Enantiodivergence in alkylation of 1-(6-methoxynaphth-2-yl)ethyl acetate by potassium dimethyl malonate catalyzed by chiral palladium-DUPHOS complex

Article abstract of DOI:10.1016/j.tetasy.2010.06.004

Alkylation of racemic 1-(6-methoxynaphth-2-yl)ethyl acetate by potassium dimethyl malonate catalyzed by a chiral palladium-DUPHOS complex afforded the substitution product with 87% ee, along with 6-methoxy-2-vinylnaphthalene that arose from an elimination process, in a 43/57 substitution/elimination ratio. The reaction performed on a mixture of quasi-enantiomeric substrates provided insight into the stereochemical course of the reaction, establishing that-for a given enantiomer of the catalyst, one enantiomer of the substrate afforded mainly the substitution product whereas the other enantiomer underwent elimination.

Full text of DOI:10.1016/j.tetasy.2010.06.004

Tetrahedron: Asymmetry 21 (2010) 1701–1708
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiodivergence in alkylation of 1-(6-methoxynaphth-2-yl)ethyl acetate
by potassium dimethyl malonate catalyzed by chiral palladium-DUPHOS
complex
Martine Assié a, Abdelkrim Meddour b, Jean-Claude Fiaud a, Jean-Yves Legros a,
*
a Laboratoire de Catalyse Moléculaire, ICMMO, Université de Paris-Sud, 91405 Orsay cedex, France
b Laboratoire de RMN en milieu orienté, ICMMO, Université de 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:
Alkylation of racemic 1-(6-methoxynaphth-2-yl)ethyl acetate by potassium dimethyl malonate catalyzed
by a chiral palladium-DUPHOS complex afforded the substitution product with 87% ee, along with
6-methoxy-2-vinylnaphthalene that arose from an elimination process, in a 43/57 substitution/elimina-
tion ratio. The reaction performed on a mixture of quasi-enantiomeric substrates provided insight into
the stereochemical course of the reaction, establishing that—for a given enantiomer of the catalyst,
one enantiomer of the substrate afforded mainly the substitution product whereas the other enantiomer
underwent elimination.
Received 22 March 2010
Accepted 3 June 2010
Available online 10 July 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
carbonates 1.2 Both the product of nucleophilic substitution 2
and the 1,3-diene 3 as the elimination product were obtained in
Production of optically active organic compounds can be
achieved from optically active substrates (through stereoselective
reactions or transfer of chirality) from achiral substrates (asym-
metric synthesis) or from chiral racemic substrates. In this latter
case, kinetic resolution may give access to the enantiomerically en-
riched substrate, and may lead to an optically active product. The
total conversion of a racemic substrate into an optically active
product may be achieved through dynamic kinetic resolution or
parallel kinetic resolution. Interesting cases are known where—un-
der the influence of an external chiral agent (either reagent or cat-
alyst)—each enantiomer of the substrate affords regioisomers or
different products, one of them being enantioenriched (enantiodi-
vergent reactions). The chirality of the optically active reagent or
catalyst can then control the selectivities of such reactions.
For enantiodivergent chemical transformations of a racemic
mixture under the influence of external chirality (chiral reagent,
chiral catalyst) into two products, it was shown that (i) the chiral-
ity (configuration) of the reagent or the catalyst may control the
distribution of the products; (ii) a quantitative relationship may
be established between ees and relative quantities of the products;
(iii) the analysis of the product distribution allows the prediction of
the distribution of products when using an enantiomerically pure
substrate.1
moderate enantiomeric excesses. The substitution product arose
mainly from one enantiomer of the substrate while the elimination
product came from the other enantiomer (Scheme 1).
Herein we report a novel example of the analysis of the control
of the distribution and enantiomeric purity of the products formed
in a Pd-catalyzed benzylic alkylation reaction of a racemic sub-
strate by a chiral Pd-catalyst.
2. Results and discussion
2.1. The enantioselective Pd-catalyzed benzylic alkylation
In 1992, we disclosed the palladium-catalyzed benzylic alkyl-
ation of 1-naphthylethyl acetates and carbonates with malonates.3
This benzylic substitution by nucleophiles and organometals was
further developed by Kuwano.4 We investigated the stereochemis-
try of this reaction and the asymmetric synthesis of alkylated prod-
ucts5 and showed the reaction to be regio- and stereoselective
proceeding with overall retention of configuration at the benzylic
carbon center. We suggested that the reaction would take place
through the formation of
inversion of configuration, followed by a regioselective attack of
the -benzylic ligand also with inversion of configuration.
p-benzylic palladium complexes with
p
An example of such an enantiodivergent reaction has been de-
scribed for the Pd-catalyzed alkylation of racemic bicyclic allylic
Optically active alkylation products 5 could be obtained at full
conversion of the racemic substrate 4 under Pd/(S,S)-BDPP (2,4-
bis diphenyldiphosphinopentane) catalysis, albeit in low (30%) ee
(Scheme 2). Since neither the substrate nor the product racemized
under the reaction conditions, we assumed that the asymmetric
* Corresponding author.
