Regio- and stereoselectivity control in palladium-catalyzed allylic alkylation of 1-cycloalkenylmethyl acetates

Article abstract of DOI:10.1016/j.tet.2008.04.059

Enantiomerically pure allylic acetates 1a and 1b were obtained by lipase-catalyzed acylation through kinetic resolution processes of the racemates. Palladium-catalyzed alkylation of 1a with dimethyl malonate was both regio- and stereoselective, showing th

Full text of DOI:10.1016/j.tet.2008.04.059

Tetrahedron 64 (2008) 6530–6536
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journal homepage: www.elsevier.com/locate/tet
Regio- and stereoselectivity control in palladium-catalyzed allylic alkylation
of 1-cycloalkenylmethyl acetates
*
Olivier Jacquet, Jean-Yves Legros, Matthieu Coliboeuf, Jean-Claude Fiaud
Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, CNRS UMR 8182, centre d’Orsay, Universite´ Paris-Sud, 91405 Orsay Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure allylic acetates 1a and 1b were obtained by lipase-catalyzed acylation through
kinetic resolution processes of the racemates. Palladium-catalyzed alkylation of 1a with dimethyl
malonate was both regio- and stereoselective, showing that no isomerization of the acetate 1a or the
Received 22 February 2008
Received in revised form 1 April 2008
Accepted 14 April 2008
intermediate
p-allylic palladium complex took place under the conditions used. Alkylation of 1b was
Available online 18 April 2008
stereoselective but not regioselective. The regioselectivity could be partially controlled by the proper
choice of a chiral ligand. Conditions were set up to perform both the alkylation of 1b and the
decarbomethoxylation of the resulting product to afford 3-(cyclohex-1-enyl) butanoate in a one-pot,
one-step process.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Unsymmetrical allylical 1,3-disubstituted substrates are chiral
compounds. Since it is accepted that the palladium-catalyzed
The palladium-catalyzed allylation of stabilized carbo- and
heteronucleophiles by allylic alcohol derivatives is recognized as
a useful method for the synthesis of enantiomerically enriched
organic molecules.1
substitution of the allylic leaving group by stabilized carbon-
ucleophiles takes place with overall retention of configuration, the
chiral information from an enantioenriched substrate should in
principle be totally transferred to the product.
However, the control of regio- and stereoselectivity (including
enantioselectivity) is necessary to ensure the synthetic usefulness
of such a reaction.2
However, some examples are known where a loss of stereo-
chemistry is observed. Hayashi early reported a loss of enantio-
meric purity in alkylation of an enantiomerically enriched allylic
acetate in the presence of an achiral Pd-catalyst, especially when
high amounts of palladium are used. A likely explanation was given,
Different situations are met according to the structure of the
intermediate
p-allylpalladium complex: monosubstituted, sym-
metrically or dissymmetrically 1,3-disubstituted and trisubstituted
allylic complex. A great deal of work has been published on reaction
of symmetrically substituted allylic substrates under chiral Pd-
complexes catalysis. In this case the asymmetric induction arises
from the selection of diastereotopic sites of a chiral meso allylpal-
ladium complex.
which involves epimerization of the chiral intermediate p-allyl-
palladium complex, via a displacement of the palladium by a pal-
ladium(0) complex (a SN2-type displacement) (Scheme 2). This
process has been documented.3 Another explanation has been put
forward for the scrambling of stereochemistry: isomerization of the
allylic substrate (namely an acetate) through attack of the acetate
The control of regioselectivity is, however, crucial for the mono-
substituted allylic derivatives, since only the branched isomer of
the substitution product is chiral. The asymmetric induction may be
regarded as the selection by an achiral nucleophile of two di-
astereomeric palladium complexes, which may interconvert via a
ion to the palladium atom of the p-allypalladium intermediate
complex, followed by reductive elimination.4
Therefore, the palladium-catalyzed alkylation of a chiral, enan-
tiomerically enriched allylic 1,3-disubstituted substrate may result
in a perfect chirality transfer to give a single product provided: (i)
p–
s
–p
isomerization process (Scheme 1).
the regioselectivity is controlled; (ii) the p-allylpalladium in-
To be synthetically useful, the substitution reaction from
unsymmetrical 1,3-disubstituted (i.e., with different substituents)
allylic substrate should be regio- and stereocontrolled.
termediate complex is stereochemically stable, i.e., the above de-
scribed a SN2-type displacement process is not operating.
Since optically active allylic alcohols are easily available from the
racemic compounds either via kinetic resolution by enzymatic acy-
lation or Sharpless epoxidation, we estimate that the problems of
the control of regioselectivity and inhibition of the potential
p-
allylpalladium epimerization process would be important to
investigate.
* Corresponding author.
E-mail address: fiaud@icmo.u-psud.fr (J.-C. Fiaud).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.059

O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
6531
PdLn
[Pd]
OAc
Nu
Nu
R1
R1
R1
Nu
PdLn
[Pd]
PdLn
R1
OAc
R1
Nu
PdLn
[Pd]
OAc
Nu
Nu
R1
R1
R1
PdLn
Scheme 1. Asymmetric induction processes in regioselective palladium-catalyzed substitution of monosubstituted allylic acetates.
product. We thus intended to look at the palladium-catalyzed al-
kylation of enantioenriched 1a and 1b, since we anticipated that
through the evaluation of the chirality transfer level, the in-
vestigation of the occurrence and efficiency of the possible SN2
process would be easier to perform.
