Synthesis of chiral, nonracemic α-sulfanylphosphonates and derivatives

Article abstract of DOI:10.1016/S0957-4166(03)00316-1

Optically active α-sulfanylphosphonates and the corresponding methyl sulfides were prepared in three steps starting from chiral, nonracemic (ee 93-97%) α-hydroxyphosphonates obtained by enzymatic resolution. Reaction conditions for the reduction of racemi

Full text of DOI:10.1016/S0957-4166(03)00316-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1829–1836
Synthesis of chiral, nonracemic a-sulfanylphosphonates and
derivatives
Mihaela Gulea,a Friedrich Hammerschmidt,b,* Patrice Marchand,a Serge Masson,a,* Violeta Pisljagicb
and Frank Wuggenigb
aLaboratoire de Chimie Mole´culaire et Thioorganique, ISMRA-Universite´ de Caen et CNRS, 6 boulevard du Mare´chal Juin,
F-14050 Caen, France
bInstitut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringerstrasse 38, A-1090 Wien, Austria
Received 11 March 2003; accepted 7 April 2003
Abstract—Optically active a-sulfanylphosphonates and the corresponding methyl sulfides were prepared in three steps starting
from chiral, nonracemic (ee 93–97%) a-hydroxyphosphonates obtained by enzymatic resolution. Reaction conditions for the
reduction of racemisation-prone substrates were found to preserve the enantiomeric excesses. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
fanylcarboxylic acid derivatives in moderate to poor
enantiomeric excesses at good conversions.3b,4 Almost
enantiopure a-hydroxyphosphonates were obtained by
kinetic resolution of a-acetoxy- and a-chloroace-
toxyphosphonates using hydrolases.7 Therefore, in pre-
liminary investigations, we tested the hydrolysis of
racemic diethyl 1-(acetylthio)benzylphosphonate ( )-I
(R1=Et, R=Ph) using, amongst others, enzymes
known to give good results for the corresponding
dimethyl and diisopropyl 1-(acetoxy)benzylphos-
phonates under similar reaction conditions8 (Scheme 1).
Certain sulfanylcarboxylic acid derivatives are strong
inhibitors of zinc containing metalloenzymes such as
angiotensin-converting
enzyme1
(ACE),
neutral
endopeptidase1 (NEP) and matrix metalloproteinases.2
Increasing efforts have lately been directed towards the
synthesis of chiral, nonracemic sulfanyl substituted car-
boxylic acids including a-lipoic acid and their deriva-
tives by stereospecific syntheses3 and lipase-catalysed3b,4
resolutions. Therefore, phosphonic acid analogues of
a-sulfanyl carboxylic acids are interesting candidates as
metalloenzyme inhibitors. Several chiral a-hydroxy-
and a-aminophosphonic acids (analogues of natural
hydroxy- and aminocarboxylic acids) are important for
their biological activity,5 but to the best of our knowl-
edge the corresponding thiols have not been the subject
of biological tests. Recently, some of us reported the
first asymmetric synthesis of a-sulfanylphosphonates by
a diastereoselective asymmetric [2,3]-sigmatropic rear-
rangement of dimenthyl (allylsulfanyl)methylphos-
phonate.6
However, a rapid, complete and non-enantioselective
hydrolysis was observed with lipases AP 6, Prozyme 6
and protease Chirazyme P-2 yielding racemic diethyl
(1-sulfanyl)benzylphosphonate. Furthermore, lipases
from Candida rugosa and C. cylindracea and lipase
FAP-15 did not hydrolyse racemic diethyl 1-
(acetylthio)benzylphosphonate and the starting material
was recovered unchanged. These failures show that the
enzymatic resolution, successful for the preparation of
The preparation of chiral thiols by enzymatic hydroly-
sis of acetylthio derivatives (thioesters) has not often
been described. Lipase-catalysed resolution gave a-sul-
* Corresponding authors. E-mail:
univie.ac.at; serge.masson@ismra.fr
friedrich.hammerschmidt@
Scheme 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00316-1

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M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
Scheme 2.
Scheme 3.
chiral, nonracemic a-hydroxyphosphonates, cannot be
readily extended to the sulfur analogues. Therefore, we
did not investigate further the hydrolase-catalysed
enantioselective hydrolysis of 1-acetylthiophosphonates
or the enantioselective esterification of a-sulfanylphos-
phonates, but decided to explore chemical procedures
(Scheme 2). The stereospecific conversion of easily
accessible a-hydroxyphosphonates III of high ee into
their a-sulfanyl analogues II was very attractive. The
results of the synthesis of chiral, nonracemic a-sul-
fanylphosphonates and the corresponding methyl
sulfides are described herein.
or an ethyl group, the p-nitrobenzenesulfonates ( )-2a,b
were obtained in excellent yields. In the optically active
series, the alcohols (S)-1a,8b10 obtained with high enan-
tiomeric excesses by enzymatic resolution gave p-
nitrobenzenesulfonates (S)-2a,b without racemisation
(Table 1). The nucleophilic substitution of the p-
nitrobenzenesulfonyloxy group with thiocyanate
afforded a-thiocyanatophosphonates 3a,b in good
yields and with inversion of configuration (Table 2).