E-mail address: jean-yves.legros@u-psud.fr (J.-Y. Legros).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.004

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M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
1) [(1-Me-allyl)PdCl]2 (2.5 mol%)
(S)-(-)-BINAP (10 mol%)
+
E
MeO2CO
NaCH(CO2Me)2 (1.5 eq.)
THF, 60 °C, 3 h
E = CO2Me
E
( )-1
3
(R)-
2
(2S,4aS)-
46%
54%
47% ee
cis : trans 93:7
cis: 65% ee
Scheme 1. Enantiodivergent Pd-catalyzed alkylation of bicyclic allylic acetates.2
two postulated diastereomeric
p-benzylic palladium complexes.
OAc
Pd(dba)2 (2.mol%)
These complexes 11 and epi-11 may interconvert (k, kꢀ1) through
an SN2 displacement of the palladium catalyst, resulting in epimer-
isation by inversion of the stereochemistry. The Pd-complexes may
react at different rates with the malonate anion to give (R)-8 and
(S)-8, the alkylation products ðk0S–kR0 Þ, or elimination product 10
ðk0S0–k0R0Þ. The data obtained (substitution/elimination ratio, enan-
tiomeric purity of the substitution product) did not allow rational-
ization of the stereochemical course of the reaction, since, for
example, the origin of the elimination product could not be
determined.
(S,S)-BDPP (2.5 mol%)
CHE2
NaCH(CO2Me)2 (1.5 eq.)
DMF, 60 °C, 48 h
( )-4
(S)-5
63%, 30% ee
Scheme 2. Enantioselective Pd-catalyzed benzylic alkylation.
induction arose from an equilibration of the diastereomeric p-ben-
zyl intermediate palladium complexes 6, through a SN2 mechanism
(Scheme 3). Such an isomerization process has been documented
2.2. The use of a quasi-enantiomer mixture as substrate
for equilibration (interconversion, epimerization) of
p-allylic Pd-
complexes.6
In order to get a deeper insight into the implication of each pro-
cess for the control of the distribution of substitution/elimination
products and the enantioselectivity of the process, we undertook
a study of the reaction performed on quasi-enantiomeric8 sub-
strates (R)-7[d3] and (S)-7. This would allow us to determine the
origin of the elimination product 10. Six compounds (S)- and (R)-
8, (S)- and (R)-8-[d3], 10, and 10-[d3] would then be produced
(products arising from decarbomethoxylation were neglected,
since they were in small amounts and with the same ee as the mal-
onate they come from) (Scheme 6). For the mechanism it was con-
PdL2*
PdL2*
[PdL2*]
[PdL2*]
epi-6
6
Scheme 3. Equilibration of
p-benzylic Pd-complexes through SN2 displacement.
sidered that (i) the
p-benzylpalladium complexes have a syn
Later on, in order to improve the enantioselectivity, we investi-
gated the role of various chiral ligands.7 The study was conducted
on the reaction of racemic 6-methoxy-1-(2-naphthylethyl) acetate
7 with potassium dimethyl malonate in DMSO in the presence of
Pd(dba)2 as the palladium source and a diphosphine as the chiral li-
gand. We found that i-Pr-DUPHOS ligand was the best compromise
in terms of distribution of products (substitution vs elimination) and
enantioselectivity for the substitution product (Scheme 4).
The substitution product 8 was obtained along with some
decarbomethoxylated compound 9 and the vinyl naphthalene 10
as the elimination product. The decarbomethoxylation of 8 into 9
was shown to proceed without loss of stereochemistry. The com-
bined isolated yield of substitution products of 8 and 9 was 31%
versus 42% for the elimination product.
stereochemistry; (ii) the discrimination of enantiomers is not so
relevant for the enantioselectivity, since a rough estimate of the ra-
tio of rate constants showed a small value for kR/kS ꢁ2; (iii) there is
no primary kinetic isotope effect since the deuterium labels are lo-
cated far from the reactive center (this point was confirmed exper-
imentally), the relative amounts c–h of these six products may be
calculated on the basis of two hypotheses.
