Palladium-catalyzed allylic nucleophilic substitution reactions of (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides

Article abstract of DOI:10.1016/S0957-4166(01)00189-6

Regio- and diastereoselective nucleophilic allylic substitutions of optically pure (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides 2 and 3 with sodium dimethyl malonate have been carried out. The reactivity of these substrates is controlled by both the ch

Full text of DOI:10.1016/S0957-4166(01)00189-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1089–1094
Palladium-catalyzed allylic nucleophilic substitution reactions of
(E)-g-acetoxy-a,b-unsaturated p-tolylsulfoxides
Victor Guerrero de la Rosa,a Mario Ordo´n˜ezb and Jose´ Manuel Lleraa,*
aDepartamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia Universidad de Sevilla, Apdo. de Correos No. 874,
E-41071 Seville, Spain
bCentro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Morelos Av., Universidad No. 1001,
62210 Cuernavaca, Morelos, Mexico
Received 4 April 2001; accepted 26 April 2001
Abstract—Regio- and diastereoselective nucleophilic allylic substitutions of optically pure (E)-g-acetoxy-a,b-unsaturated p-tolyl-
sulfoxides 2 and 3 with sodium dimethyl malonate have been carried out. The reactivity of these substrates is controlled by both
the chiral sulfinyl group and the size of the alkyl group attached at the g-terminus of the allylic system. This process constitutes
an example of palladium-mediated resolution of a 1:1 mixture of acetates 2 and 3. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
deprotonation of the p-allylpalladium intermediate to
give 1,3-dienes by b-elimination. In all of these sub-
strates, it is well known that substitution takes place at
the most electron deficient position of the allylic system
(the g-carbon atom with respect to the electron-with-
drawing group).4–7
During the last 20 years, the palladium-catalyzed nucle-
ophilic substitution reaction of allylic oxygenated com-
pounds (esters, carbonates and epoxides) has emerged
as a powerful methodology for the formation of car-
bonꢀcarbon and carbonꢀheteroatom bonds.1 Both the
regio- and stereoselectivity of the process, as well as the
nature of the nucleophile have been widely studied.
Stereoselective variants of the reaction have focused
primarily on enantioselective processes, which employ
chiral ligands and achiral substrates.2 When chiral sub-
strates and soft nucleophiles are used the configuration
of the allylic carbon atom bearing the oxygenated
leaving group always controls the configuration of the
product through a double inversion mechanism (reten-
tion of the configuration). In contrast, little attention
has been paid to diastereoselectivity in the nucleophilic
addition to p-allyl palladium complexes with an adja-
cent stereocenter.3 Usually, allylic alcohols substituted
at the double bond with alkyl, aryl or electron-donating
substitutents have been used in this reaction, while
those allylic systems bearing an electron-withdrawing
ester,4 carbonyl,5 cyano,6 or sulfonyl7 groups at the
double bond have been studied much less. This is due
to the lower reactivity of these compounds toward the
palladium catalysts, their high tendency to undergo
conjugate addition of the nucleophile, and the easier
We are interested in developing methods for the asym-
metric synthesis of optically active sulfoxides with a
second stereogenic center in a 1,4-relationship tethered
by a carbonꢀcarbon double bond, since they are attrac-
tive building blocks for preparing optically active natu-
ral products and bioactive molecules.8,9 We report
herein our results on the regio- and diastereoselective
palladium-catalyzed allylic nucleophilic substitution
reactions with soft carbon nucleophiles to give new
g-carbon-substituted vinyl sulfoxides, which could be
used in further stereoselective transformations. To the
best of our knowledge this process constitutes the first
example of palladium-mediated allylic substitutions on
enantiomerically pure g-oxygenated-a,b-unsaturated
sulfoxides.
2. Results and discussion
2.1. Preparation of allylic acetates 2 and 3
The starting materials for palladium-catalyzed allylic
substitution (chiral non-racemic allylic acetates 2 and 3)
were readily prepared using the SPAC (sulfoxide pipe-
* Corresponding author. Fax: (95) 423 37 65; e-mail: llera@fafar.us.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00189-6

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V. Guerrero de la Rosa et al. / Tetrahedron: Asymmetry 12 (2001) 1089–1094
ridine aldehyde condensation) protocol developed pre-
viously by us,8 followed by enzymatic resolution9 and
acetylation (Scheme 1). First, (E)-g-hydroxy-a,b-unsat-
urated p-tolylsulfoxides 1 were prepared as inseparable
1:1 mixtures of diastereomers (epimers at the hydroxylic
carbon atom) through Knoevenagel condensation of
methylene active (S,S)-bis-p-tolylsulfinylmethane with
enolizable aldehydes, followed by in situ olefin
migration and sulfoxide–sulfonate [2,3]sigmatropic
rearrangement.
