Synthesis and evaluation of enantiopure 6-thiabicyclo[3.2.1]octanes for asymmetric epoxidation of benzaldehyde

Article abstract of DOI:10.1055/s-2008-1077878

A one-step synthesis of 6-thiabicyclo[3.2.1]octan-3-one from carvone is reported. Chiral sulfides were subsequently elaborated in a few steps and used as competent sulfonium ylide promoters for the asymmetric epoxidation of aldehydes. Their odourant characteristics are also described. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077878

LETTER
1679
Synthesis and Evaluation of Enantiopure 6-Thiabicyclo[3.2.1]octanes for
Asymmetric Epoxidation of Benzaldehyde
Synthesis of
E
nan
e
tiopure 6-
T
n
hiabicyclo[3
j
.2. 1]oc
a
tane
s
min Lefranc,a Alain Valla,a Krishna Ethiraj,a Jean-Noël Jaubert,d Patrick Metzner,*a Jean-François Brière*a,b,c
a
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Caen, CNRS, 6 Boulevard du Maréchal Juin,
14050 Caen, France
Fax +33(2)31452865; E-mail: patrick.metzner@ensicaen.fr
INSA de Rouen, IRCOF, Rue Tesnière, 76131 Mont-Saint-Aignan, France
Fax +33(2)35522962; E-mail: jean-francois.briere@insa-rouen.fr
CNRS, Université de Rouen, UMR 6014 COBRA, rue Tesnière, 76131 Mont Saint Aignan, France
IAP-SENTIC, 8 Ter de la Roquette, 27000 Evreux, France
b
c
d
Received 5 March 2008
We envisaged the 6-thiabicyclo[3.2.1]octan-3-one 5 as an
interesting platform for the synthesis of original chiral sul-
fur architectures making use of the ketone functionality.
We disclose herein a robust one-step synthesis of 5 based
on the use of polysulfide species. Sulfide 5 served as use-
ful precursor to novel 6-thiabicyclo[3.2.1]octanes which,
in preliminary studies, turned out to be both competent for
the enantioselective sulfonium ylide epoxidation
processes7 and featured interesting odorant characteris-
tics.
Abstract: A one-step synthesis of 6-thiabicyclo[3.2.1]octan-3-one
from carvone is reported. Chiral sulfides were subsequently elabo-
rated in a few steps and used as competent sulfonium ylide promot-
ers for the asymmetric epoxidation of aldehydes. Their odourant
characteristics are also described.
Key words: sulfur, ylides, epoxidations, catalysis, asymmetric
Specific enantiopure sulfides are of interest in many in-
stances as chiral ligands for metals1a,1b or asymmetric
organocatalysis promoters,1c–1e as well as for their organo-
leptic properties, etc.2 For example, Firmenich company
established that the naturally occurring R-thiol 3 displays
a genuine flavour of grapefruit juice at the ppb-level,3a and
the S-enantiomer has a weak odour (Scheme 1).2,3b Inter-
estingly, the cyclised counterpart 2 accounts for an un-
pleasant sulfur note.3b Enantioenriched 2 and 3 were either
synthesised in multiple steps from limonene 13a or extract-
ed from grapefruit in minute quantities among a myriad of
sulfur compounds.2,3 Early on, the reaction of elemental
sulfur to limonene afforded these derivatives in poor
yields along with a complex mixture.4 Strangely, the sim-
ilar reaction from the cheap and readily available carvone
4 was not much investigated.5 In 1993, Aizenshtat5b
showed the unique reactivity of polysulfide6 species to-
wards carvone, which allowed the one-pot elaboration of
diastereopure bicyclic sulfide 5, albeit in 4% yield after
repeated crystallisations (Scheme 1).
We reinvestigated the polysulfide species formation by
mixing elemental sulfur and a commercial aqueous solu-
tion of diammonium sulfide,5b,8 followed by the addition
of carvone (Scheme 2).9
O
Me
O
S8 (1.6 equiv)
Me
S(NH4)2 (1.6 equiv)
n-Bu4NBr (0.05 equiv)
S
Me
H2O, cosolvent, r.t.
