Enantioselective 1,4-conjugate addition of diethylzinc to (E)-alkenyl aryl ketones catalysed by Cu/DiPPAM complex

Article abstract of DOI:10.1016/j.tet.2011.05.011

We report here the use of the DiPPAM-L1 ligand for copper-catalysed asymmetric conjugate addition (ACA) of diethylzinc to various (E)-alkenyl aryl ketones where the aryl ring is either a phenyl group substituted by nitro, chloro or methoxy groups or not s

Full text of DOI:10.1016/j.tet.2011.05.011

Tetrahedron 68 (2012) 3507e3511
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Tetrahedron
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Enantioselective 1,4-conjugate addition of diethylzinc to (E)-alkenyl aryl ketones
catalysed by Cu/DiPPAM complex
,
,
b
a
,
b
,
a,b,
*
Magaly Magrez a b, Joanna Wencel-Delord a , Christophe Crevisy
, Marc Mauduit
*
ꢀ
a
ꢀ
ꢀ ꢀ
Ecole Nationale Superieure de Chimie de Rennes, CNRS, UMR 6226, avenue du General Leclerc, CS 50837, 35708 Rennes Cedex 7, France
Universite europeenne de Bretagne, 35000 Rennes, France
b
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the use of the DiPPAM-L1 ligand for copper-catalysed asymmetric conjugate addition
(ACA) of diethylzinc to various (E)-alkenyl aryl ketones where the aryl ring is either a phenyl group
substituted by nitro, chloro or methoxy groups or not substituted, or a naphthyl group. When the
conjugate addition was performed in the greener AcOEt solvent with 1 or 2 mol % of Cu(OTf)2/DiPPAM
complex, moderate to good yields (45e83%) and high enantioselectivities (up to 98%) were reached.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 4 March 2011
Received in revised form 21 April 2011
Accepted 3 May 2011
Available online 10 May 2011
Keywords:
Asymmetric catalysis
Copper
Conjugate addition
DiPPAM ligand
Alkenyl aryl ketones
1. Introduction
has developed a new chiral ligand L1, called DiPPAM (or DiPhe-
nylPhosphinoAzoMethinylate salts), structurally related to Hovey-
Among chiral ligands, the Schiff-base family is probably the
most useful and accessible chiral scaffold used to promote enan-
tioselective inductions in many metal-catalysed transformations.1
Indeed, their simple access (in one or few steps) from a wide
range of chiral amines and/or chiral aldehydes and ketones makes
them really attractive for the chemists. Historically, the first enan-
tioselective induction promoted by a chiral organometallic complex
was originally proposed by Nozaki et al. in 1966 and involved the
chiral Schiff-base copper complex 1 for the cyclopropanation of
styrene2 (Fig. 1). Since these pioneering works, Schiff-base ligands
have been intensively studied through many structural modifica-
tions enabling to promote excellent enantioselections in various
organometallic reactions.1 Among all these modifications, the in-
troduction of a peptidic moiety, originally disclosed by Inoue’s
group in 1992,3 allowed to access to a really efficient class of chiral
ligands. Important breakthroughs were achieved in this direction
notably by Hoveyda’s group with their well-known small-peptide
ligands,4 which allowed remarkable enantioselectivities in many
CeC bond-forming reactions, including notably the copper-cata-
lysed Asymmetric Conjugate Addition (ACA).5 Recently, our group
da’s ligands. Advantageously, it is synthesized in
quantitative step of direct condensation of o-diphenylphosphino-
benzaldehyde and the carboxylate sodium salt of ( )-tert-leucine. It
shows excellent stability in storage, probably owing to the car-
boxylate function.6 DiPPAM-L1 proved its efficiency in both 1,4-Cu/
ACA7 and Palladium-catalysed Tsuji-Trost8 reactions.
