Novel chiral dithioethers derived from L-tartaric acid

Article abstract of DOI:10.1016/S0957-4166(01)00504-3

The synthesis of a new family of systematically modified chiral dithioethers to be used as ligands is described. Phenylthioether derivative 5 and fluorine-containing dithioether ligands 6-8 and 13-15 were prepared by direct reaction of phenylthiol and o-,

Full text of DOI:10.1016/S0957-4166(01)00504-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3029–3034
Novel chiral dithioethers derived from -tartaric acid
L
Leticia Flores-Santos,a Erika Martin,a,* Montserrat Die´guez,b,* Anna M. Masdeu-Bulto´b and
Carmen Claverb
aDepartamento de Qu´ımica Inorga´nica, Facultad de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Cd. Universitaria,
04510 Mexico DF, Mexico
bDepartament de Qu´ımica F´ısica i Inorga`nica, Universitat Rovira i Virgili Plac¸a Imperial Ta`rraco, 1, E-43005 Tarragona, Spain
Received 5 November 2001; accepted 6 November 2001
Abstract—The synthesis of a new family of systematically modified chiral dithioethers to be used as ligands is described.
Phenylthioether derivative 5 and fluorine-containing dithioether ligands 6–8 and 13–15 were prepared by direct reaction of
phenylthiol and o-, m- or p-fluorophenylthiol with two different ditriflate derivatives based on the L-tartaric skeleton. The chiral
ditriflate 12 containing a dioxolane moiety was reacted with ethane- and propanedithiol, producing cyclic dithioethers 16 and 17,
respectively, in good yields (:50%). The analogous ditriflate 4 with benzyl ether protecting groups, having a skeleton without
restricted rotation, gave the thiolane 9 as the main product. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
catalysts can be modulated to improve their activity
and selectivity. Therefore, to better understand how
structural factors affect the performance of dithio
donor ligands, we synthesised a family of chiral
Over the last ten years, the potential of chiral sulfur-
containing ligands in transition-metal-catalysed asym-
metric syntheses has been explored.1 In particular,
heterodonor ligands such as (P,S),2 (N,S)3 and (O,S)4
have been used successfully in enantioselective reactions
such as the hydrogenation of itaconic acid and a-enam-
ide methyl esters,2a,2b,3d the allylic substitution reactions
of 1,3-diphenylpropenyl acetate,2c–e,3a–c the hydrosilyla-
tion of ketones,2f alkene epoxidation4 and cross-cou-
pling reactions.3e Catalysts with chiral homodonor
sulfur ligands, however, have not been investigated as
much, mainly because electronic dissimilarity between
the two donor sites is claimed to be important for
obtaining favourable enantioselectivity for some pro-
cesses.2a,2d Nevertheless, chiral homodonor dithioether
ligands have provided good results in iridium-catalysed
asymmetric hydrogenation under mild conditions5 and
they have recently been effective chiral inductors in
palladium-catalysed allylic alkylations, where they have
afforded e.e. of up to 81%.6
dithioethers derived from L-diethyl tartrate that share a
1,4-butanedithioether backbone. We present herein two
design strategies. The first one is to introduce phenyl-
thioether 5 and o-, m- or p-fluorophenylthioether 6–8,
13–15 moiety to fine-tune the electronic properties of
the sulfur donor atom.3a The second strategy is to
construct cyclic dithioether structures 16 and 17 to
modulate the ligand rigidity and avoid sulfur inversion
upon metal coordination, which is considered to erode
the enantioselectivity in asymmetric catalytic pro-
cesses.2e,7 Although some authors have already tried to
diminish sulfur inversion using bulky thioethers,2a,2e our
objective is to explore strategies focusing on the total
eradication of it.
2. Results and discussion
The new compounds 5–8 were prepared from
L
-(+)-
Since systematic chemical modification of dithioethers
is easily achieved, the electronic and steric properties of
diethyl tartrate, 1 (Scheme 1). Diol 3, prepared in
accordance with a previously described procedure,8,9
was converted into ditriflate 4 by adding pyridine and
triflic anhydride to a dichloromethane solution of 3.