Me
(R)-carvone (4)
5
Me
Scheme 2 According to Table 1
Pleasingly, we found that a 1:1 mixture of sulfur reagents,
in the presence of a phase-transfer catalyst, furnished the
4,7,7-trimethyl-6-thiabicyclo[3.2.1]octan-3-one (5) in
52% yield after column chromatography, as an insepara-
ble mixture of two epimers (Table 1, entry 1). According
to Aizenshtat’s publication,5b the main isomer possesses
an equatorial methyl group adjacent to the carbonyl
(Scheme 2). A thick aqueous solution was formed and
was difficult to stir during this slow process. At higher
temperature (entry 2), a complete transformation of car-
vone took place in only one day but the product featured
a lower equatorial/axial ratio. This could be explained by
a thermodynamically controlled equilibration, in which
the equatorial derivative is the most stable one. However,
we improved the yield and the amount of equatorial deriv-
ative by adding a small amount of THF at room tempera-
ture, which facilitated the stirring (entry 3). The use of
other co-solvents (DMSO, EtOH) and phase-transfer cat-
alyst counterions (I–, Cl–) did not show significant chang-
es. In optimised conditions, the complete reaction was
demonstrated with both (R)- and (S)-carvone (entry 4), af-
Me
Me
X
Me
X
1
'Sx'
Me
S
or
Me
O
Me
SH
Me
2 X = CH2
5 X = C=O
3 X = CH2
6 X = C=O
Me
Me
4
Me
Scheme 1 6-Thiabicyclo[3.2.1]octanes from limonene or carvone
SYNLETT 2008, No. 11, pp 1679–1683
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1077878; Art ID: G03908ST
© Georg Thieme Verlag Stuttgart · New York

1680
B. Lefranc et al.
LETTER
Me
ter three days at room temperature. We successfully sepa-
rated the enantiomers 5 (the main equatorial epimers) by
enantioselective gas chromatography and proved, there-
by, that no racemisation had occurred.9 The ammonium
salt (PTC) was not required although it slightly improved
the epimeric ratio (entry 5). Eventually, the reaction was
successfully performed on 15 mL scale into a more
concentrated solution of ammonium sulfide (entry 6), pro-
viding a straightforward synthesis of 6-thiabicyc-
lo[3.2.1]octan-3-one 5 from cheap carvone.9
Mg, TiCl4
5
5
S
Me
THF, CH2Cl2
32%, dr = 95:5
Me
7
Ph
Me
Me
Ph
PhLi (1.5 equiv)
TFA (10 equiv)
OH
S
S
THF, –78 to 0°C
45% conv
Me
CH2Cl2, r.t.
29% (two steps)
dr = 80:20
Me
Me
Me
Me
8
9
Me
Table 1 Sulfuration of Carvone 4 to Sulfide 5 (According to
NaH (1.2 equiv)
MeI (1.5 equiv)
Scheme 2)
OH
OMe
Me
NaBH4 (3 equiv)
S
S
5
Me
Entrya 4
S(NH4)2 Additive
(H2O, %)
Co-
solvent (d)
Time Yield eq/
THF, 0 °C to r.t.
63% (two steps)
EtOH, r.t.
100% conv
(%)
52
58
66
67
65
59
axa
Me
Me
10
11
dr = 98:2
1
(S)
20
20
20
20
20
50
n-Bu4NBr
n-Bu4NBr
–
–
15
1
77:23
58:42
82:18
82:18
75:25
86:14
Scheme 3 Elaboration of the 6-thiabicyclo[3.2.1]octan-3-one 5
2b
3
(S)
(S)
(R)
(S)
(R)
the end of this sequence. This chemistry was easily per-
formed and gave a rapid access to these new sulfides 7–9.
Nevertheless, the difficulties encountered to transform 5
in good yields reflect the steric hindrance of the ketone
function. So, we envisaged a small hydride nucleophile by
means of NaBH4. The reduction proceeded smoothly, and
the obtained alcohol 10 was easily methylated to furnish
ether 1115 in a high diastereomeric ratio. At this stage, it is
not clear whether the compound was diastereoenriched
during either the reduction process or the purification on
silica gel. We have disclosed thereby sequences, which al-
low the synthesis of original bicyclic sulfides, in two or
three steps, from the cheap carvone.
n-Bu4NBr THF
n-Bu4NBr THF
7
4
3
5
–
THF
3
6
n-Bu4NBr THF
4
a Determined by NMR.
b Reaction was carried out at 60 °C.