PdLn
PdLn'
Nu
OAc
Nu
R1
R2
R1
R2
R1
R2
PdLn'
The present paper thus describes the preparation of enantio-
merically enriched allylic substrates 1a and 1b, the study of the
palladium-catalyzed alkylation of these substrates with dimethyl
malonate, and the search for experimental conditions to set up
some control of regiochemistry and ensure a total asymmetry
transfer. We report that conditions can be found for alkylation of
the substrates and concomitant decarbomethoxylation of the
resulting products. Moreover, we show that the chirality of the
catalyst can control to some extent the regioselectivity for sub-
stitution of 1b.
PdLn SN2 process
PdLn'
PdLn
Nu
OAc
Nu
R1
R2
R1
R2
R1
R2
PdLn'
Scheme 2. Asymmetric induction processes in regioselective palladium-catalyzed
substitution of 1,3-disubstituted allylic acetates.
We aimed at looking at these considerations for the synthesis of
enantiomerically enriched methyl 3-cyclopent-1-enyl and 3-
cyclohex-1-enyl butanoates 2a and 2b from enantiomerically pure
allylic acetates 1a and 1b.
2. Results and discussion
Enantiomerically enriched alcohol 4a (89% ee) has been
obtained by Ti-catalyzed enantioselective alkylation of the corre-
sponding aldehyde by dimethylzinc.6 Kinetic resolution of racemic
alcohol 4b has been performed through Ti-catalyzed Sharpless
epoxidation7a and chiral phosphine-catalyzed acylation with iso-
butyric anhydride,7b to give enantiomerically enriched alcohol 4b
in 88% and >96% ee, respectively. Enantioselective Ru-catalyzed
hydrogenation of the corresponding ketone (100% ee) afforded 99%
of enantiomerically pure 4b.7c
CH2CO2CH3
OAc
n
n
2
1
a n = 1; b n = 2
In this work, racemic alcohols 4a and 4b were resolved by li-
pase-catalyzed acylation, either with isopropenyl acetate (Scheme
4), or succinic anhydride (Scheme 5) as acylating agent.
The first procedure required a separation of the acetate pro-
duced (R)-1 from the unreacted substrate 4 (Scheme 4). This latter
was converted into the enantiomeric acetate (S)-1. Both acetates
obtained in this way showed >99%ee, as shown by chiral GLC
analysis.
In a second procedure, the mixture of products resulting from
acylation was subjected to Mitsunobu reaction conditions to afford
(R)-1a in >95% ee (Scheme 4).8 This one-pot acylation/inversion
procedure did not require a chromatographic separation but fur-
nished only one enantiomer of 1.
A related problem has been addressed by Trost in his pioneering
work on enantioselective catalysis dealing with palladium-cata-
lyzed alkylation of racemic substrates 1a and 1b (Scheme 3). He
reported that the reaction of sodium dimethyl malonate with ra-
cemic allylic acetate 1a, upon catalysis by a chiral palladium cata-
lyst afforded regioselectively optically active product 3a.5
Examination of both the yields of alkylated product 3a and
decarbomethoxylated product 2a (98% and 60%, respectively) to-
gether with the ee (37%) of product 2a when DIOP was used as
chiral ligand suggests that either an epimerization of the in-
termediate
p-allyl palladium complex or a palladium-catalyzed
acetate ion induced racemization of 1a should have occurred.
These processes could alter the efficiency of asymmetry transfer
of chirality from optically active substrates 1 to the alkylation
A third procedure allowed to get both enantiomers without
chromatographic separation. The use of succinic anhydride as
CHE2
CH2E
OAc
[Pd / (+)-DIOP]cat
LI / NaCN / DMF
120 °C
+
E2CH Na
E = CO2Me
THF, reflux
2a (60%, 37% ee)
( )-1a
3a (98%)
Scheme 3. Palladium-catalyzed alkylation of (ꢀ)-1a.5

6532
O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
OAc
DIAD, AcOH
PPh3, Et2O
n
(R)-1a: 60%, 95% ee
(R)-1b: 90%, 96% ee
OH
OAc
OH
PS-Amano
OAc
+
, Et2O, rt, 5 d
n
n
n
OAc
( )-4a
(R)-1a, 45%, > 99% ee
(R)-1b, 42%, > 99% ee
a n = 1
b n = 2
Ac2O, NEt3, DMAP, Et2O
n
(S)-1a, 28%, > 99% ee
(S)-1b, 34%, > 99% ee
Scheme 4. Lipase-catalyzed resolution of 4a and 4b through acylation with isopropenyl acetate.
O
OH
O
OH
OH
O
PS-Amano
+
O
n
n
n
OH
, Et2O, rt, 5 d
O
( )-4
(S)-4a, 40%, > 99% ee
(S)-4b, 45%, > 99% ee
i) NaOH
ii) H3O+
a n = 1
b n = 2
O
n
(R)-4a: 26%, > 99% ee
(R)-4b: 30%, > 99% ee
Scheme 5. Lipase-catalyzed resolution of 4a and 4b through acylation with succinic anhydride.
acylating agent afforded a hemisuccinate easily separated from the
unreacted alcohol (Scheme 5).9 Subsequent saponification of
hemisuccinate gave the enantiomeric alcohol. In that way, both
enantiomers of alcohols were obtained in >99% ee.
Enantiomerically enriched or racemic acetate 1a was subjected
to palladium-catalyzed alkylation with potassium dimethylmalo-
nate, in the presence of various achiral or chiral catalysts. Results
are collected in Table 1. The substitution of (R)-1a was indeed
regioselective affording (S)-3a as the product, with >95%ee, as
determined by 1H NMR using Eu(hfc)3 as chiral shift reagent.