Very recently, excellent regio- and enantioselectivities (up to
99%) were observed in the more challenging copper-catalysed 1,6-
addition of diorganozinc reagents to cyclic dienones.9 We decided
to extend the scope of DiPPAM-L1 in 1,4-ACA through its evaluation
in the Cu-catalysed addition of diethylzinc to (E)-alkenyl aryl ke-
tones 2 substituted by nitro, chloro or methoxy groups, that could
afford interesting new chiral building-blocks,10 and we report here
our results.
a single
L
2. Results and discussion
We evaluated first the influence of the copper source (Cu(I)
versus Cu(II)) and also the effect of the solvent media (THF vs
AcOEt) on the enantioselection of the addition of diethylzinc to
standard acyclic enones 3 and 5 (Table 1). Although no significant
difference in reactivity occurred when copper(I) triflate was used in
both solvents, we were delighted to observe a higher enantiose-
lection (96%) for the adduct 4 when the addition was performed in
the greener AcOEt solvent11 (entries 1 and 2). When copper(II)
* Corresponding authors. Tel.: þ33 2 23 23 81 12; fax: þ33 2 23 23 81 08; e-mail
ꢀ
addresses: christophe.crevisy@ensc-rennes.fr (C. Crevisy), marc.mauduit@en-
sc-rennes.fr (M. Mauduit).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.011

3508
M. Magrez et al. / Tetrahedron 68 (2012) 3507e3511
Br
Br
F
P
N
O
N
O
OH
N
Ph
Ph
Ph
Cu
OH
N
O
P
N
O
Ph
Ph
Ph
O
O
NH
N
O
O
NH
Ph
OtBu
N
ONa
1
NHnBu
OMe
(1996)
Nozaki/Noyori (1966)
Inoue (1992)
(2001)
DiPPAM-L1
Hoveyda's
small peptide ligands
Fig. 1. Selected chiral Schiff-base ligands.
Table 2
Table 1
Optimisation of reaction conditions for ACA of Et2Zn to (E)-1-phenylbuten-2-en-1-
one 2a catalysed by Cu(OTf)2/DiPPAM-L1
Influence of the copper source and solvent for ACA of Et2Zn to (E)-alkenyl methyl
ketones 3 and 5 involving DiPPAM-L1
O
O
Cu(OTf)2/L1 (1/1)
HCl 1N
15 min.
O
O
O
Cu/L1
(S)
(R)
or
(S)
R1
Et2Zn (3 equiv.)
AcOEt, temperature
Et2Zn (3 equiv.)
Solvent, rt
2a
7a
3 R1 = nPent
5 R1 = Ph
4
6
Entry Cu(OTf)2/L1 (mol %) Temp (ꢀC) Time (h) conv.a/yieldc (%) eeb (%)
1
2
3
4
2
2
2
1
1
2
2
20
0
0.45
1
2
3.5
4
1
>99/51
>99/61
>99
>99/41
>99/73
>99/68
>99/67
83
96
Entry Substrate Cu/L1 (ratio,a mol %)
Solvent Time (h) Conv.b (%) eec (%)
ꢁ18
89
83.5
86
93
90
1
2
3
4
5
6
7
3
5
(CuOTf)2-Tol/L1 (2/1, 1) THF
(CuOTf)2-Tol/L1 (2/1, 1) AcOEt
4
4
20
1
14
6
1
97
80
96
82
97
83
98
0
>99
>99
>99
57
5
ꢁ18
0
0
6d
7e
Cu(OTf)2/L1 (1/1, 2)
Cu(OTf)2/L1 (1/1, 2)
THF
AcOEt
1
(CuOTf)2-Tol/L1 (2/1, 1) THF
(CuOTf)2-Tol/L1 (2/1, 2) AcOEt
The italic values represents the best result in term of enantioselectivity.
>99
a
Determined by 1H NMR.
Cu(OTf)2/L1 (1/1, 2)
AcOEt
>99 (71)d 99
b
Determined by chiral GC (average of two experiments).
Isolated yield after purification by SiO2 chromatography.
