Michael addition to a chiral non-racemic 2-phosphono-2,3-didehydrothiolane S-oxide

Article abstract of DOI:10.1016/j.tetasy.2008.12.034

The Michael addition of selected sulfur and nitrogen nucleophiles to a chiral non-racemic 2-phosphono-2,3-didehydrothiolane S-oxide is fully diastereoselective. The enantiomeric excesses of the adducts obtained could be determined by ³¹P NMR sp

Full text of DOI:10.1016/j.tetasy.2008.12.034

Tetrahedron: Asymmetry 20 (2009) 293–297
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Tetrahedron: Asymmetry
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Michael addition to a chiral non-racemic 2-phosphono-
2,3-didehydrothiolane S-oxide
b
b
a
Mihaela Gulea a, , Małgorzata Kwiatkowska , Piotr Łyzwa , Remi Legay ,
*
_
a
b,
*
´
Annie-Claude Gaumont , Piotr Kiełbasinski
a Laboratoire de Chimie Moléculaire et Thio-Organique, ENSICAEN, Université de Caen Basse-Normandie, CNRS, 6 Boulevard du Maréchal Juin, 14050 Caen, France
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódz, Poland
b
´
a r t i c l e i n f o
a b s t r a c t
Article history:
The Michael addition of selected sulfur and nitrogen nucleophiles to a chiral non-racemic 2-phosphono-
2,3-didehydrothiolane S-oxide is fully diastereoselective. The enantiomeric excesses of the adducts
obtained could be determined by 31P NMR spectroscopy using (R)-(+)-tert-butyl(phenyl)phosphinothioic
acid as a chiral solvating agent. The addition of thiophenol was monitored by 31P NMR spectroscopy
which made it possible to observe the formation and evolution of the kinetic and thermodynamic adducts
in the reaction mixture. The structures of both enantiomeric thiophenol adducts have been determined
by X-ray analysis.
Received 17 November 2008
Accepted 12 December 2008
Available online 14 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
its ee was at least 98%.2 Control of the enantiomeric excess by
chiral HPLC was impossible since no conditions to separate enanti-
Chiral
a
,b-unsaturated sulfoxides are well known for their
omers could be found. The X-ray analysis of an isolated single crys-
tal of 1 showed that it was a single enantiomer whose absolute
configuration at sulfur atom was assigned as (S).2 This was in
agreement with other results already obtained in the enantioselec-
tive sulfoxidation with the same oxaziridine.1c,5
applications in asymmetric syntheses as efficient Michael accep-
tors.1 Various compounds of this class have been described; how-
ever, new structures are still being investigated to access
stereoselectively original, highly functionalized products.
Earlier, we reported the synthesis of 2-phosphono-2,3-didehy-
drothiolane S-oxide 1,2 which represents an interesting Michael
acceptor, due to the particular geometry of the unsaturated five-
membered ring and the double activation of the C–C double bond
by both phosphonyl and sulfinyl groups. In a previous communica-
tion, we described investigations on the addition of several nucle-
ophiles to the racemic substrate 1.3 Herein we report the
asymmetric version of these reactions using non-racemic 1 and re-
port a study of the reaction course using 31P NMR spectroscopy.
2.1. Asymmetric Michael addition to 1
Having in hand the presumably enantiopure sulfoxide (+)-1, we
decided to perform the asymmetric version of the Michael addi-
tions which had been described previously.3
The addition reactions with benzenethiol, p-toluenethiol, tert-
butanethiol, and aniline were performed with the (+)-1 obtained
previously (Scheme 1, Table 1). As already observed in the racemic
series under the same conditions (rt, THF, and, in the case of thiols,
addition of a catalytic amount of NEt3), the reactions were fully
diastereoselective. Adducts 2–5 were obtained in good yields after
simple precipitation. All adducts exhibited positive values for their
specific rotations (Table 1). However, we were surprized to find
that in all cases, the enantiomeric excesses of the resulting adducts
2, measured by 31P NMR spectroscopy using again (+)-TBPPTA,
2. Results and discussion
As previously described,2 5,5-dimethyl-1,3,2-dioxaphosphori-
nanyl-2,3-didehydro-thiolane was oxidized by commercially
available enantiopure (+)-(2S,8aR)-8,8-dichloro-camphorsulfonyl-
oxaziridine to give the title sulfoxide 1 with a positive specific
rotation value. When an attempt was made to measure the enan-
tiomeric excess of product 1 using (R)-(+)-tert-butyl(phenyl)-phos-
phinothioic acid [(+)-TBPPTA] as a chiral solvating agent,4 only one
signal was detected in 31P NMR, which led us to the conclusion that
O
O
O
O
P
O
P
O
O
NuH
S
S
THF, rt
O
1
Nu
2-5
* Corresponding authors.
