Asymmetric hydrogenation of alkyl(vinyl)thioethers: a promising approach to α-chiral thioethers

Article abstract of DOI:10.1016/j.tetasy.2007.11.020

This paper describes the enantioselective hydrogenation of vinylthioethers. We show that thioether derivatives of maleic esters can be hydrogenated with full conversion and up to 60% ee, and that α-thioether cinnamic acids can be hydrogenated in 51% ee with modest conversion.

Full text of DOI:10.1016/j.tetasy.2007.11.020

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2849–2858
Asymmetric hydrogenation of alkyl(vinyl)thioethers: a promising
approach to a-chiral thioethers
Alex F. Meindertsma,a Michael M. Pollard,a,* Ben L. Feringa,a,*
Johannes G. de Vriesa,b and Adriaan J. Minnaarda,*
aStratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
bDSM Pharmaceutical Products, Advanced Synthesis, Catalysis and Development, PO Box 18, 6160 MD, Geleen, The Netherlands
Received 27 August 2007; accepted 19 November 2007
Abstract—This paper describes the enantioselective hydrogenation of vinylthioethers. We show that thioether derivatives of maleic esters
can be hydrogenated with full conversion and up to 60% ee, and that a-thioether cinnamic acids can be hydrogenated in 51% ee with
modest conversion.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Currently, the industrial scale synthesis of enantiopure
a-chiral thioethers typically involves nucleophilic displace-
ment of thiols onto enantiopure activated alcohols or epox-
ides.5,6 This indirect approach requires several additional
steps compared with the direct, catalytic asymmetric meth-
odology. Moreover, when the stereocenter resides at an
electron-rich benzylic position, this route introduces the
danger of racemization with a competing SN1 mechanism.
In an academic context, a-chiral thioethers have been pre-
pared by asymmetric conjugate addition to a,b-unsatu-
rated carbonyl compounds, first reported with high ee by
Wynberg, with mixed success.5,7 Recently, the diastereo-
selective lithiation–alkylation of thiocarbamates was pre-
sented as an alternative approach.8
a-Chiral thioethers are of academic and industrial interest
since they are a common structural element present in
many pharmaceuticals, natural products, and synthetic
intermediates.1 Their importance to the pharmaceutical
industry is illustrated by the dihydrobenzoxanthiins,2
(selective estrogen receptor modulators), Diltiazem3 (a cal-
cium channel blocker used in the treatment of hyperten-
sion), and Singulair4 (used in the treatment of chronic
asthma) (Fig. 1).
OH
HO
S
S
Hydrogenation of vinylthioethers9 and asymmetric hydro-
genation of sulfur containing olefins have been reported
only sporadically.10 However, no examples of the catalytic
asymmetric hydrogenation of alkyl(vinyl)thioethers or
alkyl(vinyl)thioesters are known.
N
N
OMe
O
OAc
Diltiazem
CO2Na
Me2N
O
O
dihydrobenzoxanthiin
S
The absence of asymmetric hydrogenation as a tool for pre-
paring enantiopure thioethers seems surprising considering
its widespread application, especially on an industrial
scale.11 It is likely that most researchers have avoided this
approach in the preparation of a-chiral thioethers because
of (at least in part) the conventional wisdom that sulfur in
its lower oxidation states is a poison for transition metal
catalysts. This potentially limiting stigma is highlighted
by the paucity of examples of hydrogenations of
Cl
N
HO
Figure 1. Important pharmaceuticals containing a-chiral thioethers.
Singulair
*
Corresponding authors. Tel.: +31 50 3634258; fax: +31 50 3634296
(M.M.P.); e-mail addresses: M.M.Pollard@rug.nl; B.L.Feringa@rug.nl;
A.J.Minnaard@rug.nl
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.020

2850
A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
alkyl(vinyl)thioethers reported in the literature,9,12–17 none
of which are asymmetric.
CO2Me
CO2Me
CO2Me
SR
CO2H
SBn
MeO2C
HO2C
SR
Herein, we report the first examples of the catalytic, asym-
metric hydrogenation of alkyl(vinyl)thioethers, where
rhodium catalyzed hydrogenation affords the a-chiral
thioethers with enantioselectivities of up to 60%. We are
convinced that this proof of principle demonstrates that
the asymmetric hydrogenation of alkyl(vinyl)thioethers is
a feasible and potentially practical route to this class of
target molecules.
Z-4 R=CN
Z-5 R=Ph
Z-6 R=Bn
Z-7 R=Et
Z-8 R=Bn
E-4 R=CN
E-5 R=Ph
E-6 R=Bn
E-7 R=Et
Figure 3. Substituted maleic and fumaric acid derivatives made by
conjugate addition to DMAD.
to be promising inhibitors of glutathione (S)-transferases.22
Moreover, substrates for their preparation by asymmetric
hydrogenation can be conveniently obtained by the conju-
gate addition of a thiol onto dimethyl acetylenedicarboxyl-
ate (DMAD). In this way, substrates E-4, Z-4,23 E-5, and
Z-524 were prepared by the literature procedures. Similarly,
diesters E-6, Z-6, E-7, and Z-7 were prepared by the conju-
gate addition of benzyl mercaptan and ethanethiol to
DMAD in 75% (3:2, E:Z) and 88% (8:1, E:Z) yield, respec-
tively, and their stereochemistry was verified by NOESY
experiments. Since cinnamic acid derivatives are sometimes
better substrates for asymmetric hydrogenation than their
corresponding esters,20 acid Z-8 was also prepared by
saponification of Z-6.
Additionally, we show that within the scope of the 12
ligands used in this study, bidentate phosphine ligands
are the most promising since they lead to cleaner reactions,
faster hydrogenations, and higher conversions. While phos-
phoramidites18 sometimes gave comparable enantioselec-
tivities, with some substrates, we observed a competing
desulfurization side process under the conditions used for
the reaction.
1.1. Substrate selection
Since the asymmetric hydrogenation of alkyl(vinyl)-
thioethers was previously unknown, we decided to first
investigate the catalytic asymmetric hydrogenation of
compounds, which resemble benchmark substrates used
in the preparation of amino acids19 and dihydrocinnamic
acid derivatives20 (Fig. 2).
a- and b-Thioether dihydrocinnamic acids and esters are
also a pharmaceutically relevant class of compounds as is
illustrated by the major effort dedicated to the asymmetric
synthesis of these products.5 To investigate their prepara-
tion by asymmetric hydrogenation, we needed to have
access to the corresponding vinyl ethers as substrates.
Substrates Z-9, E-9, Z-10, and E-10 were prepared by the
triethylamine-catalyzed conjugate addition of the corre-
sponding thiol on ethyl phenylpropiolate in good yields
(Fig. 4).
