Chiral phosphinoazomethinylate salts as new 'one-step available' ligands for copper-catalyzed asymmetric conjugate addition

Article abstract of DOI:10.1016/j.tetasy.2008.07.011

Herein, we report the use of phosphinoazomethinylate salts as chiral efficient ligands for the copper-catalyzed asymmetric conjugate addition (ACA) of dialkylzinc to various enones. These tridentate P,N,O ligands are straightforwardly obtained in a one-step procedure from commercially available enantiopure α-aminoacids. Performing the conjugate addition in the greener AcOEt solvent, high enantioselectivities were reached for both cyclic and acyclic enones ranging between 72% to 98% ee and 96% to >99%, respectively. The 2/1 Cu/ligand ratio required to obtain high enantioselectivities, led us to envisage a copper-copper bi-metallic catalytic system for this transformation.

Full text of DOI:10.1016/j.tetasy.2008.07.011

Tetrahedron: Asymmetry 19 (2008) 1804–1809
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral phosphinoazomethinylate salts as new ‘one-step available’ ligands
for copper-catalyzed asymmetric conjugate addition
*
*
Joanna Wencel, Diane Rix, Thomas Jennequin, Stéphane Labat, Christophe Crévisy , Marc Mauduit
UMR CNRS 6226 ‘Sciences Chimiques de Rennes’, Equipe Chimie Organique et Supramoléculaire, Ecole Nationale Supérieure de Chimie de Rennes, Av. du Général Leclerc,
35700 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report the use of phosphinoazomethinylate salts as chiral efficient ligands for the copper-cat-
alyzed asymmetric conjugate addition (ACA) of dialkylzinc to various enones. These tridentate P,N,O
ligands are straightforwardly obtained in a one-step procedure from commercially available enantiopure
Received 27 May 2008
Accepted 8 July 2008
Available online 9 August 2008
a
-aminoacids. Performing the conjugate addition in the greener AcOEt solvent, high enantioselectivities
were reached for both cyclic and acyclic enones ranging between 72% to 98% ee and 96% to >99%, respec-
tively. The 2/1 Cu/ligand ratio required to obtain high enantioselectivities, led us to envisage a copper–
copper bi-metallic catalytic system for this transformation.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
H
H
Copper-catalyzed Asymmetric Conjugate Addition is a funda-
mental method for the formation of C–C bonds.1 This reaction
has been extensively studied over the last decade, and most efforts
have been realized through the development of copper2 and rho-
dium3 asymmetric conjugate addition of various alkylmetal
(organozinc reagents,4 organoaluminum reagents,5 and Grignard
reagents6) and arylboronic acids7 to cyclic and acyclic unsaturated
carbonyls. Moreover, various chiral ligands have been evaluated on
both cyclic and acyclic Michael acceptors and proven to be effi-
cient, giving full conversions and very high ee’s.7 As examples, pep-
tidic phosphane ligands developed first by Hoveyda8 and more
recently by Tomioka9 have proven to be highly efficient in this
reaction with various Michael acceptors. Nevertheless, in a general
way, many chiral ligands, are synthesized through lengthy and
expensive routes, which compromises any possible industrial
development. In the context of sustainable chemistry, there is a
need for chiral ligands which are not only very efficient, but also
available via step (transformation and purification) economy and
costless processes.10 Phosphoramidites are representative exam-
ples of a family of ligands that partly fulfills these criteria.11 In
the area of the Hoveyda’s peptidic phosphane ligands8 A (Fig. 1)
and the P,N,O Schiff base ligands B (Fig. 1) recently reported by
Gau,12 we report here a novel family of ligands, the diph-
enylphosphinoazomethinylate salts 1 (Scheme 1).
R
R
PPh2 N
PPh2 N
O
H
H
NH peptide
B
Gau's
OH
A
Hoveyda's small peptide ligands
P,N,O Schiff base ligands
R
H2N
H
H
H
+
R
H
O
O
PPh2 N
PPh2 O
X
3
2
1
O
O
X
Figure 1. Easily available phosphino-azomethinylate salts 1.
These ligands, which are a simplified version of Hoveyda’s
peptide ligands, can be readily obtained from -aminoacids in a
a
one-step procedure and do not require any purification.
Diphenylphosphinoazomethinylate salts 1 are thus compatible
with the concept of sustainable chemistry but have also proven
to be very efficient in the copper-catalyzed conjugate addition of
dialkylzinc reagents. Their synthesis and their evaluation in the
above-mentioned reaction are reported herein.
2. Results and discussion
* Corresponding authors. Tel.: +33 (0) 2 23 23 81 12; fax: +33 (0) 2 23 23 81 08
(M.M.); tel.: +33 (0) 2 23 23 80 74; fax: +33 0 2 23 23 81 08 (C.C.).
E-mail addresses: christophe.crevisy@ensc-rennes.fr (C. Crévisy), marc.mauduit@
ensc-rennes.fr (M. Mauduit).
Ligands 1 bear a diphenylphosphinoaryl and a chiral imino-
carboxylate chelating groups. They are readily accessible from
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.011