E-mail addresses: mihaela.gulea@ensicaen.fr (M. Gulea), piokiel@bilbo.cbmm.
bdz.pl (P. Kiełbasin´ ski).
Scheme 1.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.034

294
M. Gulea et al. / Tetrahedron: Asymmetry 20 (2009) 293–297
Table 1
Table 3
Michael additions to (+)-1
Melting points of various samples of (+)-1
eeb (%)
Isolated yield (%)
Sample
ee (%)
% (+)-1b
Mp (°C)
a
NuH
Adduct
[a]
D
PhSH
2
3
4
5
+13.2
+16.5
+8.5
68
70
60
70
98
89
78
74
rac-1
1b
1a
0
50
68
84
95
134
114
112
116
4-TolSH
t-BuSH
PhNH2
36a
68a
90a
+30.0
1c
a
a
See Section 4 for the measurements conditions.
Estimated by correlation with ees of adducts 2a–c (see Table 2).
Calculated percentage (from ee) of enantiopure (+)-1 in the mixture.
b
b
Measured by 31P NMR spectroscopy using (+)-TBPPTA.
were only ca. 70% (Table 1). As partial racemization under the reac-
tion conditions used is unlikely, the low ees obtained for adducts
2–5 could only be due to the enantiopurity of the starting material,
that is, substrate 1 should only be enantioenriched and not enan-
tiopure as supposed. This hypothesis prompted us to re-examine
the stereoselectivity of the asymmetric oxidation leading to 1
and to verify the preservation of the integrity of the sulfur config-
uration during the Michael addition.
We performed a series of reactions starting from various sam-
ples of substrate 1 (1a–c) using benzenethiol as the nucleophile.
Sample 1a was directly taken from the crude product 1 obtained
by oxidation of 5,5-dimethyl-1,3,2-dioxaphosphorinanyl-2,3-dide-
hydrothiolane with (+)-oxaziridine. Samples 1b and 1c were ob-
tained from 1 after crystallization from DMSO/Et2O (1:9) as the
precipitate and as the solid resulting from evaporation of the fil-
trate, respectively. First, we measured the ees [by 31P NMR spec-
(+)-1 > 50%
(+)-1 < 50%
140
135
130
125
120
115
110
troscopy using (+)-TBPPTA] and the optical rotations [
a]
of
D
0
20
40
60
80
100
substrates 1a–c, then of the corresponding adducts 2a–c. The re-
sults are shown in Table 2.
% (+)-1
Graph 1. Melting point diagram of (+)-1 and (ꢀ)-1 mixture.
Table 2
Michael additions of benzenethiol to various samples of (+)-1
2.2. Determination of the stereochemistry of adduct 2
Substrate
(c acetone)
Adduct
(c acetone)
(+)-1
[
a
]
D
eea (%)
(+)-2
[a
]
D
eea (%)
Recrystallization of sample 2c (obtained from 1c and having
ꢁ90% ee) from Et2O/AcOEt (9:1) afforded enantiopure (+)-2, from
which a single crystal could be isolated. The X-ray analysis showed
that the absolute configuration at the sulfur atom was (S), as ex-
pected (Fig. 1). We also prepared compound 2 enantioenriched in
the (ꢀ)-enantiomer and succeeded in the isolation of a single crys-
b
1a
1b
1c
+59.8 (c 0.60)
+27.7 (c 0.45)
+77.0 (c 0.55)
—
2a
2b
2c
+13.2 (c 0.25)
+7.5 (c 0.30)
+18.6 (c 0.55)
68d
36d
90d
32c
b
—
Measured by 31P NMR spectroscopy using (+)-TBPPTA.
Not determined.
a
b
c
31P NMR: d in ppm: 3.14 (minor); 3.21 (major).