Table 1. Transformation of a-hydroxyphosphonates 1 to
p-nitrobenzenesulfonates 2
2. Results and discussion
Entry
R
Starting alcohol Product 2 (ee %) Yield (%)
1 (ee %)
The stereospecific substitution of the hydroxyl (OH) for
the sulfanyl (SH) group on a carbon a to a carbanion-
stabilizing group is not trivial. We tested mesylates,
tosylates and p-nitrobenzenesulfonates of a-hydroxy-
phosphonates as substrates with a variety of sulfur
nucleophiles such as potassium thioacetate, potassium
ethyl xanthate, sodium hydrogen sulfide or potassium
thiocyanate.3a,9 We also examined the Mitsunobu pro-
cedure using thiolacetic acid3a as nucleophile, but the
yield was low and could not be improved by modifica-
tion of the ratio of reagents. The various experiments
performed in the racemic and optically active series
allowed us finally to select the p-nitrobenzenesulfonyl-
oxy group as nucleofuge and thiocyanate as nucleo-
phile. Good yields and high stereoselectivities were
observed under these conditions (Scheme 3, only trans-
formation for (S)-1 is given). Starting from racemic
a-hydroxyphosphonates ( )-1a,b with R being a phenyl
1
2
3
4
Ph
Et
Ph
Et
( )-1a
( )-1b
(S)-1a (98)
(S)-1b (96)
( )-2a
( )-2b
(S)-2a (98)
(S)-2b (96)
92
80
92
78
Table 2. Transformation of p-nitrobenzenesulfonates 2 to
a-thiocyanatophosphonates 3
Entry
R
Starting
product 2
(ee %)
Product 3 (ee %) Yield (%)
1
2
3
4
Ph
Et
Ph
Et
( )-2a
( )-2b
(S)-2a (98)
(S)-2b (96)
( )-3a
( )-3b
(S)-3a (97)
(S)-3b (93)
90
92
91
92

M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
1831
hydride anion at the cyanide carbon to give intermedi-
ate 6 which undergoes fragmentation to the thiolate
anion and hydrogen cyanide (Scheme 4, only transfor-
mation for (R)-3 is given). Then, thiolate 7 attacks
starting material 3 at the sulfur atom, leading to
disulfide 8 and cyanide anion. This step has been
confirmed by an independent experiment12 and a simi-
lar mechanism was reported for the base-catalysed
methanolysis of a thiocyanate.13 Disulfide 8 is then
slowly reduced to the thiolate 7.
To be useful for the preparation of chiral, nonracemic
a-sulfanylphosphonates, the third step of the sequence,
the conversion of the thiocyanates to the thiols, had to
occur without racemisation. Different reductive
conditions11 were first tested in the racemic series (Zn/
AcOH, NaBH4/EtOH, LiBH4/THF, LiAlH4/THF,
EtMgBr/THF). The best results were obtained using an
excess of NaBH4 in EtOH (95%) at rt. By trapping the
intermediate thiolate 6 with HCl/H2O (Method A) or
MeI (Method B) the expected racemic thiols 4a,b or
racemic sulfides 5a,b were obtained (Table 3, entries
1–4).
We then applied the same conditions (Methods A or B)
to thiocyantophosphonates (S)-3a,b of ee 93–97%.
Unexpectedly, the resulting thiols (S)-4a,b and methyl
sulfides (S)-5a,b (Table 3, entries 5–8) had only enan-
tiomeric excesses of 14–50%.
The reduction of ( )-3a was monitored by 31P NMR
spectroscopy. After 5 min, the thiocyanate was con-
verted completely into an equimolar mixture of
disulfide 8a (as a 1:1 mixture of two diastereomers:
l=20.7 and 21.4 ppm) and thiolate 7a (l=29.6 ppm).
After an additional 90 min, only 7a could be detected in
the reaction mixture. These observations suggest a
mechanism proceeding by an initial attack of the
The racemisation of the stereogenic center could occur
via a prototropic equilibrium between anion 6 or thio-
late 7 and their respective a-carbanions. Indeed, partial
racemisation was more significant for (S)-3a (R=Ph)
Table 3. Conversion of a-thiocyanatophosphonates 3 to sulfanyl- and methylsulfanylphosphonates 4 and 5, respectively
Entry
R
R%
Starting product 3 (ee %)
Conditions
Product 4 or 5 (ee %)
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Et
Et
Ph
Ph
Et
Et
Ph
Ph
Et
Et
H
Me
H
Me
H
Me
H
Me
H
Me
H
( )-3a
( )-3a
( )-3b
( )-3b
(S)-3a (97)
(S)-3a (97)
(S)-3b (93)
(S)-3b (93)
(S)-3a (97)
(S)-3a (97)
(S)-3b (93)
(S)-3b (93)
A
B
A
B
A
B
A
B
C
D
C
D
( )-4a
( )-5a
( )-4b
( )-5b
(S)-4a (27)
(S)-5a (14)
(S)-4b (60)
(S)-5b (50)
(S)-4a (97)
(S)-5a (97)
(S)-4b (92)
(S)-5b (88)
96
82
51
74
94
80
50
71
76
77
61
70
9
10
11
12
Me
Method A: (1) NaBH4/EtOH/2 h/rt; (2) 2N HCl. B: (1) NaBH4/EtOH/2 h/rt; (2) MeI. C: (1) Me3SiCl; (2) LiBH4/THF/5 min/rt. D: (1) MeI; (2)
LiBH4/THF/5 min/rt.