The synthesis of (R)-7[d3] was achieved by methylation, reduc-
tion of 6-hydroxy-2-acetyl-naphthalene, followed by lipase-cata-
lyzed resolution (Scheme 7). This latter compound was obtained
from the commercially available 6-bromo-2-naphthol.
Identification of products (S)-8 and (R)-8-d3 will be the indica-
tion of the equilibration of Pd-complexes operating by a SN2 pro-
cess. Ratios for elimination of deuterated compounds versus
elimination of non-deuterated compounds (ED/END), and substitu-
tion of deuterated compounds versus/non-deuterated compounds
(SD/SND) will be indicative of diastereoselection in the elimination
process.
The stereochemical course of the reaction might be the result of
several processes, according to the mechanistic scheme depicted in
Scheme 5.
The chiral catalyst may discriminate (kS – kR) between the two
enantiomers in the oxidative addition step (ionization) to produce
OAc
CHE2
CH2E
i)
+
+
MeO
MeO
MeO
MeO
( )-7
8
9
10
24%, 87% ee (R)
7%, 87% ee (R)
42%
Scheme 4. Alkylation of ( )-7 with potassium dimethyl malonate under Pd-(R,R)-i-Pr-DUPHOS catalysis. Reagents and conditions: (i) KCH(CO2Me)2 (2 equiv), Pd(dba)2
(2 mol%), (R,R)-i-Pr-DUPHOS (2 mol%), DMSO, 70 °C, 48 h.

M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
1703
[PdL*2]
CHE2
OAc
*
KCHE2
*
[PdL*2]
Me
Me
Me
AcO
DMSO, 70 °C
kS
MeO
MeO
MeO
k'R
11
[PdL*2]
(S)-7
(R)-8
k"R
[PdL*2]
[PdL*2]
k
L* = (R,R)-i-Pr-duphos]
k-1
MeO
k"S
10
[PdL*2]
Me
OAc
CHE2
KCHE2
*
*
[PdL*]2
Me
Me
AcO
DMSO, 70 °C
kR
MeO
MeO
MeO
k'S
(R)-7
(S)-8
[PdL*2]
11
epi-
Scheme 5. Processes likely to be involved for the control of product distribution and asymmetric induction.
CHE2
[Pd/L*]
c
H3CO
H3CO
(S)-8
syn-(S)-11
KCHE2
d
e
[Pd/L*]
OAc
*
H3CO
H3CO
10
[Pd/L*]
CHE2
H3CO
H3CO
11
syn-(R)-
a
(S)-7
(R)-8
L* = (R,R)-i-Pr-DUPHOS
CHE2
*
[Pd/L*]
OAc
*
f
[Pd/L*]
D3CO
D3CO
D3CO
(S)-8-d3
10-d3
syn-(S)-11-d3
b
(R)- 7-d3
g
h
KCHE2
D3CO
D3CO
[Pd/L*]
CHE2
*
D3CO
syn-(R)-11-d3
(R)-8-d3
Scheme 6. Palladium-catalyzed alkylation of quasi-enantiomeric substrates. The 6 compounds produced and their relative molar amounts c–h.
OAc
O
iii), iv), v)
Br
i), ii)
HO
D3CO
HO
(R)-7-d3
Scheme 7. Synthesis of (R)-7-d3. Reagents and conditions: (i) Et3N, TMSCl, toluene, 99%; (ii) TlOAc (1.1 equiv), n-Bu–O–CH@CH2 (5 equiv), DMF, 80 °C, 24 h, 87%; (iii) NaH,
CD3I, THF, 55 °C, 12 h, 70%; (iv) NaBH4, MeOH, 3 h, quant; (v) isopropenyl acetate, RGLipase, 43%; (iv) Ac2O, DMAP, CH2Cl2, 68%.

1704
M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
Six independent relationships are needed to estimate the rela-
Under this hypothesis, and with a = b = 0.5, one may establish
tive amounts c–h of the 6 products.
that ED/END = g/d = [2b ꢀ s(1 + ee)]/[2a ꢀ s(1 ꢀ ee)] and SD/SND = f/
e = (1 + ee)]/(1 ꢀ ee) where s = e + f and ee = (f ꢀ e)/(e + f).
The reaction with (R,R)-i-Pr-DUPHOS afforded (R)-8 with 87% ee
(ee = ꢀ0.87) and a selectivity for substitution/elimination 43/57
(s = 0.43). Using the above equations, the relative molar portions
of the 4 products should be d = 0.10 for 10, e = 0.40 for (R)-8, and
f = 0.03 for (S)-8-d3, g = 0.47 for 10-d3.