31P NMR: d in ppm: 12.88 (minor); 12.74 (major).
d
In the substrate series, only the ee of sample 1b could be mea-
sured and was found to be about 32% (Table 2). In all other cases,
the two signals overlapped and did not allow ee measurement by
31P NMR spectroscopy.6 In the Michael adduct series, the ees of
samples 2a–c could be measured and were found to be 68%, 36%,
and 90%, respectively (Table 2). The enantiomeric excesses of the
substrate 1b and its adduct 2b were compared. A good correlation
between the enantiopurities of the substrate and product was
found (32% and 36% ee, respectively). On this basis, we can assume
that the enantiomeric excess of the starting material 1 is identical
to that of the corresponding adduct.
The observed influence of the crystallization of 1 on its enantio-
meric purity prompted us to check the physical properties of rac-1
and that of samples 1a-c, for which the ee was considered to be
identical to the ee of the corresponding adducts 2a–c (Table 2).
Thus, melting points were measured for each sample as a function
of the percentage of (+)-1 in the mixture of the two enantiomers
(Table 3, Graph 1).7 The highest melting point was measured at
134 °C (for the racemic mixture) and the lowest at 112 °C [for a
84/16 mixture of (+)-1/(ꢀ)-1]. This is typical of the behavior of a
true racemate.8 In our case, the non-racemic mixture of 1 with
an enantioselectivity of 68% could be enantioenriched by
crystallization.
Figure 1. X-ray structure of (+)-2.

M. Gulea et al. / Tetrahedron: Asymmetry 20 (2009) 293–297
295
tal of the opposite enantiomer (ꢀ)-2,9 of which the X-ray structure
In an NMR tube, benzenethiol and a catalytic amount of trieth-
ylamine were added to a solution of racemic 1 in THF at ꢀ60 °C and
the first spectrum was recorded. The peak corresponding to the
substrate (at 3.2 ppm) quickly disappeared, and the spectra re-
vealed three new peaks at 12.5, 10.0, and 7.7 ppm (in a 6:34:60 ra-
tio), which can be attributed to three diastereomers, d1, d2, and
d3, respectively (Table 4, entry 1). Temperature was then gradually
increased (from ꢀ60 to 20 °C) and the ensuing spectra were re-
corded. Data given in Table 4 and Graph 2 represent the ratio
changes of the three products with the temperature. The ratio
d1:d2:d3 did not substantially change until the temperature
reached 0 °C, where the ratio was 17:34:49 (entry 6). Then, a fast
increase in the amount of d1 in the mixture at the expense of d3
was observed (entries 7–9). At 20 °C, the ratio was 61:34:5 (entry
9), meaning only two diastereomers were still present, d1 and d2.
When the temperature was increased to 25 °C, the peak corre-
sponding to d2 completely disappeared and only d1 remained (en-
try 10). The overall time of the experiment was about 2 h.
is shown in Figure 2.
Table 4
31P NMR study of the reaction course
Entry
Temp (°C)
Timea (min)
Product content (%)
d1b
d2c
d3d
1
2
3
4
5
6
7
8
9
ꢀ60
ꢀ40
ꢀ30
ꢀ20
ꢀ10
0
12
35
40
44
48
52
74
89
94
130
6
10
34
35
34
38
36
34
38
35
34
0
60
55
54
52
52
49
20
6
12
12
12
17
42
59
61
100
Figure 2. X-ray structure of (ꢀ)-2.
+5
It is noteworthy that the enantiomeric purity of
1 with
+15
+20
+25
[a]D = +60.5 is about 70% ee, indicating that the enantioselective
5
0
sulfoxidation of the 5,5-dimethyl-1,3,2-dioxaphosphorinanyl-2,3-
didehydro-thiolane with enantiopure 8,8-dichloro-camphorsulfo-
nyl-oxaziridine led to a non-racemic sulfoxide 1 with 70% ee, and
not to enantiopure 1 as originally reported.2 Nevertheless, the orig-
inally reported stereochemistry at the sulfur atom determined by
X-ray analysis of an isolated single crystal of (+)-1 was correct.
10
a
Cumulated reaction time starting from t0 = 0 min.
Diastereomer d1 (d31P = 12.5 ppm).
Diastereomer d2 (d31P = 10 ppm).
b
c
d
Diastereomer d3 (d31P = 7.7 ppm).
The 1H NMR spectra showed, as expected, that d1 corresponds
2.3. Study of benzenethiol addition to 1 by 31P NMR
spectroscopy
to the structure of the most stable diastereomer 2A, of which the
relative configuration was already demonstrated by NMR spectros-
copy in our previous study3 and by X-ray analysis in the present
study. It is very likely that the other diastereomers d2 and d3 cor-
respond to two of the structures 2B, 2C, or 2D. They should isom-
erize via an equilibrium to give the thermodynamically more
stable 2A.