HCl 1 N 30 min.
c
The italic values represents the best result in term of enantioselectivity.
a
d
Ratio between metal Copper and L1.
b
Determined by 1H NMR.
e
NH4Cl solid 1 h.
c
Determined by chiral GC (average of two experiments).
Isolated yield after purification by SiO2 chromatography.
d
worth highlighting that the selectivity for adduct 7a obtained here
(96%) is close to the best reported result in the literature so far (95%
ee),12 attesting the attractive capacity of the Cu/DiPPAM complex to
produce highly enantioenriched 1,4-adducts.
triflate was used in AcOEt, both reactivity and enantioselectivity
were improved, the adduct 4 being obtained in complete conver-
sion after only 1 h (vs 20 h in THF) and 97% ee (entries 3 and 4).
Concerning the acyclic enone 5, AcOEt proved also to be superior in
term of ee (98% vs 83% in THF), while copper(II) salts allowed us to
reduce the reaction time to 1 h (vs 6 h with Cu-(I) triflate). The
adduct 6 could be isolated in 71% yield when the reaction was run
in AcOEt in the presence of Cu(OTf)2/DiPPAM-L1. Therefore, these
conditions appeared to us as the most efficient for the 1,4-addition
of acyclic enone substrates.
These two crucial parameters being studied, we started the
evaluation of (E)-alkenyl aryl ketones 2. Different reaction condi-
tions (temperature, catalyst loading and reaction time) were tested
using (E)-1-phenylbuten-2-en-1-one 2a as model substrate. As
depicted in Table 2, the adduct 7a was isolated in 61% of yield and
an excellent enantioselectivity of 96% when the reaction was run at
0 ꢀC in presence of 2 mol % of copper/DiPPAM-L1 (entry 2). The
decrease of the temperature of the media down to ꢁ18 ꢀC led to
reduce the rate of the addition without any improvement of the
selectivity (89% ee, entry 3). When catalyst loading was diminished
to 1 mol %, the catalytic system remained active even at ꢁ18 or 0 ꢀC
(total conversion after 4 h, entries 4 and 5) but the adduct 7a was
obtained with lower enantiomeric excesses (83.5 and 86%, re-
spectively). Finally, in order to improve the isolated yield of 7a, we
tried to modify the work-up procedure either by increasing the
time of the acidic hydrolysis (30 vs 15 min) or by replacing aqueous
HCl with solid NH4Cl. Curiously, although better-isolated yields
were reached as expected, the enantioselectivity was slightly di-
minished down to 93 and 90%, respectively (entries 6 and 7). It is
After having validated the suitability of our catalytic system
towards the model substrate 2a, we were interested in extending
the scope to other (E)-alkenyl aryl ketones 2bee bearing different
substituents on the aryl moiety, in order to evaluate their influence
on the selectivity of the addition. Such structureereactivity re-
lationship had never been examined previously. We started with
the addition of diethylzinc to the aryl ketone 2b where the aromatic
group is substituted by a 4-NO2 function (Table 3). As expected, the
electronic withdrawing effect of the nitro improved the reactivity of
the enone leading to a completion of the addition within 1 h even at
ꢁ18 ꢀC in presence of 1 mol % of Cu/DiPPAM-L1 complex. In these
conditions, the corresponding adduct 7b was isolated in 57% of
yield and an enantioselectivity ranged between 83 and 86% (entries
1 and 2). Both reaction time and chiral induction were significantly
improved by using 2 mol % of catalyst at ꢁ18 ꢀC, affording the de-
sired 1,4-adduct in 65% yield and 95% ee (entry 3). It must be no-
ticed that the isolated yield could be improved by employing
4 mol % of chiral complex (79%, entry 4). We suspect that a pre-
mature degradation of the catalytic species could occur during this
addition. Excellent results were obtained with the aryl ketones 2c
bearing a chlorine atom in para position (entries 5 and 6). Within
1 h at ꢁ18 ꢀC in presence of 2 mol % of catalyst, the corresponding
1,4-adduct 7c was isolated in 78% yield with an enantio-induction
of 98%. In the case of 4-methoxy substituted aryl ketones 2d, the
electron-donating effect of the methoxy group decreased the rate of
the addition of the organozinc, as 6 h of reaction were required to

M. Magrez et al. / Tetrahedron 68 (2012) 3507e3511
3509
Table 3
astonished by this lack of selectivity as excellent ee’s (95e99%)
were reached with enones 2a and 4 bearing a phenyl group at the
1- or 4-position, respectively (Tables 1 and 2). This last result shows
clearly that it is really difficult to predict the enantioselective in-
duction of any chiral ligand in asymmetric catalysis even for the
same class of substrates. Some theoretical calculations need to be
achieved to rationalize the selectivity of our Cu/DiPPAM-L1 cata-
lytic system in ACA of acyclic enones.