Scheme 4.

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M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
than (S)-3b (R=Et), which parallels the carbanion
stabilizing effect of these groups in a-position to the
phosphonyl group. Neither low temperature nor the use
of LiBH4 in THF as aprotic solvent could stop racemi-
sation. However, under the latter conditions, the reduc-
tion of the thiocyanates was found to be much faster
(after 10 min, only thiolate 7 was observed by 31P
NMR spectroscopy in the reaction mixture) and the
yield remained good.
ences in exchange of H for D reflect the higher acidity
of the a-hydrogen in 3a (R=Ph) compared to 3b
(R=Et).
We therefore presumed that racemisation could be
avoided by the addition of an appropriate electrophile
able to react at the sulfur atom of the anionic species 6
or 7 (see Scheme 4), as soon as they are formed to give
neutral product 9 (Scheme 6). We chose Me3SiCl and
MeI as electrophiles, which could afford the desired
thiols 4 or methyl sulfides 5 after acidic work-up. The
mixture of the electrophile and thiocyanate 3 in THF
was added to a solution of LiBH4 in THF (conditions
required by the use of Me3SiCl14). This time, intermedi-
ates thiolate 7 and disulfide 8 could not be observed by
31P NMR spectroscopy. Only the silylated or methyl-
ated product was detected. Thus, starting from thio-
cyanates (S)-3a,b and using Me3SiCl or MeI as elec-
trophiles, the enantiomeric excesses for the resulting
thiols 4a,b and sulfides 5a,b were excellent (almost
complete preservation of the configuration) and yields
were good (Table 3, entries 9–12).
Some additional experiments were performed to cor-
roborate the proposed reaction mechanism. When thio-
cyanate ( )-3b was reduced with NaBH4-deuteriated
ethanol (EtOD) at rt for 15 min and then worked up,
the crude product was a mixture of starting material
(3%), a 1:1 mixture of diastereomeric disulfides ( )-
[1,1%-Dx]8b (82%) and a-sulfanylphosphonate ( )-[1-
Dx]4b (14%) as determined by 1H and 31P NMR
spectroscopy (Scheme 5). The incorporation of deu-
terium for both products was at most 10% (1H NMR).
When the reduction was performed under the same
conditions, except for a reaction time of 3 h instead of
15 min, only a-sulfanylphosphonate ( )-[1-Dx]4b was
detected and isolated in 65% yield. This time the
labelling was significantly higher (25% D at a-position).
Additionally, disulfide ( )-8b obtained by iodine/Et3N
catalysed oxidation of (a-sulfanyl)propylphosphonate
( )-4b, was reduced with NaBH4 in EtOH to starting
( )-4b cleanly. Finally, ( )-3a was reduced similary.
When the reaction was worked up after 3 h, only
(a-sulfanyl)benzylphosphonate was detected which was
highly labelled (98% D). Alternatively, the reaction was
quenched by adding MeI after 10 min. Again no
disulfide could be detected. The (a-methylsul-
fanyl)benzylphosphonate ( )-5a was isolated in 73%
yield. This time the labelling was only 51%. The differ-
3. Conclusion
In conclusion, as an alternative to unsuccessful
attempts of kinetic enzymatic resolution of a-acetylthio-
phosphonates, we succeeded in the stereoselective trans-
formation of chiral a-hydroxyphosphonates easily
obtained with high enantiomeric excess by hydrolase-
catalysed resolutions into a-sulfanyl- and a-methylthio-
phosphonates. An efficient and general procedure was
developed to reduce chiral, nonracemic a-thiocyana-
tophosphonates to the corresponding a-sulfanylphos-
phonates without racemisation.
Scheme 5.
Scheme 6.

M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
1833
4. Experimental
1H, PCH); 7.10–7.32 (m, 5H, C6H5); 7.94 (AA%BB%
system, J=8.9, 4H, C6H4). 13C NMR (CDCl3, 100.61
MHz): 23.20 (d, J=5.4, CH3); 23.70 (d, J=5.4, CH3);
24.11 (d, J=3.1, CH3); 24.14 (d, J=3.1, CH3); 72.84 (d,
J=6.9, CHOP); 73.13 (d, J=6.9, CHOP); 79.32 (d,
J=174.4, PCH); 123.74 (2×CHarom); 128.31 (d, J=2.1,
2×CHarom); 128.84 (d, J=6.1, 2×CHarom); 129.13 (2×
CHarom); 129.54 (d, J=3.1, 2×CHarom); 130.98 (d, J=
4.1. General
Most of the reactions were monitored by TLC and
some by 31P NMR spectroscopy. TLC was carried out
on 0.25 mm thick Merck plates, silica gel 60 F254. Spots
were visualized by dipping the plate into a solution of
24 g of (NH4)6Mo7O24·4H2O and 1 g of Ce(SO4)2·4H2O
in 500 ml of 10% H2SO4 in water, followed by heating
with a heat gun. Products were purified by flash column
chromatography on Merck silica gel 60 (230–400 mesh).
Solvents were dried by distillation prior to use. The
NMR spectra were recorded in CDCl3 or C6D6 with a
Brucker DP spectrometer at 250 MHz or 400 MHz.
