A convenient route to the phosphorus and sulfur stereoisomers of ethyl menthyl (methylsulfinyl)methylphosphonate

Article abstract of DOI:10.1016/j.tetasy.2004.03.022

The four phosphorus and sulfur stereoisomers of ethyl menthyl (methylsulfinyl)methylphosphonate were obtained by preparing the corresponding sulfides from commercially available diethyl (methylthio)methylphosphonate and subjecting them to a highly diastereoselective hydroperoxide oxidation in the presence of catalytic amounts of a titanium (R)- or (S)-BINOL complex. The configuration at the sulfur stereogenic centre was assigned by a chemical correlation based upon a displacement reaction with Grignard reagents, whereas the configuration at the phosphorus stereogenic centre was assigned by taking advantage of a reaction sequence based upon the use of menthyl (R _P)-methylphosphonothioic acid as a starting material.

Full text of DOI:10.1016/j.tetasy.2004.03.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1471–1476
A convenient route to the phosphorus and sulfur stereoisomers
of ethyl menthyl (methylsulfinyl)methylphosphonate
c
Cosimo Cardellicchio,a Francesco Nasoa,b, and Maria Annunziata M. Capozzi
*
aConsiglio Nazionale delle Ricerche, Istituto di Chimica dei Composti OrganoMetallici (ICCOM),
Sezione di Bari, via Orabona 4, 70126 Bari, Italy
bDipartimento di Chimica, Universitꢀa di Bari, via Orabona 4, 70126 Bari, Italy
cDipartimento Agro-ambientale di Chimica e Difesa Vegetale, Facoltꢀa di Agraria, Universitꢀa degli Studi di Foggia,
via Napoli 25, 71100 Foggia, Italy
Received 16 February 2004; accepted 4 March 2004
Abstract—The four phosphorus and sulfur stereoisomers of ethyl menthyl (methylsulfinyl)methylphosphonate were obtained by
preparing the corresponding sulfides from commercially available diethyl (methylthio)methylphosphonate and subjecting them to a
highly diastereoselective hydroperoxide oxidation in the presence of catalytic amounts of a titanium (R)- or (S)-BINOL complex.
The configuration at the sulfur stereogenic centre was assigned by a chemical correlation based upon a displacement reaction with
Grignard reagents, whereas the configuration at the phosphorus stereogenic centre was assigned by taking advantage of a reaction
sequence based upon the use of menthyl (RP)-methylphosphonothioic acid as a starting material.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
protozoa of the genera Trypanosoma, Leishmania,
Toxoplasma and Plasmodium.15;16
Chiral nonracemic sulfoxides are widely used interme-
diates in asymmetric synthesis1–3 while some of them
also have interesting pharmacological activities.4;5 In
connection with our continuing efforts on chiral sulf-
oxides,6–12 we reported the synthesis and applications of
chiral nonracemic dialkyl (arylsulfinyl)- or (alkylsulf-
inyl)methylphosphonates (Fig. 1).6–8
Dimethyl (S)- or (R)-(p-tolylsulfinyl)methylphosphonate
was prepared according to the Andersen procedure or
by resolution.17 Additionally, we have reported7;8 that
diethyl (arylsulfinyl)- or (alkylsulfinyl)methylphospho-
nates can be produced by an enantioselective oxidation
of the corresponding sulfides with hydroperoxides in the
presence of a chiral titanium complex. In particular,
diethyl
(methylsulfinyl)methylphosphonate
was
O
S
O
P
obtained with up to 80% ee by using a complex between
titanium and diethyl (R,R)-tartrate (DET)7 and in >98%
ee by performing the oxidation in the presence of a
catalytic amount of a complex between titanium and
(S)- or (R)-1,10-bi-2-naphthol (BINOL)8 (Scheme 1).
R
OR"
OR'
R= aryl, alkyl
R', R" = alkyl
Figure 1.
These compounds can be considered structurally related
to bisphosphonates.13 The latter phosphorus com-
pounds represent a family of molecules, which have anti-
resorbing activities and are currently used against
osteoporosis as well as being employed in antitumour
therapy.14 More recently, some bisphosphonates have
been reported to display activity against parasitic
O
S
O
P
O
P
TBHP or CHP
*
S
Me
OEt
OEt
Me
OEt
OEt
Ti(O-i-Pr)4/L*
L*= DET or BINOL
Scheme 1.
At variance with other reports,18;19 the titanium/BINOL
catalysed oxidation of sulfides occurred in high yields
with the formation of only negligible amounts of sulfone.