This means that under these conditions, neither the in-
decarbomethoxylated products 2b/6b (59:41). Decarbomethox-
ylation of 3b and 5b thus took place with identical rates.
The efficiency of the decarbomethoxylation process was de-
pendent upon the nature of the counter cation of the dimethyl
malonate ion. The decarboxylation was more or less efficient
according to the base used for the production of this anion (Table 2).
Table 1
Palladium-catalyzed alkylation of 1a with potassium dimethylmalonatea
OAc
CH(CO2CH3)2
2 mol% [Pd(dba)2], ligand
THF, reflux, 12 h
KCH(CO2CH3)2
+
termediate p-allyl palladium complex epimerizes nor the substrate
1a undergoes racemization. Indeed under the same conditions al-
kylation of racemic substrate 1a with a chiral catalyst afforded ra-
cemic 3a at full conversion. Kinetic resolution of the racemic
substrate 1a took place when using 0.7 equiv of nucleophile and Pd/
(R)-Tol-BINAP as catalyst. At 69% conversion, unreacted (R)-1a was
recovered in 50% yield and 35% ee, corresponding to an enantio-
selectivity factor of approximately 2.10
Whereas the palladium-catalyzed substitution of 1a by potas-
sium dimethyl malonate was highly regioselective (>95:5), the
regioselectivity of substitution of 1b under analogous conditions
was poorly controlled (3b/5b¼60:40), as noticed by Trost.4b
Moreover the reaction was slower. In order to improve the reaction
rate, the substitution was carried out in DMSO. After 12 h at 120 ꢁC,
the substrate was fully converted into a 24:76 mixture of non-
decarboxylated 3b/5b and decarboxylated products 2b/6b. Each
product showed the same regioisomeric composition (3b/5b and
2b/6b of 59:41 ratio each). Complete conversion and de-
carboxylation proceeded when the reaction was performed at
120 ꢁC for 24 h, with the same ratio of regioisomeric
(R)-1a
(S)-3a
Entry
Substrate
Ligand
Product
Yieldb (%)
% eec (Config.)g
1
2
3
4
5
6
7
(R)-1a
(R)-1a
(R)-1a
(R)-1a
rac-1a
rac-1a
rac-1a
dpped
84
79
81
83
86
70
74
>95 (S)
>95 (S)
>95 (S)
>95 (S)
(R)-BINAPe
(ꢂ)-(R,R)-DIOPf
(þ)-(S,S)-DIOPf
dppe
(R)-BINAPe
<5
<5
(þ)-(S,S)-DIOPf
a
All reactions were carried out with 1a (1 mmol), dimethyl malonate (2 equiv),
Pd(dba)2 (2 mol %), ligand (2 mol %), t-BuOK (2 equiv), in THF (4 mL) at reflux for
12 h.
b
Yield of isolated product.
c
Determined by 1H NMR in the presence of Eu(hfc)3.
d
1,2-Bis-diphenylphosphinoethane.
(R)-2,20-Bis(diphenylphosphino)-1,10-binaphthalene.
DIOP is 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane.
Assigned on the basis of the stereochemistry of substitution (overall retention).
e
f
g

O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
6533
Table 2
Alkylation of 1b followed by decarbomethoxylation of substituted malonates 3b–5ba
CH2E
OAc CHE2
CH2E
CHE2
[Pd(dba)2 / ligand*]cat
DMSO, 120 °C, 12 h
+
+
+
E2CH K
+
6b
5b
2b
E = CO2Me
3b
( )-1b
Base
Ligand
(3bþ5b)/(2bþ6b)b
3b/5bb
2b/6bb
LiH
NaH
dppe
dppe
dppe
dppe
dppe
(R)-Tol-BINAP
(R,R)-i-PrDuphosc
(S)-i-PrPOX
89:11
74:26
24:76
8:92
41:59
18:82
58:42
27:73
58:42
59:41
59:41
60:40
61:39
86:14
78:22
62:38
59:41
59:41
59:41
60:40
61:39
85:15
78:22
62:38
t-BuOK
Cs2CO3
NaHþMe4NBr
t-BuOK
t-BuOK
t-BuOK
a
Compound (ꢀ)-1b (1 mmol), dimethyl malonate (2 equiv), Pd(dba)2 (2 mol %), ligand (2 mol %), base (2 equiv), DMSO, 120 ꢁC, 12 h, 100% conversion.
b
c
Conversion and product ratio were determined by GLC.
85% Conversion.
The best efficiency was obtained when the malonate anion was
produced by deprotonation with cesium carbonate.
Attack of the nucleophile occurred onto the -allylic palladium
and also the regioselectivity. Noteworthy is the same ratio of non-
decarboxylated and decarboxylated regioisomers, indicative of
similar rates of decarboxylation for both regioisomers.
p
intermediate complex obtained from 1a at the exocyclic carbon
atom whatever the ligand was. This presumably indicates that the
reaction pathway is over steric approach control: the nucleophile
attacks the less hindered carbon atom.
The last point investigated was to know whether the use of
enantiomeric complexes could induce some control of the regio-
selectivity. Since both enantiomers of the substrate were available
(vide supra), they were subjected to alkylation by the malonate ion
with (R)-Tol-BINAP- and (S)-i-Pr-POX-palladium catalytic system.
The use of the former catalytic system allowed to produce two
regioisomers from (R)-1b and a single regioisomer from (S)-1b,
whereas with the latter a reversal of the regiochemistry was
recorded from (R)-1b (Table 3).