The first step of this process might be a conjugated addi-
tion of polysulfide species to enone 4 (Scheme 2), giving
a dihydrocarvone derivative having a sulfide or polysul-
fide chain (Sx) at 4-position.5b The subsequent ring-forma-
tion mechanism could occur via a radical scenario,3 the
reaction of polarised polysulfide chain4b or the addition of
the terminal thiol moiety to the isopropylidene moiety.10
In our hands, the addition of 2,6-di-tert-butyl-4-meth-
ylphenol did not inhibit the process, which would exclude
the formation of radicals. More studies are required to
shed light on this fascinating cascade mechanism, never-
theless, the reaction outcome and selectivity are already
useful as the regioisomers (with respect to the isopropy-
lidene moiety) were not observed (the only other minor
products identified are polymers and the dihydrocarvone).
Then, we undertook the evaluation of these potentially
asymmetric promoters for the catalytic sulfonium ylide
epoxidation of benzaldehyde (Scheme 4). Despite major
advances that have been recently achieved for this organo-
catalytic synthesis stilbene oxide,7 a limited number of
readily available sulfides provides high asymmetric in-
ductions.16 With respect to our previous studies in that
field,16d dealing with a-methylthiolanes with a locked
conformation {the three-carbon bridge of 6-thiabicyc-
lo[3.2.1]octanes 5–11 fixed indeed the thiolane shape},
we screened these newly synthesised sulfides (20% load-
ing) under regular conditions over 24 hours (Table 2,
Scheme 4).
Then, we elaborated the sulfide 5 backbone by transform-
ing the ketone moiety in a minimum of steps (Scheme 3).
The Wittig methylenation did not proceed in our hands.
So, we employed Yan’s procedure,11 mediated by Mg–
TiCl4 complexes, which afforded the exo-alkene 7 with a
moderate yield but in one step.12 The diastereomeric ratio
was increased during column-chromatography purifica-
tion. The addition of phenyllithium gave the tertiary alco-
hol 813 in 45% conversion likely due to competitive
enolisation events. Interestingly, the crude alcohol under-
took a regioselective elimination, under acidic conditions,
to form the less substituted alkene 9.14 One can suppose
that a steric opposition between adjacent methyl and phe-
nyl groups prevented the tetrasubstituted C–C double-
bond formation. The remaining ketone 5 was recovered at
R
R
(0.2 equiv)
NaOH (2 equiv)
n-Bu4NI (1 equiv)
S
Me
R
O
Ph
O
PhCHO
Ph
Me
S
H
Ph
2 BnBr t-BuOH–H2O (9:1)
r.t., 24 h
Ph
(S,S)
Me
Scheme 4 Epoxidation of benzaldehyde (refers to Table 2)
The ketone 5, together with the alcohol derivatives 8 and
10, afforded very little epoxidation. On the other hand, the
ether analogue 11 furnished the major trans-stilbene ox-
ide in good yield and 55% ee after 24 hours. However, the
Synlett 2008, No. 11, 1679–1683 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiopure 6-Thiabicyclo[3.2.1]octanes
1681
sulfides were not present in the crude product and their in concentration as dimethyl disulfide (cabbage) or propyl-
situ stability was questioned. Then, we turned our atten- thiol references. The use of the described synthetic meth-
tion to the alkene derivatives 7 and 9, lacking the oxygen odology from carvone for giving access to both sulfide
functionality. We were pleased to observe that the enan- enantiomers and/or epimers (with respect to the 4-methyl
tiomeric excesses increased up to 82% by means of the group) is currently under investigation in order to further
sulfides 7 or 9, having an exo or endo C–C double bond, probe the structure–olfactory relationship.
although in moderate conversions. The yield and conver-
Table 3 Olfactometric Evaluation of Sulfides 7 and 11
sion could be slightly improved by increasing the reaction
time from one to four days with sulfide 9, without affect-
References
7a
7 (100 × 11a
11 (100 ×
ing the selectivities (84% ee and 82:18 dr). Indeed, the
alkene sulfides 7 and 9 were identified on the NMR crude
product spectra, which showed, to some extent, the ro-
bustness of these organocatalytic promoters. In all cases,
the main (S,S)-trans-stilbene oxide was obtained. We as-
sume that benzyl bromide approaches the less hindered
convex face of the sulfur atom to form, after deprotona-
tion, the major exo-ylide (Scheme 4). The re face would
be shielded by the downwards methyl group. Then, the
more accessible backwards ylide face would connect to
the re benzaldehyde face to offer the (S,S)-stilbene ox-
ide.17 The ready availability of these 6-thiabicyc-
lo[3.2.1]octanone from 5 offers great opportunities for
further structure–performance optimisation.