Finally, we decided to complete the screening of (E)-alkenyl aryl
ketones by the substrate 10 bearing an aliphatic pentyl chain instead
of the methylone (Table 5). We observeda significant decrease of the
addition rate in comparison with the crotyl aryl ketone 2a under the
same conditions (ꢁ18 ꢀC and 2 mol % of copper complex; 18 h vs
2 h). However, adduct 11 was isolated in very good yield and ee
(65 and 94%, respectively). This last result is really close to the best
enantioselectivity reported in the literature for 11 (97% ee).13
ACA of Et2Zn to various substituted (E)-alkenyl aryl ketones 2b-2e catalysed by
Cu(OTf)2/DiPPAM-L1
O
Cu(OTf)2/L1 (1/1)
HCl 1N
30 min.
O
Ar
Ar
Et2Zn (3 equiv.)
AcOEt, temperature
*
2b Ar = 4-NO2C6H4
2c Ar = 4-ClC6H4
2d Ar = 4-MeOC6H4
2e Ar = 2-Naptyl
7b-e
Entry
2
Cu(OTf)2/L1 (mol %) Temp (ꢀC) Time (h) conv.a/yieldc (%) eeb (%)
1d
2d
3
2b
1
1
2
4
2
2
2
1
1
2
2
0
ꢁ18
ꢁ18
ꢁ18
0
ꢁ18
ꢁ18
0
0.45
1
0.15
0.1
0.45
1
>99/56
>99/57
>99/65
>99/79
>99/83
>99/78
>99/63
>99/83
>99/44
>99/66
>99/73
83
86
95
96
88
98
>97
89
94
96
4
5d
6
2c
7d
8
2d
2e
6
3.5
Table 5
ACA of Et2Zn to (E)-alkenyl aryl ketone 10 catalysed by Cu(OTf)2/DiPPAM-L1
9
10
11
ꢁ18
18
1
O
O
Cu(OTf)2/L1 (1/1)
HCl 1N
15 min.
0
ꢁ18
2.5
96
*
Et2Zn (3 equiv.)
AcOEt, temperature
The italic values represents the best result in term of enantioselectivity.
10
11
a
Determined by 1H NMR.
b
Determined by chiral GC for 2b and 2c and by chiral HPLC for 2d and 2e (average
Entry Cu(OTf)2/L1 (mol %) Temp (ꢀC) Time (h) conv.a/yieldc (%) eeb (%)
of two experiments).
c
Isolated yield after purification by SiO2 chromatography.
HCl 1 N 15 min.
1
2
ꢁ18
18
>99/65
94
d
Determined by 1H NMR.
a
b
c
Determined by chiral HPLC (average of two experiments).
Isolated yield after purification by SiO2 chromatography.
reach a full conversion at ꢁ18 ꢀC (entry 7). However, the desired
adduct was isolated in 63% of yield and an enantiomeric excess of
>97%. The last substrate of this series was (E)-1-(2-naphthyl)buten-
2-en-1-one 2e. As showed in the entries 8 and 9, at 1 mol % of
catalyst loading, a decrease of temperature led to an improvement
of the ee (94 vs 89%) along with a significant drop of the isolated
yield (44 vs 83%). Nevertheless, at higher catalyst loading (2 mol %),
the reaction time, the yield and the selectivity could be improved
(2 h 30 min, 76% and 96% ee, entry 11).