CO2H
CO2H
SR4
Ph
Ph
1
O
SR4
NHAc
2
R1
OR3
CO2Me
CO2Me
CO2Me
Ph
Ph
R2
CO2Me
MeO2C
MeO2C
Me
SR4
3
Et3N
Ph
CO2Et
SR
Ph
CO2Et
CO2Et
Figure 2. Benchmark substrates for hydrogenation (left), adapted to
incorporate thioethers (right).
EtOH
+
+
RS
Ph
HS R
R=Bn Z-9 (42%)
R=Et Z-10 (23%)
R=Bn E-9 (36%)
R=Et E-10 (37%)
Acid 1 was prepared in 99% ee by asymmetric hydrogena-
tion of the corresponding cinnamic acid derivative20 using
Rh(COD)2BF4 with a mixture of a phosphoramidite and
an achiral phosphine. N-Acetyl b-phenyl alanine 2 and
dimethyl 2-methyl succinate 3 have been prepared in
excellent ee’s by the asymmetric hydrogenation of the cor-
responding enamide and dimethyl itaconate, respectively.21
We reasoned that structurally similar substrates possessing
vinylthioethers could also be good candidates for hydro-
genation (Fig. 2, right).
Figure 4. Conjugate addition of thiols to ethyl phenylpropiolate.
The preparation of 2-(alkylthio)cinnamic acids and esters
proved to be more challenging. Initially we pursued the
Knoevenagel condensation of ethyl thioglycolates with
aromatic aldehydes, reported by Paranjpe and Bagavant.25
Unfortunately, this route failed in our hands, despite
attempts to change the base and solvent. This difficulty
has been corroborated by Larrson.26
We then explored an alternative approach to prepare these
derivatives. Wadsworth and Detty reported27 the synthesis
of (Z)-2-(phenylthio)cinnamic acid by refluxing ethyl phe-
nylpropiolate with thiophenol in the presence of air, which
likely proceeds through a radical addition. When aliphatic
thiols were employed in this procedure, mixtures of b- and
a-adducts were formed as the major and minor products,
respectively. However, we found that the addition of
2. Results and discussion
2.1. Synthesis of the substrates
2-(Alkylthio)succinic acids, esters, and derivatives (Fig. 3)
are an attractive class of structures to prepare in an enan-
tioselective way because their racemates have been found

A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
2851
O
O
Ph
O
Ph
CO2Et
NaOH
AIBN
70oC
+
Ph
OEt
Ph
OH
OEt
+
H2O
91%
SBn
SBn
SBn
E-11
7%
HSBn
Z-11
67%
Z-12
Figure 5. Radical addition of benzyl mercaptan to ethyl phenylpropiolate, followed by saponification.
0.2 equiv of AIBN allowed the reaction to be performed
CO2Me
CO2Me
15
16
5 mol% Rh(COD)2BF4
PipPhos
CO2Me
CO2Me
MeO2C
MeO2C
cleanly at lower temperature (70 °C) to give the a-substi-
tuted product 11 as a mixture of Z and E isomers in 67%
and 7% yields, respectively (Fig. 5). Acid Z-12 was also pre-
pared by saponification of Z-11.
+
25 Bar H2
SPh
E-5
CH2Cl2 30 oC
5% total
2.2. Asymmetric hydrogenation28
Figure 8. Hydrogenation of substrate E-5 gives desulfurized products 15
and 16.
Initially we pursued the hydrogenation of thiocyanate E-4
under the assumption that the electron-withdrawing cyano
function might diminish the electron density on sulfur,
making it less likely to coordinate to the rhodium. Unfor-
tunately, conditions, which have been used successfully to
hydrogenate similar substrates (without the thiocyanate
function) including Rh(I) and PipPhos (Fig. 6) in CH2Cl2,
failed to give any conversion to the desired product 13
(Fig. 7). Competitive hydrogenation of benchmark sub-
strate 14 in the presence of E-4 gave no conversion of either
substrate, thus confirming that the thiocyanate was most
probably a catalyst poison.
phenolate. Unfortunately, this reaction gave racemic pro-
duct. When preliminary optimization of these conditions
showed minimal improvements in conversion with no
enantioselectivity, we chose to investigate bidentate
ligands,29 which we reasoned might be less likely to be
influenced by competitive coordination by thioethers.
We adapted the reaction conditions to those previously
used in asymmetric hydrogenation with high enantioselec-
tivity using bidentate ligands.30 As might be expected,
1 equiv of the bidentate ligands with respect to
Rh(COD)2BF4 gave the highest conversions. After subject-
ing E-6 to asymmetric hydrogenation with Rh(I) and a ser-
ies of bidentate ligands in MeOH at 25 bar at 30 °C, we
found several ligands including BINAP, Josiphos, and
SL-J002-1 induced promising enantioselectivities (Table 1,
Figs. 9–11).
R2
L1 R1 = piperidine, R2 = H (PipPhos)
L2 R1 = NMe2, R2 = H
O
O
L3 R1 = N[(R)-α-MeBn]2, R2 = H
L4 R1 = NMe2, R2 = Me
P R1
L5 R1 = N(i-Pr)2, R2 = H
R2
Figure 6. Phosphoramidites used in this study.
Table 1. Optimization of the ligand for the hydrogenation of E-6
The attempted hydrogenation of E-5 (Fig. 8) using rho-
dium(I) and PipPhos L1 in CH2Cl2 gave dimethyl fumarate
15 and dimethyl succinate 16 in approximately 5% overall
yield, and the remaining starting material left unreacted.
Longer reaction times did not change the conversion. The
1:1 stoichiometry between rhodium used (5%) and total
eliminated thiol (5%) strongly supports catalyst poisoning
by thiophenol.
5 mol%
Rh(COD)2BF4
ligand
CO2Me
CO2Me
CO2Me
CO2Me
*
MeOH 30 oC
25 Bar H2, 24 h
SBn
E-6
SBn
17
Ligand (5 mol %)
Conversion (%)
ee (%)
rev-Josiphos
BINAP
12
12
45
27
0
22
41
52
17
0
Josiphos
In contrast, rhodium(I) with 2 equiv of PipPhos and 25 bar
of H2 in CH2Cl2 hydrogenated E-6 gave 17 with 25%
conversion and with minimal desulfurized product. This
change in reactivity may be related to the poorer leaving
group ability of the benzylthiolate when compared to thio-
Taniaphos
SL-J005
SL-J011-1
SL-J002-1
11
36
26
46
Rh(COD)2BF4
PipPhos
CO2Me
S
CO2Me
CO2Me
NHAc
14
N
N
*
MeO2C
MeO2C
S
25 bar H2
CH2Cl2
E-4
13
Figure 7. Attempted hydrogenation of E-4 with and without methyl 2-acetamidoacrylate.

2852
A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
PPh2
N
PPh2
PPh2
PCy2
PPh2
Ph2P
Cy2P
Fe
Fe
PPh2
Fe
S-BINAP
(R,S) -Taniaphos
(R,S)-Josiphos
F3C
(S,R)-Rev. Josiphos
P
P
P
Fe
P
P
Fe
P
Fe
F3C
SL-J005-1
Figure 9. Structures of the bidentate ligands used in this study.