dilution)b
dilution)b
Menthol
–
+
+
+
+
–
–
+
+
+
–
–
–
+
–
+
–
+
+
–
–
–
–
–
Camphor
Isobutylquinoline
Limonene-thiol (3)
Propylthiol
Dimethyl disulfide
a Solution 1 described in ref. 19.
b Solution 2 described in ref. 19.
In conclusion, we have demonstrated that the addition of
polysulfide species to cheap and readily available carvone
afforded a powerful method for the one-step synthesis of
6-thiabicyclo[3.2.1]octan-3-one 5. Compound 5 served as
a useful chiral building block to rapidly form new bicyclic
sulfides, which turned out to be competent for the asym-
metric epoxidation of benzaldehyde mediated by catalytic
sulfonium ylide species. These sulfides also revealed
powerful and interesting odorant properties. The elabora-
tion of other 6-thiabicyclo[3.2.1]octanes type sulfides, in
a more selective fashion, is currently under investigation
for improving the performance of these compounds.
Table 2 Enantioselective Epoxidation of Benzaldehyde (See
Scheme 4)
Sulfide Time
(d)
Yield
(%)
Conversion ee
dr
(%)a
(%)a
(trans/cis)b
5
7
1
1
1
1
4
1
1
–
5
nd
79
nd
82
84
nd
55
nd
35
–
44
19
32
75
7
86:14
nd
8
9
30
54
–
85:15
88:12
nd
9
10
11
Acknowledgment
80
100
82:18
We gratefully acknowledge financial support from the ‘Ministère
de la Recherche’, CNRS (Centre National de la Recherche Scienti-
fique), the ‘Région Basse-Normandie’, and the European Union
(FEDER funding). We also warmly thank Cédric Bouteiller, Leslie
Fousse, and Florian Cahagne for their initial contribution to this
work. We are grateful to Vincent Dalla for his collaboration.
a Determined by HPLC for the main trans-epoxide.
b Determined by 1H NMR of the crude product.
The olfactory evaluation of these sulfides was carried out
by dynamic olfactometry.18 Although, the styrene sulfide
derivative 9 did not have a significant odour, the exo-alk-
ene 7 and ether 11 derivatives displayed odorant factors of
72·103 and 8·106, respectively, which account for intense
odours.19 The qualitative aspects were subsequently anal-
ysed with respect to some recognised substances used as
odorant references in the so-called ‘field-of-odours’ meth-
od (Table 3).20 Interestingly, compounds 7 and 11 re-
vealed terpenic notes between camphor and menthol,
especially for more dilute solution of 11. The limonene-
thiol 3 analogy, namely the grapefruit note, is detectable
for alkene 7. This note is only reported for the ether coun-
terpart 11 at higher concentration. The isobutylquinoline
characteristic, roughly reminiscent to humus, is also
found for 11. The ‘sulfur aspect’ only appeared at higher
References and Notes
(1) For recent reviews on sulfide in enantioselective catalysis,
see: (a) Pellissier, H. Tetrahedron 2007, 63, 1297.
(b) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007,
107, 5133. (c) McGarrigle, E. M.; Myers, E. L.; Illa, O.;
Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev.
2007, 107, 5841. (d) McGarrigle, E. M.; Aggarwal, V. K.
Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH:
Weinheim, 2007, Chap. 10. (e) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719.
(2) For recent reviews on chiral odorants, see: (a) Goeke, A.
Sulfur Rep. 2002, 23, 243. (b) Brenna, E.; Fuganti, C.;
Serra, S. Tetrahedron: Asymmetry 2003, 14, 1. (c) Bentley,
R. Chem. Rev. 2006, 106, 4099.
Synlett 2008, No. 11, 1679–1683 © Thieme Stuttgart · New York

1682
B. Lefranc et al.
LETTER
(3) (a) Demole, E.; Enggist, P.; Ohloff, G. Helv. Chim. Acta
1982, 65, 1785. (b) Lehmann, D.; Dietrich, A.; Hener, U.;
Mosandl, A. Phytochem. Anal. 1995, 6, 255; and references
cited therein.