The chemical shifts (l) are expressed in ppm relative to
2.3, Carom); 142.79 (d, J=1.5, Carom); 150.26 (Carom). 31
P
NMR (CDCl3, 161.98 MHz): 13.80. Anal. calcd for
C19H24NO8PS: C, 49.88; H, 5.29; N, 3.06. Found: C,
49.76; H, 5.23; N, 2.96.
4.2.2. ( )- and (S)-Diisopropyl 1-(p-nitrobenzenesulfonyl-
oxy)propylphosphonate ( )- and (S)-2b. ( )-2b was pre-
pared from a-hydroxyphosphonate ( )-1b according to
the general procedure A. The crude product was
purified by flash chromatography (PE/AcOEt=2/1,
Rf=0.3) to give a crystalline solid, mp 50–52°C (hex-
ane/few drops of CH2Cl2). (S)-2b was prepared simi-
larly from (S)-1b,10, ee 96%; [h]2D0 +10 (c 0.8, acetone).
TMS for H, 13C (in part J modulated) nuclei and to
1
H3PO4 for 31P nucleus (broad band decoupling); the
coupling constants (J) are given in Hz; conventional
abbreviations are used. Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter. Melting
points are uncorrected. Infrared spectra were recorded
with a Perkin–Elmer 16 PC FT-IR spectrometer from
films on a Si disc15 or between NaCl discs. Enan-
tiomeric excesses of chiral compounds 2, 3, 4 and 5
( )-2b: IR (Si) wmax cm−1: 991, 1188, 1257, 1351, 1376,
1
1535, 2982. H NMR (CDCl3, 400.13 MHz): 1.05 (t,
J=7.4, 3H, CH3CH2); 1.25 (d, J=6.1, 3H, CH3); 1.27
(d, J=6.1, 3H, CH3); 1.31 (d, J=6.1, 6H, 2×CH3);
1.86–1.98 (m, 2H, CH3CH2); 4.63–4.74 (m, 2H, 2×
CHOP); 4.83 (dt, J=4.7, J=8.8, 1H, PCH); 8.30
(AA%BB% system, J=8.3, 4H, C6H4). 13C NMR (CDCl3,
100.61 MHz): 10.20 (d, J=10.5, CH3); 23.68 (d, J=5.0,
CH3); 23.88 (d, J=4.6, CH3); 23.94 (CH2); 23.95 (d,
J=3.9, CH3); 24.01 (d, J=3.7, CH3); 72.08 (d, J=8.2,
CHOP); 72.20 (d, J=7.0, CHOP); 79.72 (d, J=170.8,
PCH); 124.11 (2×CHarom); 129.30 (2×CHarom); 142.79
(Carom); 150.62 (Carom). 31P NMR (CDCl3, 161.98
MHz): 17.24. Anal. calcd for C15H24NO8PS: C, 44.01;
H, 5.91; N, 3.42; S, 7.83. Found: C, 43.93; H, 5.93; N,
3.48; S, 7.69.
were
determined
using
(R)-(+)-t-butyl(phenyl)-
phosphinothioic acid as chiral shift reagent (40 mmol of
shift reagent for 20 mmol of a-substituted phosphonate
in 0.6 mL of C6D6) and by 31P NMR or by H NMR
1
spectroscopy.16,17
4.2. Preparation of p-nitrobenzenesulfonates 2 (general
procedure A)
p-Nitrobenzenesulfonylchloride (5.1 mmol, 1.2 equiv.),
NEt3 (1.5 mL) and 4-(N,N-dimethylamino)pyridine (50
mg) were added to a solution of hydroxyphosphonate 1
(4.3 mmol) in dry CH2Cl2 (20 mL) under argon at 0°C.
The reaction mixture was stirred at rt for 18 h. After
the addition of a mixture of water (10 mL) and 12N
HCl (15 mL), the organic phase was separated and the
aqueous phase was extracted twice with CH2Cl2 (10
mL). The combined organic phases were washed with a
saturated aqueous solution of NaHCO3, dried with
MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography
(yields and ee are given in Table 1).
4.3. Preparation of thiocyanates 3 (general procedure
B)
A mixture of p-nitrobenzenesulfonate 2 (2 mmol),
KSCN (8 mmol) and 18-crown-6 (210 mg) in dry
acetonitrile (20 mL) was heated at reflux for 40 h under
argon. After addition of water (10 mL), the mixture
was extracted three times with AcOEt (3×10 mL). The
combined organic phases were dried (MgSO4) and con-
centrated under reduced pressure. The crude product
was purified by flash chromatography (yields are given
in Table 2).
4.2.1. ( )- and (S)-Diisopropyl 1-(p-nitrobenzenesulfonyl-
oxy)benzylphosphonate ( )- and (S)-2a. ( )-2a was pre-
pared from a-hydroxyphosphonate ( )-1a according to
the general procedure A. The crude product was
purified by flash chromatography (PE/AcOEt=2/1,
Rf=0.2) to give a white solid, mp 105–107°C (hexane/
few drops of CHCl3). (S)-2a was prepared similarly
from (S)-1a,8 ee 98%; mp 120–122°C; [h]2D0 −36.8 (c 1.0,
acetone).
4.3.1. ( )- and (S)-Diisopropyl 1-thiocyanatobenzylphos-
phonate ( )- and (S)-3a. ( )-3a was prepared from
p-nitrobenzenesulfonate ( )-2a according to the general
procedure B. The crude product was purified by flash
chromatography (PE/AcOEt=2/1, Rf=0.32) to give a
yellow solid, mp 48–50°C (hexane/few drops of CHCl3).