J. Wencel et al. / Tetrahedron: Asymmetry 19 (2008) 1804–1809
1805
It was then observed that the nature of the stereogenic R-group
has a great influence on the enantioselectivity (Table 1, entries 3–
7), with the best ee (89%) being obtained with tert-Leu-derived li-
gand (R = tBu) 1a. Consequently, the following experiments were
performed using 1a as the ligand. On the contrary, the nature of
the counter-cation has no noticeable influence on both the conver-
sion and the enantioselectivity (entries 3 and 8–10). Sodium salts
were used in the following experiments. It was observed that the
nature of the copper source was critical for obtaining an efficient
catalysis. Either Cu(I) or Cu(II) salts can be used in the reaction,
since Cu(II) salts are in situ reduced by dialkyzinc.15 So, both
Cu(I) and Cu(II) salts were tested, and while many copper salts
gave poor to fairly good results (entries 11–17), high ee (89%)
and conversion (>99%) were obtained when (CuOTf)2ꢀC7H8 was
used (entry 3). Various solvents were also screened; AcOEt, THF,
R
H3N
O
1. XOH, MeOH
2.
H
H
R
PPh2 N
1a-e
O
H
3
H
2a R =
2b R =
t
i
Bu
Pr
O
O
X
PPh2 O
quantitative yield
2c R = MeEtCH
2d R = Bu
2e R = Ph
X= Li, Na, K, Cs
i
Scheme 1. Synthesis of ligands 1a–e.
o-diphenylphosphinobenzaldehyde 3 and the carboxylate salt of a-
aminoacid 2 (Scheme 1). Eight different ligands were obtained,
varying both the nature of the cation and the nature of the amino
acid. Amino acids 2a–e were first converted to the corresponding
carboxylate salts, which were then condensed with aldehyde 3 to
give ligands 1a–e in quantitative yields (Scheme 1).13 Crude prod-
uct 1 was sufficiently pure enough for catalytic applications and no
purification was required.
Table 2
Enantioselective Copper-catalyzed conjugate addition of diethylzinc to cyclic and
acyclic enones 4–9 with ligand 1a-Na catalyzed by (CuOTf)2ꢀC7H8 complexa
Entry Substrate
Product
T
Time Conv.b eeb
(°C) (h)
(%)
(%)
The ligands were then examined in the copper-catalyzed conju-
gate addition of dialkylzinc to enones. Firstly, search for optimal
conditions was carried out using diethylzinc and cyclohexenone
4 as model reagents (Table 1). For the first experiments, reactions
were performed with (CuOTf)2ꢀC7H8 at rt for 2 h. As AcOEt is con-
sidered as a green solvent,14 it was chosen for the preliminary
experiments. Unexpectedly, it was observed that a 2/1 Cu/ligand
ratio was necessary to have good results. When the ratio was chan-
ged to 2/2 (mol %) and 2/4 (mol %), respectively, 53% and 25% con-
versions along with 80% and 50% ee were obtained (Table 1, entries
1–3). It should be noted that the Cu/ligand ratio employed in the
case of Hoveyda’s small peptide ligands A (Fig. 1), a ratio of 1/1
is required, which may suggest differences in the mechanisms
between these two classes of ligands.
O
O
1c
ꢁ18
6
94
98 (R)
Et
10
4
O
O
2c
ꢁ18 14
ꢁ18 14
ꢁ18 14
83
90
88 (R)
87 (R)
72 (R)
iPr
11
4
O
O
3c
Et
5
12
Table 1
Optimization of the reaction conditions with ligand 1a
O
O
(1.5 equiv)
Et2Zn
4d
96
O
O
x mol% L, y mol% "Cu salt"
iPr
6
13
(R)
AcOEt, T°C
Et
O
Et
O
10
4
5d
rt
14
>99
>99
(R)
Entry
Ligand
Cu salt
Ratio x/y
Temp
Time
(h)
Conv.a
(%)
eea(%)
14
Et
7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a-Na
1a-Na
1a-Na
1b-Na
1c-Na
1d-Na
1e-Na
1a-Li
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
CuCl
4/1
2/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/1
1/1
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
6
6
25
53
>99
85
98
87
90
>99
>99
>99
51
50
80
89
72.5
74.5
51
22
85
87
86
44
26.5
75
34
34
27.5
53
94.5
98
O
O
O
O
6c
30
rt
4
>99
>99
96 (S)
97 (S)
C5H11
C5H11
8
15
iPr
1a-K
7d
14
C5H11
C5H11
1a-Cs
1a-Na
1a-Na
1a-Na
1a-Na
1a-Na
1a-Na
1a-Na
1a-Na
1a-Na
8
16
CuCl2
Cu(OTf)2
CuTC
Cu(acac)2
53
>99
>99
83
64
69
>99
94
97
O
Et
O
8d
rt
6
>99
98 (R)
Ph
Ph
CuMes
CuBr–SMe2
(CuOTf)2ꢀC7H8
(CuOTf)2ꢀC7H8
rt
17
9
0 °C
ꢁ18 °C
18 °C
a
All reactions were performed in AcOEt using 1.5–3 equiv of R2Zn.
Determined by chiral GC analysis (chiraldex GTA).
b
c
Isolated Cu-1a complex
97
1 mol % of (CuOTf)2ꢀC7H8 and 1 mol % of 1a-Na were used.
a
d
Determined by chiral GC analysis (Lipodex E).
2 mol % of (CuOTf)2ꢀC7H8 and 2 mol % of 1a-Na were used.