* Corresponding author. E-mail: naso@area.ba.cnr.it
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.022

1472
C. Cardellicchio et al. / Tetrahedron: Asymmetry 15 (2004) 1471–1476
The oxidation process was also performed on ethyl
menthyl (methylthio)methylphosphonate, which had a
stereogenic phosphorus centre.7 Indeed, ethyl menthyl
(methylthio)methylphosphonate was prepared as a
mixture of diastereomers, which were epimeric at the
phosphorus centre (Scheme 2). The diastereomers were
separated by column chromatography.
solution of commercially available diethyl (methyl-
thio)methylphosphonate in THF (Scheme 2).7 Herein
we found that, in order to increase the amount of the
less abundant isomer, which was necessary for the oxi-
dation process, it is sufficient to reduce the THF/hexane
ratio used in the reaction. Indeed, as detailed in the
Experimental section, with a suitable ratio of the sol-
vents couple, an almost 1:1 mixture of the sulfides was
obtained. The diastereomers can be separated by col-
umn chromatography on silica gel. On the basis of the
spectral properties (see below, configuration assign-
ments), the (RP)-configuration can be attributed to the
prevailing stereoisomer obtained in the previous work.7
O
P
OMent
O
P
O
P
MentOLi
S
S
+
S
Me
OEt
Me
OMent
OEt
Me
OEt
OEt
(S )-1
(R )-1
P
P
Scheme 2.
2.2. Diastereoselective oxidation of ethyl menthyl (meth-
ylthio)methylphosphonate
The prevailing phosphorus stereoisomer was oxidised
with cumene hydroperoxide in the presence of a complex
between titanium and diethyl (R,R)- or (S,S)-tartrate, to
yield the corresponding (methylsulfinyl)methylphospho-
nates 2 (76–82% de).7 Using diethyl (S,S)-tartrate as
ligand, sulfoxide 2 was obtained in a diastereomerically
pure form7 (>98% de, upon recrystallisation) and was
shown to have an (SS)-configuration (Scheme 3).
Both stereoisomers of ethyl menthyl (methylthio)meth-
ylphosphonate, (RP)-1 and (SP)-1, were oxidised with
tert-butyl hydroperoxide in the presence of a complex
between titanium and (R)- or (S)-BINOL according to
our previously reported procedure.8 Ethyl menthyl
(methylsulfinyl)methylphosphonate 2 was obtained in
high yield (82–90%) and in high diastereomeric purity
(>95% de, >98% de after purification) at the sulfur
stereogenic centre. As occurred in the reaction previ-
ously reported,8 in this new highly stereoselective tita-
nium/BINOL catalysed oxidation the amount of sulfone
produced was very low (<5%).
O
P
OEt
O
S
O
P*
OEt
TBHP, CH Cl
2
2
*
S
Me
OMent
OMent
Me
Ti(O-i-Pr) /(S,S)-DET/H O
4
2
(S
)-2
1
S
Scheme 3.
We were able to oxidise both (RP)-1 and (SP)-1 by using
(S)-BINOL as a chiral ligand, with the formation of
(RP,RS)-2 and (SP,RS)-2, respectively (Scheme 4). The
configuration at the sulfur stereogenic centre was
attributed by a correlation based upon a stereocon-
trolled reaction with Grignard reagents (see below).
Furthermore, in view of the results obtained with a
sample of a mixture of the four stereoisomers of 2 in
some preliminary tests as anticancer agents,20 we deci-
ded to set up a procedure for the synthesis of all these
isomers in enantiomerically pure form and with an
established configuration at both the heteroatom stereo-
genic centres, for a better evaluation of their biological
properties.
O
P
O
S
O
P
TBHP, CCl4
S
Me
OMent
OMent
Ti(O-i-Pr)4/(S)-BINOL/H2O
OEt
OEt
Me
(RP,RS)-2
(RP)-1
88%
2. Results and discussion
O
S
Me
O
P
O
TBHP, CCl4
Our strategy directed towards the synthesis of the ste-
reoisomers of compound 2 was developed along the
following lines:
S
P
OEt
OEt
Me
Ti(O-i-Pr)4/(S)-BINOL/H2O
OMent
OMent
(SP,RS)-2
(SP)-1
82%
1. Synthesis of ethyl menthyl (methylthio)methylphos-
phonate 1.
Scheme 4.
2. Diastereoselective oxidation of ethyl menthyl (methyl-
thio)methylphosphonate 1.
3. Configuration assignments.
Similar results were obtained in the oxidation performed
in the presence of (R)-BINOL as a chiral ligand (90%
isolated yield, >95% de). However, in this case, rather
than separating the sulfides before effecting the oxida-
tion, it was found experimentally more convenient to
oxidise the mixture of the sulfides (RP)-1 and (SP)-1, and
to subject the mixture of the resulting sulfoxides (RP,SS)-
2 and (SP,SS)-2 to an easier chromatographic separation
(Scheme 5).
2.1. Synthesis of ethyl menthyl (methylthio)methyl-
phosphonate 1
The diastereomers of the ethyl menthyl (methyl-
thio)methylphosphonate were prepared in a 4:1 ratio by
treating a solution of (1R,2S,5R)-(ꢀ)-menthol in THF
with n-butyllithium in n-hexane, and then adding a

C. Cardellicchio et al. / Tetrahedron: Asymmetry 15 (2004) 1471–1476
1473
sion that the (SS)-configuration can be attributed to the
sulfinylmethylphosphonates 2 used in these reactions.
Hence, the tert-butyl hydroperoxide oxidation of
(methylthio)methylphosphonate in the presence of a
complex between titanium and (R)-BINOL produced
sulfoxides with the (SS)-configuration, as it had been
reported also for the oxidation of the diethyl ester of
(methylthio)methylphosphonate.8 On the other hand,
the (RS)-configuration could be assigned to the (meth-
ylsulfinyl)phosphonates, which were obtained in the
reaction involving (S)-BINOL as a ligand.