(S)-3a was prepared similarly from (S)-2a (ee 98%); mp
36–38°C; ee 97%; [h]D20 +111.6 (c 0.9, acetone).
( )-2a: IR (Si) wmax cm−1: 997, 1189, 1351, 1377, 1535,
2983, 3108. H NMR (CDCl3, 400.13 MHz): 0.97 (d,
1
J=6.2, 3H, CH3); 1.26 (d, J=6.2, 3H, CH3); 1.33 (d,
J=6.2, 3H, CH3); 1.34 (d, J=6.2, 3H, CH3); 4.51 (m,
1H, CHOP); 4.77 (m, 1H, CHOP); 5.67 (d, JHP=15.6,
( )-3a: IR (Si) wmax cm−1: 994, 1103, 1256, 1376, 1387,
1454, 2156, 2935, 2982. 1H NMR (CDCl3, 400.13

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M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
MHz): 0.91 (d, J=6.2, 3H, CH3); 1.27 (d, J=4.0, 3H,
CH3); 1.36 (d, J=6.0, 3H, CH3); 1.37 (d, J=6.0, 3H,
CH3); 4.48 (d, JHP=18.3, 1H, PCH); 4.59 (m, 1H,
CHOP); 4.79 (m, 1H, CHOP); 7.30–7.68 (m, 5H, C6H5).
13C NMR (CDCl3, 100.61 MHz): 22.96 (d, J=5.4,
CH3); 23.79 (d, J=5.5, CH3); 23.99 (d, J=3.6, CH3);
24.18 (d, J=3.0, CH3); 48.34 (d, J=149.1, PCH); 72.80
(d, J=7.3, CHOP); 73.57 (d, J=7.2, CHOP); 110.78 (d,
J=11.2, SCN), 129.06 (2×CHarom); 129.30 (d, J=6.1,
2×CHarom);129.35 (d, J=2.0, CHarom), 132.51 (d, J=
4.0, Cipso). 31P NMR (CDCl3, 161.98 MHz): 16.63.
Anal. calcd for C14H20NO3PS: C, 53.66; H, 6.43; N,
4.47; S, 10.23. Found: C, 53.55; H, 6.39; N, 4.52; S,
10.03.
( )-4a: IR (Si) wma1x cm−1: 987, 1105, 1178, 1251, 1385,
1453, 2932, 2979. H NMR (CDCl3, 400.13 MHz): 0.87
(d, J=6.4, 3H, CH3); 1.17 (d, J=4.0, 3H, CH3); 1.24
(d, J=6.0, 3H, CH3); 1.27 (d, J=6.0, 3H, CH3); 2.57
(dd, JHH=8.4, JHP=10.9, 1H, SH); 3.94 (dd, JHH=8.4,
J
HP=19.2, 1H, PCH); 4.38 (m, 1H, CHOP); 4.68 (m,
1H, CHOP); 7.15–7.88 (m, 5H, C6H5). 13C NMR
(CDCl3, 100.61 MHz): 23.08 (d, J=6.1, CH3); 23.77 (d,
J=5.3, CH3); 23.95 (d, J=3.1, CH3); 24.18 (d, J=3.1,
CH3); 39.01 (d, J=149.9, PCH); 72.00 (d, J=7.7,
CHOP); 72.39 (d, J=6.9, CHOP); 127.81 (d, J=3.0,
CHarom); 128.48 (d, J=1.5, 2×CHarom); 128.88 (d, J=
7.0, 2×CHarom); 136.86 (d, J=3.8, Cipso). 31P NMR
(CDCl3, 161.98 MHz): 22.28. Anal. calcd for
C13H21O3PS: C, 54.15; H, 7.34. Found: C, 53.84; H,
7.32.
4.3.2. ( )- and (S)-Diisopropyl 1-thiocyanatopropylphos-
phonate ( )- and (S)-3b. ( )-3b was prepared from
p-nitrobenzenesulfonate ( )-2b according to the general
procedure B. The crude product was purified by flash
chromatography (PE/AcOEt=1/1, Rf=0.32) to give a
yellow viscous oil. (S)-3b was prepared similarly from
(S)-2b (ee 96%); ee 93%; [h]2D0 +9 (c 1.1, acetone).
4.4.2. ( )-Diisopropyl 1-sulfanylpropylphosphonate ( )-
4b. ( )-4b was prepared from thiocyanate ( )-3b
according to the general procedure C. The crude
product was purified by flash chromatography (PE/
AcOEt=1/1, Rf=0.3) to give ( )-4b as a pale yellow
oil.