Compound 4 was treated with the appropriate sodium
phenylthiolate salt to afford the dithioethers 5–8 in
good yields. We tried several times to prepare cyclic
* Corresponding authors. Tel.: +525-622-3720; fax: +525-622-3531
(E.M.); tel.: +34-977-558146; fax: +34-977-559563 (M.D.); e-mail:
erikam@servidor.unam.mx; dieguez@quimica.urv.es
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00504-3

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L. Flores-Santos et al. / Tetrahedron: Asymmetry 12 (2001) 3029–3034
Scheme 1. (a) BnBr, NaH, THF; (b) LiAlH4, THF; (c) O(SO2CF3)2, CH2Cl2; (d) NaH, ArSH, THF; (e) NaH, HS(CH2)nSH, n=2,
3, THF, reflux.
ously been reported as the main product in the reaction
of potassium thioacetate and 2,2,3,3-tetramethyl-1,4-
butanediolditosylate (90%)13 or as a by-product when
sodium methylthiolate is treated with (S,S)-(+)-3,4-
dimethoxytetramethyleneditosylate (45%).14
thioethers by reacting 1,2-ethanedithiol and 1,3-
propanedithiol with 4 or the corresponding ditosylate
derivative under different temperatures, reaction times
and solvents, but instead of the cyclic compound we
obtained the thiolane 9.
Using a dioxolane skeleton, which is more rigid than 4,
we prepared the fluorinated phenyldithioethers 13–15
from ditriflate 125a and the corresponding sodium
phenylthiolate (Scheme 2). Since free rotation of C(2)
and C(3) of the butane backbone is restrained by the
O-isopropylidene group, the thiolane formation was
The analogous non-chiral cyclic dithioethers 1,4-dithia-
cyclooctane and 1,5-dithiacyclononane have been syn-
thesised in very low yields (e.g. 0.2%,10 6%11 and
0.6%,12 7%,4 respectively) starting from sodium dithio-
late and 1,4-dibromobutane; thiolane was not formed
in either case. However, thiolane derivatives have previ-
Scheme 2. (a) 2,2-Dimethoxypropane, PTSA, MeOH; (b) LiAlH4, Et2O; (c) O(SO2CF3)2, CH2Cl2; (d) NaH, ArSH, THF; (e)
NaH, HS(CH2)nSH, THF, reflux.

L. Flores-Santos et al. / Tetrahedron: Asymmetry 12 (2001) 3029–3034
3031
disfavoured. This therefore allowed coupling between
12 and ethanedithiol or propanedithiol to produce 16
and 17 in good yields in very short reaction times.
Similar results have been obtained when an aromatic
backbone is used to prepare cyclic thioethers such as
cyclophanes15 and benzodithiecines16 but this required
slow additions and stirring over a long period.
in vacuum. TLC (Merck, silica gel 60) was used to
monitor the progress of the reactions under study. The
starting materials 1–38,9 and 10–1215 were prepared
according to literature methods.
3.1. Synthesis of triflates
3.1.1. Synthesis of (2R,3R)-2,3-bis(benzyloxy)butane-
1,4-bis(trifluoromethanesulfonate) 4. Pyridine (0.17 mL,
2.11 mmol) was added to a solution of compound 38
(0.30 g, 1 mmol) in dichloromethane (12 mL). The
resulting solution was stirred for 15 min. It was then
cooled to −20°C and triflic anhydride (CF3SO2)2O (0.4
mL, 2.4 mmol) was added dropwise. The reaction was
monitored using TLC (hexane–ethyl acetate 3:2), and
after 1 h the reaction was complete. The solvent was
evaporated under vacuum and the residue purified by
column chromatography (hexane–ethyl acetate 3:2) to
give 4 as a white solid (0.52 g, 92%): [h]2D5=+7.4 (c 0.96
CHCl3); IR (film) (cm−1) (wSO2) 1417 (s), (wSO2) 1209
If compound 16 is synthesised at 25°C with more
concentrated solutions, the new chiral macrocyclic
polythioether 18 is obtained as a by-product. Interest-
ing applications are also expected for this.17
All of the new compounds were fully characterised by
NMR spectral analysis. These exhibit C2 symmetry for
5–8 and 13–15. For cyclic dithioethers 16 and 17, we
must consider a fast equilibrium between conforma-
tions at 25°C to explain the NMR spectra, which show
two independent magnetic systems. These correspond
to the butane and ethane/propane fragments, respec-
tively. The presence of the O-isopropylidene moiety
restricts C(2) and C(3) free rotation and induces very
1
(s), (wCF) 1144 (m); H NMR: l 7.3 (m, 10H, C6H5),
4.691, 4.690 (AB, 4H, CHAHB-C6H5, JAB=−11.67),
4.628, 4.525, 3.793, 3.793, 4.525, 4.628 (AA%MM%BB%,
6H, CHAHA%-CHM-CHM%-CHBHB%, JA–A%=JB%–B=−10.7,
3
3
different JCH
and JCH
–CH, which remain
H
A%
H
–CH
A
A
A%
unaltered even at 50°C. The difference in chemical
shifts between the two diastereotropic protons HA and
HA% when compared to their acyclic analogues, accounts
for the additional restricted rotation imposed by the
eight- and nine-membered cycles. Pseudoaxial proton
HA is more shielded than pseudoequatorial proton HA%
which may be related to the lone-pair arrangement of
the neighbouring sulfur.18
J
A–M=JB%–M%=3.23, JA%–M=JB–M%=6.18, JA–M%=JB%–M=
0.13, JA%–M%=JB–M=−0.37, JM–M%=4.88); 13C NMR: l
136.2 (Ci), 128.8 (Cm), 128.6 (Cp), 128.3 (Co), 118.5 (q,
CF3, JC–F=320.5), 74.8 (CH), 74.4 (CH2-C6H5), 73.6
(CH2-OS(O)2CF3); 19F NMR: l −74.9 (CF3). FAB+:
565 m/z (M−1). Anal. calcd for C20H20F6O8S2: C,
42.41; H, 3.56; S, 11.32. Found: C, 42.78; H, 3.58; S,
11.22.