In our previous study3 we tried to rationalize the experimental
results obtained in the Michael addition using the title thiolane S-
oxide as a substrate. The nucleophile can attack either syn or anti to
the S@O group, leading to four possible diastereomers A–D (addi-
tion of benzenethiol is shown in Scheme 2). The relative energies
for these diastereomers were estimated by theoretical calculations
and found to decrease in the order: B > C > D > A.3 Indeed, in all the
cases investigated, the only isolated adduct was A, the most stable,
resulting from thermodynamic control. We decided to undertake a
study by NMR spectroscopy, which could made it possible to ob-
serve the formation and evolution of the kinetic and thermody-
namic adducts in the reaction mixture.
To gain information on their structures, we attempted to trap
d2 and d3 before isomerization and to immediately record a 1H
NMR spectrum. To this end, the reaction was started at -60 °C,
and, after raising the temperature to about ꢀ20 °C, the reaction
was stopped by pouring the solution in ethyl ether cooled to
ꢀ60 °C.10 The small amount of the resulting precipitate was ana-
lyzed by NMR spectroscopy. The 31P NMR spectrum showed two
peaks at 13.3 and 10.6 ppm in a 10:90 ratio, corresponding to d1
and d2, respectively.11 It was, however, possible to characterize
the major component d2 by NMR spectroscopy. The coupling con-
stant between H2 (PCH) and H3 (PhSCH) in the 1H NMR spectrum of
d2 is similar to that measured in 2A (7.4 Hz and 7.2 Hz, respec-
tively), indicating a relative trans relationship between these two
protons, therefore also between the phosphoryl and the phen-
ylsulfanyl groups. Apart from 2A, the only structure with this ste-
reochemistry is 2C, of which the difference between 2A consists of
a relative cis-arrangement between the phosphoryl group and the
oxygen of the sulfinyl group. On this basis, we assume the assign-
ment of the structure 2C to the diastereoisomer d2 observed at
10 ppm in 31P NMR. By leaving the sample in a CDCl3 solution at
O
S
O
S
O
P
O
P
O
O
O
O
+
+
O
O
syn attack
PhSH
anti attack
O
P
O
2A
PhS
2B
PhS
S
O
S
O
O
P
O
P
O
O
O
O
S
2D
PhS
PhS
2C
Scheme 2.

296
M. Gulea et al. / Tetrahedron: Asymmetry 20 (2009) 293–297
d1
d2
d3
100
using R-(+)-tert-butyl(phenyl)phosphinothioic acid as
solvating agent.
a chiral
90
80
70
60
50
40
30
20
10
0
Non-racemic 1 (ee = 68–70%), with a positive specific rotation
value, was prepared according to the literature from 5,5-dimethyl-
1,3,2-dioxaphosphorinanyl-2,3-didehydro-thiolane by oxidation with
enantiopure (+)-(2S,8aR)-8,8-dichloro-camphorsulfonyl-oxaziridine.2
The separation of the product from the imine resulting from the
oxaziridine was improved by first using pure CH3CN as the eluent
to remove the less polar imine, then a mixture of CH3CN/DMSO
10/1.
4.2. Michael addition of thiols to non-racemic 2-phosphono-
2,3-didehydrothiolane 1-oxide 1. General procedure
-60
-50
-40
-30
-20
-10
0
10
20
30
°C
Graph 2. Graphical presentation of the 31P NMR study.
To a mixture of thiol (2 mmol) and non-racemic 2-phosphono-
2,3-didehydrothiolane 1-oxide 1 (1 mmol) in THF (20 mL) was
added NEt3 (0.1 mmol), at room temperature. The resulting mix-
ture was stirred until the reaction was completed (monitored by
TLC). The solvent was evaporated and the product was precipitated
from the residue using Et2O.
room temperature overnight, 2C was completely transformed into
2A. Unfortunately, our attempts to isolate and characterize the dia-
stereomer d3 were unsuccessful and therefore its structure, 2B or
2D, remains unassigned.
4.2.1. 3-Phenylsulfanyl-2-[20-(5,5-dimethyl-1,3,2-dioxa-
phosphorinanyl)]thiolane 1-oxide 2
3. Conclusions
It (diastereomer 2A) was prepared according to the general pro-
cedure from non-racemic 2-phosphono-2,3-didehydrothiolane 1-
oxide 1 and benzenethiol.