O
S
O
P
O
P
S
OMent
Me
Me
OMent
Me
OEt
OEt
TBHP, CCl4
+
+
Ti(O-i-Pr)4/(R)-BINOL/H2O
O
S
O
P
O
S
P
OEt
OEt
Me
OMent
OMent
(RP)-1 + (SP)-1
Scheme 5.
(RP,SS)-2 + (SP,SS)-2
Also in this case, the configuration of the sulfur stereo-
genic centre was attributed by reacting these products
with Grignard reagents (see below). Furthermore,
(RP,SS)-2 had identical spectral properties with the
compound, which had been obtained in a previous work
by subjecting the (RP)-stereoisomer of ethyl menthyl
(methylthio)methylphosphonate 1 to a diastereoselective
oxidation with cumene hydroperoxide in the presence of
a complex between titanium and diethyl (S,S)-tartrate.7
2.3.2. Configuration at the phosphorus centre. The con-
figuration at the phosphorus stereogenic centre was
attributed by analysing the pair of epimeric ethyl men-
thyl methylphosphonates 4. These diastereoisomers had
different 31P NMR chemical shift (d ¼ 30:3 and 29.9).
Thus, we decided to prepare (RP)- or (SP)-4 by a dif-
ferent method, in order to compare the spectral prop-
erties with the phosphonates, which were produced from
the reactions depicted in Scheme 6.
Menthyl methyl (RP)-methylphosphonate was prepared
starting from the resolved menthyl (RP)-meth-
ylphosphonothioic acid 5.21 We repeated the same
reactions sequence to obtain ethyl menthyl meth-
ylphosphonate 4 on a satisfactory scale for NMR
2.3. Configuration assignments
2.3.1. Configuration at the sulfur centre. In our previous
work,8 the diethyl (methylsulfinyl)methylphosphonate
obtained from the oxidation in the presence of (R)-BI-
NOL was reacted with Grignard reagents. Since the
obtained aryl or alkyl methyl sulfoxide had an (R)-
configuration and these reactions occur with inversion
of configuration, an (S)-configuration was attributed to
the starting material. For example, (R)-(ꢀ)-n-dodecyl
methyl sulfoxide 3 can be obtained from diethyl (S)-
(methylsulfinyl)methylphosphonate. On the other hand,
the (R)-configuration was attributed to the sul-
finylmethylphosphonate obtained in the oxidation,
which employed (S)-BINOL.
analysis.
For
this
purpose,
menthyl
meth-
ylphosphonothioic acid 5 was prepared by treating
commercially available methylphosphonothioic dichlo-
ride with 1 equiv menthol, according to a procedure used
in similar cases.22 Following a literature protocol,21;23
compound 5 was partially resolved with (R)-phenyleth-
ylamine, with formation of a mixture of menthyl (RP)-
and (SP)-methylphosphonothioic acid in 86% de. We
observed that (RP)-5, which is known to be the pre-
dominant isomer,21 had a 31P NMR chemical shift
dP ¼ 87:4, whereas the signal of the residual (SP)-isomer
was d ¼ 88:7.
Herein, the sulfinylmethylphosphonates 2 obtained from
the oxidation of the sulfides (RP)-1 and (SP)-1 by using
(R)-BINOL as a ligand of titanium were reacted with
The mixture having (RP)-5 as the predominant isomer
was alkylated with ethyl bromide resulting in S-ethyl
O-menthyl methylphosphonothioate 6 being produced
(Scheme 7). The predominant (RP)-6 had a 31P NMR
chemical shift d ¼ 52:1, whereas the signal of the resid-
ual (SP)-isomer was d ¼ 52:8.
n-dodecylmagnesium
bromide.
(R)-(ꢀ)-n-Dodecyl
methyl sulfoxide 3 was produced together with ethyl
menthyl (RP)- or (SP)-methylphosphonate 4 (Scheme 6).
O
S
O
P
O
S
O
P
i) C12H25MgBr
ii) NH4Cl (aq)
OMent
+
Me
Me
Me
OMent
OEt
O
P
Me
O
P
C12H25
O
P
OEt
EtBr
EtONa
SEt
EtO
Me
SH
Me
MentO
Me
MentO
(RP)-4
(R)-3
(RP,SS)-2
OMent
41%
46%
(RP)-5
(RP)-4
29.9 δ
(RP)-6
52.1 δ
O
S
O
P
O
P
O
S
i) C12H25MgBr
ii) NH4Cl (aq)
87.4 δ
OEt
31P-NMR
Me
OEt
OMent
+
Me
C12H25
OMent
Scheme 7.
(SP)-4
49%
(R)-3
46%
(SP,SS)-2
Scheme 6.