( )-3b: IR (Si) wmax cm−1: 992, 1252, 1386, 1456, 2156,
1
( )-4b: IR (Si) wmax cm−1: 986, 1107, 1248, 1375, 1386,
2935, 2980. H NMR (CDCl3, 400.13 MHz): 1.20 (t,
1
2935, 2979. H NMR (CDCl3, 400.13 MHz): 1.03 (t,
J=7.3, 3H, CH3CH2); 1.38 (d, J=6.2, 12H, 2×
(CH3)2CH); 1.88 (m, 1H, CH3CHH); 2.26 (m, 1H,
CH3CHH); 2.97 (ddd, JHH=4.2, JHH=9.9, JHP=15.5,
1H, PCH); 4.61–4.80 (m, 2H, 2×CHOP). 13C NMR
(CDCl3, 100.61 MHz): 11.86 (d, J=11.3, CH3CH2);
23.29 (CH2); 23.85 (d, J=3.6, CH3); 23.90 (d, J=3.5,
CH3); 24.01 (d, J=4.0, CH3); 24.06 (d, J=3.8, CH3);
45.30 (d, J=150.4, PCH); 72.39 (d, J=7.1, CHOP);
72.56 (d, J=7.2, CHOP); 110.42 (d, J=5.0, SCN). 31P
NMR (CDCl3, 161.98 MHz): 19.83. Anal. calcd for
C10H20NO3PS: C, 45.27; H, 7.60; N, 5.28. Found: C,
45.53; H, 7.45; N, 5.23.
J=6.8, 3H, CH3CH2); 1.27 (d, J=6.3, 12H, 2×
(CH3)2CH); 1.49 (m, 1H, CH3CHH); 1.77 (t, JHH
J
=
HP=8.6, 1H, SH); 2.05 (m, 1H, CH3CHH); 2.60
(dddd, J=3.8, 8.6, 8.9, 15.6, 1H, PCH); 4.61–4.76 (m,
2H, 2×CHOP). 13C NMR (CDCl3, 100.61 MHz): 12.38
(d, J=13.0, CH3CH2); 24.25 (d, J=3.0, CH3); 24.30 (d,
J=3.1, CH3); 24.51 (d, J=3.1, CH3); 24.59 (d, J=3.0,
CH3); 26.04 (d, J=1.6, CH3CH2); 37.04 (d, J=150.2,
PCH); 71.66 (d, J=6.8, CHOP); 71.88 (d, J=6.9,
CHOP). 31P NMR (CDCl3, 161.98 MHz): 25.48. Anal.
calcd for C9H21O3PS: C, 44.98; H, 8.81. Found: C,
44.76; H, 8.63.
4.4. Preparation of 1-sulfanylphosphonates ( )-4 (gen-
eral procedure C, Method A)
4.5. Oxidation of 1-sulfanylphosphonate ( )-4a to
disulfide ( )-8b and reduction of ( )-8b to ( )-4b
A solution of thiocyanate ( )-3 (0.5 mmol) in EtOH
95% (5 mL) was added dropwise to a stirred solution of
NaBH4 (5 equiv., 2.5 mmol) in of EtOH 95% (5 mL) at
rt. The mixture was stirred for 2 h (the reaction was
monitored by TLC), then poured into a cooled solution
of 2N HCl (10 mL) at 0°C and extracted with AcOEt
(3×15 mL). The combined organic phases were dried
(MgSO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
Compounds 4 were stored under argon in the freezer to
avoid their oxidation to disulfides.
Triethylamine (0.02 mL, 0.14 mmol) was added to a
solution of a-sulfanylphosphonate ( )-4b (29 mg, 0.12
mmol) in dry THF (0.6 mL). After cooling to 0°C a
solution of iodine (18 mg, 0.072 mmol) in dry THF (0.3
mL) was added dropwise. The mixture was stirred at rt
for 2 h and then concentrated. The residue was taken
up in dichloromethane. After washing with water and
an aqueous solution of Na2S2O3, the organic layer was
dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash chromatography (PE/AcOEt=1/1;
Rf=0.29, AcOEt) to give disulfide ( )-8b as an oil, 1:1
mixture of two diastereomers (1H and 13C NMR).
When EtOH was replaced by EtOD, partially labeled
products were obtained.
1
IR (Si) wmax cm−1: 983, 1107, 1248, 1386, 2933, 2978. H
NMR (CDCl3, 400.13 MHz): 1.075 (t, J=7.3, 3H,
CH3CH2); 1.072 (t, J=7.3, 3H, CH3CH2);1.27 (overlap-
ping d, J=6.1, 24H, 4×(CH3)2CH); 1.74 (m, 2H, 2×
CH3CHH); 1.99 (m, 2H, 2×CH3CHH); 2.95 (ddd,
J=4.8, 8.8, 16.4, 2H, 2×PCH); 3.00 (ddd, J=4.8, 8.6,
16.7, 2H, 2×PCH); 4.68 (m, 4H, 4×CHOP). 13C NMR
(CDCl3, 100.61 MHz): 11.78 (d, J=9.9, CH3CH2);
4.4.1. ( )-Diisopropyl 1-sulfanylbenzylphosphonate ( )-
4a. ( )-4a was prepared from thiocyanate ( )-3a
according to the general procedure C. The crude
product was purified by flash chromatography (PE/
AcOEt=1/1, Rf=0.5) to give ( )-4a as a pale yellow
oil.

M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
1835
11.82 (d, J=10.0, CH3CH2); 22.61 (CH2); 23.95 (d,
J=5.4, CH3); 23.98 (d, J=5.4, 3×CH3); 24.15 (d, J=
3.8, 4×CH3); 51.01 (d, J=144.6, PCH); 51.03 (d, J=
144.6, PCH); 51.15 (d, J=144.6, PCH); 51.17 (d,
J=144.6, PCH); 71.08 (d, J=6.9, CHOP); 71.12 (d,
J=6.9, CHOP); 71.14 (d, J=6.9, CHOP); 71.17 (d,
J=7.7, CHOP). 31P NMR (CDCl3, 161.98 MHz): 24.6.