The Michael addition of several sulfur and nitrogen nucleo-
philes to a chiral non-racemic 5,5-dimethyl-1,3,2-dioxaphosphori-
nanyl-2,3-didehydro-thiolane 1-oxide was fully diastereo- and
enantioselective. Although it was not possible to measure the
enantiomeric excess of the substrate obtained after the asymmet-
ric oxidation of the thiolane precursor, the enantiomeric excess of
the obtained Michael adduct could be determined by 31P NMR
spectroscopy using (R)-(+)-tert-butyl(phenyl)phosphinothioic acid
as a chiral solvating agent. This also enabled us to deduce the ee
of the starting Michael acceptor. The Michael addition of ben-
zenethiol was monitored by 31P NMR spectroscopy at low tem-
perature and allowed us to follow the formation and evolution
of the kinetic and thermodynamic adducts in the reaction mix-
ture. The structures and absolute configurations of both enantio-
mers of the benzenethiol adduct have been determined by X-ray
analysis.
Yield = 98%; white solid, mp 112 °C; [a]D = +13.2 (c 0.25, ace-
tone); 31P NMR (161.9 MHz, C6D6) in the presence of 2 equiv of
(+)-tBuPhP(O)SH: d 12.88 minor/12.74 major; ee = 68%. 31P NMR
(161.9 MHz, CDCl3) d 13.2; 1H NMR (400 MHz, CDCl3) d 0.99 (s,
3H, CH3), 1.22 (s, 3H, CH3), 2.77–2.81 (m, 2H, CH2), 3.00 (m, 1H,
4
3
CHHSO), 3.20 (m, 1H, CHHSO), 3.31 (ddd, JHH = 1.1, JHH = 7.2,
2JHP = 14.6, 1H, PCH), 3.92–4.01 (m, 3H), 4.11–4.16 (m, 2H), 7.35–
7.37 (m, 3H,
H
arom), 7.54–7.57 (m, 2H, Harom); 13C NMR
(100.6 MHz, CDCl3) 20.98 (CH3), 21.69 (CH3), 32.43 (d, J = 6.8,
(CH3)2C), 34.77 (d, J = 7.8, CH2), 48.26 (CHS), 53.29 (d, J = 3.4,
CH2SO), 68.52 (d, J = 130.8, PCH), 77.05 (d, J = 6.6, CH2O), 77.33
(d, J = 6.5, CH2O), 128.57 (CHarom), 129.37 (2 ꢂ CHarom), 133.50
(SCarom), 133.55 (2 ꢂ CHarom); IR (neat, cmꢀ1) 2969, 2894, 1582,
1475, 1270, 1055, 1006, 979, 836, 816, 746, 693; MSMS: m/z (%)
361 (MH+, 22), 161 (100); HRMS calcd for C15H21PO4S2:
361.0697. Found: 361.0706.
4. Experimental
Enantiopure (+)-2 and (ꢀ)-2 were prepared according to the
general procedure from enantioenriched 2-phosphono-2,3-didehy-
drothiolane 1-oxide (+)-1 or (ꢀ)-1 (having ee >90%), respectively,
and subsequent recrystallization from Et2O/AcOEt (9:1).
4.1. General remarks
Most reactions were carried out under nitrogen with mag-
netic stirring, unless otherwise specified, and monitored by TLC
using silica plates. Synthesized products were purified by col-
umn chromatography on silica gel or crystallized, if necessary.
THF was purified with a PURESOLVTM apparatus developed by
Innovative Technology Inc. NMR spectra were recorded on Bru-
ker spectrometers: 250 MHz or 400 MHz (indicated in each case).
Chemical shifts (d) are indicated in ppm using TMS (for 1H NMR)
as an internal standard. Coupling constants J were given in hertz
(Hz). Mass spectra were obtained on a GC/MS Saturn 2000 or on
a Waters QTOF micro. IR spectra were recorded with a Perkin El-
mer 16 PC FT-IR instrument. Analytical data were obtained using
a THERMOQUEST NA 2500 instrument. Flash chromatography
(1Ss,2R,3R)-(+)-2: [
(1Rs,2S,3S)-(ꢀ)-2: [
a
a
]
]
D = +19.5 (c 1.0, acetone).
D = ꢀ19.1 (c 1.1, acetone).