SL-J011-1
SL-J002-1
nue was explored (Table 2).20 In this case, the use of water
as co-solvent at proportions up to 60% does not signifi-
cantly influence the conversion or ee. The use of larger
amounts of water leads to a significant drop in the
enantioselectivity.
5 mol%
CO2Me
CO2Me
Rh(COD)2BF4
phosphoramidite
CO2Me
SEt
18
MeO2C
MeOH 80 oC
25 Bar H2, 48 h
SEt
E-7
Figure 10. Hydrogenation of E-7.
Table 2. Influence of water on the ee and conversion in the hydrogenation
of E-6
Water/MeOH
Conversion (%)
ee (%)
i) 5 mol% Rh(COD)2BF4
CO2H
CO2Me
SBn
17 (14% e.e.)
HO2C
Josiphos, MeOH, 80oC MeO2C
25 Bar H2, 48 h
10:90
30:70
50:50
60:40
90:10
95
91
Full
97
83
51
54
54
52
14
SBn
Z-8
ii) TMSCHN2, MeOH
Figure 11. Hydrogenation of diacid 8.
Conditions: 5% Rh(COD)2BF4, Josiphos, 80 °C, 25 bar H2, 48 h.
Josiphos induced the highest conversion (45%) and ee
(52%). Interestingly, both isomers, E-6 and Z-6, of the
remaining starting material were recovered, indicating that
the substrate isomerizes to some extent (typically 5%)
under the reaction conditions. Importantly, these condi-
tions minimized the desulfurization side reaction to ꢀ10%.31
Modest changes in the structure of the substrate had min-
imal influence on the enantioselectivity, suggesting that this
method could be quite general. As observed with E-6,
hydrogenation of the related substrate E-7 gave complete
conversion and similar enantioselectivity (56% ee) to pro-
vide product 18. Compound Z-7 gave lower enantioselec-
tivities (36%) with considerably lower conversion (72%)
and more desulfurized product (30%).
Several solvents were screened to further optimize the
conversion and ee. Out of the solvents tested (THF,
CH2Cl2, EtOAc, MeOH, and iPrOH) the only ones which
allowed even modest conversion were alcohols. We focused
our attention on MeOH since it gave the best conversion
and because the substrate contains methyl esters.
After having pursued several approaches to optimize the
enantioselectivity of this hydrogenation it became clear
that significant improvements in ee would likely necessitate
screening for alternative ligands. We focused on using
phosphoramidite ligands, which offer the possibility of sig-
nificant structural diversity, and are often prepared in a
one-pot procedure.
Increasing the temperature from 30 °C to 80 °C, as well as
extending the reaction time to 48 h resulted in full conver-
sion of E-6 to 17 with a small increase in the enantioselec-
tivity.32 Hydrogenation of Z-6 under these optimized
conditions gave comparable enantioselectivities (59% ee),
but lower conversion (59%) and with a more desulfurized
product (24% with respect to 17).
In contrast to the lack of reactivity, which we observed
during previous attempts to hydrogenate E-6 catalyzed
by Rh(I) with phoshoramidite ligands in CH2Cl2, in MeOH
this catalysis system gave moderate to good conversion
(Table 3). Slightly lower ee’s (30–46%) were obtained in
comparison to Josiphos (51–60%) (Table 4). Disappoint-
Since the amount of water in the solvent has been shown to
have a significant effect on the conversion and ee, this ave-

A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
2853
Table 3. Monodentate ligands in the hydrogenation of E-6
ingly, the proportion of the desulfurized product was larger
than that observed with the bidentate ligands.
5 mol%
CO2Me
CO2Me
CO2Me
CO2Me
Rh(COD)2BF4
phosphoramidite
Since cinnamic acid derivatives were reported to be hydro-
genated with improved conversion and enantioselec-
tiv;ity when compared with their corresponding esters, we
saponified substrate E-6 in the hope that it would also
show a similar improvement. Unfortunately hydrogenation
of acid 8 only resulted in a slightly lower conversion (95%),
much lower enantioselectivity (14%) with 10% desulfurized
product (Fig. 11).
*
MeOH 80 oC
25 Bar H2, 48 h
SBn
E-6
SBn
17
Ligand (10 mol %) Conversion (%) Desulfurizeda (%) Temp (°C)
L2
L2
Full
Full
Full
69
60
34
36
22
35
50
80
80
80
80
L2:PPh3, 2:1b
L3
L4
After having shown that asymmetric hydrogenation can be
successfully achieved on maleic esters containing the vinyl-
ether functionality, we wanted to explore this approach to
prepare a- and b-thioether dihydrocinnamic acids and
esters.
60
a Calculated as a percentage of desulfurization product relative to the
amount of hydrogenated product.
b 15 mol % of ligand.
Asymmetric hydrogenation of Z-9 and Z-10 gave complex
mixtures containing some of the desired products 19 and
20, respectively, along with multiple unidentified side prod-
ucts, making analysis difficult. In contrast, E-9 and E-10
both gave excellent conversion, albeit with 0% and 28%
ees, respectively (Table 5). Hydrogenation of both cin-
namic esters E-11 and Z-11 with the sulfur at the a-position
cleanly gave racemic 21 with moderate conversion. Inter-
estingly, however, hydrogenation of acid Z-12 to 22 gave
promising enantioselectivities with Josiphos (42%) and
with the ‘mixed ligand’ approach20 with 5 mol % PPh3
and 10 mol % L3 (51% ee).
Table 4. Sensitivity of the desulfurization of E-6 to ligand
Ligand (10 mol %) Conversion (%) Desulfurizationa (%) ee (%)
L3
L2
72
31
85
Full
47
38
34
9
46
40
30
60
b
L4/PPh3
Josiphosc
Conditions: 5% Rh(COD)2BF4, 80 °C, 25 bar H2, 48 h, in MeOH.
a Calculated as the percentage of desulfurization product relative to the
amount of hydrogenated product.
b 15 mol %.
c 5 mol %.
Table 5. Hydrogenation of cinnamic acid derivatives
Substrate
Ph
Product
Ligand (5 mol %)
Josiphos
Conversion (desulfurized product) (%)
Full (11)
ee (%)
0
Ph
CO2Et
CO2Et
CO2Et
EtS
EtS
19
E-
9
Ph
Ph
CO2Et
Josiphos
Josiphos
Josiphos
Josiphos
Full (0)
36 (0)
50 (0)
62 (0)
28
0
BnS
BnS
E-10
CO2Et
SBn
20
O
Ph
Ph
OEt
OEt
OH
E-11
SBn
21
O
CO2Et
SBn
Ph
0
Ph
Z-11
SBn
O
21
CO2H
SBn
Ph
42
Ph
12
Z-
SBn
O
22
CO2H
SBn
Ph
L4:PPh3 10:5 mol %
24 (0)
51
Ph
22
OH
Z-12
SBn
Conditions: 5% Rh(COD)2BF4, ligand, 80 °C, 25 bar H2, 48 h.