(d, J=13.0, CH3CH2); 14.91 (SCH3); 21.81 (CH3CH2);
23.84 (d, J=2.3, CH3); 23.89 (d, J=2.3, CH3); 24.15 (d,
J=2.3, CH3); 24.18 (d, J=3.0, CH3); 43.55 (d, J=
150.7, PCH); 70.96 (d, J=7.6, 2×CHOP). 31P NMR
(CDCl3, 161.98 MHz): 25.61. Anal. calcd for
C10H23O3PS: C, 47.23; H, 9.12. Found: C, 46.99; H,
8.84.
Disulfide ( )-8b (19 mg, 0.041 mmol) was reduced with
NaBH4 (2.5 equiv.) to ( )-4b in 78% yield in 6 h by
general procedure C.
4.7. Preparation of chiral, nonracemic 1-sulfanylphos-
phonates 4 (general procedure E, Method C)
At rt, a solution of chiral thiocyanate (S)-3 (0.25 mmol)
and Me3SiCl (5 equiv., 1.25 mmol) in THF (3 mL) was
added dropwise into a stirred solution of LiBH4 (5
equiv., 1.25 mmol) in THF (3 mL) under argon. The
mixture was stirred for 5 min, then poured into a
solution of 2N HCl (10 mL) cooled to 0°C and
extracted with AcOEt (3×15 mL). The combined
organic phases were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified
by flash chromatography. The spectroscopic data of
(S)-4a {[h]2D0 −19.6 (c 0.56, acetone)} and (S)-4b {[h]2D0
−19.6 (c 0.56, acetone)} are identical with those of the
racemic compounds. The enantiomeric excess of (S)-4a
and (S)-4b were determined by use of (R)-(+)-t-
butyl(phenyl)phosphinothioic acid as chiral shift
4.6. Preparation of racemic 1-(methylsul-
fanyl)benzylphosphonates ( )-5 (general procedure D,
Method B)
A solution of thiocyanate ( )-3 (0.5 mmol) in EtOH
95% (5 mL) was added dropwise to a stirred solution of
NaBH4 (5 equiv., 2.5 mmol) in of EtOH 95% (5 mL) at
rt. The mixture was stirred for 2 h, then pure CH3I (2
equiv., 1 mmol) was added and stirring continued for 1
h. The reaction mixture was hydrolysed with a solution
of 2N HCl (10 mL) and extracted with AcOEt (3×15
mL). The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure. The crude
product was purified by flash chromatography.
1
reagent and by H NMR spectroscopy (C6D6, 250.13
4.6.1. ( )-Diisopropyl 1-(methylsulfanyl)benzylphos-
phonate ( )-5a. ( )-5a was prepared from thiocyanate
( )-3a according to the general procedure D. The crude
product was purified by flash chromatography (PE/
AcOEt=1/1, Rf=0.53) to give ( )-5a as a pale yellow
oil.
MHz). The resonances of the SH groups of the
diastereomeric complexes were well separated and
allowed the accurate determination of the ee.
( )-4a: 3.11 (dd, JHH=8.4, JHP=10.9, SH); 3.21 (dd,
J
J
HH=8.4, JHP=10.9, SH). (S)-4a: 3.11 (dd, JHH=8.4,
HP=10.9, SH); ee 97%. ( )-4b: 2.29 (t, JHH=JHP
=
( )-5a: IR (Si) wmax cm−1: 986, 1106, 1250, 1374, 1385,
8.6, SH); 2.40 (t, JHH=JHP=8.6, SH). (S)-4b: 2.29 (t,
1
2922, 2979. H NMR (CDCl3, 400.13 MHz): 0.94 (d,
J
HH=JHP=8.6, SH); ee 92%.
J=6.3, 3H, CH3); 1.18 (d, J=6.0, 3H, CH3); 1.22 (d,
J=6.1, 3H, CH3); 1.25 (d, J=6.3, 3H, CH3); 2.02 (d,
J=1.0, 3H, SCH3); 3.79 (d, J=20.2, 1H, PCH); 4.48
(m, 1H, CHOP); 4.67 (m, 1H, CHOP); 7.18–7.41 (m,
5H, C6H5). 13C NMR (CDCl3, 100.61 MHz): 15.74 (d,
J=6.8, S CH3); 23.20 (d, J=6.1, CH3); 23.83 (d, J=
5.4, CH3); 24.08 (d, J=3.1, CH3); 24.23 (d, J=3.1,
CH3); 47.95 (d, J=148.4, PCH); 71.52 (d, J=7.7,
CHOP); 71.85 (d, J=6.9, CHOP); 127.58 (d, J=3.1,
4.8. Preparation of chiral, nonracemic 1-(methylsul-
fanyl)phosphonates 5 (general procedure F, Method D)
At rt, a solution of chiral thiocyanate (S)-3 (0.25 mmol)
and CH3I (5 equiv., 1.25 mmol) in THF (3 mL) was
added dropwise into a stirred solution of LiBH4 (5
equiv., 1.25 mmol) in THF (3 mL) under argon. The
mixture was stirred for 5 min, then poured into a
solution of 2N HCl (10 mL) and extracted with AcOEt
(3×15 mL). The combined organic phases were dried
(MgSO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
The spectroscopic data of (S)-5a {[h]2D0 +58.6 (c 0.58,
acetone)} and (S)-5b {[h]2D0 −23.0 (c 0.65, acetone)} are
identical with those of the racemic compounds. The
enantiomeric excesses of (S)-5a and (S)-5b were deter-
mined by use of (R)-(+)-t-butyl(phenyl)phosphinothioic
acid as chiral shift reagent and by 1H NMR spec-
troscopy (C6D6, 250.13 MHz). The resonances of the
SMe groups of the diastereomeric complexes were well
separated and allowed the accurate determination of
the ee.