Denoting a and b as the molar fractions of non-deuterated and
deuterated substrates, and c–h the molar fractions of the 6 prod-
ucts, the following data could be obtained:
– ED/END = g/d ratio will be obtained by GC–MS.
– SD/SND = (f + h)/(c + e) will also be obtained by GC–MS.
– The ‘quasi-enantiomeric excess’ denoted as [(c + f) ꢀ (e + h)]/
(c + e + f + h) can be measured by chiral stationary-phase HPLC.
This is positive when the (S)-substitution product is the major.
– The ee of the deuterated substitution product eeD = (f ꢀ h)/(f + h)
One would measure by GC–MS spectrometry ED/END = g/d = 4.7
and SND/SD = e/f = 13.
A selectivity substitution/elimination factor, which is character-
istic of the enantiopure ligand used in the transformation, can then
be determined for each enantiomer of the substrate: AR and AS. In
this case AR = kR sub/kR elim = f/g and AS = kS sub/kS elim = e/d.
Using molar ratios obtained for hypothesis 1, one calculates AR
<0.1 and AS = 4.
will be determined by 2H NMR in poly-
c-benzyl-L-glutamate
(PBLG) anisotropic phase,9 being positive when (S)-8-d3 is the
major enantiomer.
– The material balance for the deuterated and non-deuterated
products affords the two last needed equations: a = c + d + e
and b = f + g + h.
2.3.2. Second hypothesis
The elimination is not diastereoselective. The rate constants for
substitution and for elimination are the same whatever the config-
uration of the complexes (Scheme 9).
The resolution of this system of equations would deliver the rela-
tive amounts of products c–h.
Under this hypothesis, the origin of the asymmetric induction
would arise solely from a fast isomerization of intermediate Pd-
complexes (S)-11/(R)-11 and complexes (S)-11-d3/(R)-11-d3, which
interconvert—with the same efficiency—more rapidly than they re-
act with the nucleophile.
2.3. Two hypotheses depicting the stereochemical course of the
reaction
One may anticipate the distribution of the six products obtained
in the reaction of a 1:1 mixture of the quasi-enantiomeric sub-
strates with potassium dimethyl malonate under Pd/i-Pr-DUPHOS
catalysis. For the reaction that afforded substitution and elimina-
tion products 8 and 10 in a 43:57 ratio and 87% ee for the substi-
tution product the two following hypotheses can be made.
One may calculate the molar ratio for each product, when
a = b = 0.5, c = f = 0.015 for (S)-8-d3 and (S)-8, e = h = 0.20 for (R)-
8-d3 and (R)-8, d = g = 0.285 for 10 and 10-d3. The deuterated and
non-deuterated pathways would afford the same data when the
reaction is performed from the racemic substrate. Hence, mass
spectrometry will afford ED/END = g/d = 1 and SD/SND = f/e = 1. In fact
these values should be corrected for the real values of a and b, if
different from 0.5.
2.3.1. First hypothesis
There is no equilibration of the diastereomeric intermediate
palladium complexes (Scheme 8). This implies that:
If the intermediate Pd-complexes interconvert more rapidly than
they react with the nucleophile (Curtin–Hammett conditions), one
may calculate the equilibrium constant between the complexes to
be K = [(S)-11]/[(R)-11] = 0.1, while AR = AS = ksub/kelim = 0.8.
– The asymmetric induction arises only from a diastereoselective
elimination.
2.4. Results of the Pd-catalyzed alkylation of quasi-
enantiomeric substrates
– (R)-8 and (S)-8-d3 are the sole substitution products obtained
from the corresponding acetates with overall retention of the
configuration at the benzylic carbon atom and thus c = h = 0.
– The elimination products 10 and 10-d3 come from two separate
routes.
The reaction was actually performed on a a/b = 53/47 mixture of
quasi-enantiomers (S)-7 and (R)-7-d3. Under these conditions, a
36/64 selectivity in favor of elimination products was obtained.
[Pd/L*]
d = 0.10
OAc
*
H3CO
10
[Pd/L*]
CHE2
H3CO
H3CO
KCHE2
11
syn-(R)-
e = 0.40
(S)-7
a
H3CO
(R)-8
L* = (R,R)-i-Pr-DUPHOS
OAc
CHE2
*
[Pd/L*]
*
f = 0.03
[Pd/L*]
D3CO
D3CO
D3CO
(S)-8-d3
11
syn-(S)-d3-
KCHE2
7
(R)- -d3
b
g = 0.47
D3CO
10
-d3
Scheme 8. Hypothesis 1: predicted distribution of products upon the hypothesis that no equilibration of the
p-benzylic palladium complexes takes place.