Iridium and palladium complexes of these ligands are
currently being prepared and used in the iridium-
catalysed asymmetric hydrogenation of acrylic and ita-
conic acid derivatives and palladium-catalysed allylic
substitution reactions.
3.2. Synthesis of thioethers
3.2.1. Synthesis of (2R,3R)-2,3-bis(benzyloxy)-1,4-dithio-
phenylbutane 5. A solution of phenylthiol (0.36 mL,
3.52 mmol) in THF (4 mL) was slowly added to a
suspension of NaH (0.69 g at 60%, 17.36 mmol) in
THF (4 mL) at 0°C. The resulting solution was stirred
for 1 h at 25°C. A solution of compound 4 (0.74 g, 1.30
mmol) in THF (2 mL) was added dropwise at 0°C.
3. Experimental
Solvents were dried over standard drying agents and
freshly distilled before use. 1H, 19F and 13C NMR
spectra were measured with a Varian Unity INOVA
300 MHz spectrometer operating at 299.7, 282, and 75
MHz, respectively. Chemical shifts were relative to
TMS l=0 (1H); CF3COOH, l=−77 ppm (19F) and
CDCl3 l=77 ppm (13C). All species were studied in
deuteriochloroform. 1H and 19F NMR spectra were
simulated using gNMR V4.1.0 program.19 Infrared
spectra were recorded with a Nicolet AVATAR 320
FT-IR spectrometer. Electronic Impact and FAB+ mass
spectra were performed with a Jeol SX102A inverse
geometry spectrometer. EI/GC spectra were obtained
with a coupled HP5890 series II gas chromatograph
using a capillary column HP5MS 30 m×0.25 mm ID
0.25 mm. FAB+ mass spectra were acquired using 3-
nitrobenzyl alcohol matrix. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter, and [h]D
values are in units of 10−1 deg cm2 g−1. Elemental
analyses were determined using FISONS EA1108
(CHNS-0) equipment. Organic solutions were dried
over anhydrous MgSO4 and concentrated below 40°C
After
3 1/2 h the solvent was evaporated and
dichloromethane (5 mL) was added. The solution was
cooled to 0°C and carefully treated with water (5 mL).
Phases were separated and the aqueous phase was
extracted with dichloromethane (3×3 mL). The organic
phase was then dried and concentrated. The residue
was purified by flash column chromatography (hexane–
ethyl acetate, 20:1) and 5 was obtained as a pale yellow
oil (0.54 g, 85%): [h]D20=+31.2 (c 0.75 CHCl3); IR (film)
1
(cm−1): (l CHar) 739 (s), 695 (s); H NMR: l 7.3 (m,
20H, Har), 4.567, 4.398 (AB, 4H, CHAHB-C6H5, JAB
=
−11.39), 3.171, 3.059, 3.78, 3.78, 3.059, 3.171
(AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-CHBHB%, JA–A%
=JB–B%=−13.4,
J
A–M=JB%–M%=6.41,
JA%–M=JB–M%=
6.55, JA–M%=JB%–M=−0.26,
JA%–M%=JB–M=−0.25,
JM–M%=2.48); 13C NMR: l 137.8 (Ci), 136 (Ci-S), 129.7
(Co), 128.9 (Co-S), 128.4 (Cm-S), 128.3 (Cm), 127.8 (Cp),
126.2 (Cp-S), 77.1 (CH), 73 (CH2-C6H5), 33.8 (CH2).
EIMS: 486 m/z (M+.); High-resolution EIMS:
486.1710, C30H30O2S2 (Err[ppm/mmu]=+4.6/+2.2).