S-Ethyl O-menthyl methylphosphonothioate 6 was
treated with sodium ethoxide according to the liter-
ature21 to give ethyl menthyl methylphosphonate 4 in an
almost quantitative yield (97%). This type of reaction
Since these reactions occur with inversion of configu-
ration,7;8 the formation of (R)-3 lead us to the conclu-

1474
C. Cardellicchio et al. / Tetrahedron: Asymmetry 15 (2004) 1471–1476
has been reported to occur with full inversion of con-
figuration21 and, consequently, the predominant (RP)-6
should lead to (RP)-4 (Scheme 7). Ethyl menthyl (RP)-
methylphosphonate 4, which was the predominant
product of this reaction, had a 31P NMR chemical shift
dP ¼ 29:9. The signal of the residual (SP)-isomer was
d ¼ 30:3.
Having clearly established the 31P NMR chemical shift
of compounds (RP)-4 and (SP)-4 (Scheme 7), it was
possible to assign the configurations to compounds 4,
which were obtained in the reactions depicted in Scheme
6. Furthermore, the identical phosphorus configuration
could then be attributed to the sulfinylmethylphospho-
nates 2, which had produced (RP)-4 and (SP)-4
(Scheme 6) and to the corresponding sulfides (Schemes 4
and 5).
distillation (T ¼ 60–65 °C, p ¼ 3 ꢁ 10ꢀ4 mbar). The two
diastereomeric sulfides were obtained in a ca. 1:1 mix-
ture (77% overall yield) and were separated by column
chromatography (silica gel, eluent petroleum ether/ethyl
acetate 7:3).
4.1.1. Ethyl menthyl (SP)-(methylthio)methylphosphonate
1
(first eluted stereoisomer). Colourless liquid.
25
½aꢂ ¼ ꢀ78:5 (c 1, CHCl3). MS 70 eV m=e (relative
D
intensity) 308 (Mþ, 5), 171 (46), 170 (56), 143 (25), 124
1
(100), 97 (29). H NMR (CDCl3, 500 MHz) 4.24 (ddt,
J ¼ 4:5, J ¼ 7:1, J ¼ 10:8 Hz, 1H), 4.15 (ddq, J ¼ 7:7,
J ¼ 10:0, J ¼ 7:1 Hz, 1H), 4.11 (ddq, J ¼ 7:3, J ¼ 10:0,
J ¼ 7:1 Hz, 1H), 2.70–2.59 (m, 2H), 2.25 (d, J ¼ 1:2 Hz,
3H), 2.19–2.14 (m, 1H), 2.13–2.07 (m, 1H), 1.65–1.59
(m, 2H), 1.48–1.38 (m, 2H), 1.31 (td, J ¼ 7:1,
J ¼ 0:5 Hz, 3H), 1.13 (q-like, J ¼ 12:6 Hz, 1H), 1.02–
0.92 (m, 1H), 0.88 (d, J ¼ 6:6 Hz, 3H), 0.87 (d,
J ¼ 7:2 Hz, 3H), 0.85–0.80 (m, 1H), 0.78 (d, J ¼ 7:0 Hz,
3H). 13C NMR (CDCl3, 125 MHz) 78.04 (d, J ¼ 7:9 Hz),
62.40 (d, J ¼ 6:2 Hz), 48.47 (d, J ¼ 7:3 Hz), 43.41, 34.01,
31.50, 27.85, (d, J ¼ 151:9 Hz), 25.59, 22.80, 21.98,
20.98, 17.43, 16.44 (d, J ¼ 6:4 Hz), 15.74. 31P NMR
(CDCl3, 202 MHz) 24.2. Anal. Calcd for C14H29O3PS:
C, 54.52; H, 9.48. Found: C, 54.38; H, 9.22.
3. Conclusion
According to the protocol reported herein, the four
sulfur and phosphorus stereoisomers of ethyl menthyl
(methylsulfinyl)methylphosphonate have been prepared
by taking advantage of a highly diastereoselective oxi-
dation of the corresponding sulfides conducted in the
presence of catalytic amounts of a titanium/BINOL
complex. The configuration of both sulfur and phos-
phorus stereogenic centres were unambiguously estab-
lished through a correlation involving compounds and
reactions of known stereochemistry. In view of the
results of the preliminary tests performed on the mixture
of stereoisomers 2,20 the same compounds obtained in a
pure stereochemical form appear now of undoubted
interest from a pharmacological point of view.
4.1.2. Ethyl menthyl (RP)-(methylthio)methylphosphonate
1 (second eluted stereoisomer). 31P NMR (CDCl3,
202 MHz) 24.0. Other spectroscopic and physical data
were identical to those reported.7
4.2. Diastereoselective oxidation of ethyl menthyl (meth-
ylthio)methylphosphonate with tert-butyl hydroperoxide
in the presence of a titanium/BINOL complex.
Representative procedure
4. Experimental
The purified reaction products were characterised by 1H,
13C and 31P NMR spectra, recorded in CDCl3 at 500,
125 and 202 MHz, respectively. Their mass spectra were
determined by GC/MS analysis (SE30, 30 m, capillary
columns and Mass Selective Detector, 70 eV). The
composition of the diastereoisomeric mixtures of 1 was
determined by GC analysis (capillary column, SE30).