group. The regioselectivity found in the reaction is in
complete agreement with the precedents4–7 and can be
explained taking into account that the terminus of the
allylic unit not bearing the electron withdrawing sulfi-
nyl group is the most electron deficient position of the
system. Results for sulfoxide 2a (R=Me; entry 1), as
compared with those obtained for the rest of the series,
show that both chemical yield of the process and
reactivity of the acetate decrease with the steric bulk of
the R alkyl group. Despite the large steric requirement
of the iso-Pr group, g-acetoxy sulfoxide 2e (entry 5) was
reactive enough to give the substitution product in
good chemical yield, although the reaction rate was
about three times slower than that of g-acetoxy sulfox-
ide 2a (entry 1). In all instances the d.e.s of the final
substitution products were similar to those of the start-
Efficient kinetic resolution of (E)-g-hydroxy-a,b-unsat-
urated p-tolylsulfoxides 1 via irreversible enzymatic
acylation with lipase PS (Pseudonomas cepacia) and
vinyl acetate, yielded the acetate (RS,RC)-2 and unre-
acted alcohol (RS,SC)-1 with very high diastereoselectiv-
ity.9 (E)-g-Acetyl-a,b-unsaturated sulfoxides (RS,SC)-3
were conveniently prepared (in 87–93% yield) by stan-
dard acylation of alcohols (RS,SC)-1 with acetic anhy-
dride, DMAP and N,N-di-iso-propylethylamine in
dichloromethane.
1
ing acetates, as determined by H NMR at 500 MHz
and HPLC.
Next, we tried to extend the reaction conditions used
for the palladium(0)-catalyzed allylic substitutions on
acetates (RS,RC)-2 to (E)-g-acetoxy-a,b-unsaturated sulf-
oxides (RS,SC)-3 (Table 2). Surprisingly, after 24 h, only
the g-acetoxy sulfoxide 3a reacted using Pd(Ph3P)4 as
catalyst.
2.2. Palladium-catalyzed allylic substitution
With (E)-g-acetoxy-a,b-unsaturated sulfoxides (RS,RC)-
2 and (RS,SC)-3 in hand, the standard palladium-cata-
lyzed allylic alkylation with dimethyl malonate was
investigated. Two common catalysts, Pd(Ph3P)4 and
[Pd2(dba)3]CHCl3/PPh3 were used in order to carry out
the nucleophilic displacement using the pre-formed soft
nucleophile sodium dimethyl malonate (NaH/
CH2CO2Me/THF). Results are collected in Table 1.
Results collected in Tables 1 and 2 show that palla-
dium(0)-catalyzed allylic substitution reactions on
acetates (RS,RC)-2b and (RS,SC)-3b are controlled by
the chiral sulfinyl group and the size of the R (alkyl)
group attached to the allylic system. Both the yield and
rate of the process were similar for diastereomers 2a
and 3a (R=Me), however, the starting allylic acetates
3b–3e were recovered unaffected using the same reac-
tion conditions under which their diastereomers 2b–2e
gave the substitution products 4.
For allylic acetates (RS,RC)-2, both catalysts were simi-
larly effective affording exclusively the g-substituted
product 4 regardless of the steric size of the R alkyl
O
O
S
O
S
a
R
S
R
CHO
+
p-Tol
p-Tol
p-Tol
OH
1
b
O
S
O
S
R
R
+
p-Tol
p-Tol
OR1
OAc
(RS,RC)-2; d.e. ≥ 96%
R1=H : (RS,SC)-1; d.e. ≥ 96%
R1=Ac: (RS,SC)-3; d.e.≥ 96%
c
Scheme 1. (a) Piperidine, CH3CN; (b) Lipase PS, iso-Pr2O, vinyl acetate, molecular sieve; (c) Ac2O, iso-Pr2NEt, DMPA, CH2Cl2.

V. Guerrero de la Rosa et al. / Tetrahedron: Asymmetry 12 (2001) 1089–1094
1091
Table 1. Palladium-catalyzed reactions of acetates (RS,RC)-2 with sodium dimethyl malonate
O
O
S
Pd0
R
S
R
p-Tol
p-Tol
NaCH(CO2Me)2
THF, 700C
CH(CO2Me)2
OAc
(RS,SC)-4; d.e. ≥ 96%
(RS,RC)-2; d.e. ≥ 96%
Entry
R
Pd0
Time (h)
Yield (%)
1
2
3
4
5
Me, 2a
Et, 2b
n-Pr, 2c
n-Pen, 2d
iso-Pr, 2e
[Pd2(dba)3]CHCl3/PPh3
[Pd2(dba)3]CHCl3/PPh3
[Pd2(dba)3]CHCl3/PPh3
[Pd2(dba)3]CHCl3/PPh3
[Pd2(dba)3]CHCl3/PPh3
4
8
10
12
12
93 (92)a
89 (87)a
86 (83)a
78 (76)a
71 (64)a
a Using Pd(PPh3)4 as catalyst.