2854
A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
2.3. On the mechanism of desulfurization
5 mol%
Rh(COD)2BF4
ligand
CO2Me
CO2Me
MeO2C
MeO2C
The desulfurization side reaction is problematic because it
reduces yield, conversion, and likely poisons the catalyst.
This desulfurization reaction was also observed by Ricci
and co-workers.9 Herein we report some preliminary obser-
vations that may give insight into the possible mechanism
of desulfurization.
CO2Me
SBn
17
or
MeO2C
MeOH 80 oC
25 Bar H2
Figure 13. Stability of product
9 to the conditions optimized for
hydrogenation.
Using E-6 as an example, we suggest that three of the more
plausible mechanisms, which lead to this desulfurization
process, include simple elimination of the thiol (path A,
Fig. 12), insertion of the rhodium into the carbon–sulfur
bond (path B), or a syn-elimination of a rhodium sulfide fol-
lowing the addition of the rhodium hydride to the olefin
(path C).
methanol for 48 h at 80 °C. The use of monodentate phos-
phoramidite ligands leads to modest enantioselectivities,
though also results in lower rates of hydrogenation, as well
as reduced yields because of competing desulfurization. We
find that this competing side reaction complicates the asym-
metric hydrogenation of substrates possessing the thiol
moiety in the b-position relative to acids and esters.
We believe that the simple elimination mechanism (path A)
is unlikely because (1) treatment of the purified product
thioether 17 with the conditions used for the hydrogenation
does not lead to the formation of desulfurized product
(Fig. 13) and (2) asymmetric hydrogenation of diacid 8 also
leads to the formation of eliminated product. The base
mediated elimination is less likely in the presence of the car-
boxyl groups, which are more acidic and more likely to be
deprotonated. Taken together, these data suggest that an
alternative mechanism is operating.
Moreover, we also determined that a-thioether–cinnamic
acid derivatives can be hydrogenated with 51% ee with
no apparent desulfurization, albeit with incomplete conver-
sion. As a result of this, and their ease of preparation, this
substrate class is particularly promising for future study.
4. Experimental
4.1. General remarks
We also found that when using the Josiphos ligand, the addi-
tion of 1 equiv of thiol relative to substrate (hence 20 times
that of the Rh(I)) led to only a small drop in conversion.
All chemicals were purchased from Aldrich unless other-
wise stated, and used without purification. THF was dried
over sodium.33 All reactions were performed under a nitro-
gen atmosphere in oven dried glassware. Compounds 423
and 524 as well as phosphoramidites L1,34 L2,35 L3 and
L4,36 and L537 were prepared according to the literature
procedures. The Rh(COD)2(BF4) and the Josiphos family
ligands were purchased from Strem. Flash chromatogra-
phy was carried out using Merck silica gel 60 (230–400
mesh ASTM). NMR spectra were obtained using a Varian
3. Conclusions
This work offers a proof of principle that asymmetric hydro-
genation can be used to prepare a-chiral thioethers from
alkyl(vinyl)thioethers. This is highlighted by the hydrogena-
tion of substrate E-6 in quantitative yield and 60% ee using
5 mol % of Rh(COD)2BF4/Josiphos, and 25 bar of H2 in
CO2Me
SBn
MeO2C
H
B
H
Path A
CO2Me
CO2Me
HSBn
CO2Me
SBn
+
+
MeO2C
MeO2C
MeO2C
*P Rh
*P
Hydrogenation
H
17
15
CO2Me
SBn
MeO2C
CO2Me
H2
*P
Path B
MeO2C
*P Rh SBn
H
Rh SBn
P*
1,2 insertion
*P Rh
P*
*P
*P
*P Rh SBn
MeO2C
H
*P Rh
CO2Me
SBn
MeO2C
H
*P Rh
CO2Me
SBn
CO2Me
SBn
MeO2C
Path C
H
+
H
*P Rh
*P
Addition/
Elimination
P*
P*
MeO2C
CO2Me
H
15
Figure 12. Possible pathways leading to desulfurization of E-6.

A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
2855
Gemini-200, a Varian 300, or a Varian Mercury Plus oper-
4.1.3.2. Racemic product. To a solution of benzyl mer-
captan (0.25 mL, 2.1 mmol, 1.0 equiv), triethylamine
(0.29 mL, 2.1 mmol, 1.0 equiv) in ethanol (50 mL) was
added dimethyl fumarate (0.30 g, 2.1 mmol, 1.0 equiv).
The solution was heated to 40 °C and stirred overnight.
Solvent was removed in vacuo. Purification by column
chromatography (SiO2, 9:1, heptane/EtOAc) gave 17
(0.35 g, 62%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d 7.32–7.25 (m, 5H), 3.84 (ABX, Japp = 13.2,
22.0 Hz, 2H), 3.72 (s, 3H), 3.63 (s, 3H), 3.58 (ABX,
Japp = 5.4, 9.9 Hz, 1H), 2.94 (ABX, Japp = 10.2, 16.8 Hz,
1H), 2.78 (ABX, Japp = 5.4, 17.1 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d 172.3 (C), 171.2 (C), 137.3 (C), 129.3
(CH), 128.8 (CH), 127.6 (CH), 52.7 (CH3), 52.2 (CH3),
41.1 (CH), 36.2 (CH2); HRMS (EI) calcd for C13H16O4S:
268.0769; found, 268.0756.
1
ating at 201.2, 301.8, or 399.93 MHz for the H nucleus or
at 50.32, 75.48, or 100.57 MHz, respectively, for the 13C
nucleus. 13C NMR spectra were referenced to residual
chloroform (1H: 7.24 ppm, 13C: 77.1 ppm) or residual
DMSO (1H: 2.49 ppm, 13C: 49.5 ppm).
4.1.1. Standard operating procedure for hydrogenation
4.1.1.1. General procedure. The standard operating
procedure for hydrogenation using the EndeavorTM semi-
automated autoclave was as follows: To a glass reaction
vessel was added 0.10 mmol of substrate, bidentate ligand
(0.0050 mmol) or monodentate ligand (0.010 mmol),
Rh(COD)2BF4 (0.0050 mmol), and 4.0 mL of solvent.