3032
L. Flores-Santos et al. / Tetrahedron: Asymmetry 12 (2001) 3029–3034
3.2.2. Synthesis of (2R,3R)-2,3-bis(benzyloxy)-1,4-
bis(thio-o-fluorophenyl)butane 6. solution of 2-
JA–M%=JB%–M=JA%–M%=JB–M=0,
JM–M%=2.69);
13C
A
NMR: l 161.8 (Ci-F, JC–F=247.2), 137.6 (Ci), 132.5
(Co-S, JC–F=8.1), 130.8 (Ci-S, JC–F=3), 128.4 (Co),
128.3 (Cm), 127.9 (Cp), 116 (Cm-S, JC–F=22.2), 76.7
(CH), 72.8 (CH2-C6H5), 34.8 (CH2); 19F NMR: l
fluorophenylthiol (0.74 mL, 7.01 mmol) in THF (6 mL)
was treated sequentially—as described for 5—with a
suspension of NaH (1.47 g at 60%, 36.7 mmol) in THF
(6 mL) and compound 4 (1.29 g, 2.28 mmol) in THF
(10 mL). Compound 6 was obtained as a pale yellow oil
(0.69 g, 58%): [h]2D0=+26.9 (c 0.77 CHCl3); IR (film)
−116.7 (A2B2X, (HA)2(HB)2FX, 3JA–X=8.63, JB–X=5.2);
4
EIMS: 522 (m/z); High-resolution EIMS: 522.1523,
C30H28F2O2S2 (Err[ppm/mmu]=+4.6/+2.4). Anal. calcd
for C30H28F2O2S2: C, 68.94; H, 5.4; S, 12.27. Found: C,
68.38; H, 5.45; S, 12.16%.
1
(cm−1): (wCarꢀF) 1156 (m); H NMR: l 7.2 (m, 18H,
Har), 4.58, 4.406 (AB, 4H, CHAHB-C6H5, JAB=−11.54),
3.067, 3.141, 3.756, 3.756, 3.141, 3.067 (AA%MM%BB%,
6H, CHAHA%-CHM-CHM%-CHBHB%, JA–A%=JB–B%=−13.4,
J
A–M=JB%–M%=6.82, JA%–M=JB–M%=6.38, JA–M%=JB%–M
=
3.2.5. Synthesis of (3R,4R)-3,4-O-bis(benzyloxy)thiolane
9. A solution of ethanedithiol (0.05 mL, 0.59 mmol) in
THF (1.7 mL) was slowly added to a suspension of
NaH (0.14 g at 60%, 4 mmol) in THF (4 mL). The
resulting solution was stirred for 1 h at 25°C. Then a
solution of compound 4 (0.3 g, 0.53 mmol) in THF (0.6
mL) was slowly added. After 2.5 h the mixture was
heated and kept at reflux temperature for 3 h. The
mixture was allowed to cool, the solvent evaporated
and dichloromethane (5 mL) was added. The solution
was cooled to 0°C and water (5 mL) was added slowly.
Phases were separated and the aqueous phase was
extracted with dichloromethane (3×3 mL). The organic
phase was then dried and concentrated. The residue
was purified by flash column chromatography (hexane–
ethyl acetate, 20:1) and 9 was obtained as a white solid
JA%–M%=JB–M=0, JM–M%=3.11); 13C NMR: l 161.6
4
(Ci-F, JC–F=245.2), 137.7 (Ci), 132.4 (Cm-S, JC–F=2),
128.6 (Cp-S, JC–F=8.1), 128.4 (Co), 128.3 (Cm), 127.9
(Cp), 124.5 (Co-S, JC–F=4), 122.7 (Ci-S, JC–F=17.2),
2
115.7 (Cm-S, JC–F=22.2), 77.3 (CH), 73 (CH2-C6H5),
33.2 (CH2); 19F NMR:
l
−110.4 (ABCDX,
3
4
4
HAHBHCHDFX, JA–X=9.48, JB–X=7.32, JC–X=0.05,
3JD–X=5.34,); EIMS: 522 (m/z); High-resolution
EIMS: 522.1523, C30H28F2O2S2 (Err[ppm/mmu]=+4.6/
+2.4). Anal. calcd for C30H28F2O2S2: C, 68.94; H, 5.4;
S, 12.27. Found: C, 68.36; H, 5.45; S, 12.19%.
3.2.3. Synthesis of (2R,3R)-2,3-bis(benzyloxy)-1,4-
bis(thio-m-fluorophenyl)butane 7.