A solution of Ti(O-i-Pr)4 (35 mg, 0.12 mmol) in 20 mL of
CCl4 was added to a solution of (R)- or (S)-1,10-bi-2-
naphthol (70 mg, 0.24 mmol) in 10 mL of CCl4. Water
(44 lL) was then added and the mixture stirred for 1 h at
rt. After addition of 1.5 g of sulfide 1 (4.86 mmol) in
20 mL of CCl4, the mixture was stirred for 30 min. A
commercial 80% solution (0.7 mL) of tert-butyl hydro-
peroxide (in di-tert-butylperoxide/water 3:2) were then
added. After stirring the mixture at rt for 5 h, the solvent
was removed in vacuo. The crude reaction mixture was
separated by column chromatography (silica gel, eluent
ethyl acetate/petroleum ether 9:1) and the obtained
products crystallised.
4.1. Synthesis of ethyl menthyl (methylthio)methyl-
phosphonate 1
A ca. 1:1 diastereomers mixture was prepared according
to the following protocol. A solution (25.3 mL) of
n-BuLi (1.6 M in hexane) was added at 0 °C to a solution
of 6.3 g (40.4 mmol) of (1R,2S,5R)-(ꢀ)-menthol in
70 mL of anhydrous THF. After 10 min stirring, a
solution of 4 g of commercially available diethyl
(methylthio)methylphosphonate (20.2 mmol) in 20 mL
of anhydrous THF was added. The mixture was stirred
at rt for 24 h, and then quenched with a saturated
NH4Cl solution. The mixture was extracted with meth-
ylene chloride and the extracts dried and evaporated.
The excess menthol was distilled off by a Kugelrohr
4.2.1. Ethyl menthyl (RP,RS)-(methylsulfinyl)meth-
ylphosphonate 2. White solid. mp 103–105 °C (hexane)
25
½aꢂ ¼ þ4:1 (c 1, CHCl3). MS 70 eV m=e (relative
D
intensity) 187 (100), 170 (8), 124 (54), 97 (65), 61 (90). 1H
NMR (CDCl3, 500 MHz) 4.28 (ddt, J ¼ 4:4, J ¼ 7:4,
J ¼ 10:8 Hz, 1H), 4.19 (ddq, J ¼ 8:1, J ¼ 10:1,
J ¼ 7:0 Hz, 1H), 4.14 (ddq, J ¼ 7:8, J ¼ 10:1,
J ¼ 7:0 Hz, 1H), 3.36 (ddd, J ¼ 18:2, J ¼ 14:1,
J ¼ 0:7 Hz, 1H), 3.21 (t-like, J ¼ 14:1 Hz, 1H), 2.84

C. Cardellicchio et al. / Tetrahedron: Asymmetry 15 (2004) 1471–1476
1475
(d, J ¼ 0:7 Hz, 3H), 2.20–2.14 (m, 1H), 2.09–2.00 (m,
4.3. Reaction of ethyl menthyl (methylsulfinyl)methyl-
phosphonates with n-dodecylmagnesium bromide
1H), 1.69–1.62 (m, 3H), 1.49–1.40 (m, 1H), 1.34 (dt,
J ¼ 0:5 Hz, J ¼ 7:0, 3H), 1.19 (q-like, J ¼ 12:1 Hz, 1H),
1.03–0.93 (m, 1H), 0.91 (d, J ¼ 6:6 Hz, 6H), 0.88–0.81
(m, 1H), 0.79 (d, J ¼ 7:0 Hz, 3H). 13C NMR (CDCl3,
125 MHz) 79.25 (d, J ¼ 8:0 Hz), 62.93 (d, J ¼ 7:2 Hz),
53.09 (d, J ¼ 134:5 Hz), 48.29 (d, J ¼ 6:3 Hz), 43.09,
41.32 (broad), 33.84, 31.56, 25.62, 22.79, 21.84, 20.83,
16.33 (d, J ¼ 6:3 Hz), 15.57 ppm. 31P NMR (CDCl3,
202 MHz) 15.0. Anal. Calcd for C14H29O4PS: C, 51.83;
H, 9.01. Found: C, 52.16; H, 9.11.
A solution of n-dodecylmagnesium bromide in THF was
reacted with a solution of the sulfoxide 2 in benzene at
0 °C, according to our previously reported procedure.6–8
The crude reaction mixture was subjected to a chro-
matographic separation (silica gel, eluent ethyl acetate/
petroleum ether 9:1). Yields of isolated products are
reported in Scheme 6.
4.3.1. (R)-n-Dodecyl methyl sulfoxide 3. White solid. mp
25
D
60–62 °C (hexane) (lit.24 mp 53 °C). ½aꢂ ¼ ꢀ62:5 (c 1,
4.2.2. Ethyl menthyl (SP,RS)-(methylsulfinyl)meth-
ylphosphonate 2. White solid. mp 63–65 °C (pentane)
acetone).
25
D
½aꢂ ¼ ꢀ6:3 (c 1, CHCl3). MS 70 eV m=e (relative
intensity) 187 (100), 170 (11), 124 (60), 97 (66), 61 (99).