(11) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang,
P.-C. Org. Lett. 2004, 6, 4961.
(12) 4,7,7-Trimethyl-3-methylene-6-thiabi-
cyclo[3.2.1]octane (7)
(4) (a) Weitkamp, A. W. J. Am. Chem. Soc. 1959, 81, 3437.
(b) Moore, C. G.; Porter, M. Tetrahedron 1959, 6, 10.
(c) Bertaina, C.; Cozzolino, F.; Fellous, R.; George, G.;
Rouvier, E. Parfums Cosmét. Arômes 1986, 71, 69.
(d) Janes, J. F.; Marr, I. M.; Unwin, N.; Banthorpe, D. V.;
Yusuf, A. Flavour Frag. J. 1993, 8, 289.
(5) (a) Hargreaves, M.; McDougall, R.; Rabari, L. Z.
Naturforsch., B: Anorg. Chem. Org. Chem. 1978, 33, 1535.
(b) Krein, E. B.; Aizenshtat, Z. J. Org. Chem. 1993, 58,
6103. (c) Sirazieva, E. V.; Startseva, V. A.; Nikitina, L. E.;
Sofronov, A. V.; Artemova, N. P.; Fedyunina, I. V. Chem.
Nat. Compd. 2007, 43, 52.
(6) (a) Review on polysulfane: Steudel, R. Chem. Rev. 2007,
102, 3905. (b) Recent paper: Aebisher, D.; Brzostowska, E.
M.; Mahendran, A.; Greer, A. J. Org. Chem. 2007, 72, 2951;
and references cited therein.
(7) For recent reviews, see: (a) Aggarwal, V. K.; Richardson, J.
Chem. Commun. 2003, 2644. (b) Aggarwal, V. K.; Winn, C.
L. Acc. Chem. Res. 2004, 37, 611; see also ref. 1c.
(8) The aqueous solutions of (NH4)2S (20% or 50%) are
commercially available from Aldrich.
Obtained as a mixture of epimers (58 mg, 95:5 eq/ax) after
column-chromatography purification (pentane–Et2O, 30:1);
colourless liquid. 1H NMR (250 MHz, CDCl3): d = 1.02 (d,
J = 6.5 Hz, 3 H, eq), 1.15 (d, J = 7.3 Hz, 3 H, ax), 1.39 (s, 3
H, eq + ax), 1.43 (s, 3 H, eq), 1.50 (s, 3 H, ax), 1.98–2.22 (m,
3 H, eq + ax), 2.44–2.54 (m, 3 H, eq + ax), 3.47 (br s, 1 H,
eq + ax), 4.80–4.90 (m, 2 H, eq + ax). 13C NMR (63 MHz,
CDCl3): d (main equatorial isomer) = 148.3, 112.8, 54.9,
53.8, 48.2, 42.6, 42.4, 38.5, 34.4, 25.5, 17.3. IR (neat): 1641,
1455, 886. HRMS: m/z calcd for C11H18S [M]+: 182.1129;
found: 182.1126.
(13) 4,7,7-Trimethyl-3-phenyl-6-thiabicyclo[3.2.1]octan-3-ol
(8)
A small sample was purified on column chromatography
(heptane–Et2O, 30:1) for analytical purposes. Only one
diastereomer is seen by NMR. White solid; mp 116–118 °C.
1H NMR (250 MHz, CDCl3): d = 0.77 (d, J = 6.9 Hz, 3 H),
1.51 (s, 3 H), 1.72 (s, 3 H) 2.05 (dd, J = 4.5, 15.2 Hz, 1 H),
2.15 (d, J = 12.0 Hz, 1 H), 2.19–2.26 (m, 1 H), 2.27–2.38 (m,
2 H), 2.58–2.67 (m, 1 H), 3.46 (br d, J = 7.1 Hz, 1 H), 5.20
(s, 1 H, OH), 7.16–7.35 (m, 3 H), 7.46–7.50 (m, 2 H).