The reaction vessel was placed in the autoclave and purged
four times with nitrogen, heated to 30 °C and then pressur-
ized to 15 bar of hydrogen. The reaction vessel was then
heated to the desired temperature and pressurized to
25 bar of hydrogen. The sample was stirred at 700 rpm
for 48 h, after which the stirrer was stopped and the hydro-
gen input to the reaction vessel was closed. The sample was
filtered over a silica plug (1:1, EtOAc/heptane) after which
4.1.4. Dimethyl-2-(ethylthio)maleate E-7 and dimethyl-2-
(ethylthio)fumarate Z-7.38 To a solution of dimethyl
acetylenedicarboxylate (1.70 mL, 14.0 mmol, 1.00 equiv)
in MeOH (50 mL) was added ethanethiol (1.10 mL,
14.0 mmol, 1.0 equiv). The solution was stirred for 1 h,
and the solvent removed in vacuo. Purification by column
chromatography (SiO2, 9:1, heptane/EtOAc) gave 2.22 g
(78%) of the Z-isomer as a yellow oil and 0.27 g (9.5%)
of the E-isomer as a colorless oil. E-7: 1H NMR
(400 MHz, CDCl3) d 5.70 (s, 1H), 3.86 (s, 3H), 3.68 (s,
3H), 2.81 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H);
13C NMR (50 MHz, CDCl3) d 166.3 (C), 164.3 (C), 150.8
(C), 112.5 (CH), 53.3 (CH3), 52.0 (CH3), 26.2 (CH2) 13.4
(CH3); HRMS (EI) calcd for C8H12O4S: 204.0456; found,
204.0458. Z-7: 1H NMR (400 MHz, CDCl3) d 6.31 (s,
1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.84 (q, J = 7.2 Hz, 2H),
1.24 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3) d
165.9 (C), 165.1 (C), 149.5 (C), 119.0 (CH), 53.3 (CH3),
52.0 (CH3) 27.1 (CH2) 14.8 (CH3). HRMS (EI) calcd for
C8H12O4S: 204.0456; found, 204.0455.
1
the conversion and ee were determined by H NMR and
chiral HPLC, respectively. The ee and conversion of sub-
strates containing carboxylic acids were determined after
methylation by TMS–diazomethane in methanol (titrated
until the yellow color persisted) to give the corresponding
methyl esters.
4.1.2. Dimethyl-2-(benzylthio)maleate E-6 and dimethyl-2-
(benzylthio)fumarate Z-6. To a solution of benzyl mer-
captan (2.3 mL, 20 mmol, 1.0 equiv) in methanol (75 mL)
was added dimethyl acetylenedicarboxylate (2.5 mL,
20 mmol, 1.0 equiv). The mixture was heated to reflux for
1.5 h, cooled, and the solvent was removed in vacuo. Puri-
fication by column chromatography (SiO2, 9:1, heptane/
EtOAc) gave the Z-isomer (2.4 g, 45%) as a yellow oil
and the E-isomer (1.6 g, 30%) as a white solid. E-6: mp
4.1.5. (Z)-Ethyl-3-(ethylthio)-3-phenylacrylate Z-9 and (E)-
ethyl-3-(ethylthio)-3-phenylacrylate E-9. To a solution of
ethyl phenylpropiolate (1.5 mL, 9.0 mmol, 1.0 equiv) in
ethanol (10 mL) were added ethanethiol (0.68 mL,
9.0 mmol, 1.0 equiv) and triethylamine (1.5 mL, 9.0 mmol,
1.0 equiv). The mixture was stirred overnight, after which
the solvent was removed in vacuo. Purification by column
chromatography (SiO2, 9.7:0.3, heptane/EtOAc) gave the
Z-isomer (0.76 g, 36%) and the E-isomer (0.90 g, 42%) both
as colorless oils. Z-9: 1H NMR (400 MHz, CDCl3) d 7.34–
7.27 (m, 5H), 5.73 (s, 1H), 3.76 (q, J = 7.2 Hz, 2H), 2.79 (q,
J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.05 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 164.4
(C), 159.8 (C), 137.5 (C), 128.7 (CH), 128.1 (CH), 127.8
(CH), 110.5 (CH), 59.6 (CH2) 26.7 (CH2), 14.0 (CH3),
12.9 (CH3); HRMS (EI) calcd for C13H16O2S: 236.0871;
found, 236.0879. E-9: 1H NMR (400 MHz, CDCl3) d
7.32–7.24 (m, 5H), 5.84 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H),
2.33 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H), 0.98 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 165.6
(C), 160.4 (C), 138.5 (C), 128.6 (CH), 128.3 (CH), 127.8
(CH), 115.8 (CH), 59.8 (CH2), 26.7 (CH2), 14.3 (CH3),
14.2 (CH3); HRMS (EI) calcd for C13H16O2S: 236.0871;
found, 236.0879.
1
69–70 °C, H NMR (400 MHz, CDCl3) d 7.33–7.24 (m,
5H), 5.77 (s, 1H), 4.03 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H);
13C NMR (100 MHz, CDCl3) d 165.8 (C), 164.1 (C),
149.9 (C), 134.1 (C), 128.9 (CH), 128.0 (CH), 113.2 (CH),
53.1 (CH), 51.9 (CH3), 36.5 (CH2). HRMS (EI) calcd for
C13H14O4S: 266.0613; found, 266.0600. Z-6: 1H NMR
(400 MHz, CDCl3) d 7.28–7.24 (m, 5H), 6.32 (s, 1H),
4.09 (s, 2H), 3.73 (s, 6H); 13C NMR (100 MHz, CDCl3) d
165.5 (C), 164.6 (C), 148.3 (C), 136.2 (C), 129.2 (CH),
128.6 (CH), 127.5 (CH), 119.7 (CH), 53.0 (CH3), 51.8
(CH3), 36.9 (CH2); HRMS (EI) calcd for C13H14O4S:
266.0613; found, 226.0601.
4.1.3. Dimethyl-2-(benzylthio)succinate 17
4.1.3.1. Enantioselective hydrogenation. The hydroge-
nation was performed with 0.1 mmol of E-6 using standard
conditions with MeOH as the solvent. Purification by col-
umn chromatography (SiO2, 9:1, heptane/EtOAc) gave
28 mg (97%) of the diester as a colorless oil contaminated
with 9% of desulfurization product. The ee was determined
on an OB-H column eluted with n-heptane/iso-propanol
(99:01, flow rate, 0.5 mL/min). Enantiomer 1 eluted at
88 min, enantiomer 2 at 96 min.