We then decided to extend further the scope by evaluating the
well-known chalcone 8, which has been intensively studied with
many chiral ligands. Although some of them were able to promote
the addition of diethylzinc with excellent enantioselectivities (up to
>98%),12,13 our Cu/DiPPAM-L1 catalyst met some difficulties to
achieve this simple addition both in terms of reactivity and chiral
induction (Table 4). Indeed, the best result (77% ee, 45% yield, entry
2) was observed when the reaction was run 4 h at 0 ꢀC with 2 mol %
of catalyst. Either lengthening the reaction time, or decreasing
temperature to ꢁ18 ꢀC or increasing the catalyst loading to 4 mol %
did not allow us to improve the results (entries 1, 3 and 4). We were
3. Conclusion
In summary, we have successfully extended the application
of our Cu/DiPPAM-L1 catalytic system to the 1,4-addition of
diethylzinc to various (E)-alkenyl aryl ketones, as moderate to
good yields and excellent ee values up to 98% were obtained.
The evaluation of the Cu/DiPPAM-L1 catalytic system to the
more challenging 1,6-ACA on (E,E)-dienyl aryl ketones is cur-
rently underway in our group and the results will be published
in the future.
4. Experimental
4.1. General information
1H (400 MHz), 13C (100 MHz), NMR spectra were recorded on
a Bruker ARX400 spectrometer with complete proton decoupling
for nucleus other than 1H. Chemical shifts are reported in parts per
million with the solvent resonance as the internal standard (CDCl3,
Table 4
1H:
d d 77.00 ppm). Data are reported as follows:
7.26 ppm, 13C:
ACA of Et2Zn to chalcone 8 catalysed by Cu(OTf)2/DiPPAM-L1
chemical shift [
d
in ppm, multiplicity (s¼singlet, d¼doublet,
O
O
Cu(OTf)2/L1 (1/1)
HCl 1N
15 min.
t¼triplet, m¼multiplet), coupling constants (Hz), integration and
attribution]. Optical rotations were recorded using a polarimeter
PerkineElmer 341. High resolution mass spectroscopy analyses
(S)
Et2Zn (3 equiv.)
AcOEt, temperature
9
8
ꢀ
were performed at the Centre Regional de Mesures Physiques de
ꢀ
l’Ouest (CRMPO), Universite de Rennes 1.
Entry Cu(OTf)2/L1 (mol %) Temp (ꢀC) Time (h) conv.a/yieldc (%) eeb (%)
All non-aqueous reactions were performed under an argon at-
mosphere using oven-dried glassware. Et2Zn 1 M solution in hex-
anes was purchased from AldrichÒ. Ethyl acetate was distilled from
calcium hydride under argon. Tetrahydrofuran was desiccated on
drying column under nitrogen. Copper complexes and solvents
were obtained from commercial sources and used without further
purification. All (E,E)-dienyl aryl ketones were synthesized via
a Wittig reaction according the literature procedures.17
1
2
3
4
2
2
2
4
20
0
5
4
20
20
>99/42
90/45
95/29
73
76.5
77
ꢁ18
ꢁ18
>99/36
74
The italic values represents the best result in term of enantioselectivity.
a
Determined by 1H NMR.
Determined by chiral HPLC (average of two experiments).