13C NMR (63 MHz, CDCl3): d = 148.2, 127.9, 126.3, 125.4,
75.9, 55.2, 53.4, 49.5, 46.1, 44.4, 41.7, 35.0, 27.3, 14.3.
IR (neat): 3369, 2929, 1492, 1448, 1382. MS (EI):
m/z (%) = 262 (46), 244 (80).
(9) Synthesis of 4,7,7-Trimethyl-6-thia-1,5-
bicyclo[3.2.1]octan-3-one (5)
A 50% aq solution of diammonium sulfide (20 mL, 146.8
mmol) was added dropwise to a mixture of TBAB (1.544 g,
4.8 mmol) and elemental sulfur (4.689 g, 146.2 mmol). The
solution was stirred for 5 min. Then, THF (9 mL) was added
and carvone (15 mL, 93.8 mmol) was slowly introduced.
The obtained red solution was vigorously stirred at r.t. for 3–
4 d (until carvone disappeared on TLC). The solution was
diluted in H2O (100 mL), and the product was extracted with
Et2O (3 × 50 mL). The combined organic layers were
washed with a sat. aq solution of NH4Cl (15 mL), a sat. aq
solution of K2CO3 (15 mL) and brine (15 mL). The organic
layer was dried over MgSO4, filtrated, and concentrated in
vacuo. The obtained oil was purified by flash column
chromatography (heptane–EtOAc, 5:1) to afford an
inseparable mixture of diastereomers as an oil which
crystallised as a yellow powder (59%, 86:14 eq/ax).
Trituration in i-PrOH facilitated the crystallisation without
changing the diastereomeric ratio. This is a stable
compound, which could be stored for at least a year in the
fridge. Melting point and optical rotation of the 86:14
mixture of diastereomers are given for indication: mp 65–
67 °C (lit5b 67–68 °C for the pure equatorial compound 5),
[a]D20 +116 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3):
d = 1.08 (d, J = 6.5 Hz, 3 H, eq), 1.19 (d, J = 7.5 Hz, 3 H, ax),
1.38 (s, 3 H, eq), 1.43 (s, 3 H, ax), 1.44 (s, 3 H, eq + ax),
2.27–2.43 (m, 3 H, eq + ax), 2.62–2.71 (m, 3 H, eq + ax),
3.47 (br s, 1 H, eq + ax). 13C NMR (63 MHz, CDCl3):
d (eq) = 209.1, 54.8, 52.5, 52.1, 49.6, 44.9, 41.1, 34.0, 27.1,
13.7; d (ax) = 212.6, 54.3, 49.9, 48.9, 42.1, 33.9, 33.8, 24.5,
17.4. IR (neat): 2951, 1698. HRMS: m/z calcd for C10H17OS
[M + H]+: 185.1000; found: 185.1007. GC-MS: 2 peaks with
the same mass(184). Enantioselective GC was performed on
a CYDEX-B chiral capillary column (25 m × 0.22 mm), 10
psi at 130 °C; tR (enantiomers of the major epimer 5) = 47.7
and 49.5.
(14) 4,7,7-Trimethyl-3-phenyl-6-thiabicyclo[3.2.1]oct-2-ene
(9)
Obtained as a mixture of epimers (191 mg, 80:20 eq/ax) after
column-chromatography purification (heptane–Et2O, 50:1).
Yellow oil. 1H NMR (250 MHz, CDCl3): d = 0.64 (d, J = 6.4
Hz, 3 H, ax), 0.91 (d, J = 7.2 Hz, 3 H, eq), 1.44 (s, 3 H, ax),
1.47 (s, 3 H, eq), 1.49 (s, 3 H, eq), 1.51 (s, 3 H, ax), 2.19–
2.27 (m, 1 H, eq + ax), 2.31–2.44 (m, 1 H, eq + ax), 2.45–
2.55 (m, 1 H, eq + ax), 3.15–3.23 (m, 1 H, eq + ax), 3.58 (t,
J = 4.4 Hz, 1 H, eq + ax), 5.27–5.37 (m, 1 H, ax), 5.82 (br d,
J = 6.6 Hz, 1 H, eq), 7.18–7.28 (m, 5 H, eq + ax). 13C NMR
(63 MHz, CDCl3): d (eq) = 141.9, 141.4, 128.4, 128.2, 126.8,
126.8, 60.5, 53.6, 48.4, 39.9, 38.8, 33.4, 27.6, 17.3; d (ax) =
143.6, 128.3, 128.1, 127.1, 127.0, 54.8, 48.8, 48.1, 47.0,
35.0, 33.0, 25.9, 13.5; one sp2 signal is overlapping with one
equatorial signal. IR (neat): 2927, 1777, 1599, 1453. HRMS:
m/z calcd for C16H21S [M + H]+: 245.1364; found: 245.1360.