A solution of 3-
fluorophenylthiol (0.36 mL, 3.43 mmol) in THF (2 mL)
was treated sequentially—as described for 5—with a
suspension of NaH (0.69 g at 60%, 17.3 mmol) in THF
(3 mL) and compound 4 (0.73 g, 1.30 mmol) in THF (3
mL). Compound 7 was obtained as a pale yellow oil
(0.5 g, 74%): [h]2D0=+24.9 (c 0.85 CHCl3); IR (film)
(cm−1): (wCarꢀF) 1159 (m); 1H NMR: l 7 (m, 18H, Har),
4.589, 4.461 (AB, 4H, CHAHB-C6H5, JAB=−11.39),
3.057, 3.18, 3.766, 3.766, 3.18, 3.057 (AA%MM%BB%, 6H,
1
(0.11 g, 65%); H NMR: l 7.2 (m, 18H, Har) 4.596,
4.541 (AB, JAB=12.14, 4H, CHAHB-C6H5), 2.898,
3.066, 4.175, 4.175, 3.066, 2.898 (AA%MM%BB%, 6H,
CHAHA%-CHM-CHM%-CHBHB%, JA–A%=11.42, JB–B%
=
=
11.46, JA–M=3.46, JB%–M%=3.02, JA%–M=4.94, JB–M%
4.54,
J
JA–M%=0.25,
J
B%–M=0.51,
JA%–M%=−0.63,
B–M=−0.25, JM–M%=4.32); 13C NMR: l 138 (Ci), 128.4
(Co), 127.8 (Cm), 127.6 (Cp), 83.5 (CH), 71.4 (CH2-
C6H5), 33 (CH2); EIMS: 300 (m/z) (M); High-resolu-
tion EIMS: 300.1176 (m/z), C18H20O2S (Err
[ppm/mmu]=−2.7/−0.8).
CHAHA%-CHM-CHM%-CHBHB%,
JA–A%=JB–B%=−13.86,
JA–M=JB%–M%=J
=JB–M%=6.58, JA–M%=JB%–M=JA%–M%
A%–M
=JB–M=0, JM–M%=2.7); 13C NMR: l 162.8 (Ci-F, JC–F
=249.2), 138.4 (Ci-S, JC–F=8.1), 137.5 (Ci), 130.2 (Cm-
S, JC–F=9.1), 128.4 (Co), 128.4 (Cm), 128 (Cp) 124.5
4
(Co-S, JC–F=3.1), 115.8 (Cp-S, JC–F=22.2), 113 (Co-S,
3.2.6. Synthesis of (2R,3R)-2,3-O-isopropylidene-1,4-
bis(thio-o-fluorophenyl)butane 13. A solution of 2-
fluorophenylthiol (0.46 mL, 4.36 mmol) in THF (1.5
mL) was treated sequentially—as described for the
preparation of 5—with a suspension of NaH (1.11 g at
60%, 27.75 mmol) in THF (1.5 mL) and compound 12
(0.55 g, 1.29 mmol) in THF (5 mL). Compound 13 was
obtained as a transparent oil (0.45 g, 92%): [h]2D5=+35.8
2JC–F=21.1), 76.8, (CH), 73.1 (CH2-C6H5), 33.3 (CH2);
19F NMR: −113.5 (A2BCX, (HA)2HBHCFX, JA–X
=
3
8.69, 4JB–X=6.06, 5JC–X=0.09); EIMS: 522 (m/z);
High-resolution EIMS: 522.1523, C30H28F2O2S2
(Err[ppm/mmu]=+4.6/+2.4).
Anal.
calcd
for
C30H28F2O2S2: C, 68.94; H, 5.4; S, 12.27. Found: C,
68.45; H, 5.45; S, 12.25%.
(c 0.75 CHCl3); IR (film) (cm−1): (wCarꢀF) 1161(m); H
1
3.2.4. Synthesis of (2R,3R)-2,3-bis(benzyloxy)-1,4-
NMR: l 7.3 (m, 8H, Har) 3.195, 3.19, 4.054, 4.054, 3.19,
3.195 (AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-CHBHB%,
JA–A%=JB–B%=−12.77, JA–M=JB%–M%=5.31, JA%–M=JB–M%
=6.47, JA–M%=JB%–M=−0.46, JA%–M%=JB–M=−0.28,
JM–M%=6.94), 1.4 (s, 6H, CH3); 13C NMR: l 161.5
bis(thio-p-fluorophenyl)butane 8.