M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
1705
CHE2
[Pd/L*]
c = 0.015
H3CO
H3CO
(S)-8
syn-(S)-11
KCHE2
[Pd/L*]
d = 0.285
e = 0.20
OAc
H3CO
10
[Pd/L*]
CHE2
H3CO
H3CO
11
syn-(R)-
a
(S)-7
H3CO
D3CO
8
(R)-
L* = (R,R)-i-Pr-DUPHOS
OAc
CHE2
[Pd/L*]
f = 0.015
[Pd/L*]
D3CO
D3CO
8
(S)- -d3
syn-(S)-11-d3
b
(R)-7-d3
g = 0.285
h = 0.20
KCHE2
D3CO
D3CO
[Pd/L*]
10
-d3
CHE2
D3CO
syn-(R)-11-d3
(R)-8-d3
Scheme 9. Second hypothesis: predicted distribution of products upon the hypothesis that for each isomer of palladium complex there is no stereoselection for the
substitution/elimination process. The asymmetric induction then arises from the equilibration of the diastereomeric -benzyl intermediate palladium complexes.
p
Chiral HPLC analysis gave a ‘quasi-enantiomeric excess’ of 86%
(ee = ꢀ0.86). The relative amount of each product was measured
through a combination of GC–MS, chiral HPLC, and chirally
oriented 2H NMR analyses (Scheme 10). This latter was performed
in PBLG/chloroform/THF liquid crystal on the diacids obtained after
hydrolysis of substitution products 8 and 8-d3.
CHE2
*
CHE2
*
g
H3CO
D3CO
H3CO
D3CO
H3CO
GLC / MS
f
8
(R)-
h
(S)-8
CHE2
*
CHE2
*
(g/d ratio)
d
D3CO
c
e
8
(R)- -d3
(S)-8-d3
(c + f)/(e + h) ratio
chiral HPLC
CHE2
CHE2
CHE2
*
CHE2
*
H3CO
H3CO
D3CO
D3CO
8
e
c
(S)- -d3
(S)-8
(R)-8
h
CHE2
*
D3CO
2H NMR
in anisotropic
medium
e
8
(S)- -d3
CHE2
*
f
8
(e/c ratio)
(R)- -d3
D3CO
c
(R)-8-d3
(c + e)/(f + h) ratio
Scheme 10. Analyses of sets of quasi-enantiomers and isotopomers.
GLC / MS

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M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
Table 1
Comparison between predicted and experimental data for the Pd/(R,R)-i-Pr-DUPHOS-catalyzed alkylation of the quasi-racemate with potassium dimethyl malonate
Product
1st Hypothesis
2nd Hypothesis
Experimental resultsc
a
b
a
b
CHE2
0
0
0.015
0.013
0.02
0.17
0.34
H3CO
H3CO
(S)-8
0.10
0.40
0.195
0.335
0.285
0.200
0.339
0.177
10
CHE2
H3CO
(R)-8
CHE2
*
0.03
0.47
0
0.025
0.445
0
0.015
0.285
0.200
0.012
0.301
0.157
<0.01
0.47
0.01
D3CO
D3CO
(S)-8-d3
10-d3
10-d3
CHE2
*
D3CO
(R)-8-d3
ED/END
SD/SND
4.7
0.07
2.3
0.07
1
1
0.9
0.9
2.8
<0.1
a
b
c
Calculated values with a quasi-enantiomeric substrate (a = b = 0.5) afforded a 43/57 substitution/elimination ratio (8/10) and ee = 87% (ee = ꢀ0.87).
Calculated values with a mixture of quasi enantiomers showing a = 0.53 and b = 0.47 afforded a 36/64 substitution/elimination ratio (8/10) and ee = 86% (ee = ꢀ0.86).
Measured values with a mixture of quasi enantiomers showing a = 0.53 and b = 0.47 afforded a 36/64 substitution/elimination ratio (8/10) and ee = 86% (ee = ꢀ0.86).
Table 1 collects the data of predicted and experimental values
The observation of small amounts of (S)-8 and (R)-8-d3 is indic-
ative of the existence of an equilibrium involving the Pd-com-
plexes. This is however a slow and poorly effective process, since
the substitution products show an overall retention of configura-
tion. The elimination process taking place from (R)-7 via syn-(S)-
for the amounts of the 6 products. It is found that the set of exper-
imental values is closer to the set expected for the first hypothesis
(no equilibration of the Pd-intermediate complexes) than to the
second one (equilibration of the Pd-intermediate complexes).