Isolated yield after purification by SiO2 chromatography.
b
c

3510
M. Magrez et al. / Tetrahedron 68 (2012) 3507e3511
4.2. General procedure for the Cu-catalysed ACA of enone
with Et2Zn
CH2CH3), 1.33e1.22 (m, 1H, CH2CH3), 0.95 (d, J¼6.4 Hz, 3H, CH3CH),
0.92 (t, J¼6.8 Hz, 3H, CH3CH2); 13C NMR:
d 199.2 (CO), 139.2 (Car),
135.7 (Car), 129.5 (2 CHar), 128.8 (2 CHar), 45.5 (CH2CO), 31.4
A flame-dried Schlenk tube was charged with copper source
(1e4 mol %) and ligand (1e4 mol %). Next, 3 mL of ethyl acetate
was added and the resulting green mixture was stirred at room
temperature for 15 min, after which Et2Zn (3 mmol) was added
dropwise. Finally, acyclic enone (1 mmol, 1 equiv) was added at
required temperature. The resulting brown solution was
allowed to stir at the required temperature for 0.1e20 h and the
reaction was quenched by the addition of 5e8 mL of a 1 N HCl
solution. The product was extracted with AcOEt. The organic
phase was washed with a saturated NaHCO3 solution and brine,
dried over MgSO4, filtrated and concentrated under vacuo. The
product was purified by silica gel column chromatography
(pentane/Et2O).
(CHCH3), 29.7 (CH2CH3), 19.5 (CH3CH), 11.4 (CH3CH2). The ee was
determined by chiral GC: Capillary column Chiraldex GTA (0.12 mm,
30 m, 0.25 mm), pression 105 kPa, total He flow 50 mL/min; 85 ꢀC
(140 min)e0.2 ꢀC/mine120 ꢀCe10 ꢀC/mine160 ꢀC (8 min); tR (1)¼
261.8 min, tR (2)¼263.5 min. [
a
]
D20
þ9.1 (c 1.5, Et2O, ee¼98%).
HRMS: [MþNa]þ (C12H15O3ClNa) calcd 233.07091; found 233.0708
(0 ppm).
4.3.6. Compound 7d: 1-(4-methoxyphenyl)-3-methylpentan-1-one.-
Yellow oil. 1H NMR (CDCl3):
d 7.96e7.92 (m, 2H, Har), 6.95e6.91
(m, 2H, Har), 3.87 (s, 3H, OCH3), 2.89 (dd, J¼15.4, 5.7 Hz, 1H, CH2CO),
2.68 (dd, J¼15.4, 8 Hz, 1H, CH2CO), 2.13e2.01 (m, 1H, CHCH3),
1.48e1.37 (m, 1H, CH2CH3), 1.32e1.21 (m, 1H, CH2CH3), 0.94 (d,
J¼6.8 Hz, 3H, CH3CH), 0.92 (t, J¼7.2 Hz, 3H, CH3CH2); 13C NMR:
4.3. Analytical data
d 199.2 (CO), 163.3 (Car), 130.6 (Car), 130.4 (2 CHar), 113.6 (2 CHar),
55.4 (OCH3), 45.3 (CH2CO), 31.6 (CHCH3), 29.7 (CH2CH3), 19.5
(CH3CH), 11.4 (CH3CH2). The ee was determined by chiral HPLC: two
4.3.1. Compound 4: 4-ethylnonan-2-one. The ee was determined by
chiral GC: Capillary column Chiraldex GTA (0.12
m
m, 30 m,
OD-H columns; n-hexane/i-PrOH: 99.9/0.1; flow: 0.5 mL minꢁ1
;
0.25 mm), pression 104 kPa, total He flow 9.9 mL/min; 80 ꢀC
(60 min)e2 ꢀC/mine100 ꢀCe10 ꢀC/mine160 ꢀC (5 min); tR (R)¼
254 nm; tR (1): 220.63 min, tR (2) 234.7 min. [
a
]
þ16.7 (c 1.5,
D20
Et2O, ee >97%). HRMS: [MþNa]þ (C13H18O2Na) calcd 229.12045;
44.4 min, tR (S)¼47.6 min. [
a
]
D20
þ2.4 (c 2.3, CHCl3, ee¼97%) {lit.
found 229.1204 (0 ppm).
þ2.7 (c 2.3, CHCl3, ee¼90%, (R) enantiomer)16}.