A solution of 4-
fluorophenylthiol (0.36 mL, 3.38 mmol) in THF (2 mL)
was treated sequentially—as described for 5—with a
suspension of NaH (0.7 g at 60%, 17.38 mmol) in THF
(3 mL) and compound 4 (0.74 g, 1.30 mmol) in THF (4
mL). Compound 8 was obtained as a pale yellow oil
(0.6 g, 87.9%): [h]2D0=+33.0 (c 0.746 CHCl3); IR (film)
(cm−1): (wCarꢀF) 1157(m); 1H NMR: l 7.1 (m, 18H,
Har), 4.543, 4.376 (AB, JAB=−11.54, 4H, CHAHB-
C6H5), 2.981, 3.104, 3.719, 3.719, 3.104, 2.981
(AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-CHBHB%, JA–A%
4
(Ci-F, JC–F=246.2), 132.5 (Cm-S, JC–F=2), 128.8 (Cp-
S, JC–F=8.1), 124.5 (Co-S, JC–F=4), 122.3 (Ci-S, JC–F
=
2
17.1), 115.8 (Cm-S, JC–F=22.2), 109.8 (C(CH3)2), 79.0
(CH), 36.5 (CH3), 36.5 (CH3), 27.2 (CH2); 19F NMR: l
3
4
−110.3 (ABCDX, HAHBHCHDFX, JA–X=9.65, JB–X
=
5
4
7.44, JC–X=0.19, JD–X=5.08); EIMS: 382 m/z (M);
High-resolution EI 382.0849 (m/z), C19H20F2O2S2
(Err[ppm/mmu]=−6.1/−2.3).
=JB–B%=−13.46,
JA–M=JB%–M%=JA%–M=JB–M%=6.37,

L. Flores-Santos et al. / Tetrahedron: Asymmetry 12 (2001) 3029–3034
3033
3.2.7. Synthesis of (2R,3R)-2,3-O-isopropylidene-1,4-
bis(thio-m-fluorophenyl)butane 14. A solution of 3-
fluorophenylthiol (0.34 mL, 3.24 mmol) in THF (2.5
mL) was treated sequentially—as described for the
preparation of 5—with a suspension of NaH (0.72 g at
60%, 18 mmol) in THF (2.5 mL) and compound 12
(0.41 g, 0.96 mmol) in THF (1 mL). Compound 14 was
obtained as a transparent oil (0.35 g, 94%): [h]2D5=+38.7
=−15.64, JA–B=JA%–B%=2.49, JA–B%=6.45, JA%–B=9.39),
1.4 (s, 6H, CH3); l (50°C) 2.853, 3.27, 4.282, 4.282,
3.27, 2.853 (AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-
CHBHB%,JA–A%=−14.78,JB–B%=−14.77,JA–M=7.43, JB%–M%
=7.62, JA%–M=4.07, JB–M%=4.19, JA–M%=−0.37, JB%–M
=
−0.61, JA%–M%=−0.22, JB–M=−0.23, JM–M%=8.23), 2.935,
2.9, 2.9, 2.935 (AA%BB%, 4H, S-CHAHA%-CHBHB%-S, JA–A%
=JB–B%=−15.64, JA–B=JA%–B%=2.49, JA–B%=6.45, JA%–B
=9.39), 1.5 (s, 6H, CH3); 13C NMR: l 107.7 (C(CH3)2),
79.9 (CH), 35.2 (S-CH2-CH2-S), 34.2 (CH2-CH), 27
(CH3); EIMS: 220 (m/z) (M); High-resolution EIMS:
(m/z): 220.0578 (m/z), C9H16O2S2 (Err [ppm/mmu]=
−6.2/−1.4).
1
(c 0.77 CHCl3); IR (film) (cm−1): (wCarꢀF) 1161 (m); H
NMR: l 7.2 (m, 8H, Har), 3.236, 3.202, 4.087, 4.087,
3.202, 3.236 (AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-
CHBHB%, JA–A%=JB–B%=−13.78, JA–M=JB%–M%=5.56, JA%–M
=JB–M%=6.42, JA–M%=JB%–M=−0.07, JA%–M%=JB–M
=
−0.66, JM–M%=7.01), 1.4 (s, 6H, CH3); 13C NMR: l
162.8 (Ci-F, JC–F=248.2), 138.1 (Ci-S, JC–F=8.1), 130.2
3.2.10. Synthesis of (R,R)-7,8-O-isopropylidene-1,5-
dithiacyclononane 17. A solution of 1,3-propanedithiol
(0.36 mL, 3.59 mmol) in THF (34.5 mL) was slowly
added to a suspension of NaH (1.78 g at 60%, 44.56
mmol) in THF (120 mL). The resulting solution was
stirred for 1 h at 25°C and treated as described for 16.