[PdL*2]
CHE2
OAc
KCHE2
*
*
[PdL*2]
Me
Me
Me
AcO
DMSO, 70 °C
kS
MeO
MeO
MeO
k'R
[PdL*2]
(S)-7
syn-(R)-11
8
(R)-
k"R
slow
[PdL*2]
k-1
k
L* = (R,R)-i-Pr-duphos]
slow
MeO
k"S
10
fast
[PdL*2]
Me
OAc
CHE2
KCHE2
*
*
[PdL*2]
Me
Me
AcO
0 °C
DMSO, 7
kR
MeO
MeO
MeO
k'S
(R)-7
syn-(S)-11
(S)-8
[PdL*2]
kR / kS ~ 2
k, k-1 << k'R and k"S
k'S / k'R ~ 18
k"R / k"S ~ 3
Scheme 11. Asymmetric induction scheme: estimated rate constant ratio values.

M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
1707
11 is highly favored over nucleophilic substitution (by a factor of
ꢁ20) since g/(f + h) = [0.46/0.02] = 23. Conversely, for the enantio-
mer (S)-7 via syn-(R)-11, substitution is favored over elimination
by a factor 2 since (c + e)/d = (0.34 + 0.02)/0.17. The measured 2.7
ratio for ED/END means that complex syn-(S)-11 undergoes faster
elimination than syn-(R)-11. This experimental ratio is closer to
the calculated value for hypothesis 1 (no equilibrium between
the palladium complexes and a diastereoselective elimination
process).
On the basis of these data, an asymmetric induction scheme can
now be depicted (Scheme 11). The complex arising from the (R)-
substrate undergoes elimination around three times faster than
the one formed from the (S)-substrate. The complex arising from
the (S)-substrate reacts with the nucleophile 18 times faster than
the one formed from the (R)-substrate.
low speed (600 rpm) bench top centrifuge, turning the tube up-
side-down between each centrifugation, in order to homogenize
the viscous mixture.
4.3. Deuterium NMR measurements in PBLG liquid crystal
2H–{1H} NMR spectra were recorded at 61.4 MHz on a Bruker
DRX-400 spectrometer equipped with a selective deuterium probe.
The temperature was held at 300 K using a BVT3000 variable tem-
perature unit. Proton broad-band decoupling was achieved using
the WALTZ-16 composite pulse sequence.
4.4. Preparation of substrates
4.4.1. (6-Bromonaphth-2-yloxy)trimethylsilane
One may conclude that the (S)-7 substrate and the (R,R)-i-Pr-
DUPHOS ligand are matched for the production of the substitution
product (R)-8. Indeed, to produce high yields of (R)-8 one has to re-
act enantiomerically pure (S)-7 with dimethylmalonate using Pd/
(R,R)-i-Pr-DUPHOS as the catalyst. Conversely, reaction of enantio-
merically enriched (>95% ee) (R)-7 with sodium dimethylmalonate
under Pd/(S,S)-i-Pr-DUPHOS catalysis will afford (S)-8 with re-
duced amounts of elimination product.
A two-necked round-bottomed flask with condenser was
charged with 6-bromo-2-naphthol (2.0 g, 9 mmol), triethylamine
(2.53 mL, 18 mmol), and dry toluene (15 mL). Trimethylsilyl
chloride (1.4 mL, 11 mmol) was added dropwise and the reaction
mixture was stirred for 2 h at reflux. After cooling to room temper-
ature, the mixture was filtered and the organic solvents were re-
moved in vacuo to give (6-bromonaphth-2-yloxy)trimethylsilane
(2.63 g, 99%) as a crude product, mp 129 °C. 1H NMR (CDCl3,
250 MHz): d 0.31 (s, 9H, 3CH3Si), 7.08 (dd, 1H, 3J = 8.5 Hz, 4J =
2.4 Hz, Ar), 7.15 (br s, 1H, Ar), 7.46 (dd, 1H, 3J = 8.5 Hz, 4J =
1.8 Hz, Ar), 7.55 (d, 1H, 3J = 8.5 Hz, Ar), 7.62 (d, 1H, 3J = 8.5 Hz,
Ar), 7.90 (1H, Ar). 13C NMR (CDCl3, 62.9 MHz): 0.38, 115.0, 117.5,
123.1, 128.4, 128.7, 129.5, 129.7, 130.4, 133.1, 153.3. VS m/z
(%): 295.9 (100.0), 293.9 (97.1), 280.8 (45.1), 278.8 (43.5), 199.9
(56.4).