2856
A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
4.1.6. (E)-Ethyl-3-(benzylthio)-3-phenylacrylate E-10 and
(Z)-ethyl-3-(benzylthio)-3-phenylacrylate Z-10. To a solu-
tion of ethyl phenylpropiolate (1.0 mL, 6.0 mmol,
1.0 equiv) in EtOH (30 mL) were added benzyl mercaptan
(0.70 mL, 6.0 mmol, 1.0 equiv) and triethylamine (0.84 mL,
6.0 mmol, 1.0 equiv). The solution was stirred overnight,
after which the solvent was removed in vacuo. Purification
by column chromatography (SiO2, 9.5:0.5, heptane/
EtOAc) gave the E-isomer (0.65 g, 37%) and the Z-isomer
0.42 g (23%) both as colorless oils. E-10: 1H NMR
(400 MHz, CDCl3) d 7.40–6.97 (m, 10H), 5.90 (s, 1H),
4.22 (q, J = 7.0 Hz, 2H), 3.63 (s, 2H), 1.29 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 165.3 (C), 159.6
(C), 138.2 (C), 136.6 (C), 128.6 (CH), 128.5 (CH), 128.2
(CH), 128.0 (CH), 127.8 (CH), 126.8 (CH), 115.9 (CH),
59.7 (CH2), 37.0 (CH2), 14.1 (CH3); HRMS (EI) calcd
for C18H18O2S: 298.1027; found, 298.1013. Z-10: 1H
NMR (200 MHz, CDCl3) d 7.38–7.28 (m, 10H), 5.84 (s,
1H), 4.00 (s, 2H), 3.98 (q, J = 7.0 Hz, 2H), 1.06 (t,
J = 7.0 Hz, 3H); 13C NMR (100.32 MHz, CDCl3) d 164.3
(C), 159.4 (C), 137.0 (C), 135.0 (C), 128.9 (CH), 128.8
(CH), 128.7 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH),
127.9 (CH), 127.6 (CH), 127.0 (CH), 111.3 (CH), 59.8
(CH2), 37.3 (CH2), 14.0 (CH3); HRMS (EI) calcd for
C18H18O2S: 298.1027; found, 298.1016.
(C), 144.6 (CH), 137.6 (C), 134.9 (C), 130.9 (CH), 129.6
(CH), 129.2 (CH), 128.6 (CH), 128.3 (CH), 127.4 (CH),
126.8 (C), 62.0 (CH2), 38.7 (CH2), 14.6 (CH3); HRMS
(EI) calcd for C18H18SO2: 298.1027; found, 298.1040. E-
1
11: H NMR (400 MHz, CDCl3) d 7.39–7.18 (m, 10H),
6.86 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.99 (s, 2H), 1.18
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 167.4
(C), 144.6 (CH), 137.6 (C), 137.2 (C), 130.6 (CH), 129.6
(CH), 129.3 (CH), 128.7 (CH), 128.7 (CH), 127.9 (C),
127.5 (CH), 61.5 (CH2), 38.3 (CH2), 14.1 (CH3). HRMS
(EI) calcd for C18H18O2S: 298.1027; found, 298.1040.
4.1.9. (Z)-2-(Benzylthio)-3-phenylacrylic acid Z-12. To
(Z)-ethyl 2-(benzylthio)-3-phenylacrylate Z-11 (0.20 g,
0.67 mmol, 1.0 equiv) was added 5.0 mL of 4 M aqueous
NaOH (7.5 equiv), and the mixture was stirred overnight.
The aqueous layer was acidified with concd HCl (aq) to
pH 1 and extracted with EtOAc (3 Â 25 mL). The com-
bined organic layers were dried with Na2SO4, filtered,
and the solvent removed in vacuo. Recrystallization from
heptane/EtOAc gave 0.13 g (74%) of Z-12 as yellow nee-
1
dles, mp 120.5–121.5 °C. H NMR (400 MHz, CDCl3) d
8.11 (s, 1H), 7.75–7.73 (m, 2H), 7.39–7.36 (m, 4H), 7.26–
7.18 (m, 4H), 4.09 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 171.9 (C), 148,1 (CH), 137.4 (C), 134,5 (C), 131.3 (CH),
130.3 (CH), 129.3 (CH), 128.7 (CH), 128.5 (CH), 127.5
(CH), 125.1 (CH), 39.0 (CH2); HRMS (EI) calcd for
C16H14SO2: 270.0714; found, 270.0702; Anal. Calcd for
C16H14SO2: C, 71.11; H, 5.19; S, 11.95. Found: C, 71.09;
H, 5.25; S, 11.97.
4.1.7. 2-(Benzylthio)fumaric acid Z-8. To dimethyl-2-
(benzylthio)fumarate Z-6 (5.70 g, 21.4 mmol, 1.0 equiv) in
ethanol (30 mL) was added 2 M (aq) NaOH (50 mL,
0.10 mol, 4.7 equiv). This solution was heated to 80 °C
for 3 h, cooled and washed three times with EtOAc
(40 mL). The aqueous layer was acidified with concd HCl
(aq) and extracted three times with EtOAc (40 mL). The
organic layers were dried with Na2SO4 and the solvent
removed in vacuo. Purification via recrystallization from
methanol gave 3.8 g (74%) of the product as a yellow solid,
4.1.10. Ethyl-3-(benzylthio)-3-phenylpropanoate 20
4.1.10.1. Enantioselective. Hydrogenation and purifi-
cation was performed using standard conditions with etha-
nol as the solvent. The ee determination was performed on
an OD-H column eluted with n-heptane/iso-propanol
(99:01, flow rate, 0.5 mL/min). Enantiomer 1 eluted at
21.6 min, enantiomer 2 at 24.4 min.
1
mp 162–164.5 °C. H NMR (400 MHz, DMSO) d 7.34–
7.26 (m, 5H), 6.23 (s, 1H), 4.10 (s, 2H); 13C NMR
(100 MHz, DMSO) d 166.4 (C), 165.6 (C), 149.4 (C),
137.0 (C), 129.4 (CH), 128.9 (CH), 127.7 (CH), 118.8
(CH), 36.2 (CH2); Mass (EI) 238.9; Anal. Calcd for
C11H10O4S: C, 55.46; H, 4.23; S, 13.46. Found: C, 55.54;
H, 4.34; S, 14.17. HRMS (EI) calcd for C11H10O4S:
238.0330; found, 238.0297.
4.1.10.2. Racemic. To a solution of benzyl mercaptan
(0.33 mL, 2.8 mmol, 1.2 equiv), triethylamine (0.40 mL,
2.8 mmol, 1.2 equiv) in ethanol was added trans-ethyl cin-
namate (0.40 mL, 2.4 mmol). The solution was heated to
40 °C and stirred overnight. Solvent was removed in vacuo.
Purification by column chromatography (SiO2, 9.7:0.3,
heptane/EtOAc) gave 10 (0.41 g, 51%) as a colorless oil.
1H NMR (400 MHz, CDCl3) d 7.30–7.18 (m, 10H), 4.15
(t, J = 8.0 Hz, 1H), 4.02–3.99 (m, 2H), 3.49 (ABX,
Japp = 13.2, 36.0 Hz, 2H), 2.81 (ABX, Japp = 15.6, 7.2 Hz,
2H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.5 (C), 141.1 (C), 137.8 (C), 129.0 (CH), 128.6 (CH),
128.5 (CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 60.6
(CH2), 45.0 (CH), 41.5 (CH2), 35.7 (CH2), 14.1 (CH3);
HRMS (EI) calcd for C18H20O2S: 300.1184; found,
300.1171.