Table 2. Palladium-catalyzed reactions of acetates (RS,SC)-3 with sodium dimethyl malonate
O
S
O
S
Pd(Ph3P)4
R
R
p-Tol
p-Tol
NaCH(CO2Me)2
THF, 700C
CH(CO2Me)2
OAc
(RS,SC)-3; d.e. ≥ 96%
(RS,RC)-5; d.e. ≥ 96%
Yield (%)
Entry
R
Time (h)
1
2
3
4
5
Me, 3a
Et, 3b
n-Pr, 3c
n-Pen, 3d
iso-Pr, 3e
4
24
24
24
24
87
–
–
–
–
Taking into account that, as stated above, allylic alco-
hols 1 were obtained as an inseparable 1:1 mixture of
epimers at the carbinol center,8 enzyme mediated
resolution9 was carried out to effect their separation
(see Scheme 1), it occurred to us that the higher reactiv-
ity of 2b–2d towards Pd(0)/NaCH(CO2Me)2 with
respect to that of their epimers 3b–3d, could be used for
the resolution of the mixture, directly available by
acetylation from (E)-g-hydroxy-a,b-unsaturated sulfox-
ides 1.
3. Conclusion
In conclusion, the presence of an (RS)-configured chiral
sulfinyl group attached to the double bond of an allylic
system allows the discrimination between (SC)- or (RC)-
allylic acetates in the palladium-catalyzed nucleophilic
reaction, provided that an alkyl group bulkier than Me
is present at the g-terminus of the allylic system. In this
way, allylic acetates with (RC)-configuration at carbon
are reactive enough towards soft nucleophiles, although
the reaction rates and chemical yields decrease slightly
with the steric bulk of the alkyl substituent. In contrast,
the allylic esters with (SC)-configuration at carbon
remained unaffected under these experimental condi-
tions. The palladium-catalyzed substitution reaction on
(E)-g-acetoxy-a,b-unsaturated sulfoxides constitutes an
example of palladium-mediated resolution of this type
of substrate.
In order to evaluate the palladium-mediated resolution
of (E)-g-acetoxy-a,b-unsaturated sulfoxides we studied
the most reactive substrates (apart from 2a and 3a,
R=Me) derivatives 2b and 3b (R=Et). A (1:1)
diastereomeric mixture of acetates (RS,RC)-2b and
(RS,SC)-3b was prepared from alcohols 1b by standard
acylation, and treated with 10 mol% of Pd(PPh3)4 and
sodium dimethyl malonate in THF at 70°C for 8 h.
Column chromatography of the reaction mixture
yielded (RS,RC)-4b and unreacted acetate (RS,SC)-3b
4. Experimental
1
with very high diastereoselectivity, as confirmed by H
Melting points were determined in open capillary tubes
1
NMR at 500 MHz and comparison with the optical
rotation of previously prepared samples of 3b and 4b
(Scheme 2).
on a Gallenkamp apparatus and are uncorrected. H
NMR spectra were recorded on a Bruker AC-200 (200
MHz) or AMX-500 (500 MHz) and 13C NMR on

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V. Guerrero de la Rosa et al. / Tetrahedron: Asymmetry 12 (2001) 1089–1094
O
S
O
S
O
S
Pd(Ph3P)4
Et
Et
Et
+
p-Tol
p-Tol
p-Tol
NaCH(CO2Me)2
THF, 700C
CH(CO2Me)2
OAc
OAc
(RS,SC)-3b, 38% yield
(RS,SC)-4b; 42% yield
[α]D = +97 (3.5, CHCl3)
(RS,RC)-2b + (RS,SC)-3b
[α]D = +154 (2.7, CHCl3)
Scheme 2.
AC-200 (50.3 MHz) or AMX-500 (125.72 MHz). All
spectra were obtained using CDCl3 as solvent and TMS
as internal standard. Chemical shifts are reported in
ppm and coupling constants in Hz. Optical rotations
were measured on a Perkin–Elmer 241-MC polarimeter
in a 1 dm tube; concentrations are given in g/100 mL.
High resolution mass measurements were performed on
a Kratos MS-80-RFA spectrometer. HPLC analysis
was carried out on a Waters, Millipore 600A model
using a Chiral OD (Diacel) column or reverse phase
column Lichrocart C-18. Routine monitoring of reac-
tions was performed using Merck 60 F 254 silica gel,
aluminum supported TLC plates. For the flash chro-
matography,10 silica gel 60 (230–400 mesh ASTM,
Merck) was used.
ꢁCH-S(O)), 6.41 (dd, J=15.1 Hz, J=4.7 Hz, 1H, CHꢁ),
7.16–7.36 (AA%BB% system, 4H, aromatics). 13C NMR
(50.29 MHz, CDCl3) l 19.5, 20.7, 21.0, 68.5, 124.5,
129.8, 135.1, 136.1, 139.7, 141.5, 169.4. HRMS calcd
m/z for C13H16O3S: 252.0832. Found: 252.0851.
4.2.2.
(RS,SC)-(E)-3-Acetoxy-1-(p-tolylsulfinyl)-1-pen-
tene (RS,SC)-3b. The general procedure was followed
for the acylation of (RS,SC)-1b (80 mg, 0.357 mmol).