3. Conclusion
In conclusion, the use of quasi-enantiomeric substrates pro-
duced a deep insight into the course of the enantiodistinctive Pd-
catalyzed alkylation reaction of naphthylethyl acetates with the di-
methyl malonate anion. For a given configuration of the catalyst,
one enantiomer of the substrate affords mainly the substitution
product whereas the other enantiomer is converted mainly into
the elimination product.
This informs the choice of the proper matched pair chiral sub-
strate/chiral catalyst in order to minimize the unwanted elimina-
tion reaction and optimize the yield and ee of the alkylation
product.
4.4.2. 6-Hydroxy-2-acetonaphthone
A DMF solution (9 mL) of Pd(OAc)2 (34 mg, 9.15 mmol), dppp (69
mg, 0.165 mmol), (6-bromonaphth-2-yloxy)trimethylsilane (888
mg, 3 mmol), and TlOAc (868 mg, 3.3 mmol) was stirred at room
temperature under argon for 0.25 h. Then, n-butyl vinyl ether
(4.85 mL, 15 mmol) in DMF (6 mL) was added. The resulting reaction
mixture was stirred at 60 °C for 24 h. After cooling to room temper-
ature, 20 mL of 3 M aqueous HCl was added and the hydrolysis was
monitored by tlc. The mixture was then neutralized with 1 M aque-
ous NaOH and extracted with ethyl acetate (3 ꢂ 20 mL). The
combined organic phases were dried (MgSO4) and concentrated.
The crude product was purified by flash chromatography (silicagel,
heptane/ethyl acetate: 85/15), to give 6-hydroxy-2-acetonaph-
thone, mp 161 °C (95% yield). 1H NMR (CDCl3, 250 MHz): d 2.70
(s, 3H, CH3–C(O)), 7.19–7.24 (m, 2H, Ar), 7.69 (d, 1H, 3J = 8.8 Hz,
Ar), 7.85 (d, 3J = 9.3 Hz, Ar), 7.97 (d, 1H, 3J = 8.8 Hz, Ar), 8.04 (br s,
1H, Ar).
4. Experimental
4.1. General
HPLC analyses were performed on a Thermo Separation Product
Pump P100 with an UV detector and chiral stationary-phase col-
umns (Chiralcel OD-H, Chiralpak IA).
1H and 13C NMR spectra were recorded on Bruker AM 360, AM
300, and AM 250 spectrometers, operating at 360, 300, and
250 MHz for 1H and at 90.6, 75, and 62.5 MHz for 13C in CDCl3.
Chemical shifts for 1H and 13C spectra were referenced internally
according to the residual solvent resonances and reported in ppm
relative to CDCl3 (7.27 ppm for 1H and 77 ppm for 13C). High reso-
lution mass spectra were measured on a Finnigan MAT 95 S spec-
trometer or at 70 eV (EI) with a Trace DSQ Thermo Electron
spectrometer.
HRMS: calcd for C12H10O2 186.0675; found: 186.0675.
4.4.3. 6-Methoxy-d3-2-acetonaphthone
An oven-dried Schlenk tube was charged with NaH (290 mg,
12.1 mmol), 6-hydroxy-2-acetonaphthone (2.045 g, 11 mmol),
and purged with argon before adding THF (24 mL). To the cooled
The Rabbit Gastric Lipase (RGL) is a crude lipase extracted
from rabbit stomach and was obtained from Sipsy-Jouveinal Com-
pany. It is a lyophilized powder showing 20 U/mg (tributyrin as
substrate).10
mixture (ice-bath) was added dropwise methyl-d3 iodide (820 lL,
13.2 mmol) and the resulting solution was stirred overnight at
55 °C. After cooling to room temperature, the solution was concen-
trated and 20 mL of aqueous ammonium chloride was added. The
mixture was extracted with ethyl acetate (3 ꢂ 20 mL) and the com-
bined organic layers were washed with aqueous saturated NaCl
solution, dried over MgSO4, and concentrated. The crude product
was purified by flash chromatography (silicagel, heptane, ethyl
acetate: 80/20) to give 6-methoxy-d3-2-acetonaphthone (1.56 g,
70%), mp 110 °C. 1H NMR (CDCl3, 250 MHz): d 2.69 (s, 3H, CH3–
C(O)), 7.13–7.22 (m, 2H, Ar), 7.76 (d, 1H, 3J = 8.5 Hz, Ar), 7.84 (d,
1H, 3J = 8.5 Hz, Ar), 8.00 (dd, 1H, 3J = 8.5 Hz and 4J = 1.8 Hz, Ar),
4.2. Liquid crystalline NMR sample preparation
PBLG (100 mg, Mol. Wt. 70.000–150.000 purchased from Sig-
ma–Aldrich) and 10 mg of the chiral deuterated solute were
weighted into a 5-mm od NMR tube. 380
12 l of THF were added. After complete dissolution of the poly-
mer, the NMR tube was repeatedly centrifuged (20 times) on a
ll of chloroform and
l

1708
M. Assié et al. / Tetrahedron: Asymmetry 21 (2010) 1701–1708
8.39 (br s, 1H, Ar). 13C NMR (CDCl3, 62.9 MHz): 26.6, 54.7 (h,
J = 21.8 Hz, OCD3), 105.8, 123.1, 119.8, 124.7, 127.2, 127.9, 130.1,
131.2, 132.7, 137.4, 159.8, 197.9.
