Convenient enantioselective synthesis of new 1,4-sulfanylalcohols from γ-lactones

Article abstract of DOI:10.1016/S0040-4039(02)01268-6

A synthetic strategy based upon three basic reactions - enzymatic resolution, oxygen-sulfur exchange, reduction - allowed us to carry out an easy and useful synthesis of a series of new 1,4-sulfanylalcohols from aliphatic γ-lactones. Final products have been obtained in good yields with enantiomeric excesses in a 66-91% range.

Full text of DOI:10.1016/S0040-4039(02)01268-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6267–6270
Convenient enantioselective synthesis of new 1,4-sulfanylalcohols
from g-lactones
Jean-Jacques Filippi, Xavier Fernandez, Louisette Lizzani-Cuvelier* and Andre´-Michel Loiseau
Laboratoire Aroˆmes Synthe`ses Interactions, Universite´ de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice Cedex 2, France
Received 6 June 2002; accepted 25 June 2002
Abstract—A synthetic strategy based upon three basic reactions—enzymatic resolution, oxygen–sulfur exchange, reduction—
allowed us to carry out an easy and useful synthesis of a series of new 1,4-sulfanylalcohols from aliphatic g-lactones. Final
products have been obtained in good yields with enantiomeric excesses in a 66–91% range. © 2002 Elsevier Science Ltd. All rights
reserved.
In the last few years, sulfanylalcohols have forged
ahead in flavour chemistry. Since their identification in
fruits and vegetables, they have been the subject of
intense research for many flavourists.1 This class of
organosulfur compounds, generally found within a
unique stereomeric form in natural products, presents
both various odours and low thresholds.2 Moreover,
they are thought to be the precursors of many natural
compounds known for their contribution to food aro-
mas and their application in flavour chemistry. For
example, 3(S)-sulfanylhexanol3 identified in yellow pas-
sion-fruit and guava, gives rise to 3(S)-methylthiohex-
anol,3 2(R)-methyl-4(S)-propyl-1,3-oxathiane4 and
3(S)-propyl-g-sultine.5
particularly their stereoselective synthesis have, to our
knowledge, been reported in few cases. The preparation
of 1,4-sulfanylalcohols is usually carried out using
nucleophilic sulfur reagents and leads to racemic mix-
tures.7 Recently, Schellenberg et al.8 have reported the
synthesis of enantiomerically pure 1,4-sulfanylalcohols:
the racemic compounds resulting from reduction of
g-thiolactones were derivatised with a chiral auxiliary in
order to separate the stereomers by means of semi-
preparative HPLC.
Herein, we describe the first enantioselective synthesis
of new 1,4-sulfanylalcohols from aliphatic g-lactones.
The first step consisted in the enzymatic resolution of
g-lactones 1a–f using porcine pancreatic lipase (PPL).
The enantiomerically enriched g-lactones 2a–f were
Even though 1,3-sulfanylalcohols have already been
extensively investigated,2,6 1,4-sulfanylalcohols, and
Scheme 1. Synthesis of 1,4-sulfanylalcohols.
Keywords: 1,4-sulfanylalcohols; g-lactones; enzymatic resolution; thionation reaction; reduction.
* Corresponding author. Fax: +33(0)492076517; e-mail: cuvelier@unice.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01268-6