Acetate (S)-1b as substrate and (R)-Tol-BINAP as ligand are
matched to produce regioselectively enantiomerically enriched (R)-
2b (>98% ee, by 1H NMR in the presence of Eu(hfc)3). Indeed, (R)-2b
was obtained as a single isomeric product (80% yield in isolated
compound) when the decarboxylation reaction was conducted to
completion (120 ꢁC, 24 h). It is then anticipated that enantiomeri-
cally enriched (>98%) (S)-2b should be produced through the use of
the other matched pair acetate, i.e., (R)-1b as the substrate and (S)-
Tol-binap as the ligand.
Results obtained from 1b would be better rationalized by taking
into account the relative stability of the initially formed
palladium complexes 7b and 8b resulting from attacks of the nu-
cleophile at the exo- or endo-cyclic allylic carbon atom of the
p-olefinic
p-
allylic palladium intermediate complex. One might infer repulsive
interactions of palladium/ligand with the axial hydrogen atoms of
the ring in complex 7b, that would be more effective than those of
the corresponding five-membered ring, thus allowing some for-
mation of 8b (Scheme 6).
These trends are similar to those invoked by Trost for the
rationalization of the stereochemical control occurring in the mo-
lybdenum-catalyzed allylation of carbon nucleophiles.11
Chiral ligands were then investigated to estimate their ability to
control the regioselectivity of substitution of 1b. The three ligands
tested show a different behavior toward the yield of substitution
OAc
CH2CO2Me
CHE2
2 mol% [Pd(dba)2], (R)-Tol-BINAP
+ KCH(CO2Me)2
CHE2
CH3
H
[PdLn]
DMSO, 120 °C, 24 h
H
[PdLn]
H
H
(S)-1b
(R)-2b
7b
8b
Scheme 6. Initially formed
p-olefinic complexes of palladium-catalyzed substitution
of 1b by dimethyl malonate anion (noted E2CHꢂ).
1H NMR of 5b reveals one doublet (
group on the double bond and one doublet (
d
1.50 ppm) for the methyl
3.78 ppm) for the
Table 3
d
Regioselectivity control by a chiral ligand in alkylation of 1b followed by de-
–CH(CO2Me)2, indicative of a single stereoisomer. Moreover, no
NOE effect could be detected between this methyl group and the
proton of the –CH(CO2Me)2 group. Both achiral and chiral GLC
analysis show a single peak for 5b and 6b. On basis of these data,
together with the known stereochemistry of palladium-catalyzed
allylic substitution (overall retention), an (E)-(R) stereochemistry
can be assigned to 5b and 6b.
carbomethoxylation of substituted malonates 3b–5ba
Ligand
dppe
(R)-Tol-BINAP (R)-1b
(S)-1b
Substrate Conversion (%) (3bþ5b)/(2bþ6b)b 3b/5bb 2b/6bb
(R)-1b
100
100
100
100
100
24:76
34:66
14:86
34:66
23:77
59:41
76:24
100:0
34:66
89:11
59:41
76:24
100:0
34:66
87:13
(S)-iPrPOX
(R)-1b
(S)-1b
Enantiomerically enriched (E)-(S)-6b would be obtained as the
major regioisomer (1:2 regioisomeric ratio for 2b/6b) when using
the combination (S)-1b as substrate and (R)-i-PrPOX as ligand.
a
Compound 1b (1 mmol), dimethyl malonate (2 equiv), t-BuOK (2 equiv),
Pd(dba)2 (2 mol %), chiral ligand (2 mol %), DMSO (3 mL), 120 ꢁC, 12 h.
b
Conversion and product ratios were determined by GLC.

6534
O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
3. Conclusion
of sodium chloride. The aqueous layers were extracted with
2ꢃ20 mL of diethylether, the organic layers were dried over
magnesium sulfate and the solvents were removed. Allylic ace-
tates were obtained as colorless oils after flash chromatography
over silica gel (eluent: heptane/ethyl acetate 90:10). For spectral
data, see below.
As a conclusion, experimental conditions have been set up to
regioselectively produce enantiomerically enriched alkylated
compounds by asymmetry transfer from enantiomerically enriched
allylic substrates 1a and 1b without loss of enantiomeric purity. The
process involved an alkylation/decarbomethoxylation sequence.
The alkylation of cyclopentenyl substrate 1a was regioselective and
stereoselective. The regioselectivity of alkylation of acetate 1b
could be controlled by the nature and the chirality of the catalyst.
One regioisomer 6b could be produced in high enantiomeric purity
(>98% ee) by a proper choice of the matched stereochemistries of
the enantiopure substrate and the catalyst.
4.4. Kinetic resolution of 4a and 4b through lipase-catalyzed
acylation
4.4.1. Acylation by isopropenyl acetate
To the allylic alcohol (1 mmol) dissolved in diethyl ether (4 mL)
were successively added isopropenyl acetate (330 mL, 3 mmol) and
PS-Amano lipase (40 mg). The heterogeneous mixture was stirred
for 4 days at room temperature. After filtration of the enzyme, the
solvent was removed. The unreacted allylic alcohol 4 and the ace-
tate produced 1 were separated by silica gel flash chromatography
(heptane/ethyl acetate 90:10).