Purification of the reaction mixture by flash chromatog-
raphy (AcOEt:hexane, 2:1) afforded (RS, SC)-3b as a
viscous oil (92 mg, 92%). [h]D=+155 (c=2.4, CHCl3).
1H NMR (200 MHz, CDCl3) l 0.82 (t, J=7.4 Hz, 3H,
CH3), 1.62 (m, 2H, CH2), 1.96 (s, 3H, CH3CO), 2.30 (s,
3H, CH3Ar), 5.28 (m, 1H, CHOAc), 6.27 (dd, J=15.0
Hz, J=0.8 Hz, 1H, ꢁCH-S(O)), 6.44 (dd, J=15.0 Hz,
J=4.9 Hz, 1H, CHꢁ), 7.21–7.41 (AA%BB% system, 4H,
aromatics). 13C NMR (50.29 MHz, CDCl3) l 8.9, 20.7,
21.2, 26.8, 73.2, 124.9, 130.0, 135.3, 135.4, 139.6, 141.8,
169.9. HRMS calcd m/z for C14H18O3S: 266.0990.
Found: 266.0968.
Flasks, stirrings bars, and hypodermic needles used for
the generation of organometallic compounds were dried
for ca. 12 h at 120°C and allowed to cool in a dessica-
tor over anhydrous calcium sulphate. Anhydrous ethers
were obtained by distillation from benzophenone
ketyl.11
4.2.3. (RS,SC)-(E)-3-Acetoxy-1-(p-tolylsulfinyl)-1-hexene
(RS,SC)-3c. The general procedure was followed for the
acylation of (RS,SC)-1c (100 mg, 0.336 mmol). Purifica-
tion of the reaction mixture by flash chromatography
(AcOEt:hexane, 2:1) afforded (RS,SC)-3c as a viscous
4.1. (E)-g-Hydroxy-a,b-unsaturated sulfoxides (RS,SC)-
1a–1e and (E)-g-acetoxy-a,b-unsaturated sulfoxides
(RS,RC)-2a–2e
The procedure described by Llera et al. was followed.9
oil (111 mg, 89%). [h]D=+163.5 (c=2.7, CHCl3). H
1
NMR (200 MHz, CDCl3) l 0.81 (t, J=7.4 Hz, 3H,
CH3), 1.25 (m, 2H, CH2), 1.56 (m, 2H, CH2), 1.94 (s,
3H, CH3CO), 2.29 (s, 3H, CH3Ar), 5.34 (m, 1H,
CHOAc), 6.26 (d, J=15.1 Hz, 1H, ꢁCH-S(O)), 6.44
(dd, J=15.1 Hz, J=5.0 Hz, 1H, CHꢁ), 7.20–7.39
(AA%BB% system, 4H, aromatics). 13C NMR (50.29
MHz, CDCl3) l 13.5, 17.9, 20.7, 21.1, 35.7, 71.8, 124.8,
129.9, 135.1, 135.7, 139.6, 141.7, 169.7. HRMS calcd
m/z for C15H20O3S: 280.1148. Found: 280.1131. Anal.
calcd for C15H20O3S: C, 64.25; H, 7.19. Found: C,
64.56; H, 7.23%.
4.2. General procedure for acylation of compounds
(RS,SC)-1a–1e
To a cold (0°C) solution of (E)-g-hydroxy-a,b-unsatu-
rated sulfoxides (RS,SC)-1a–1e (1 equiv.) and catalytic
DMAP in CH2Cl2 was added iso-Pr2EtN (5 equiv.) and
Ac2O (5 equiv.). The reaction mixture was allowed to
warm at room temperature and hydrolyzed with water,
the phases were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was
washed with
a
saturated NaCl solution, dried
(Na2SO4), filtered, and concentrated under reduced
pressure.