C
arom); 128.33 (d, J=1.5, 2×Carom); 129.43 (d, J=6.9,
2×Carom); 135.44 (d, J=4.0, Cipso). 31P NMR (CDCl3,
161.98 MHz): 21.35. Anal. calcd for C14H23O3PS: C,
55.61; H, 7.67. Found: C, 55.40; H, 7.42.
4.6.2. ( )-Diisopropyl 1-(methylsulfanyl)propylphos-
phonate ( )-5b. ( )-5b was prepared from thiocyanate
( )-3b according to the general procedure D. The crude
product was purified by flash chromatography (PE/
AcOEt=1/1, Rf=0.3) to give ( )-5b as a pale yellow
oil.
( )-5a: IR (Si) wmax cm−1: 986, 1108, 1247, 1385, 2933,
1
2977. H NMR (CDCl3, 400.13 MHz): 1.11 (t, J=6.3,
3H, CH3CH2); 1.34 (d, J=6.2, 12H, 2×(CH3)2CH); 1.55
(m, 1H, CH3CHH); 1.99 (m, 1H, CH3CHH); 2.24 (d,
J=0.9, 3H, SCH3); 2.41 (m, 1H, PCH); 4.61–4.82 (m,
2H, 2×CHOP). 13C NMR (CDCl3, 100.61 MHz): 11.97
1H NMR (C6D6, 250.13 MHz): ( )-5a: 1.88 (d, J=1.0,
SCH3); 1.99 (d, J=1.0, SCH3). (S)-5a: 1.88 (d, J=1.0,
1
SCH3); ee 97%. H NMR (C6D6, 400.13 MHz): ( )-5b:

1836
M. Gulea et al. / Tetrahedron: Asymmetry 14 (2003) 1829–1836
1.72 (d, J=0.9, SCH3); 1.80 (d, J=0.9, SCH3). (S)-5b:
1.72 (d, J=0.9, SCH3); ee 88%.
4. (a) Zhu, J.; You, L.; Zhao, S. X.; White, B.; Chen, J. G.;
Skonezny, P. M. Tetrahedron Lett. 2002, 43, 7585–7587;
(b) Fadnavis, N. W.; Babu, R. L.; Vadivel, S. K.; Desh-
panade, A. A.; Bhalerao, U. T. Tetrahedron: Asymmetry
1998, 9, 4109–4112; (c) Bianchi, D.; Cesti, P. J. Org.
Chem. 1990, 55, 5657–5659.
Acknowledgements
5. (a) Kafarsky, P.; Lejczak, B. Phosphorus Sulfur Silicon
1991, 63, 193–215; (b) Mu¨ller, B.; Schaub, C.; Schmidt,
R. R. Angew. Chem., Int. Ed. Engl. 1998, 37, 2893–2897;
(c) McLeod, A. M.; Baker, R.; Hudson, M.; James, K.;
Roe, M. B.; Knowles, M.; McAllister, G. Med. Chem.
Res. 1992, 2, 96–101.
This work was performed in the frame of the French–
Austrian cooperation programme ‘AMADEUS’. We
thank the French ‘Ministe`re des Affaires Etrange`res’
and the Austrian ‘Bu¨ro fu¨r Wissenschaftlich-Technische
Zusammenarbeit des OAD’ for their financial supports
allowing exchange of researchers.
8
6. Marchand, P.; Gulea, M.; Masson, S.; Saquet, M.; Col-
lignon, N. Org. Lett. 2000, 2, 3757–3759.
7. Hammerschmidt, F.; Lindner, W.; Wuggenig, F.; Zarbl,
E. Tetrahedron: Asymmetry 2000, 11, 2955–2964.
8. Li, Y.-F.; Hammerschmidt, F. Tetrahedron: Asymmetry
1993, 4, 109–120.
9. Effenberger, F.; Gaupp, S. Tetrahedron: Asymmetry 1999,
10, 1765–1775.
10. Hammerschmidt, F.; Wuggenig, F. Tetrahedron: Asym-
metry 1999, 10, 1709–1721.
11. Still, I. W. J. Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 8, Chapters 2 and 3, p. 413.
12. By reacting thiolate, prepared from thiol 4a and sodium,
with 1 equiv. of thiocyanate 3a in THF, only disulfide 8a
(R=Ph) was obtained in less than 2 min.
13. Hough, L.; McCarthy, K. C.; Richardson, A. C. Recl.
Trav. Chim. Pays-Bas 1991, 110, 450–458.
14. Me3SiCl cannot be used in ethanol and LiBH4 is more
soluble in THF than NaBH4.
15. Mikenda, W. Vibrational Spectroscopy 1992, 3, 327–330.
16. Omelanczuk, J.; Mikolajczyk, M. Tetrahedron: Asymme-
try 1996, 7, 2687–2694.
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