4. Experimental
4.1. General
1-Acetyl-1-cyclopentene, 1-acetyl-1-cyclohexene, (R)-(þ)-2-[2-
(diphenylphosphino)phenyl]-4-isopropyl-2oxazoline,
BINAP,
4.4.2. Acylation by succinic anhydride
Tol-BINAP, DIOP, tris[3-(heptafluoropropylhydroxymethylene)-d-
camphorato]europium (III) were purchased from Aldrich. Reactions
were performed under an argon atmosphere using Schlenk tube
technique and were monitored by TLC analysis. Bruker AM 250
spectrometer, operating at 250 MHz for 1H, and at 62.5 MHz for 13C,
was used for the recording of NMR spectra, which are referenced to
the solvent as internal standard. HRMS were obtained on a Thermo-
Finnigan-Mat 95 spectrometer. Infrared spectra were recorded in
CHCl3 solution using CaF2 cells on a Perkin–Elmer 1000 FT-IR
spectrometer. Optical rotations were obtained from a Perkin–Elmer
241 polarimeter at room temperature using a cell of 1 dm length
To the allylic alcohol (1 mmol) dissolved in diethyl ether (4 mL)
were successively added succinic anhydride (300 mg, 3 mmol) and
PS-Amano lipase (40 mg). The heterogeneous mixture was stirred
for 4 days at room temperature. The enzyme was removed by fil-
tration and the filtrate treated with a saturated aqueous solution of
sodium hydrogenocarbonate (2ꢃ5 mL). The organic layer was
separated and the aqueous phase extracted with diethyl ether
(5 mL). The combined organic layers were washed (water) and
dried (magnesium sulfate). Removal of the solvent left the
unreacted alcohol. Potassium carbonate (690 mg, 5 mmol) was
added to the aqueous layer and the resulting solution stirred for
12 h at 100 ꢁC, then cooled down and extracted with diethyl ether
(3ꢃ5 mL).
and
l
¼589 nm. Data are reported as follows: [
a]
20 (concentration in
D
g/100 mL, solvent). Enantiomeric excesses of acetates 1a and 1b
were determined by gas chromatograph (GC) analysis on Fisons
9000 apparatus equipped with Chiraldex-b-PM column
4.4.3. Acylation/Mitsunobu reaction procedure
To the allylic alcohol (1 mmol) dissolved in diethyl ether (4 mL)
were successively added isopropenyl acetate (330 mL, 3 mmol) and
PS-Amano lipase (40 mg). The heterogeneous mixture was stirred
for four days at room temperature. After dilution with dry diethyl
ether (2.5 mL), triphenylphosphine (312 mg, 1.2 mmol), acetic acid
(50 mꢃ0.25 mm) and hydrogen as carrier gas (1.0 mL/min). Ana-
lytical thin-layer chromatography (TLC) was performed on silica gel
60 F254 backed precoated plates.
4.2. Syntheses of ( )-1-(10-cyclopentenyl)ethanol 4a and
( )-( )-1-(10-cyclohexenyl)-1-ethanol 4b
(60 mL, 1.2 mmol), and diisopropylazidodicarboxylate (200 mL,
1.2 mmol) were added. The resulting mixture was stirred for 12 h at
room temperature. Filtration, then removal of the solvent left the
crude allylic acetate, which was purified by silica gel flash chro-
matography (heptane/ethyl acetate 90:10).
Dry cerium chloride (484 mg, 2 mmol) was dissolved in 2 mL of
methanol followed by addition of 1 mmol of enone [1-acetyl-1-
cyclopentene and 1-acetyl-1-cyclohexene]. After 5 min of stirring
at room temperature, 49.5 mg (1.3 mmol) of sodium borohydride is
added by portions. After 15 min of stirring at room temperature
there is no substrate remaining. Water was then added until
obtention of a homogeneous mixture. The solution was saturated
with sodium chloride and diethylether was added. The aqueous
layer is extracted with diethylether, the organic layers were dried
over magnesium sulfate and the solvents were removed. Allylic
alcohols were obtained as colorless oils. For spectral data, see
below.
4.5. (R)-1-Cyclopent-1-enylethyl acetate 1a
1
2
O
O
8
9
3
7
6
4
5
4.3. Acylation of allylic alcohols 4a and 4b: syntheses of
1-(10-cyclopentenyl)ethanol
Obtained as a colorless oil, with 45% yield, >99% ee (isopropenyl
acetate) and 60% yield, 95% ee (isopropenyl acetate/Mitsunobu),
respectively.
Allylic alcohol (1 mmol) was diluted in 4 mL of diethylether
and 12 mg (0.1 mmol) of dimethylaminopyridine was added.
1H NMR (250 MHz, CDCl3):
d
¼1.33 (d, J¼6 Hz, 3H1), 1.88 (q,
J¼7 Hz, 2H6), 2.05 (s, 3H9), 2.33 (m, 4H5 and 7), 5.48 (q, J¼7 Hz, 1H2),
5.62 (s, 1H4). 13C NMR (62.5 MHz, CDCl3):
When the mixture became homogeneous 195
triethylamine and 145 l (1.5 mmol) of acetic anhydride were
successively added. After stirring for 12 h at room temperature,
1 N
ml (1.2 mmol) of
d
¼19.5 (C1), 21.5 (C9), 23.9
m
(C6), 31.2 (C7), 31.6 (C5), 69.2 (C2), 126.2 (C4), 144.0 (C3), 172.1 (C8).
IR: 1733 cmꢂ1. GLC: the enantiomers are separable over a Chir-
the mixture was successively treated by 2ꢃ3 mL of
a
aldex-
b
-PM column, isotherm program at 90 ꢁC, t1¼33.1 min (R),
20
hydrochloric acid solution, 2ꢃ5 mL of a saturated solution of
sodium hydrogenocarbonate, and 2ꢃ5 mL of a saturated solution
t2¼37.9 min (S). [
a
]
þ85.3 (c 1.25, CHCl3) (>99% ee, by chiral GLC
D
analysis).