4.2.4. (RS,SC)-(E)-3-Acetoxy-1-(p-tolylsulfinyl)-1-octene
(RS,SC)-3d. The general procedure was followed for the
acylation of (RS,SC)-1d (90 mg, 0.338 mmol). Purifica-
tion of the reaction mixture by flash chromatography
(AcOEt:hexane, 2:1) afforded (RS,SC)-3d as a viscous
oil (102 mg, 93%). [h]D=+120.5 (c=1, CHCl3). 1H
NMR (200 MHz, CDCl3) l 0.75 (t, J=5.9 Hz, 3H,
CH3), 1.15 (m, 6H, (CH2)3), 1.71 (m, 2H, CH2), 1.92 (s,
3H, CH3CO), 2.28 (s, 3H, CH3Ar), 5.27 (m, 1H,
CHOAc), 6.23 (dd, J=15.1 Hz, J=1.1 Hz, 1H, ꢁCH-
S(O)), 6.42 (dd, J=15.1 Hz, J=5.1 Hz, 1H, CHꢁ),
7.18–7.38 (AA%BB% system, 4H, aromatics). 13C NMR
4.2.1. (RS,SC)-(E)-3-Acetoxy-1-(p-tolylsulfinyl)-1-butene
(RS,SC)-3a. The general procedure was followed for the
acylation of (RS,SC)-1a (76 mg, 0.362 mmol). Purifica-
tion of the reaction mixture by flash chromatography
(AcOEt:hexane, 2:1) afforded (RS,SC)-3a as a viscous
oil (86 mg, 89%). [h]D=+172.5 (c=1.5, CDCl3). 1H
NMR (200 MHz, CDCl3) l 1.21 (d, J=6.6 Hz, 3H,
CH3), 1.89 (s, 3H, CH3CO), 2.25 (s, 3H, CH3Ar), 5.35
(m, 1H, CHOAc), 6.27 (dd, J=15.1 Hz, J=0.9 Hz, 1H,

V. Guerrero de la Rosa et al. / Tetrahedron: Asymmetry 12 (2001) 1089–1094
1093
(50.29 MHz, CDCl3) l 13.9, 21.0, 21.4, 22.4, 24.5, 31.4,
33.9, 72.3, 125.0, 130.1, 135.6, 135.7, 140.1, 141.9,
170.0. HRMS calcd m/z for C17H24O3S: 308.1464.
Found: 308.1470.
reaction time was 8 h. Purification of the reaction
mixture by flash chromatography (Et2O:hexane, 3:2)
afforded (RS,SC)-4b as a white solid (52 mg, 89% yield)
(87% yield, method B). Mp=53.5–55.5°C, [h]D=+95.7
1
(c=2.8, CHCl3). H NMR (500 MHz, CDCl3) l 1.10
4.2.5.
(RS,SC)-(E)-3-Acetoxy-4-methyl-1-(p-tolylsulfi-
(d, J=6.8 Hz, 3H, CH3), 2.35 (s, 3H, CH3Ar), 3.10 (m,
1H, CH), 3.35 (d, J=8.5 Hz, 1H, CH(CO2Me)2), 3.59
(s, 3H, CH3O), 3.64 (s, 3H, CH3O), 6.22 (dd, J=15.1
Hz, J=0.5 Hz, 1H, ꢁCH-S(O)), 6.48 (dd, J=15.1 Hz,
J=8.0 Hz, 1H, CHꢁ), 7.25–7.43 (AA%BB% system, 4H,
aromatics). 13C NMR (125.72 MHz, CDCl3) l 17.4,
21.3, 36.3, 52.4, 52.5, 56.6, 124.6, 130.0, 136.4, 139.7,
140.5, 141.5, 167.9, 168.0. HRMS calcd m/z for
C17H22O5S: 338.1204. Found: 338.1201. Anal. calcd for
C17H22O5S: C, 60.35; H, 6.51. Found: C, 60.34; H,
6.36%.
nyl)-1-pentene (RS,SC)-3e. The general procedure was
followed for the acylation of (RS,SC)-1e (50 mg, 0.210
mmol). Purification of the reaction mixture by flash
chromatography (AcOEt:hexane, 2:1) afforded (RS,SC)-
3e as a viscous oil (54 mg, 87%). [h]D=+173 (c=2.4,
1
CHCl3). H NMR (200 MHz, CDCl3) l 0.84 (d, J=6.8
Hz, 6H, (CH3)2), 1.77 (m, 1H, CH), 1.97 (s, 3H,
CH3CO), 2.32 (s, 3H, CH3Ar), 5.19 (m, 1H, CHOAc),
6.26 (dd, J=15.1 Hz, J=1.2 Hz, 1H, ꢁCH-S(O)), 6.45
(dd, J=15.1 Hz, J=5.3 Hz, 1H, CHꢁ), 7.22–7.42
(AA%BB% system, 4H, aromatics). 13C NMR (125.72
MHz, CDCl3) l 17.6, 17.8, 20.7, 21.2, 31.9, 76.5, 124.9,
130.0, 133.9, 136.3, 140.0, 141.8, 169.8. HRMS calcd
m/z for C15H20O3S: 280.1148. Found: 280.1143. Anal.
calcd for C15H20O3S: C, 64.25; H, 7.19. Found: C,
63.77; H, 6.97%.
4.3.3. Methyl (RS,SC)-(E)-2-methoxycarbonyl-3-propyl-
5-(p-tolylsulfinyl)-4-pentenoate (RS,SC)-4c. The general
procedure (method A) was followed for the allylic
substitution of (RS,RC)-2c (60 mg, 0.214 mmol). The
reaction time was 10 h. Purification of the reaction
mixture by flash chromatography (Et2O:hexane, 7:3)
afforded (RS,SC)-4c as a white solid (59 mg, 86%) (83%
yield, method B). Mp=51–53°C, [h]D=+90 (c=2.0,
4.3. General procedure for the palladium-catalyzed allylic
substitution
1
CHCl3). H NMR (500 MHz, CDCl3) l 0.86 (t, J=7.3
To a solution of (E)-g-acetoxy-a,b-unsaturated sulfox-
ides (Rs,Rc)-2a–2e (1 equiv.) in dry THF (5 mL) was
added [Pd2(dba)3]CHCl3 (0.01 equiv.) and Ph3P (0.1
equiv.) (method A) or (Ph3P)4Pd (0.01 equiv.) (method
B). The resulting solution was vigorously shaken and
heated at 70°C and a suspension of dimethyl malonate
(1.5 equiv.) and NaH (1.6 equiv.) in anhydrous THF (2
mL) was added. The reaction mixture was stirred at this
temperature until the conversion was complete (TLC).