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J.-J. Filippi et al. / Tetrahedron Letters 43 (2002) 6267–6270
submitted to a thionation reaction to give the corre-
sponding g-thionolactones 3a–f. A subsequent LiAlH4
reduction of 3a–f afforded the expected 1,4-sulfanylalco-
hols 4a–f (Scheme 1). All results are reported in Table
1.
with a mixture of organic solvents (hexane/Et2O; 2/1) to
complete the resolution. On the other hand, g-lactones
substituted by an aliphatic side chain longer than n-pro-
pyl (R]Bu, 1d–f, entries 9–14) presented a strong
insolubility in water and tended to form hydrophobic
aggregates, involving a dramatic decrease of yields.
Carrying out the resolution at pH 7.6 and using calcium
chloride10a induced a better precipitation of the formed
enzyme inhibiting g-hydroxyacid as a calcium salt. More-
over, an emulsifier such as gum arabic was added (2%
water solution) and allowed the reaction to reach the
expected conversion.
PPL offers many possibilities to afford enantiomerically
enriched g-lactones by enantioselective lactonisation of
the corresponding g-hydroxyesters9 and enantioselective
hydrolysis of racemic lactones.10a Since the crude enzyme
is a very useful and inexpensive material, we have selected
that method to obtain optically active g-lactones.
Although PPL presents a better affinity towards the
(S)-enantiomers of the g-lactones,9,10a the resolution
needs to be carried out with more than 50% conversion
as described in previous reports.10 A 60% conversion was
set for all the performed enzymatic resolutions. However,
the solubility of the g-lactones in an aqueous medium
depends on the length of their alkyl chain. Small and
hydrophilic g-lactones (1a–c) were submitted to the PPL
hydrolysis in a phosphate buffer10a (pH 7.2, T=20°C)
Under these applied conditions, the PPL enantioselectiv-
ity (E)11,12 which is maximum in the case of g-heptalac-
tone 1c (E=12.4, ee 91%, entry 5), tended to decrease
when the length of the side chain increased. Enantiomeric
excesses, in a 26–91% range, were determined by enan-
tioselective gas chromatography.13
In order to achieve an oxygen–sulfur exchange, Lawes-
son’s reagent (L.R.)14 was used to afford selectively the
Table 1.
Entry
1
2
3
4
Starting
Resolution
conditions
Yielda
(%)
Conversion
(%)
eeb
(%)
Ec
Abs.
Yielde
(%)
eeb
Abs.
Yielde
(%)
eef
(%)
config.d
(%)
79
–
config.d
1
2
a
a
b
b
c
c
c
d
d
d
e
e
f
A: PPL 10 g,
9 days
B: PPL 10 g,
7 days
A: PPL 10 g,
6 days
B: PPL 10 g,
8 days
A: PPL 10 g,
5 days
B: PPL 10 g,
2 days
B: PPL 15 g,
2 days
A: PPL 10 g,
5 days
B: PPL 10 g,
6 days
C: PPL 10 g,
2 days
B: PPL 10 g,
9 days
C: PPL 10 g,
9 days
B: PPL 10 g,
10 days
C: PPL 10 g,
8 days
75
67
82
85
85
94
90
45
62
83
65
83
75
79
61
62
60
60
60
60
60
63
64
60
60
52
53
61
78
44
85
84
91
78
89
26
74
82
71
54
34
66
6.7
R
R
R
R
R
R
R
R
R
R
R
R
R
R
65
–
R
–
85
–
79
–
2.6
9.3
9.0
12.4
7.2
11.2
1.7
5.1
8.3
5.7
5.0
2.5
4.7
3
85
–
85
–
R
–
88
–
85
–
4
5
89
91
87
–
91
78
89
–
R
R
R
–
93
–
91
–
6
7
–
–
8
–
–
9
–
–
–
–
–
10
11
12
13
14
93
82
–
82
71
–
R
R
–
84
92
–
82
71
–
–
–
–
–
–
f
80
66
R
80
66
A: Na2HPO4/hexane/Et2O; B: CaCl2 aq. 10%; C: CaCl2 aq. 3.5%/gum arabic 2%.
a Calculated from the isolated and purified compound according to the reached conversion.
b Determined by enantioselective GC.13
c Enantioselectivity11,12 of the enzyme calculated from conversion and ee values.
d In agreement with literature reports.10a,15a
e Calculated from the isolated and purified compound.
f Determined by enantioselective GC after derivatisation into 2,2-dimethyloxathiepanes.13