The two crystal structures of (+)-2 and (ꢀ)-2 have been regis-
tered at the Cambridge Crystallographic Data Centre and allocated
the deposition numbers CCDC 610286, and CCDC 610285,
respectively:
CCDC 610286: 2(S2PC15H21O4), Mr = 720.82, monoclinic, P21,
a = 16.456(5), b = 5.8194(2), c = 18.4666(6) Å, b = 108.141(2)°, V =
1680.5(5) Å3, Z = 2, Dx = 1.424 Mg mꢀ3, k(Mo K
4.26 cmꢀ1, F(000) = 760, T = 120 K.
a) = 0.71073 Å, l =
CCDC 610285: 3(S2PC15H21O4), Mr = 1081.22, orthorhombic,
P212121, a = 5.8692(1), b = 29.0024(4), c = 29.4854(4) Å, V =
was performed on silica gel columns (40–63
l
m) using air pres-
5019.03(9) Å3, Z = 4, Dx = 1.431 Mg mꢀ3, k (Mo K
4.28 cmꢀ1, F(0 0 0) = 2280, T = 120 K.
a) = 0.71073 Å, l =
sure. Optical rotation values were measured on a Perkin–Elmer-
241 polarimeter for the sodium D line at 20 °C. The infrared
spectra were recorded with a spectrometer ATI Mattson Infinity
4.3. Procedure for the preparation and characterization of
diastereomer 2C
60 AR FTIR on the liquid film,
m
(cmꢀ1) are given. Mass spectra
were recorded with a Finnigan MAT 95 Voyager Elite spectrom-
eter in chemical ionization. Enantiomeric excesses of non-race-
mic compounds were determined by 31P NMR spectroscopy
To a mixture of benzenethiol (2 equiv, 0.8 mmol) and racemic
2-phosphono-2,3-didehydrothiolane 1-oxide 1 (100 mg, 0.4 mmol)

M. Gulea et al. / Tetrahedron: Asymmetry 20 (2009) 293–297
297
in THF (15 mL) was added NEt3 (0.1 equiv, 0.04 mmol), at ꢀ60 °C.
4.4. Michael addition of aniline to 2-phosphono-2,3-
didehydrothiolane 1-oxide 1
The dry-ice bath was removed and after ꢁ30 min, when the tem-
perature was ꢀ20 °C, the reaction mixture was poured into ethyl
ether (50 mL) and cooled to ꢀ60 °C. The resulting solution was
placed in the freezer (at ꢀ4 °C), and, after about 3 h, a precipitate
was formed (ꢁ15 mg). This precipitate was rapidly filtered, dried
under vacuum (0.1 mbar), then dissolved in CDCl3 at ꢀ20 °C, and
analyzed by NMR spectroscopy. The sample contained product
2C (90%) together with product 2A (10%).
To the non-racemic 2-phosphono-2,3-didehydrothiolane 1-
oxide 1 (1 mmol) dissolved in dry THF (20 mL), aniline (5 mmol)
was added at room temperature and the mixture was stirred for
4 h. The resulting adduct, which precipitated from THF, was fil-
tered and dried to give the pure product.
Product 2C: 31P NMR (161.9 MHz, CDCl3) d 10.6; 1H NMR
(400 MHz, CDCl3) d 1.02 (s, 3H, CH3), 1.23 (s, 3H, CH3), 2.35 (m,
1H, CHH), 2.80 (m, 1H, CHH), 2.90–3.10 (m, 2H, CH2SO), 3.31 (dd,
3JHH = 7.4 Hz, 2JHP = 20.2 Hz, 1H, PCH), 4.00–4.43 (m, 4H, 2 ꢂ CH2O),
4.48 (m, 1H, CHSPh), 7.35–7.37 (m, 3H, Harom), 7.54–7.57 (m, 2H,
4.4.1. Phenylamino-2-[20-(5,5-dimethyl-1,3,2-dioxaphosphori-
nanyl)]thiolane 1-oxide 5
Yield = 74%, white solid, mp 150 °C; [
31P NMR (161.9 MHz, C6D6) in the presence of 2 equiv of (+)-tBuPh-
P(O)SH:
12.91 minor/12.82 major; ee = 70%. 31P NMR
a]D = +30.0 (c 0.5, CHCl3);
d
H
arom); 13C NMR (62.9 MHz, CDCl3) 19.18 and 20.11 ((CH3)2C),
(101.2 MHz, CDCl3) d 12.1; 1H NMR (250 MHz, CDCl3) d 0.99 (s,
3H, CH3), 1.22 (s, 3H, CH3), 2.20–2.85 (m, 2H), 3.10–3.30 (m, 2H),
3.50 (m, 1H), 3.80 (m, 1H), 3.90–4.20 (m, 4H), 4.75 (m, 1H, NH),
6.55–6.75 (m, 2H, Harom), 7.04–7.18 (m, 2H, Harom); 13C NMR
(62.9 MHz, CDCl3) 21.51 (CH3), 21.92 (CH3), 32.93 (d, J = 6.8,
(CH3)2C), 33.65 (d, J = 4.1, CH2), 53.75 (CH2SO), 59.38 (CHN),
67.27 (d, J = 126.6, PCH),), 77.06 (d, J = 5.5, CH2O), 77.26 (d,
J = 6.5, CH2O), 114.61 (CHarom), 115.21 (CHarom), 114.94, 119.46,
129.84, 146.35; IR (neat, cmꢀ1) 3360, 2969, 2911, 1604, 1500,
1322, 1258, 1054, 1006, 836, 751; MSMS: m/z (%) 344 (MH+, 30),
176 (100), 132 (90); HRMS calcd for C15H23NPO4S: 344.1089.
