4H, m, aromatic H), 6.05 (1H, d, J 15, C(7)H), 5.77
(1H, dd, J 15 and 6, C(8)H), 5.66 (1H, quintet, J 6, C(9)H), 1.6–
1.2 (2H, m, cyclohexane H), 1.50 (3H, d, J 6, C(9)Me), 1.40
(4H, m, cyclohexane H), 1.12 (3H, s, C(5)Me), 1.05 (3H, s,
C(1)Me), 0.93 (3H, s, C(1)Me).
18 Throughout the whole work, as for epoxy-α-ionol derivatives,
diastereoisomeric excesses are used to express the ratio between the
diastereoisomeric cis and trans-epoxides.
19 Enantiomeric ratio (E) and conversion (c) were calculated according
to C. S. Chen, Y. Fujimoto, G. Girdaukas and C. J. Sih, J. Am.
Chem. Soc., 1982, 104, 7294.
(5S,6R,9R)-5,6-Epoxy-5,6-dihydro-â-ionol 9d
4-Nitrobenzoate derivative 11d (1.25 g, 3.48 mmol) was hydro-
lysed by treatment with potassium hydroxide (0.253 g, 4.52
mmol) in methanol (15 cm3) to afford, after bulb to bulb
distillation (145 ЊC, 2 mmHg), enantiopure epoxy-β-ionol 9d
(0.585 g, 80%), showing [α]2D0 = 47 (c 0.50, CHCl3); δH 5.88 (1H,
d, J 15.5, C(7)H), 5.73 (1H, dd, J 15.5 and 6.5, C(8)H), 4.38
(1H, quintet, J 6.5, C(9)H), 1.3–2.0 (6H, m, cyclohexane H),
1.29 (3H, d, J 6, C(9)Me), 1.17 (3H, s, C(5)Me), 1.07 (3H, s,
C(1)Me), 0.92 (3H, s, C(1)Me).
20 L. Lopez, G. Mele, V. Paradiso, A. Nacci and P. Mastrorilli, Gazz.
Chim. Ital., 1996, 126, 725.
21 T. Oritani and K. Yamashita, Phytochemistry, 1983, 22, 1909.
22 J. A. Bajgrowicz, P. Kraft and G. Frater, Tetrahedron, 1998, 54, 7633.
23 (a) C. Fehr and O. Guntern, Helv. Chim. Acta, 1992, 75, 1023;
(b) P. Werkhoff, W. Bretschneider, M. Guentert, R. Hopp and
H. Surburg, Flavor Science and Technology, ed. Y. Bessiere and A. F.
Thomas, Wiley, 1990, p. 33.
24 US Pat. 5 416 069 priority CH, July 23, 1993 to Givaudan Roure;
US Pat. 5 268 355 priority CH, March 3, 1992 to Firmenich.
25 S. Pereira and M. Srebnik, Aldrichim. Acta, 1993, 26, 17.
(5S,6R)-5,6-Epoxy-5,6-dihydro-â-ionone 4a
Enantiopure epoxy-β-ionol 9d (0.585 g, 2.78 mmol) was oxid-
ised by treatment with manganese() oxide (1.5 equiv.) in
methylene chloride (15 cm3), to afford, after bulb to bulb distil-
lation, enantiomerically pure (ϩ)-epoxy-β-ionone 4a (0.411 g,
Paper 8/08780F
278
J. Chem. Soc., Perkin Trans. 1, 1999, 271–278