O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
6535
4.6. (R)-1-Cyclohex-1-enylethyl acetate 1b
dry DMSO (2 mL) and stirred for 15 min. Allylic acetate 1a (154 mg,
1 mmol) dissolved in dry DMSO (2 mL) was added and the resulting
solution was transferred via cannula into a Schlenk tube containing
dimethyl malonate (230 mg, 2 mmol) and sodium hydride (48 mg,
2 mmol) in dry DMSO (1 mL). The mixture was stirred for 15 h at
60 ꢁC. After cooling to room temperature, water (5 mL) and diethyl
ether (5 mL) were added. The aqueous layer was separated and
extracted with diethyl ether (2ꢃ5 mL). The combined organic
layers were washed (saturated sodium chloride aqueous solution)
and dried over magnesium sulfate. Removal of the solvent left the
product, which was purified by silica gel flash chromatography
(heptane/ethyl acetate 90:10).
1
O
O
2
9
3
10
8
4
7
5
6
It was obtained as a colorless oil, with 42% yield, >99% ee (iso-
propenyl acetate) and 90% yield, 96% ee (isopropenyl acetate/Mit-
sunobu), respectively.
1H NMR (250 MHz, CDCl3):
d
¼1.30 (d, J¼6.6 Hz, 3H1), 1.65 (m,
4H6 and 7), 1.99–2.05 (m, 4H5 and 8), 2.06 (s, 3H10), 5.24 (q, J¼6.6 Hz,
1H2), 5.71 (s, 1H4). 13C NMR (62.5 MHz, CDCl3):
10
O
O
2
d¼18.8 (C1), 21.3
1
9
(C10), 22.3 (C7), 22.4 (C8), 24.1 (C6), 24.2 (C5), 74.1 (C2), 123.6 (C4),
137.1 (C3), 170.4 (C9). IR: 1738 cmꢂ1. HRMS (EI): 168.0149, calcu-
lated: 168.0150. GLC: the enantiomers are separable over a Chir-
8
O
10'
9'
3
7
6
O
4
aldex-
b
-PM column, column temp: 100 ꢁC, t1¼45.2 min (S) (<0.5%),
5
20
t2¼49.1 min (R) (>99.5%). [
a
]
þ61.3 (c 1, CHCl3) (>99% ee, by
D
Obtained as an oil (181 mg, 80% yield). 1H NMR (250 MHz,
CDCl3):
chiral GLC analysis).
d
¼1.05 (d, J¼7 Hz, 3H1), 1.80 (m, 2H6), 2.22 (t, J¼7 Hz,
4H5 and 7), 3.05 (dq, J¼7 and 11 Hz, 1H2), 3.44 (d, J¼11 Hz, 1H8), 3.64
4.7. (S)-1-Cyclopent-1-enyl-ethanol 4a
(s, 3H10), 3.70 (s, 3H10 ), 5.39 (s, 1H4). 13C NMR (62.5 MHz, CDCl3):
0
1
2
d
¼17.3 (C1), 23.3 (C6), 32.1 (C7), 32.2 (C5), 35.9 (C2), 52.2 (C10), 52.3
OH
0
0
(C10 ), 56.8 (C8), 125.3 (C4), 145.4 (C3), 168.9 (C 9 and 9 ). EIMS m/z (rel
int.): 226 (Mþ, 13.2), 194 (7.1), 167 (63.1), 166 (71.2), 134 (97.4), 107
(60.5), 95 (72.8), 79 (100), 67 (50.6).
3
7
4
6
5
4.9.2. Synthesis of dimethyl 2-(1-cyclohex-1-enylethyl)malonate 3b
Unseparable regioisomers 3b/5b were obtained as an oil
(171 mg, 71% yield) in a 60:40 mixture.
Obtained as a colorless oil (40%), through succinic anhydride
acylation procedure.
1H NMR (250 MHz, CDCl3):
d
¼1.30 (d, J¼6 Hz, 3H1),1.57 (s, 1HOH),
1.89 (q, J¼7 Hz, 2H6), 2.33 (t, J¼7 Hz, 4H5 and 7), 4.42 (q, J¼6 Hz, 1H2),
4.9.2.1. Dimethyl 2-(1-cyclohex-1-enylethyl)malonate 3b.
5.58 (s, 1H4). 13C NMR (62.5 MHz, CDCl3):
d¼22.2 (C1), 23.5 (C6), 31.5
11
(C7), 32.3 (C5), 67.3 (C2), 124.1 (C4), 148.2 (C5). IR: 3350 cmꢂ1. HRMS
calcd for C7H120: 112.0891, found: 112.0888. GLC: the enantiomers
O
O
10
1
9
are separable over a Chiraldex-
b
-PM column, column temp: 90 ꢁC,
O
10'
2
11'
20
t1¼30.2 min (R), t2¼32.0 min (S). [
a]
D
ꢂ13.2 (c 1.0, CHCl3) (>99% ee,
3
O
25
by chiral GLC analysis). Lit:6 [
a]
ꢂ16.3 (c 4.0, CHCl3).