Compound 17 was obtained as a white solid (0.4 g,
4
(Cm-S, JC–F=8.1), 124.3 (Co-S, JC–F=3), 115.6 (Cp-S,
2
J
C–F=23.2), 113.2 (Co-S, JC–F=21.2), 110 (C(CH3)2),
78.8 (CH), 36.4 (CH3), 27.3 (CH2); 19F NMR: l −113.4
(A2BCX, (HA)2HBHCFX, 3JA–X=9.02, 4JB–X=5.87, 5JC–X
=0.52); EIMS: 382 (m/z) (M); High-resolution EIMS:
382.0849 (m/z), C19H20F2O2S2 (Err[ppm/mmu]=−6.1/
−2.3).
1
48%): [h]2D5=+54.8 (c 0.825 CHCl3); H NMR: l (25°C)
2.874, 3.201, 4.233, 4.233, 3.201, 2.874 (AA%MM%BB%,
3.2.8. Synthesis of (2R,3R)-2,3-O-isopropylidene-1,4-
bis(thio-p-fluorophenyl)butane 15. A solution of 3-
fluorophenylthiol (0.46 mL, 4.32 mmol) in THF (5 mL)
was treated sequentially—as described for the prepara-
tion of 5—with a suspension of NaH (1.07 g at 60%,
26.75 mmol) in THF (5 mL) and compound 12 (0.55 g,
1.29 mmol) in THF (10 mL). Compound 15 was
obtained (0.42 g, 84.9%) as a transparent oil: [h]2D5=
+30.6 (c 0.83 CHCl3); IR (film) (cm−1): (wCarꢀF) 1157
6H,
−15.17, JA–M=JB%–M%=8.03, JA%–M=3.03, JB–M%=3.12,
JA–M%=−0.47, B%–M=−0.39, JA%–M%=−0.23, JB–M
CHAHA%-CHM-CHM%-CHBHB%,
JA–A%=JB–B%=
J
=
−0.38, JM–M%=7.6), 2.994, 2.89, 1.943, 1.946, 2.887, 2.994
(AA%MM%BB%, 6H, S-CHAHA%-CHMHM%-CHBHB%-S, JA–A%
=JB–B%=−14.48, JA–B=JA%–B%=JA–B%=JA%–B=0, JA–M
=
4.8, JA–M%=4.52, JA%–M=6.38, JA%–M%=7.15, JB%–M=4.33,
JB%–M%=4.79, JB%–M=7.33, JB–M%=8.58, JM–M%=−12.3),
1.4 (s, 6H, CH3); l (50°C) 2.871, 3.2, 4.237, 4.237, 3.2,
2.871 (AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-CHBHB%,
JA–A%=JB–B%=−15.17, JA–M=JB%–M%=8.03, JA%–M=3.03,
JB–M%=3.12, JA–M%=−0.47, JB%–M=−0.39, JA%–M%=−0.23,
1
(s); H NMR: l 7.2 (m, 8H, Har), 3.161, 3.139, 4.024,
4.024, 3.139, 3.161 (AA%MM%BB%, 6H, CHAHA%-CHM-
CHM%-CHBHB%, JA–A%=JB–B%=−12.77,
JA–M=JB%–M%=
5.57, JA%–M=JB–M%=6.49, JA–M%=JB%–M=−0.5, JA%–M%
=JB–M=0.05, JM–M%=6.81), 1.42 (s, 6H, CH3), 1.4 (s,
6H, CH3); 13C NMR: 161.9 (Ci-F, JC–F=247.3), 132.5
(Co-S, JC–F=8.1), 130.5 (Ci-S, JC–F=3), 116.2 (Cm-S,
J
B–M=−0.38, JM–M%=7.6), 3.004, 2.91, 1.935, 1.938,
2.905, 3.004 (AA%MM%BB%, 6H, S-CHAHA%-CHMHM%-
CHBHB%-S, JA–A%=JB–B%=−14.48, JA–B=JA%–B%=JA–B%
A%–B=0, A–M=4.8, JA–M%=4.52, A%–M=6.38,
JA%–M%=7.15, B%–M=4.33, =4.79, B–M=7.33,
=
J
J
J
J
J
C–F=22.2), 109.8 (C(CH3)2), 78.8 (CH), 38.2 (CH3),
J
J
B%–M%
27.3 (CH2); 19F NMR: l −116.4 (A2B2X, (HA)2(HB)2FX,
JB–M%=8.58, JM–M%=−12.3) 1.4 (s, 6H, CH3); 13C NMR:
l 107.8 (C(CH3)2), 82 (CH), 36.9 (CH2-CH2-CH2), 31.7
(CH2-CH), 30.9 (CH2-CH2-CH2), 27 (CH3); EIMS: 234
(m/z); High-resolution EIMS: 234.0737 (m/z),
C10H18O2S2 (Err [ppm/mmu]=−5.0/−1.2).