J.-J. Filippi et al. / Tetrahedron Letters 43 (2002) 6267–6270
6269
expected g-thionolactones15 3a–f in good yields (65–
91%). Thionation of optically active g-lactones 2a–f, in
toluene, requires exclusively the use of half an equiva-
lent of L.R. to avoid the formation of g-dithiolactones
as side-products. Enantioselective GC enabled us to
note that both enantiomeric excesses (66–91%) and
initial absolute configuration (R) of the optically active
g-lactones 2a–f were not affected by thionation, accord-
ing to the elution order previously established by Beck
et al.15a on the same chiral stationary phase.
W.; Bro¨nner-Schindler, H. Helv. Chim. Acta 1984, 67,
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Org. Chem. 1999, 64, 4959–4961.
LiAlH4 reduction (1 equiv. in dry THF) of these g-
thionolactones led to the corresponding 1,4-
sulfanylalcohols16 4a–f with high yields (80–93%)
(Table 1). These compounds were not efficiently
resolved by enantioselective GC. Therefore, an easy
8. (a) Schellenberg, A.; Schmarr, H. G.; Eisenreich, W.;
Engel, K. H. Frontiers of Flavour Science; Deutsche
Forschungsanstalt fu¨r Lebensmittelchemie: Mu¨nchen,
1999; (b) Engel, K. H.; Schellenberg, A.; Schmarr, H. G.
Abstr. Pap.-Am. Chem. Soc. 2000, 220th AGFD-051.
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derivatisation
into
their
corresponding
2,2-
dimethyloxathiepanes13 was achieved to determine the
final enantiomeric excesses (66–91%), by enantioselec-
tive GC.13 Since the absolute configuration of the stere-
ocentre was not affected by reduction,17 we assume that
the 1,4-sulfanylalcohols were enantiomerically enriched
into the (R)-form.
Conclusion
11. Chen, C. S.; Fujimoto, Y.; Giradaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294–7299.
A new and convenient enantioselective synthesis of a
series of new 1,4-sulfanylalcohols has been achieved in
good yields with enantiomeric excesses in a 66–91%
range. The works are currently in progress to improve
the enantiomeric excesses, to obtain the reverse configu-
ration (S) and to further extend this new synthesis to
other substrates.
12. The enantiomeric ratios (E),11 a measure of the enan-
tioselectivity of the lipase, can be related to the extent of
conversion and the enantiomeric excess and were calcu-
lated using the following equation,
ln[(1−c)(1−ee)]
E=
ln[(1−c)(1+ee)]
where c is the lactone conversion, and ee is the enan-
tiomeric excess of the unreacted lactone. This equation is
based on the assumption that resolution proceeds irre-
versibly, that the two enantiomers compete for the same
active site, and that there is no product inhibition.
These 1,4-sulfanylalcohols constitute a new class of
potent flavouring compounds and very interesting key-
intermediates for the synthesis of heterocyclic
derivatives.
13. Experimental section: Enzymatic resolution of the g-lac-
tones 1a–f: in a typical experiment, the crude lipase
(purchased from Sigma chemicals Co., L3126.) was care-
fully diluted, at 20°C, in 100 ml of the appropriate
medium (A, B or C) adjusting pH at the desired value
(7.2 or 7.6) with 0.5N NaOH. 15 ml of an hexane/Et2O
mixture was added in the case of phosphate buffer.
5×10−2 mole of g-lactone was quickly added. The reaction
course was monitored with a pH-stat with continuous
addition of the same freshly prepared 0.5N NaOH solu-
tion. The reaction was stopped at 60% conversion (60 ml
added), by filtering off the enzyme over Celite. The
aqueous filtrate was, then, extracted three times with 100
ml of a Et2O/EtOAc mixture (1/1), the combined organic
layers were dried over MgSO4, and evaporated to afford
the optically active g-lactone. All the enantiomeric
excesses were determined by gas chromatography on a
Chiraldex B-TA silica capillary column (30 m×0.25 mm)
(Astec, Whippany, USA) (80°C to 220°C, 2°C/min).
Thionation of the optically active g-lactones 2a–f: 10 mmol
of optically active g-lactone, 0.5 equiv. of L.R. and 20 ml
of toluene were refluxed, under nitrogen atmosphere,
during 4 h. After cooling and filtration, toluene was
evaporated in vacuo. At room temperature, the crude
mixture was stirred in hexane/Et2O (80/20) to precipitate
Acknowledgements
We wish to thank Maxens S.A. (Grasse) for acquiring
HRMS data.
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hexane/Et2O (85/15). Enantiomeric excesses were deter-
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m×0.25 mm) (Macherey & Nagel, Du¨ren, Germany)
(80°C to 220°C, 2°C/min) after derivatisation into their
corresponding 2,2-dimethyloxathiepanes from condensa-
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16. All new compounds were characterised by 1H and 13C
NMR, MS and HRMS. Data for the 1-sulfanylheptan-4-
ol 4c: 1H NMR (500 MHz, CDCl3): l 0.93 (3H, m),
1.35–1.47 (2H, 2m), 1.36 (1H, t, J=7.6 Hz), 1.44 (1H,
m), 1.51 (1H, m), 1.60 (1H, m), 1.69 (1H, m), 1.79 (1H,
m), 2.57 (2H, q, J=7.6 Hz), 3.63 ppm (1H, m). 13C
NMR (200 MHz, CDCl3): l 14.11, 18.92, 24.77, 30.17,
36.05, 39.80, 71.22 ppm. MS (EI, 70 eV): m/z (%) 148
(M+, 0.1), 101 (14.6), 87 (100), 81 (13.3), 71 (25.9), 59
(45.1), 55 (51.9), 43 (54.1), 42 (20.3), 41 (32.8), 39 (13.8).
HRMS calculated for C7H16OS: 148.0922, found:
148.0916.
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