3J = 10.9 Hz, CH2@CH), 7.09 (br s, 1H, Ar), 7.12 (dd, 1H, 3J = 8.8 Hz
and 4J = 2.5 Hz, Ar), 7.66–7.71 (m, 3H, Ar). MS (EI) m/z (%): 188.1
(12.5), 187.1 (100.0), 168.9 (23.5), 140.9 (52.9), 138.9 (10.6),
114.9 (21.9).
4.4.4. 1-(6-Methoxy-d3-naphth-2-yl)ethyl acetate
(R)-7-[d3] was prepared by RGL-catalyzed kinetic resolution of
the racemic corresponding alcohol obtained by NaBH4 reduction of
6-methoxy-d3-2-acetonaphthone. The procedure is as follows: to a
diethyl ether solution (25 mL) of racemic 1-(6-methoxy-d3-naph-
th-2-yl)ethanol (1.025 g, 5 mmol) and isopropenyl acetate (1.5 g,
15 mmol), RGL (200 mg) was added. After 24 h stirring at room tem-
perature, the reaction mixture was filtered over Celite and the or-
ganic solution was concentrated in vacuum. The crude product
was purified by flash chromatography (silica, heptane/ethyl acetate:
80/20) to give (R)-7-[d3] (531 mg, 43%) enantiomerically pure and
remaining alcohol (369 mg, 35%) with an enantiomeric excess of
37% for the (S)-configuration.
4.6.2. Dimethyl 2-[6-methoxy-d3-naphth-2-yl)ethyl]malonate 8-
d3
Isolated as a colorless oil; 1H NMR (CDCl3, 250 MHz): d 1.39 (d,
3H, 3J = 6.3 Hz, CH3–CH), 3.42 (s, 3H, OCH3), 3.56–3.76 (m, 2H,
2CH), 3.78 (s, 3H, OCH3), 7.09 (s, 1H, Ar), 7.12 (dd, 1H, 3J = 8.8 Hz,
4J = 2.5 Hz, Ar), 7.33 (dd, 1H, 3J = 8.3 Hz, 4J = 1.5 Hz, Ar), 7.59 (br s,
1H, Ar), 7.66–7.70 (m, 2H, Ar).
MS (EI) m/z (%): 319.1 (14.5), 189.1 (13.9), 188.0 (100.0).
Enantiomers of 8-d3 were analytically resolved by HPLC with a
chiral stationary-phase column Chiralcel OD-H [hexane/isopro-
panol: 99/1, 0.5 mL minꢀ1, tR = 30.5 min [(R)-enantiomer] and tS =
33.9 min [(S)-enantiomer].
A second RGL-catalyzed kinetic resolution of remaining alcohol
(ee = 37%) provided (R)-7-[d3] (123 mg) and (S)-1-(6-methoxy-d3-
naphth-2-yl)ethanol which could be obtained enantiomerically
pure after recrystallization with EtOAc/hexane.
Acknowledgments
Enantiomers of 1-(6-methoxy-d3-naphth-2-yl)ethanol and of
7-[d3] were resolved by HPLC analysis with a chiral stationary-phase
Financial support from the CNRS and the University of Paris-Sud
is gratefully. One of us (M.A.) is indebted to the French Ministère de
l’Enseignement Supérieur et de la Recherche for a Fellowship.
column Chiracel OD-H [hexane/isopropanol: 90/10, 0.5 mL minꢀ1
,
t = 17 min ((S)-enantiomer), t = 23 min ((R)-enantiomer)] and t =
10 min ((S)-enantiomer), t = 11 min ((R)-enantiomer)], respectively.
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