3JA–X=8.46, JB–X=5.22). EIMS: 382 m/z (M); High-
4
resolution EIMS: 382.0849(m/z), C19H20F2O2S2
(Err[ppm/mmu]=−6.1/−2.3).
3.2.9. Synthesis of (6R,7R)-6,7-O-isopropylidene-1,4-
dithiacycloctane 16. A solution of 1,2-ethanedithiol (0.2
mL, 2.38 mmol) in THF (28 mL) was slowly added to
a suspension of NaH (1.19 g at 60%, 29.66 mmol) in
THF (60 mL). The resulting solution was stirred for 30
minutes at 25°C The solution was heated under reflux
(64°C) and a solution of compound 12 (1 g, 2.35 mmol)
in THF (60 mL) was slowly added over 35 min. The
solution was left to cool with continuous stirring. The
solvent was evaporated and the crude purified as
described for 5. Compound 16 was obtained as a white
solid (0.25 g, 49%): [h]2D5=+95.8 (c 0.79 CHCl3); 1H
NMR: l (25°C) 2.846, 3.274, 4.282, 4.282, 3.274, 2.846
(AA%MM%BB%, 6H, CHAHA%-CHM-CHM%-CHBHB%, JA–A%
=−14.78, JB–B%=−14.77, JA–M=7.43, JB%–M%=7.62, JA%–M
=4.07, JB–M%=4.19, JA–M%=−0.37, JB%–M=−0.61, JA%–M%
=−0.22, JB–M=−0.23, JM–M%=8.23), 2.944, 2.88, 2.88,
2.944 (AA%BB%, 4H, S-CHAHA%-CHBHB%-S, JA–A%=JB–B%
3.2.11. Synthesis of (6R,7R,14R,15R)-6,7,14,15-bis(O-
isopropylidene)-1,4,9,12-tetrathiacyclohexadecane 18. A
solution of ethanedithiol (0.06 mL, 0. 71 mmol) in THF
(1.5 mL) was treated sequentially—as described for the
preparation of 5—with a suspension of NaH (0.19 g at
60%, 4.8 mmol) in THF (1.5 mL) and compound 12
(0.31 g, 0.71 mmol) in THF (1.5 mL). Compound 16
was obtained as the major product (0.04 g, 28%) and
compound 18 was also isolated as a white solid (0.03 g,
1
9%); [h]2D5=−10.8 (c 0.06, CHCl3); H NMR: l 4 (m,
4H, CH), 2.9 (m, 8H, CH2-CH), 2.841–2.899 (m, 8H,
S-CH2-CH2-S), 1.42, 1.425 (s, 12H, CH3); 13C NMR: l
110.3, 110.1 (C(CH3)2), 80.1, 79.8 (CH), 36.5, 35.7
(CH2-CH), 33.6, 33.5 (CH2-CH2), 28 (CH3); EIMS: 440
(m/z) (M); High-resolution EIMS: (m/z): 440.1170 (m/
z); C18H32O4S4 (Err [ppm/mmu]=−3.0/−1.3).

3034
L. Flores-Santos et al. / Tetrahedron: Asymmetry 12 (2001) 3029–3034
Ruiz, A.; Claver, C.; Pereira, M. M.; d’A. Rocha, G. A.
Acknowledgements
M. J. Chem. Soc., Dalton Trans. 1998, 3517–3522.
6. Jansat, S.; Go´mez, M.; Muller, G.; Die´guez, M.; Aghmiz,
A.; Claver, C.; Masdeu-Bulto´, A. M.; Flores-Santos, L.;
Martin, E.; Maestro, M. A.; Mah´ıa, J. Tetrahedron:
Asymmetry 2001, 12, 1469–1474.
7. Albinati, A.; Eckert, J.; Pregosin, P.; Ru¨egger, H.; Salz-
mann, R.; Sto¨ssel, C. Organometallics 1997, 16, 579–590.
8. Nemoto, H.; Takamatsu, S.; Yamamoto, Y. J. Org.
Chem. 1991, 56, 1321–1322.
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We would like to thank the CONACYT-34982, Gener-
alitat de Catalunya (AIRE2000-12) and Ministerio de
Ciencia y Tecnolog´ıa (PB97-0407-C05-01) for their
financial support and DGAPA for a research grant for
L. Flores-Santos.
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