D20
[
a]
4.3.7. Compound 7e: 1-(2-naphthyl)-3-methylpentan-1-one. Yellow
4.3.2. Compound 6: 4-phenylhexan-2-one. The ee was determined
oil. 1H NMR (CDCl3):
d 8.46 (s, 1H, CHar), 8.05e7.87 (m, 4H, CHar),
by chiral GC: Capillary column Chiraldex GTA (0.12
m
m, 30 m,
7.62e7.53 (m, 2H, CHar), 3.08 (dd, J¼15.6, 5.7 Hz, 1H, CH2CO), 2.88
(dd, J¼15.6, 7.9 Hz, 1H, CH2CO), 2.22e2.10 (m, 1H, CHCH3),
1.54e1.43 (m, 1H, CH2CH3), 1.38e1.27 (m, 1H, CH2CH3), 1.00 (d,
J¼6.8 Hz, 3H, CH3CH), 0.96 (t, J¼7.6 Hz, 3H, CH3CH2); 13C NMR:
0.25 mm), pression 108 kPa, total He flow 9.7 mL/min; 90 ꢀC
(85 min)e2 ꢀC/mine120 ꢀCe10 ꢀC/mine160 ꢀC (5 min); tR (R)¼
83.5 min, tR (S)¼86.9 min. [
a]
þ30.6 (c 1, EtOH, ee¼99%) {lit.
D20
[
a]
þ27 (c 1.32, EtOH, ee¼81%, (S) enantiomer)16}.
d 200.5 (CO), 135.5 (Car), 134.8 (Car), 132.5 (Car), 129.6 (CHar), 129.5
D20
(CHar), 128.4 (CHar), 128.3 (CHar), 127.7 (CHar), 126.7 (CHar), 124.0
(CHar), 45.6 (CH2CO), 31.6 (CHCH3), 29.7 (CH2CH3), 19.6 (CH3CH),
11.5 (CH3CH2). The ee was determined by chiral HPLC: OD-H col-
umn; n-hexane/i-PrOH: 99.9/0.1; 0.8 mL minꢁ1; 254 nm; tR (1)¼
4.3.3. Compound 7a: 1-phenyl-3-methyl pentan-1-one. Colourless
oil. 1H NMR (CDCl3):
7.97e7.93 (m, 2H, Har), 7.58e7.52 (m,1H, Har),
d
7.48e7.43 (m, 2H, Har), 2.95 (dd, J¼15.6, 5.6 Hz, 1H, CH2CO), 2.74
(dd, J¼15.6, 7.8 Hz, 1H, CH2CO), 2.15e2.03 (m, 1H, CH), 1.49e1.38
(m, 1H, CH2CH3), 1.33e1.22 (m, 1H, CH2CH3), 0.95 (d, J¼6.4 Hz, 3H,
84.4 min, tR (2)¼93.7 min. [
a
]
D20
þ22.1 (c 1.5, Et2O, ee¼94%). HRMS:
[MþNa]þ (C16H18ONa) calcd 249.12554; found 249.1256 (0 ppm).
CH3CH), 0.93 (t, J¼7.6 Hz, 3H, CH3CH2); 13C NMR:
d 200.5 (CO), 137.4
(Car), 132.8 (CHar), 128.5 (2 CHar), 128.1 (2 CHar), 45.6 (CH2CO), 31.4
4.3.8. Compound 9: 1,3-diphenylpentan-2-one. The ee was de-
termined by chiral HPLC: OD-H column; n-hexane/i-PrOH: 99.75/
0.25; flow: 1 mL minꢁ1; 254 nm; tR (S): 25.1 min, tR (R): 30.5 min.