4.1.8. (Z)-Ethyl 2-(benzylthio)-3-phenylacrylate Z-11 and
(E)-ethyl 2-(benzylthio)-3-phenylacrylate E-11. To stirred
neat ethyl phenylpropiolate (1.0 mL, 6.0 mmol, 1.0 equiv)
and benzyl mercaptan (0.70 mL, 6.0 mmol, 1.0 equiv) was
added AIBN (0.20 g, 1.2 mmol, 0.2 equiv). This mixture
was heated to 70 °C for 1.5 h, cooled to rt diluted with
water (20 mL) and extracted with EtOAc (3 Â 30 mL).
The organic layers were dried over Na2SO4 and the solvent
removed in vacuo to give a colorless oil. Purification via
column chromatography (SiO2, 99:1 heptane/EtOAc) gave
the Z-isomer as a colorless oil (1.2 g, 67%) contaminated
with 20% of the E-isomer and 0.12 g (7%) of E-isomer con-
taminated with ꢀ20% of Z-isomer. Both compounds were
obtained as colorless oils Z-11: 1H NMR (400 MHz,
CDCl3) d 7.86 (s, 1H), 7.67–7.65 (m, 2H), 7.35–7.18 (m,
8H), 4.33 (q, J = 7.2 Hz, 2H), 4.02 (s, 2H), 1.39 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.4
4.1.11. Ethyl-3-(ethylthio)-3-phenylpropanoate 19
4.1.11.1. Enantioselective. Hydrogenation and purifi-
cation was performed using standard conditions with etha-
nol as the solvent. The ee was determinated on an OD-H
column eluted with n-heptane/iso-propanol (99:01, flow

A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
2857
rate, 0.5 mL/min). Enantiomer 1 eluted at 13 min, enantio-
mer 2 at 22 min.
(ABX, Japp = 13.6, 7.6 Hz, 1H), 1.21 (t, J = 24.0 Hz, 3H);
13C NMR (50 MHz, CDCl3) d 172.3 (C), 138.1 (C), 137.5
(C), 129.3 (CH), 129.2 (CH), 128.7 (CH), 128.6 (CH),
127.4 (CH), 126.9 (CH), 61.3 (CH2), 47.6 (CH), 37.7
(CH2), 36.4 (CH2), 14.4 (CH3); HRMS (EI) calcd for
C18H20O2S: 300.1184; found, 300.1171.
4.1.11.2. Racemic. To
a solution of ethanethiol
(0.36 mL, 4.7 mmol, 2.0 equiv) and triethylamine (0.40
mL, 2.8 mmol, 1.2 equiv) in ethanol was added 10 mL
trans-ethyl cinnamate (0.40 mL, 2.4 mmol, 1.0 equiv). This
solution was stirred overnight at 40 °C. The solvent was
removed in vacuo and then purified by column chromato-
graphy (SiO2, 1:1, heptane/EtOAc) to give 19 (0.30 g, 46%)
as a colorless oil. 1H NMR (300 MHz, CDCl3) d 7.33–7.16
(m, 5H), 4.28 (t, J = 10.4 Hz, 1H), 4.03 (q, J = 9.6 Hz, 2H),
2.83 (ABX, Japp = 15.3, 7.8 Hz, 2H), 2.29 (q, J = 7.2 Hz,
2H), 1.12 (t, J = 7.5 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 170.4 (C), 141.3 (C),
128.3 (CH), 127.5 (CH), 127.1 (CH), 60.3 (CH2) 44.7
(CH), 41.3 (CH2), 24.9 (CH2), 14.1 (CH3), 13.9 (CH3);
HRMS (EI) calcd for C13H18O2S: 238.1027; found,
238.1026.
4.1.14. Ethyl 2-(benzylthio)-3-phenylpropanoate 22
4.1.14.1. Enantioselective. Hydrogenation and purifi-
cation was performed using standard conditions with
methanol as the solvent. The ee determination was per-
formed on an OD-H column eluting with n-heptane/iso-
propanol (99:01, flow rate, 0.5 mL/min). Enantiomer 1
eluted at 25.7 min, enantiomer 2 at 27.5 min.
4.1.14.2. Racemic. Z-12 was hydrogenated using Pd on
carbon (10% paladium) (0.050 g, 0.005 mmol, 0.05 equiv)
using standard conditions with methanol as the solvent.
1H NMR (400 MHz, CDCl3) d 7.28–7.22 (m, 8H), 7.07
(d, J = 6.4 Hz, 2H), 3.80 (ABX Japp = 19.2, 5.6 Hz, 2H)
3.64 (s, 3H), 3.43 (t, J = 8.8 Hz, 1H), 3.16 (ABX
Japp = 15.0, 4.8 Hz, 1H), 2.89 (ABX Japp = 13.6, 7.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 172.5 (C), 137.8 (C),
137.2 (C), 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.4
(CH), 127.2 (CH), 126.7 (CH), 52.2 (CH), 47.3 (CH),
37.5 (CH2), 36.2 (CH2); HRMS (EI) calcd for
C17H18O2S: 286.1027; found, 286.1035.
4.1.12. Dimethyl-2-(ethylthio)succinate 18
4.1.12.1. Enantioselective. Hydrogenation and purifi-
cation was performed using standard conditions with
methanol as the solvent. The ee determination was per-
formed on an OD-H column eluted with n-heptane/iso-pro-
panol (97:03, flow rate, 0.5 mL/min). Enantiomer 1 eluted
at 13 min, enantiomer 2 at 30 min.
4.1.12.2. Racemic. To a solution of ethanethiol (0.30
mL, 4.2 mmol, 2.0 equiv) and triethylamine (0.35 mL,
2.5 mmol, 1.2 equiv) in methanol (10 mL) was added
dimethyl fumarate (0.30 g, 2.1 mmol, 1.0 equiv). The solu-
tion was stirred overnight, the solvent was removed in
vacuo, and the residue purified by column chromatography
(SiO2, 9:1, heptane/EtOAc) to give 18 (0.40 g, 90%) as a
Acknowledgments
We thank T. D. Tiemersma-Wegman (HPLC), A. Kiewiet
´
(MS), B. Stegink, and N. Mrsˇic (hydrogenation) for assis-
tance. A generous gift of a Josiphos ligand kit by Solvias,
Basel, is gratefully acknowledged. We also thank G. Pizzuti
and B. Ruiz for supplying phosphoramidite ligands.
1
colorless oil. H NMR (400 MHz, CDCl3) d 3.74 (s, 3H),
3.69–3.65 (m, 4H), 2.99 (ABX, Japp = 10.0, 17.2 Hz, 1H),
2.69–2.62 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 171.9 (C), 170.8 (C), 52.1 (CH3),
51.6 (CH3), 40.8 (CH), 35.9 (CH2) 25.3 (CH2) 14.0
(CH3); HRMS (EI) calcd for C8H14O4S: 206.0613; found,
206.0608.
References
1. (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341–2372; (b) Vedejs, E. Acc. Chem. Res. 1984, 17, 358–
364.
2. Blizzard, T. A.; DiNinno, F.; Chen, H. Y.; Kim, S.; Wu, J.
Y.; Chan, W.; Birzin, E. T.; Yang, Y. T.; Pai, L.-Y.; Hayes, E.