(15) 3-Methoxy-4,7,7-trimethyl-6-thiabi-
cyclo[3.2.1]octane (11)
Obtained as a mixture of epimers (379 mg, 98:2 eq/ax) after
column-chromatography purification (heptane–Et2O, 20:1).
Colourless oil. 1H NMR (400 MHz, CDCl3): d (main
equatorial isomer) = 0.99 (d, J = 6.9 Hz, 3 H), 1.43 (s, 3 H),
1.52 (s, 3 H), 1.54–1.59 (m, 1 H), 1.83–1.86 (m, 1 H), 1.96–
1.99 (m, 1 H), 2.13–2.08 (m, 1 H), 2.25–2.30 (m, 1 H), 2.45–
2.50 (m, 1 H), 3.14–3.16 (m, 1 H), 3.21 (t, J = 5.8 Hz, 1 H),
3.29 (s, 3 H). 13C NMR (63 MHz, CDCl3): d (eq) = 78.4,
57.7, 53.5, 51.7, 47.0, 42.1, 41.8, 35.5, 30.5, 26.9, 16.3. IR
(neat): 2923, 1459, 1115, 1091. HRMS: m/z calcd for
C11H21OS [M + H]+: 201.1313; found: 201.1316.
(16) For selected recent examples, see: (a) Winn, C. L.; Bellenie,
B. R.; Goodman, J. M. Tetrahedron Lett. 2002, 43, 5427.
(b) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon,
K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson,
J.; Stenson, R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L.
J. Am. Chem. Soc. 2003, 125, 10926. (c) Deng, X.-M.; Cai,
J.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu,
(10) (a) Ranu, B. C.; Mandal, T. Synlett 2007, 925. (b) Lou,
F.-W.; Xu, J.-M.; Liu, B.-K.; Wu, Q.; Pan, Q.; Lin, X.-F.
Tetrahedron Lett. 2007, 48, 2815. (c) Weïwer, M.;
Coulombel, L.; Duñach, E. Chem. Commun. 2006, 332; and
references cited therein.
Synlett 2008, No. 11, 1679–1683 © Thieme Stuttgart · New York

LETTER
Y.-D.; Dai, L. X. J. Am. Chem. Soc. 2006, 128, 9730.
Synthesis of Enantiopure 6-Thiabicyclo[3.2.1]octanes
1683
compounds were solubilised in 2 g of abs. EtOH (solution 1)
and diluted 100 times (solution 2). Then, 25 mL of either
solution 1 or 2 were injected within 10 l of air and analysed.
(19) The odorant factor is defined as the maximum volume (m3)
in which 1 g of compound could be detected (by the nose of
assessors). The odorant factor of limonene-thiol 3 (from
Sigma Aldrich – CAS 71159-90-5) was evaluated to 11·106
by the method described in ref. 18.
(d) Davoust, M.; Brière, J.-F.; Jaffrès, P.-A.; Metzner, P.
J. Org. Chem. 2005, 70, 4166; and references cited therein.
(17) (a) Silva, M. A.; Bellenie, B. R.; Goodman, J. M. Org. Lett.
2004, 61, 2559. (b) Edwards, D. R.; Montoya-Peleaz, P.;
Crudden, C. M. Org. Lett. 2007, 9, 5481. (c) For exhaustive
studies on sulfonium ylide mechanism, see also ref. 1c, 7a.
(18) The determination of odour concentration was carried out at
IAP-SENTIC company (France) by dynamic olfactometry
according to the European standard EN13725 with trained 4
or 6 sensory assessors. Sample preparation: 10–20 mg of
(20) Jaubert, J.-N.; Tapiero, C.; Dore, J.-C. Perfum. Flav. 1995,
20, 1.
Synlett 2008, No. 11, 1679–1683 © Thieme Stuttgart · New York