(CH), 29.7 (CH2CH3), 19.5 (CH3CH), 11.4 (CH3CH2). The ee was de-
termined by chiral GC: Capillary column Chiraldex GTA (0.12 mm,
30 m, 0.25 mm), pression 105 kPa, total He flow 50 mL/min; 70 ꢀC
(30 min)e0.2 ꢀC/mine100 ꢀCe10 ꢀC/mine160 ꢀC (3 min); tR (1)¼
[
a
]
þ4.1 (c 1.52, EtOH, ee¼77%, S enantiomer) {lit. [
a
]
þ7.3 (c
D20
D20
1.52, EtOH, ee¼86%, (S) enantiomer)14}. [
a]
þ1.14 (c 1.93, CHCl3,
D20
151.4 min, tR (2)¼153.4 min. [
a]
þ17 (c 1.5, Et2O, ee¼96%, (S)
ee¼77%, S enantiomer) {lit. [
a
]
þ1.83 (c 1.93, CHCl3, ee¼98%, (S)
D20
D20
enantiomer) {lit. [
a
]
ꢁ15 (c 1.5, Et2O, ee¼93%, (R) enantiomer)15}.
enantiomer)13}.
D20
4.3.4. Compound 7b: 1-(4-nitrophenyl)-3-methylpentan-1-one. Yellow
oil. 1H NMR (CDCl3):
8.32e8.28 (m, 2H, Har), 8.11e8.07 (m, 2H,
4.3.9. Compound 11: 3-ethyl-1-phenyloctan-1-one. The ee was de-
termined by chiral HPLC: OD-H column; n-hexane/i-PrOH: 99.95/
0.05; flow: 1 mL minꢁ1; 254 nm; tR (1): 23.0 min, tR (2) 24.4 min.
d
Har), 2.99 (dd, J¼16.4, 5.6 Hz, 1H, CH2CO), 2.79 (dd, J¼16.1, 7.9 Hz,
1H, CH2CO), 2.15e2.02 (m, 1H, CHCH3), 1.49e1.38 (m, 1H, CH2CH3),
1.35e1.23 (m, 1H, CH2CH3), 0.96 (d, J¼6.4 Hz, 3H, CH3CH), 0.93 (t,
D20
D20
]
[a
]
þ2.3 (c 1.6, EtOH, ee¼94%) {lit. [
a
þ1.7 (c 1.6, EtOH,
ee¼62%)16}.
J¼7.5 Hz, 3H, CH3CH2); 13C NMR:
d 198.7 (CO), 150.1 (Car), 141.7
(Car), 129.0 (2 CHar), 123.7 (2 CHar), 46.0 (CH2CO), 31.1 (CHCH3),
29.5 (CH2CH3), 19.4 (CH3CH), 11.3 (CH3CH2). The ee was deter-
Acknowledgements
mined by chiral GC: Capillary column Chiraldex GTA (0.12
mm,
30 m, 0.25 mm), pression 100 kPa, total He flow 50 mL/min; 90 ꢀC
(40 min)e0.2 ꢀC/mine150 ꢀCe10 ꢀC/mine160 ꢀC (3 min); tR (1)¼
ꢁ
This work was supported by the CNRS, the Ministere de la
Recherche et de la Technologie (grant to M.M and J.W.-D.) and by
324.5 min, tR (2)¼326.1 min. [
a
]
þ19.6 (c 1.5, Et2O, ee¼95%).
D20
ꢀ
ꢀ
the Universite europeenne de Bretagne (grant to J.W.-D.).
HRMS: [MþNa]þ (C12H15NO3Na) calcd 244.09496; found 244.0948
(1 ppm).
4.3.5. Compound 7c: 1-(4-chlorophenyl)-3-methylpentan-1-one. -
Supplementary data
White solid. 1H NMR (CDCl3):
d 7.91e7.87 (m, 2H, Har), 7.45e7.41 (m,
2H, Har), 2.91 (dd, J¼15.6, 5.7 Hz, 1H, CH2CO), 2.71 (dd, J¼15.6,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.011.
8.0 Hz, 1H, CH2CO), 2.13e2.01 (m, 1H, CHCH3), 1.47e1.37 (m, 1H,

M. Magrez et al. / Tetrahedron 68 (2012) 3507e3511
3511
Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108,
2796e2823; (f) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnard, A. J.;
Feringa, B. L. Chem. Rev. 2008, 108, 2824e2852.
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