The solvent was evaporated and the crude product was
purified by column chromatography.
Hz, 3H, CH3), 1.22 (m, 1H, CH2), 1.34 (m, 1H, CH2),
1.43 (m, 2H, CH2), 2.39 (s, 3H, CH3Ar), 2.86 (m, 1H,
CH), 3.44 (d, J=8.4 Hz, 1H, CH(CO2Me)2), 3.61 (s,
3H, CH3O), 3.65 (s, 3H, CH3O), 6.28 (dd, J=15.1 Hz,
J=0.5 Hz, 1H, ꢁCH-S(O)), 6.43 (dd, J=15.1 Hz, J=
9.6 Hz, 1H, CHꢁ), 7.29–7.47 (AA%BB% system, 4H,
aromatics). 13C NMR (125.72 MHz, CDCl3) l 13.6,
20.1, 21.2, 34.0, 41.8, 52.2, 52.4, 55.7, 124.5, 129.9,
137.9, 138.3, 140.5, 141.4, 167.8, 168.0. HRMS calcd
m/z for C18H24O5S: 352.1362. Found: 352.1365. Anal.
calcd for C18H24O5S: C, 61.34; H, 6.86. Found: C,
61.08; H, 6.56%.
4.3.1. Methyl (RS,SC)-(E)-2-methoxycarbonyl-3-methyl-
5-(p-tolylsulfinyl)-4-pentenoate (RS,SC)-4a. The general
procedure (method A) was followed for the allylic
substitution of (RS,RC)-2a (50 mg, 0.198 mmol). The
reaction time was 4 h. Purification of the reaction
mixture by flash chromatography (Et2O:hexane, 2:3)
afforded (RS,SC)-4a as a white solid (56 mg, 93%) (92%
yield, method B). Mp=77–79°C, [h]D=+119 (c=4.7,
4.3.4. Methyl (RS,SC)-(E)-2-methoxycarbonyl-3-pentyl-
5-(p-tolylsulfinyl)-4-pentenoate (RS,SC)-4d. The general
procedure (method A) was followed for the allylic
substitution of (RS,RC)-2d (40 mg, 0.130 mmol). The
reaction time was 12 h. Purification of the reaction
mixture by flash chromatography (Et2O:hexane, 7:3)
afforded (RS,SC)-4d as a viscous oil (35 mg, 78%) (76%
yield, method B). [h]D=+120.4 (c=3.3, CHCl3). 1H
NMR (500 MHz, CDCl3) l 0.83 (t, J=6.8 Hz, 3H,
CH3), 1.23 (m, 6H, (CH2)3), 1.45 (m, 2H, CH2), 2.39 (s,
3H, CH3Ar), 2.94 (m, 1H, CH), 3.44 (d, J=8.4 Hz, 1H,
CH(CO2Me)2), 3.61 (s, 3H, CH3O), 3.65 (s, 3H, CH3O),
6.27 (d, J=15.1 Hz, 1H, ꢁCH-S(O)), 6.43 (dd, J=15.1
Hz, J=3.4 Hz, 1H, CHꢁ), 7.29–7.47 (AA%BB% system,
4H, aromatics). 13C NMR (125.72 MHz, CHCl3) l
13.8, 21.3, 22.3, 26.6, 31.3, 32.0, 42.0, 52.3, 52.5, 55.8,
124.5, 129.7, 137.4, 138.1, 140.6, 141.5, 167.9, 168.1.
HRMS calcd m/z for C20H28O5S: 380.1678. Found:
360.1659. Anal. calcd for C20H28O5S: C, 63.13; H, 7.42.
Found: C, 63.09; H, 7.13%.
1
CHCl3). H NMR (500 MHz, CDCl3) l 1.10 (d, J=6.8
Hz, 3H, CH3), 2.35 (s, 3H, CH3Ar), 3.10 (m, 1H, CH),
3.35 (d, J=8.5 Hz, 1H, CH(CO2Me)2), 3.59 (s, 3H,
CH3O), 3.64 (s, 3H, CH3O), 6.22 (dd, J=15.1 Hz,
J=0.5 Hz, 1H, ꢁCH-S(O)), 6.48 (dd, J=15.1 Hz, J=
8.0 Hz, 1H, CHꢁ), 7.25–7.43 (AA%BB% system, 4H,
aromatics). 13C NMR (125.72 MHz, CDCl3) l 17.4,
21.3, 36.3, 52.4, 52.5, 56.6, 124.6, 130.0, 136.4, 139.7,
140.5, 141.5, 167.9, 168.0. HRMS calcd m/z for
C16H20O5S: 340.1046. Found: 324.1029. Anal. calcd for
C16H20O5S: C, 59.20; H, 6.21. Found: C, 59.26; H,
6.17%.