Found: 344.1085.
30.71 (d, J = 6.8, (CH3)2C), 31.18 (d, J = 7.8, CH2), 45.59 (CHS),
50.76 (d, J = 3.4, CH2SO), 63.39 (d, J = 130.8, PCH), 77.05 (d,
J = 6.6, CH2O), 77.33 (d, J = 6.5, CH2O), 126.54 (CHarom), 127.21
(2 ꢂ CHarom), 129.95 (SCarom), 131.99 (2 ꢂ CHarom).
4.3.1. 3-p-Tolylsulfanyl-2-[20-(5,5-dimethyl-1,3,2 dioxa-
phosphorinanyl)]thiolane 1-oxide 3
This compound was prepared according to the general proce-
dure from non-racemic 2-phosphono-2,3-didehydrothiolane
1-oxide 1 and 4-methylbenzenethiol.
Yield = 89%; white solid, mp 125 °C; [a]D = +16.5 (c 1.0, ace-
tone); 31P NMR (161.9 MHz, C6D6) in the presence of 2 equiv of
(+)-tBuPhP(O)SH: d 13.20 minor/13.05 major; ee = 70%.
Acknowledgments
31P NMR (101.2 MHz, CDCl3) d 13.3; 1H NMR (400 MHz, CDCl3) d
0.91 (s, 3H, CH3), 1.14 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.50–2.90 (m,
3H, CH2 and CHHSO), 2.99–3.15 (m, 1H, CHHSO), 3.21 (dd,
This work was carried out with the support of the French CNRS
and the Polish Academy of Sciences (Project No. 19485). Authors
thank Dr. Loïc Toupet (University of Rennes) for the X-ray crystal
diffraction analysis.
2
3JHH = 7.3 Hz, JHP = 14.4 Hz, 1H, PCH), 3.60–4.15 (m, 5H, 2 ꢂ CH2O
and CHSTol), 7.09 (d, 2H, J = 7.8 Hz, Harom), 7.36 (d, 2H, J = 8.0 Hz,
H
arom); 13C NMR (62.9 MHz, CDCl3) 21.37 (CH3), 21.57 (CH3),
22.09 (CH3), 32.79 (d, J = 7.0 Hz, (CH3)2C), 35.06 (d, J = 8.2 Hz,
CH2), 48.91 (CHS), 53.68 (CH2SO), 68.73 (d, J = 131.2 Hz, PCH),
77.05 (d, J = 6.6 Hz, CH2O), 77.65 (d, J = 6.5 Hz, CH2O), 129.5 (Carom),
130.53 (2 ꢂ CHarom), 134.62 (2 ꢂ CHarom), 139.42 (SCarom), 133.55
(2 ꢂ CHarom); IR (neat, cmꢀ1) 3360, 2974, 2912, 1603, 1500, 1322,
1258, 1053, 1005, 972, 956, 823, 751, 702; MSMS: m/z (%) 375
(MH+, 90); HRMS calcd for C16H24PO4S2: 375.0854. Found:
375.0848.
References
1. See for review: (a) Carreño, C. Chem. Rev. 1995, 95, 1717–1760; (b) Hanquet, G.;
Colobert, F.; Lanners, S.; Solladié, G. ARKIVOC 2003, 328–401; (c) Fernandez, I.;
Noureddine Khiar, N. Chem. Rev. 2003, 103, 3651–3705; (d) Pellissier, H.