1H NMR (CDCl3, 500 MHz) 4.29 (ddt, J ¼ 4:5, J ¼ 7:2,
J ¼ 10:8 Hz, 1H), 4.15 (ddq, J ¼ 8:0, J ¼ 10:1,
J ¼ 7:1 Hz, 1H), 4.12 (ddq, J ¼ 8:0, J ¼ 10:1,
J ¼ 7:1 Hz, 1H), 3.34 (ddd, J ¼ 17:9, J ¼ 14:2,
J ¼ 0:8 Hz, 1H), 3.24 (t-like, J ¼ 13:9 Hz, 1H), 2.84 (d,
J ¼ 0:8 Hz, 3H), 2.16–2.11 (m, 1H), 2.08–2.02 (m, 1H),
1.69–1.62 (m, 3H), 1.49–1.39 (m, 1H), 1.34 (dt,
J ¼ 0:5 Hz, J ¼ 7:1, 3H), 1.17 (q-like, J ¼ 11:9 Hz, 1H),
1.04–0.93 (m, 1H), 0.90 (d, J ¼ 7:0 Hz, 6H), 0.88–0.81
(m, 1H), 0.79 (d, J ¼ 7:0 Hz, 3H). 13C NMR (CDCl3,
125 MHz) 79.14 (d, J ¼ 7:7 Hz), 62.79 (d, J ¼ 6:4 Hz),
51.93 (d, J ¼ 136:5 Hz), 48.33 (d, J ¼ 7:2 Hz), 43.27,
41.25 (broad), 33.87, 31.54, 25.71, 22.72, 21.92, 20.92,
16.30 (d, J ¼ 6:4 Hz), 15.53. 31P NMR (CDCl3,
202 MHz) 15.4. Anal. Calcd for C14H29O4PS: C, 51.83;
H, 9.01. Found: C, 51.45; H, 9.18.
4.3.2. Ethyl menthyl (SP)-methylphosphonate 4. Colour-
25
D
(relative intensity) 125 (100), 123 (7), 97 (65). H NMR
less liquid. ½aꢂ ¼ ꢀ58:3 (c 0.5, CHCl3). MS 70 eV m=e
1
(CDCl3, 500 MHz) 4.21 (ddt, J ¼ 4:6, J ¼ 7:7,
J ¼ 10:7 Hz, 1H), 4.08 (ddq, J ¼ 7:6, J ¼ 10:0,
J ¼ 7:1 Hz, 1H), 4.01 (ddq, J ¼ 7:5, J ¼ 10:0,
J ¼ 7:1 Hz, 1H), 2.19–2.13 (m, 1H), 2.04–1.99 (m, 1H),
1.67–1.61 (m, 3H), 1.44 (d, J ¼ 17:4 Hz, 3H), 1.35–1.25
(m, 4H), 1.11 (q-like, J ¼ 12:0 Hz, 1H), 1.03–0.93 (m,
1H), 0.90 (d, J ¼ 7:0 Hz, 3H), 0.89 (d, J ¼ 6:6 Hz, 3H),
0.87–0.82 (m, 1H), 0.80 (d, J ¼ 7:0 Hz, 3H). 13C NMR
(CDCl3, 125 MHz) 77.14 (d, J ¼ 7:3 Hz), 61.03 (d,
J ¼ 6:4 Hz), 48.43 (d, J ¼ 7:4 Hz), 43.45, 34.07, 31.45,
25.63, 22.84, 21.98, 20.95, 16.33 (d, J ¼ 6:5 Hz), 15.69,
11.67 (d, J ¼ 145:4 Hz). 31P NMR (CDCl3, 202 MHz)
30.3. Anal. Calcd for C13H27O3P: C, 59.52; H, 10.37.
Found: C, 59.82; H, 10.01.
4.2.3. Ethyl menthyl (SP,SS)-(methylsulfinyl)meth-
ylphosphonate 2 (first eluted stereoisomer). White solid.
4.3.3. Ethyl menthyl (RP)-methylphosphonate 4. Colour-
25
D
(relative intensity) 125 (100), 123 (7), 97 (75). H NMR
less liquid. ½aꢂ ¼ ꢀ59:8 (c 0.5, CHCl3). MS 70 eV m=e
25
D
mp 101–103 °C (hexane) ½aꢂ ¼ ꢀ119:7 (c 1, CHCl3).
1
MS 70 eV m=e (relative intensity) 187 (100), 170 (11), 124
(43), 97 (46), 61 (31). H NMR (CDCl3, 500 MHz) 4.27
(CDCl3, 500 MHz) 4.18 (ddt, J ¼ 4:4, J ¼ 7:8,
J ¼ 10:7 Hz, 1H), 4.10 (ddq, J ¼ 7:5, J ¼ 10:1,
J ¼ 7:0 Hz, 1H), 4.03 (ddq, J ¼ 7:8, J ¼ 10:1,
J ¼ 7:0 Hz, 1H), 2.22–2.19 (m, 1H), 2.14–2.07 (m, 1H),
1.65–1.58 (m, 3H), 1.45 (d, J ¼ 17:4 Hz, 3H), 1.32–1.25
(m, 4H), 1.12 (q-like, J ¼ 11:7 Hz, 1H), 1.03–0.93 (m,
1H), 0.90 (d, J ¼ 7:0 Hz, 3H), 0.89 (d, J ¼ 6:6 Hz, 3H),
0.87–0.81 (m, 1H), 0.79 (d, J ¼ 6:9 Hz, 3H). 13C NMR
(CDCl3, 125 MHz) 77.20 (d, J ¼ 7:2 Hz), 61.29 (d,
J ¼ 5:6 Hz), 48.47 (d, J ¼ 6:6 Hz), 43.09, 34.04, 31.45,
25.48, 22.79, 21.93, 20.95, 16.40 (d, J ¼ 6:3 Hz), 15.64,
12.73 (d, J ¼ 145:3 Hz). 31P NMR (CDCl3, 202 MHz)
29.9. Anal. Calcd for C13H27O3P: C, 59.52; H, 10.37.
Found: C, 59.39; H, 10.51.