4.3.2. Methyl (RS,SC)-(E)-2-methoxycarbonyl-3-ethyl-5-
(p-tolylsulfinyl)-4-pentenoate (RS,SC)-4b. The general
procedure (method A) was followed for the allylic
substitution of (RS,RC)-2b (50 mg, 0.188 mmol). The
4.3.5. Methyl (RS,SC)-(E)-2-methoxycarbonyl-3-iso-pro-
pyl-5-(p-tolylsulfinyl)-4-pentenoate (RS,SC)-4e. The gen-
eral procedure (method A) was followed for the allylic

1094
V. Guerrero de la Rosa et al. / Tetrahedron: Asymmetry 12 (2001) 1089–1094
substitution of (RS,RC)-2e (40 mg, 0.143 mmol). The
reaction time was 12 h. Purification of the reaction
mixture by flash chromatography (Et2O:hexane, 7:3)
afforded (RS,SC)-4d as a viscous oil (36 mg, 71% yield)
References
1. For recent reviews, see: (a) Tsuji, J. Palladium Reagents
and Catalysis; Wiley: New York, 1995; (b) Hegedns, L.
In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: New York, 1994; pp. 385–459. (c) Godleski, S. A.
In Comprehensive Organic Synthesis; Trost, B. M.; Flem-
ing, I.; Semmelhock, M. F., Eds.; Pergamon: Oxford,
1991; Vol. 4, p. 585.
2. For reviews on asymmetric palladium-catalyzed allylic
substitutions, see: (a) Trost, B. M.; Van Vranken, D. L.
Chem. Rev. 1996, 96, 395; (b) Williams, J. M. J. Synlett
1996, 705; (c) Reiser, O. Angew. Chem. 1993, 105, 576; (d)
Reiser, O. Angew. Chem., Int. Ed. 1993, 32, 547; (d)
Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron:
Asymmetry 1992, 3, 1089; (f) Consiglio, G.; Waymouth,
R. M. Chem. Rev. 1989, 89, 257; (g) Organopalladium
Chemistry, recent advances; Yamamoto, Y.; Negishi, E.
(Guest Editors) J. Organomet. Chem. 1999, 576 (1–2) (16
reviews).
3. (a) Pyne, S. G.; Dong, Z. Tetrahedron Lett. 2000, 41,
5387; (b) Pyne, S. G.; Dong, Z. Tetrahedron Lett. 1999,
40, 6131; (c) Cook, G. R.; Shanker, P. S.; Pararajosing-
ham, K. Angew. Chem., Int. Ed. 1999, 38, 110; (d) Atlan,
V.; Racouchot, S.; Rubin, M.; Bremer, C.; Olliver, J.; De
Meijere, A.; Salau¨n, J. Tetrahedron: Asymmetry 1998, 9,
1131; (e) Cook, G.; Shanker, P. S. Tetrahedron Lett.
1998, 39, 3405; (f) Cook, G.; Shanker, P. S. Tetrahedron
Lett. 1998, 39, 4991; (g) Michelet, V.; Besnier, I.; Geneˆt,
J. P. Synlett 1996, 215; (h) Michelet, V.; Geneˆt, J. P. Bull.
Soc. Chim. Fr. 1996, 133, 881.
4. (a) Suzuki, T.; Sato, T.; Hirama, M. Tetrahedron Lett.
1990, 31, 4747; (b) Tanikaga, R.; Jun, T. X.; Kaji, A. J.
Chem. Soc., Perkin Trans. 1 1990, 1185; (c) Tsuda, T.;
Horii, Y.; Nakagawa, Y.; Ishida, T.; Saegusa, T. J. Org.
Chem. 1989, 54, 977; (d) Tanikaga, R.; Takeuchi, J.;
Takyu, M.; Kaji, A. J. Chem. Soc., Chem. Commun.
1987, 386; (e) Tsuji, J.; Ueno, H.; Kobayashi, Y.; Oku-
moto, H. Tetrahedron Lett. 1981, 22, 2573.
1
(64% yield, method B). [h]D=+173 (c=5.5, CHCl3). H
NMR (500 MHz, CDCl3) l 0.90 (d, J=7.0 Hz, 6H,
(CH3)2), 1.81 (m, 1H, CH), 2.38 (s, 3H, CH3Ar), 2.82 (m,
1H, CH), 3.61 (s, 6H, CH3O), 3.63 (d, J=8.8 Hz, 1H,
CH(CO2Me)2), 6.26 (d, J=15.1 Hz, 1H, ꢁCH-S(O)), 6.51
(d, J=15.1 Hz, J=10.2 Hz, 1H, CHꢁ), 7.29–7.47
(AA%BB% system, 4H, aromatics). 13C NMR (125.72
MHz, CDCl3) l 18.1, 21.3, 29.4, 48.3, 52.4, 52.5, 54.0,
124.7, 130.0, 136.0, 138.9, 140.6, 141.5, 168.0, 168.3.