8
4
5
D
7
6
4.8. (S)-1-Cyclohex-1-enyl-ethanol 4b
1H NMR (250 MHz, CDCl3):
d
¼1.00 (d, J¼7 Hz, 3H1), 1.60 (m, 4H6
1
OH
2
and 7), 2.00 (m, 4H5 and 8), 2.90 (dq, J¼7 AND 11 Hz, 1H2), 3.45 (d,
J¼11 Hz, 1H9), 3.68 (s, 3H11), 3.77 (s, 3H11 ), 5.50 (s, 1H4). 13C NMR
3
0
8
4
5
(62.5 MHz, CDCl3):
d
¼17.2 (C1); 22.1 (C7), 22.5 (C6); 25.0 (C5), 27.4
7
0
(C8), 42.2 (C2), 45.0 (C11), 52.1 (C11 ), 53.6 (C9ꢂ),1123.2 (C4), 138.1 (C3),
6
0
168.5 (C10 and 10 ). IR (CHCl3): 1763, 1740 cm
.
EIMS m/z (rel int.): 240 (Mþ, 6.1), 222 (12.7), 208 (12.2), 181
(29.7), 176 (38.1), 148 (61.9), 108 (100), 93 (52.2), 79 (65.7).
HRMS calcd for C13H20O4: 240.1362, found: 240.1371.
Obtained as a colorless oil (45%), through succinic anhydride
acylation procedure.
1H NMR (250 MHz, CDCl3):
d
¼1.26 (d, J¼6.5 Hz, 3H1), 1.57–1.67
(m, 5H6, 7 and OH), 2.03 (m, 4H5 and 8), 4.19 (q, J¼6.5 Hz, 1H2), 5.69 (s,
1H4). 13C NMR (62.5 MHz, CDCl3):
¼21.5 (C1), 22.6 (C7), 22.7 (C8),
23.7 (C6), 24.9 (C5), 72.2 (C2), 121.5 (C4), 141.3 (C3). IR: 3350 cmꢂ1
4.9.2.2. Dimethyl 2-(2-ethylidenecyclohexyl)malonate 5b.
d
11
.
1
O
O
2
20
HRMS calcd for C8H14O: 126.1045, found: 126.1047. [
a
]
ꢂ5.5 (c 1.0,
10
10'
D
3
O
CHCl3) (>99% ee, by chiral GLC analysis).
8
9
11'
4
Lit:12
[a
]
ꢂ7.4 (c 2.6, CHCl3). Chiral GLC.7b,13
20
D
7
5
O
6
4.9. Procedure for palladium-catalyzed allylic alkylation
without decarboxylation
1H NMR (250 MHz, CDCl3):
d
¼1.30 (m, 2H), 1.50 (d, J¼7 Hz, 3H1),
1.60 (m, 4H), 2.30 (m, 2H), 2.90 (m, 1H4), 3.60 (s, 3H11), 3.66 (s,
3H11 ), 3.78 (d, J¼11 Hz, 1H9), 5.24 (q, J¼7 Hz, 1H2). 13C NMR
0
4.9.1. Synthesis of dimethyl 2-(1-cyclopent-1-enylethyl)-
malonate 3a
In a Schlenk tube, Pd(dba)2 (11.5 mg, 0.02 mmol) and bis-
diphenylphosphinoethane (12 mg, 0.03 mmol) were dissolved in
(62.5 MHz, CDCl3):
(C8), 30.5 (C4), 52.2 (C11 and 11 ), 56.8 (C9), 118.0 (C2), 138.2 (C3), 168.6
d
¼12.6 (C1), 22.3 (C6), 22.4 (C7), 24.9 (C5), 29.7
0
0
(C10 and 10 ). EIMS m/z (rel int.): 240 (M,1.5), 222 (2.1), 177 (14.5),165

6536
O. Jacquet et al. / Tetrahedron 64 (2008) 6530–6536
(32.8), 148 (19.4), 133 (74.3), 108 (100), 93 (33.5), 79 (47.0). HRMS
calcd for C13H20O4: 240.1362, found: 240.1371.
1H NMR (250 MHz, CDCl3):
d
¼1.52–1.64 (m, 4H5
and
6
and
d, J¼4.7 Hz, 3H1); 1.90–2.05 (m, 2H7); 2.31 (m, 3H8 and 9); 2.56 (m,
2H4 and 9); 3.68 (s, 3H11); 5.10 (q, J¼4.7 Hz, 1H2).
13C NMR (62.5 MHz, CDCl3):
d
¼12.7 (C1), 22.6 (C6), 24.5 (C7), 26.9
4.10. General procedure for palladium-catalyzed allylic
alkylation followed by decarboxylation
(C8), 27.6 (C5), 33.8 (C9), 38.1 (C4), 51.3 (C11), 114.2 (C2), 141.3 (C3),
173.7 (C10). EIMS m/z (rel int.): 182 (Mþ, 22.9),150 (23.0), 122 (30.0),
108 (100), 93 (34.7), 79 (46.4). HRMS calcd for C11H1802: 182.1307,
found: 182.1311. IR (CHCl3): 1734 cmꢂ1. The enantiomers are sep-
4.10.1. Synthesis of dimethyl 3-(cyclohex-1-enyl)butanoate 2b and
methyl 2-(2-ethylidenecyclohexyl) acetate 6b
arable over a Chiraldex-b
-PM column, isotherm program at 140 ꢁC,
In a Schlenk tube, Pd(dba)2 (11.5 mg, 0.02 mmol) and bis-
diphenylphosphinoethane (12 mg, 0.03 mmol) were dissolved in
dry DMSO (2 mL) and stirred for 15 min. Allylic acetate 1b (168 mg,
1 mmol) dissolved in dry DMSO (2 mL) was added and the resulting
solution was transferred via cannula into a Schlenk tube containing
t1¼39.9 min, t2¼40.5 min.