1
(ddt, J ¼ 4:5, J ¼ 7:5, J ¼ 10:8 Hz, 1H), 4.18 (ddq,
J ¼ 8:2, J ¼ 10:1, J ¼ 7:1 Hz, 1H), 4.11 (ddq, J ¼ 7:8,
J ¼ 10:1, J ¼ 7:1 Hz, 1H), 3.36 (ddd, J ¼ 18:5, J ¼ 14:2,
J ¼ 0:8 Hz, 1H), 3.23 (t-like, J ¼ 14:0 Hz, 1H), 2.84 (d,
J ¼ 0:9 Hz, 3H), 2.15–2.10 (m, 1H), 2.05–1.97 (m, 1H),
1.69–1.62 (m, 3H), 1.50–1.39 (m, 1H), 1.34 (dt,
J ¼ 0:5 Hz, J ¼ 7:1, 3H), 1.17 (q-like, J ¼ 12:0 Hz, 1H),
1.05–0.94 (m, 1H), 0.91 (d, J ¼ 7:0 Hz, 3H), 0.90 (d,
J ¼ 6:6 Hz, 3H), 0.88–0.81 (m, 1H), 0.80 (d, J ¼ 6:9 Hz,
3H). 13C NMR (CDCl3, 125 MHz) 79.29 (d, J ¼ 7:8 Hz),
62.65 (d, J ¼ 6:5 Hz), 52.33 (d, J ¼ 135:7 Hz), 48.25 (d,
J ¼ 7:2 Hz), 43.39, 41.43 (d, J ¼ 2:3 Hz), 33.87, 31.57,
25.82, 22.77, 21.91, 20.89, 16.30 (d, J ¼ 6:4 Hz), 15.60.
31P NMR (CDCl3, 202 MHz) 15.3. Anal. Calcd for
C14H29O4PS: C, 51.83; H, 9.01. Found: C, 52.13; H,
8.76.
4.4. Synthesis of menthyl methylphosphonothioic acid 5
A solution of menthol (3 g, 19.2 mmol) and triethyl-
amine (2.9 mL) in 30 mL of toluene was added dropwise
to a solution of 2 mL of methylphosphonothioic
dichloride (19.1 mmol) in 20 mL of toluene. After 18 h at
rt, the solvent was removed and the crude reaction
mixture treated with 30 mL of an aqueous solution of
4.2.4. Ethyl menthyl (RP,SS)-(methylsulfinyl)meth-
ylphosphonate 2 (second eluted stereoisomer). 31P NMR
(CDCl3, 202 MHz) 15.1. Other spectral and physical
data were identical to those reported.7

1476
C. Cardellicchio et al. / Tetrahedron: Asymmetry 15 (2004) 1471–1476
NaOH 2 M and with 30 mL of dioxane. The mixture was
heated to reflux for 3 h and, after standing for 12 h at rt,
was diluted with water and washed with CHCl3. The
organic phase was discarded and the aqueous phase
acidified by adding dropwise HCl 12 M. The solution
was extracted with CH2Cl2 and the organic phase dried
and evaporated to give 1.6 g of 5 (33%). Compound 5
was subjected to resolution with (R)-(þ)-phenylethyl-
amine, according to the literature protocol.21;23
valutazione biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci innovativi’.
References and notes
1. Drabowicz, J.; Kiełbasinski, P.; Mikołajczyk, M. Synthesis
of Sulfoxides. In The Chemistry of Sulfones and Sulfoxides;
Patai, S., Rappoport, Z., Stirling, C., Eds.; John Wiley
and Sons: New York, 1988; pp 233–378.
4.4.1. Menthyl (RP)-methylphosphonothioic acid 5. White
~
2. Carreno, M. C. Chem. Rev. 1995, 95, 1717–1760.
25
D
solid. mp 78–80 °C (lit.21 82 °C), ½aꢂ ¼ ꢀ83:1 (c 1,
3. Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651–3705.
4. Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Sorensen,
H.; von Unge, S. Tetrahedron: Asymmetry 2000, 11, 3819–
3825.
25
C6H6) for a 86% de {lit.21 ½aꢂ ¼ ꢀ87:3 (C6H6)}.
D
5. Maguire, A. R.; Papot, S.; Ford, A.; Touhey, S.; O’Con-
nor, R.; Clynes, M. Synlett 2001, 41–44.
6. Cardellicchio, C.; Iacuone, A.; Naso, F.; Tortorella, P.
Tetrahedron Lett. 1996, 37, 6017–6020.