HRMS calcd m/z for C18H24O5S: 352.1362. Found:
352.1355. Anal. calcd for C18H24O5S: C, 61.34; H, 6.86.
Found: C, 61.13; H, 6.60%.
4.3.6. Methyl (RS,RC)-(E)-2-methoxycarbonyl-3-methyl-
5-(p-tolylsulfinyl)-4-pentenoate (RS,RC)-5a. The general
procedure (method B) was followed for the allylic substi-
tution of (RS,SC)-3a (30 mg, 0.119 mmol). The reaction
time was 4 h. Purification of the reaction mixture by flash
chromatography (Et2O:hexane, 2:3) afforded (RS,RC)-5a
as a white solid (32 mg, 87%). Mp=83–85°C, [h]D=+204
(c=1.8, CHCl3). 1H NMR (500 MHz, CDCl3) l 1.15 (d,
J=6.8 Hz, 3H, CH3), 2.39 (s, 3H, CH3Ar), 3.17 (m, 1H,
CH), 3.39 (d, J=8.5 Hz, 1H, CH(CO2Me)2), 3.60 (s, 3H,
CH3O), 3.72 (s, 3H, CH3O), 6.26 (dd, J=15.1 Hz, J=1.0
Hz, 1H, ꢁCH-S(O)), 6.54 (dd, J=15.1 Hz, J=7.9 Hz, 1H,
CHꢁ), 7.29–7.48 (AA%BB% system, 4H, aromatics). 13C
NMR (125.72 MHz, CDCl3) l 17.4, 21.3, 36.3, 52.4, 52.5,
56.6, 124.6, 130.0, 136.4, 139.7, 140.5, 141.5, 167.9, 168.0.
HRMS calcd m/z for C16H20O5S: 340.1046. Found:
324.1029. Anal. calcd for C16H20O5S: C, 59.20; H, 6.21.
Found: C, 59.17; H, 6.22%.
4.4. Palladium-mediated resolution of (E)-g-acetoxy-
a,b-unsaturated sulfoxides 2b and 3b
To a solution of the mixture of acetates (RS,RC)-2b and
(RS,SC)-3b (1:1 mixture, 70 mg, 0.248 mmol) in dry THF
(5 mL) was added (Ph3P)4Pd (12.8 mg, 0.012 mmol). The
resulting solution was vigorously shaken and heated at
70°C and a suspension of dimethyl malonate (34.7 mg,
0.26 mmol) and NaH (15 mg, 0.63 mmol) in anhydrous
THF (2 mL) was added. The reaction mixture was stirred
at this temperature for 4 h. The solvent was evaporated
and the crude product was purified by flash chromatog-
raphy (Et2O:hexane, 7:3) affording (RS,SC)-4b as a white
solid (35 mg, 42%), mp=53.5–55.5°C, [h]D=+97 (c=3.5,
CHCl3), and (RS,SC)-3b as a viscous oil (27 mg, 38%),
[h]D=+154 (c=2.7, CHCl3).
5. Sugiura, M.; Yagi, Y.; Wei, S.-Y.; Nukai, T. Tetrahedron
Lett. 1998, 39, 4351.
6. (a) Hunt, D. A.; Quante, J. M.; Tyson, R. L.; Dasher, L.
W. J. Org. Chem. 1984, 49, 5262; (b) Tsuji, J.; Ueno, H.;
Kobayashi, Y.; Okumoto, H. Tetrahedron Lett. 1981, 22,
2573; (c) Jackson, W. R.; Staruss, J. U. Aust. J. Chem.
1977, 30, 553.
7. (a) Garrido, J. L.; Alonso, I.; Carretero, J. C. J. Org.
Chem. 1998, 63, 9406; (b) Alonso, I.; Carretero, J. C.;
Garrido, J. L.; Magro, V.; Pedregal, C. J. Org. Chem.
1997, 62, 5682.
8. Guerrero de la Rosa, V.; Ordo´n˜ez, M.; Alcudia, F.;
Llera, J. M. Tetrahedron Lett. 1995, 36, 4889.
9. Guerrero de la Rosa, V.; Ordo´n˜ez, M.; Llera, J. M.
Tetrahedron: Asymmetry 2000, 11, 2991.
Acknowledgements
10. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
11. Brown, H. C. Organic Synthesis via Boranes; Wiley: New
York, 1975; p. 256.
We wish to thank the Spanish DIGICYT (Project
PB94-1431), the Junta de Andaluc´ıa and the CONACYT
(Project 28762-E) for financial support.
.