Tetrahedron 2006, 62, 5559–5601; (e) Delouvrié, B.; Fensterbank, L.; Najera, F.;
Malacria, M. Eur. J. Org. Chem. 2002, 3507–3525.
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2. Kiełbasinski, P.; Łyzwa, P.; Mikołajczyk, M.; Gulea, M.; Lemarié, M.; Masson, S.
Tetrahedron: Asymmetry 2005, 16, 651–655.
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3. Łyzwa, P.; Jankowiak, A.; Kwiatkowska, M.; Mikołajczyk, M.; Kiełbasin´ ski, P.; Betz,
A.; Jaffres, P-A.; Gaumont, A.-C.; Gulea, M. Tetrahedron Lett. 2007, 48, 351–355.
4. (a) Omelan´ czuk, J.; Mikołajczyk, M. Tetrahedron: Asymmetry 1996, 7, 2687–
2694; (b) Hammerschmidt, F.; Kahlig, H.; Schmidt, S.; Wuggenig, F. Phosphorus
Sulfur Silicon Relat. Elem. 1998, 140, 79–93.
4.3.2. 3-tert-Butylsulfanyl-2-[20-(5,5-dimethyl-1,3,2-
dioxaphosphorinanyl)]thiolane 1-oxide 4
5. (a) Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J. J. Am. Chem. Soc. 1992, 114,
1428–1437; (b) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–934.
6. In the presence of (+)-PhtBuP(S)OH, the 31P NMR spectrum of 1 shows two
signals for a low ee (0–40%), while in the case of a moderate to high ee (65–
95%) the signals overlap. This may explain why only one signal can be observed
for some enantiomerically enriched samples of 1.
7. Three points of the graphic between 0% and 50% on the x axis (5%, 16%, and
32%) were obtained by extrapolation (on the y axis: 116°, 112°, and 114°,
respectively).
This compound was prepared according to the general proce-
dure from non-racemic 2-phosphono-2,3-didehydrothiolane 1-
oxide
116 °C; [
1
and tert-butanethiol. Yield = 78%; white solid, mp
]
a
D = +8.5 (c 1.4, acetone); 31P NMR (161.9 MHz, C6D6)
in the presence of 2 equiv of (+)-tBuPhP(O)SH: d 14.10 minor/
13.91 major; ee = 60%. 31P NMR (81 MHz, CDCl3) d 13.5; 1H
NMR (200 MHz, CDCl3) d 0.92 (s, 3H, CH3), 1.22 (s, 3H, CH3),
1.31 (s, 9H, 3 ꢂ CH3), 2.60–2.90 (m, 3H), 3.05–3.20 (m, 2H), 3.50
(m, 1H), 3.80–4.30 (m, 4H); 13C NMR (50 MHz, CDCl3) 20.77
(CH3), 21.95 (CH3), 31.27 (3 ꢂ CH3), 32.37 (d, J = 6.9 Hz,
(CH3)2C), 37.59 (d, J = 8.8 Hz, CH2), 41.95 ((CH3)3C), 44.81 (CHS),
53.85 (d, J = 3.7 Hz, CH2SO), 69.68 (d, J = 128.4 Hz, PCH), 77.33
(d, J = 6.3, CH2O), 77.69 (d, J = 6.5, CH2O); IR (neat, cmꢀ1) 2965,
1661, 1345, 1267, 1161, 1057, 1005, 838, 815; MSMS: m/z (%)
341 (MH+, 20), 285 (100); HRMS calcd for C13H26PO4S2:
341.1010. Found: 341.0986.
8. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions;
Wiley: New York, 1981.
9. The same procedure as for the preparation of (S)-(+)-2 was used. The starting
phosphonothiolane was oxidized by (ꢀ)-8,8-dichloro-camphorsulfonyl-
oxaziridine to give a non-racemic mixture of (ꢀ)-1/(+)-1 in about an 84:16
ratio. The mixture was enantioenriched in enantiomer (ꢀ)-1 by crystallization
and substrate 1 having 90% ee was reacted with benzenethiol. The resulted
adduct was recrystallized to afford an enantiopure sample of (R)-(ꢀ)-2.
10. See Section 4.2.1.
11. The slight differences in chemical shifts observed in 31P NMR (13.3 and
10.6 ppm instead of 12.5 and 10.0 ppm) are due to the use of THF as a solvent
instead of CDCl3 as normally applied.