4.5. Synthesis of S-ethyl O-menthyl (RP)-methylphos-
phonothioate 6
A solution of 0.14 g (0.56 mmol) of acid 5 [(RP)-5 pre-
dominant] in 4 mL of DMSO was treated with 2.5 mL of
a solution of NaOH 0.25 M and then with 0.13 mL of
ethyl bromide. After 3 h, the mixture was evaporated
and the residue diluted with brine and extracted with
CH2Cl2. The organic extracts were dried and evapo-
rated. The residue was purified by column chromato-
graphy (silica gel, ethyl acetate/petroleum ether 1:1) and
then by crystallisation. Yield 39%.
7. Cardellicchio, C.; Fracchiolla, G.; Naso, F.; Tortorella, P.
Tetrahedron 1999, 55, 525–532.
8. Capozzi, M. A. M.; Cardellicchio, C.; Fracchiolla, G.;
Naso, F.; Tortorella, P. J. Am. Chem. Soc. 1999, 121,
4708–4809.
9. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Torto-
rella, P. J. Org. Chem. 2000, 65, 2843–2846.
10. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Spina, G.;
Tortorella, P. J. Org. Chem. 2001, 66, 5933–5936.
11. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Rosito, V.
J. Org. Chem. 2002, 67, 7289–7294.
12. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F. Eur. J.
Org. Chem., in press.
13. Lin, J. H. Bone 1996, 18, 75–85.
14. Body, J.-J. Eur. J. Cancer 1998, 34, 263–269.
15. Wiesner, J.; Jomaa, H. Angew. Chem., Int. Ed. 2003, 42,
5274–5293.
16. Martin, M. B.; Grimley, J. S.; Lewis, J. C.; Heath, H. T.,
III; Bailey, B. N.; Kendrick, H.; Yardley, V.; Caldera, A.;
Lira, R.; Urbina, J. A.; Moreno, S. N. J.; Docampo, R.;
Croft, S. L.; Oldfield, E. J. Med. Chem. 2001, 44, 909–916.
17. Mikolajczyk, M.; Midura, W. H.; Grzejszczak, S.; Wieczo-
rek, M. W.; Zatorski, A.; Chefczynska, A. J. Org. Chem.
1978, 43, 473–478.
18. Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S.
J. Org. Chem. 1993, 58, 7624–7626.
19. Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S.
J. Org. Chem. 1993, 58, 4529–4533.
20. The results of the screening of the National Cancer
Institute are available via the Internet http://dtp.nci.nih.
gov/dtpstandard/dwindex/index.jsp for the compound
having NSC number 717231.
4.5.1. S-Ethyl O-menthyl (RP)-methylphosphonothioate 6.
25
White solid. mp 51–53 (pentane), ½aꢂ ¼ ꢀ57:8 (c 1,
D
CHCl3) for a 83% de. 1H NMR (CDCl3, 500 MHz) 4.32
(dq, J ¼ 4:4, J ¼ 10:4 Hz, 1H), 2.90 (ddq, J ¼ 12:6,
J ¼ 11:9, J ¼ 7:4 Hz, 1H), 2.84 (tq, J ¼ 12:6, J ¼ 7.5 Hz,
1H), 2.28–2.22 (m, 1H), 2.10–2.03 (m, 1H), 1.75 (d,
J ¼ 15:6 Hz, 3H), 1.69–1.60 (m, 3H), 1.36 (t, J ¼ 7:5 Hz,
3H), 1.34–1.26 (m, 1H), 1.11 (q-like, J ¼ 12:0 Hz, 1H),
1.06–0.95 (m, 1H), 0.90 (d, J ¼ 6:6 Hz, 3H), 0.89 (d,
J ¼ 7:0 Hz, 3H), 0.87–0.82 (m, 1H), 0.81 (d, J ¼ 7:0 Hz,
3H). 13C NMR (CDCl3, 125 MHz) 77.39 (d, J ¼ 8:8 Hz),
48.63 (d, J ¼ 5:6 Hz), 42.98, 34.06, 31.54, 25.76, 25.08
(d, J ¼ 2:4 Hz), 22.94, 22.03, 21.02, 20.77 (d,
J ¼ 110:2 Hz), 16.54, 15.69 (d, J ¼ 2:4 Hz). 31P NMR
(CDCl3, 202 MHz) 52.1. Anal. Calcd for C13H27O2PS:
C, 56.09; H, 9.78. Found: C, 55.90; H, 9.91.
21. Hall, C. R.; Inch, T. D.; Pottage, C.; Williams, N. E.
Tetrahedron 1985, 41, 4909–4917.
Acknowledgements
ꢁ
ꢁ
22. Wozniak, L. A.; Chworos, A.; Pyzowsky, J.; Stec, W. J.
J. Org. Chem. 1998, 63, 9109–9112.
This work was financially supported in part by the
ꢀ
(National Project ‘Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni’), by the University of Bari
and by the FIRB project ‘Progettazione, preparazione e
Ministero dell’Istruzione, Universita e Ricerca, Rome
23. Boter, H. L.; Platemburg, D. H. J. M. Rec. Trav. Chim.
Pays-Bas 1967, 86, 399–404.
24. Colonna, S.; Banfi, S.; Annunziata, R.; Casella, L. J. Org.
Chem. 1986, 51, 891–895.