C.; DaSilva, C. A.; Rohrer, S. P.; Schaeffer, J. M.; Hammond,
M. L. Bioorg. Med. Chem. Lett. 2005, 15, 3912–3916.
4.1.13. Ethyl 2-(benzylthio)-3-phenylpropanoate 21
4.1.13.1. Enantioselective. Hydrogenation and purifi-
cation was performed using standard conditions with
methanol as the solvent. The ee determination was per-
formed on an OB-H column eluting with n-heptane/iso-
propanol (98:02, flow rate, 0.5 mL/min). Enantiomer 1
eluted at 20.1 min, enantiomer 2 at 22.3 min.
3. Mordant, C.; Cano de Andrade, C.; Touati, R.; Ratovelo-
˜
manana-Vidal, V.; Hassine, B. B.; Geneˆt, J. Synthesis 2003,
15, 2405–2409.
4. (a) Shinkai, I.; King, A. O.; Larsen, R. D. Pure Appl. Chem.
1994, 66, 1551; (b) King, A. O.; Corley, E. G.; Anderson, R.
K.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.; Xiang, Y.
B.; Belley, M.; Leblanc, Y.; Labelle, M.; Prasit, P.; Zamboni,
R. J. J. Org. Chem. 1993, 58, 3731–3735.
4.1.13.2. Racemic. To a solution of benzyl mercaptan
(0.33 mL, 4.2 mmol, 2.0 equiv) and triethylamine (0.40
mL, 2.8 mmol, 1.2 equiv) in methanol (10 mL) was added
trans-ethyl cinnamate (0.40 g, 2.4 mmol, 1.0 equiv). The
solution was stirred overnight, the solvent removed in
vacuo, and the crude residue purified by column chromato-
graphy (SiO2, 9:1, heptane/EtOAc) to give 21 (0.40 g, 51%)
as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.32–7.09
(s, 1H), 7.09 (d, J = 6.8 Hz, 2H), 4.14–4.13 (m, 2H), 3.81
(ABX, Japp = 22.0, 8.8 Hz, 2H), 3.42 (ABX, Japp = 9.2,
2.0 Hz, 1H), 3.15 (ABX, Japp = 14.0, 4.8 Hz, 1H), 2.89
5. Enders, D.; Luttgen, K.; Narine, A. A. Synthesis 2007, 7,
¨
959–980.
6. Hughes, D. L. The Mitsunobu Reaction. In Organic Reac-
tions; Overman, L. E., Ed.; Wiley, 1992; Vol. 42.
7. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103,
417–430.
8. Sonawane, R. P.; Muck-Lichtenfeld, C.; Fro¨lich, R.; Berg-
¨
ander, K.; Hoppe, D. Chem. Eur. J. 2007, 13, 6419–6429.
9. (a) Cere, V.; Massaccesi, F.; Pollicino, S.; Ricci, A. Synth.
Commun. 1996, 26, 899–907; For an example of diastereo-

2858
A. F. Meindertsma et al. / Tetrahedron: Asymmetry 18 (2007) 2849–2858
selective hydrogenation of vinylsulfoxides, see: (b) Ando, D.; 24. Truce, W. E.; Kruce, R. B. J. Am. Chem. Soc. 1959, 81, 5372–
Bevan, C.; Brown, J. M.; Price, D. W. J. Chem. Soc., Chem.
Commun. 1992, 592–594.
10. Jendralla, H. Tetrahedron: Asymmetry 1994, 5, 1183–1186.
11. Asymmetric Catalysis on Industrial Scale; Blaser, H. U.,
Schmidt, E., Eds.; Wiley-VCH, 2004.
12. Bohlmann, F.; Zdero, C. Chem. Ber. 1971, 104, 958.
13. Bohlmann, F.; Herbst, P.; Dohrmann, I. Chem. Ber. 1963, 96,
226–236.
5374.
25. Paranjpe, P. P.; Bagavant, G. S. Indian J. Chem. Sect B 1975,
14, 547–548.
26. Larsson, E. Tetrahedron 1971, 27, 865–869.
27. Wadsworth, D. H.; Detty, M. R. J. Org. Chem. 1980, 45,
4611–4615.
28. The absolute configuration of the compounds prepared in this
study is not known.
14. Schneider, H. J.; Bagnell, J. J.; Murdoch, G. C. J. Org. Chem.
1961, 26, 1987–1990.
29. Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert,
H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062–4066.
30. Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S.
E. Org. Lett. 2002, 4, 2421–2424.
31. Desulfurization is quoted as a fraction of the desired
product.
32. It should be noted that the ee of this hydrogenation is
somewhat sensitive to the quality of the Rh(COD)2BF4
employed, and drops as the material ages. A drop in ee of
10% was observed after the material had been stored and used
for 12 months outside a glove box.
33. Perrin, D. D.; Amarego, W. L. F.; Perrin, D. R. Purification
of Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1980.
34. L1: Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard,
A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L.
J. Org. Chem. 2005, 70, 943–951.
15. Bohlmann, F.; Kleine, K. Chem. Ber. 1963, 96, 1229–1233.
16. Lesuisse, D.; Gourvest, J.-F.; Benslimane, O.; Canu, F.;
Delaisi, C.; Doucet, B.; Hartmann, C.; Lefranßcois, J.-M.;
Tric, B.; Mansuy, D.; Philibert, D.; Teutsch, G. J. Med.
Chem. 1996, 39, 757–772.
17. Beck, G. Synlett. 2002, 6, 837–850.
18. Minnaard, A. J.; Feringa, B. L.; Lefort, L.; De Vries, J. G.
Acc. Chem. Res., doi:10.1021/ar7001107.
19. van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am.
Chem. Soc. 2000, 122, 11539–11540.
20. (a) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard,
A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A.
H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed.
2005, 44, 4209–4212; (b) Hoen, R.; Tiemersma-Wegman, T.;
Procuranti, B.; Lefort, L.; de Vries, J. G.; Minnaard, A. J.;
Feringa, B. L. Org. Biomol. Chem. 2007, 5, 267–275.
21. Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH, 2007.
35. L2: Hulst, R.; De Vries, N. K.; Feringa, B. L. Tetrahedron:
Asymmetry 1994, 5, 699.
36. L3, L4: Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A.
H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–
2878.
22. Brophy, P. M.; Campbell, A. M.; van Eldik, A. J.; Teesdale-
Spittle, P. H.; Liebau, E.; Wang, M. F. Bioorg. Med. Chem.
Lett. 2000, 10, 979–981.
23. Kutateladze, T. G.; Kice, J. L.; Zefirov, N. S. J. Org. Chem.
1992, 57, 5270–5271.
37. L5: de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. 1996, 35, 2374–2376.
38. This material can be prepared by radical addition, see:
Blomquist, A. T.; Wolinsky, J. J. Org. Chem. 1958, 23, 551–
554.