Acknowledgements
dimethyl malonate (230 mL, 2 mmol) and sodium hydride (48 mg,
`
O.J. acknowledges the French ‘Ministere de l’Education et de la
2 mmol) in dry DMSO (1 mL). The mixture was stirred at 120 ꢁC for
12 h. After cooling to room temperature, water (5 mL) and diethyl
ether (5 mL) were added. The aqueous layer was extracted with
diethyl ether (2ꢃ5 mL). The combined organic layers were washed
(saturated sodium chloride solution), dried (magnesium sulfate).
Removal of the solvent left the product, which was purified by silica
gel flash chromatography (heptane/ethyl acetate 90:10).
The two regioisomers (109 mg, 60% yield, 2b/6b in a 60:40 ratio)
were obtained as a yellow oil and could not be separated by silica
gel chromatography. Full conversion of 1b into the decar-
bomethoxylated product 6b (TLC) could be reached on heating at
120 ꢁC for 24 h.
Recherche’ for a grant.
References and notes
1. Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14.
2. (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422; (b) Williams, J.
M. J. Synlett 1996, 705–710; (c) Trost, B. M. Acc. Chem. Res. 1996, 29, 355–364.
3. (a) Takahashi, T.; Jinbo, Y.; Kitamura, K.; Tsuji, J. Tetrahedron Lett. 1984, 25,
5921–5924; (b) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc.
1985, 107, 2033–2046; (c) Ba¨ckvall, J. E.; Granberg, K. L.; Heumann, A. Isr. J.
Chem. 1991, 31, 17–24; (d) Granberg, K. L.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 1992,
114, 6858–6863; (e) Stary, I.; Zajicek, J.; Kocovsky, P. Tetrahedron 1992, 48,
7229–7250; (f) Moreno-Manas, M.; Morral, L.; Pleixats, R. J. Org. Chem. 1998, 63,
6160–6166; (g) Amatore, C.; Jutand, A.; Mensah, L.; Meyer, G.; Fiaud, J.-C.;
Legros, J.-Y. Eur. J. Org. Chem. 2006, 1185–1192.
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Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730–4743.
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6. Schwink, L.; Vettel, S.; Knochel, P. Organometallics 1995, 14, 5000–5001.
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B. J. Am. Chem. Soc. 1981, 103, 6237–6240; (b) MacKay, J. A.; Vedejs, E. J. Org.
Chem. 2004, 69, 6934–6937; (c) Okhuma, T.; Koizumi, M.; Doucet, H.; Pham, T.;
Kosawa, M.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1998, 120, 13529–13530.
8. (a) Steinreiber, A.; Edeger, K.; Mayer, S. F.; Faber, K. Tetrahedron: Asymmetry
2001, 12, 2067–2071; (b) Danda, H.; Furukawa, Y.; Umemura, T. Synlett 1991,
441–442; (c) Takano, S.; Suzuki, M.; Ogasawara, K. Tetrahedron: Asymmetry
1993, 4, 1043–1046; (d) Va¨nttinen, E.; Kanerva, L. T. Tetrahedron: Asymmetry
1995, 6, 1779–1786; (e) Steinreiber, A.; Stadler, A.; Mayer, S. F.; Faber, K.; Kappe,
C. O. Tetrahedron Lett. 2001, 42, 6283–6286; (f) Wallner, A.; Mang, H.; Glueck, S.
M.; Steinreiber, A.; Mayer, S. F.; Faber, K. Tetrahedron: Asymmetry 2003, 14,
2427–2432; (g) Bouzemi, N.; Aribi-Zouioueche, L.; Fiaud, J.-C. Tetrahedron:
Asymmetry 2006, 17, 797–800.
4.10.1.1. Methyl 3-(cyclohex-1-enyl)butanoate 2b.
1
9
O
10
O
2
11
3
8
4
5
7
6
1H NMR (250 MHz, CDCl3):
(m, 4H6 7), 1.90–2.05 (m, 4H5
d
¼1.05 (d, J¼7 Hz, 3H1), 1.52–1.64
8), 2.20–2.27 (dd, J¼5 and
and
and
13 Hz, 2H9), 2.4 (m, 1H2), 3.67 (s, 3H11), 5.45 (s, 1H4). 13C NMR
(62.5 MHz, CDCl3):
d¼19.2 (C1); 23.0 (C7), 25.2 (C6), 25.5 (C5), 25.8
(C8), 37.8 (C2), 40.4 (C9), 51.4 (C11), 120.7 (C4), 140.5 (C3), 173.5 (C10).
HRMS calcd for C11H1802: 182.1307, found: 182.1311.
9. (a) Fiaud, J.-C.; Gil, R.; Legros, J.-Y.; Aribi-Zouioueche, L.; Konig, W. A. Tetrahe-
dron Lett. 1992, 33, 6967–6970; (b) Gutman, A. L.; Brenner, D.; Boltanski, A.
Tetrahedron: Asymmetry 1993, 4, 839–844.
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Wiley & Sons: New York, NY, 1988; Vol. 18, pp 249–330.
4.10.1.2. Methyl 2-(2-ethylidenecyclohexyl) acetate 6b.
1
2
3
11. Trost, B. M.; Lautens, M. Tetrahedron 1987, 43, 4817–4840.
O
10
O
8
9
4
5
11
12. Cherng, Y.-J.; Fang, J.-M.; Lu, T.-J. J. Org. Chem. 1999, 64, 3207–3212.
13. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamun, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765–5780.
7
6