1806
J. Wencel et al. / Tetrahedron: Asymmetry 19 (2008) 1804–1809
and Et2O gave quite similar results, while solubility problems were
observed in toluene.
attempted (Scheme 3). The phosphino and the imine first coordi-
nate to the copper forming a six-membered metallacycle while
the carboxylate coordinates to the second Cu atom. The approach
of the enone is anti to the stereogenic group, allowing for excellent
control during the transfer of the ethyl group. Then a transmetalla-
tion occurs, leading to the regeneration of the starting copper–cop-
per bi-metallic species. The second copper entity may act as a
Lewis acid toward the enone.
Finally, we observed a noticeable influence of the temperature
(Table 1, entries 3, 18, and 19) on the enantiocontrol, but it is
worth noting that a very high ee was obtained at only moderately
low temperatures (94.5% ee at 0 °C and 98% ee at ꢁ18 °C). At this
temperature, a nearly full conversion was obtained in 6 h. Never-
theless, it should be noted that the Cu/1a-Na complex could be iso-
lated as a deep green powder; however, no clear cut difference was
noticed in the result (entry 20). For practical reasons, the following
experiments were performed with an in situ prepared catalyst.
Having established the optimum reaction conditions in the use
of diphenyphosphinoazomethinylate ligand 1a, the addition of
diethyl- and diisopropylzinc on various cyclic 4–6 and acyclic 7–
9 Michael acceptors was examined (Table 2). High ee’s (87–98%,
entries 1 and 3) and nearly full conversions were reached with
Et2Zn and cyclic enones. Lower enantioselectivities were observed
when iPr2Zn was used (72–88%, entries 2 and 4). It should be noted
that, with acyclic enones, very high ee’s (96–99%) could be reached
at room temperature both with Et2Zn and iPr2Zn (entries 5–8). Par-
ticularly noteworthy are the results observed with Et2Zn and acy-
clic enones 7 and 8 (>99% obtained at rt and 96% ee obtained at
30 °C, respectively, entries 5 and 6) since these results are similar
to the best result reported to date by Nakamura (98.1% and
97.9% ee, respectively, obtained at 0 °C).16 It is noteworthy that
an excellent result was obtained when iPr2Zn and enone 8 were
used (entry 7). This result is far better than the copper-catalyzed
addition of isopropylgrignard reagent to 8, as reported by Feringa17
(48% ee).
H
H
(CuOTf)2.C7H8
R
Ph2P
TfO
N
R
PPh2 N
Cu
- XOTf
S : Solvent
S
O
O
O
O
1
Cu
S
Et2Zn
- EtZnOTf
X
O
O
ZnEt
O
H
R
Ph2P
N
Cu
S
O
O
Cu
S
H
R
H
Ph2P
N
Cu
S
R
Ph2P
N
Finally, some experiments were carried out in order to obtain
information on the mechanism (Scheme 2). We have already noted
that the cation is not involved in the determining steps of the
mechanism, and that 2 mol of copper for one mole of ligand is
required for the reaction to proceed. The latter result, which is very
Cu
O
O
ZnEt
S
Cu
O
O
O
Et2Zn
O
Cu
Scheme 3. Proposal mechanism for the conjugate addition of diethylzinc to enones
with phosphinoazomethinylate salt 1.
unusual, is consistent with the involvement of
a bimetallic
catalytic system18 where two copper entities are linked to the
same ligand, with the second copper atom being coordinated with
the carboxylate.
3. Conclusion
In conclusion, phosphinoazomethinylate salts have been evalu-
ated in the copper-catalyzed Michael addition of organozinc
reagents to cyclic and acyclic enones. Excellent results were
obtained, particularly with acyclic enones. A proposal of mecha-
nism has been attempted and, to the best of our knowledge, the
involvement of a copper–copper bimetallic catalytic system is pro-
posed for the first time in this reaction. This behavior opens up a
new field of investigation for this new type of ligands.
H
H
t
Bu
H
PPh2 N
N
O
H
O
OMe
O
Na
1f
1g
Scheme 2. Mechanistic studies.
4. Experimental
4.1. General
This is confirmed by the experiment carried out with ligand 1f,
which exhibits a methyl ester group instead of the carboxylate. In
this case, using cyclohexenone and Et2Zn as the reagents, the prod-
uct was obtained in low enantioselectivity (30% ee, >99% conv.
with 1 mol % (CuOTf)2ꢀC7H8 and 1 mol % of 1f), which may arise
from the impossibility of the enone to coordinate to the carboxyl-
ate-copper complex. Such a chelation might activate the enone and
also increase the rigidity of the system. The presence of the phos-
phino chelating group is also critical since no reaction was ob-
served when ligand 1g was used (0% conv. with 1 mol %
(CuOTf)2ꢀC7H8 and 1 mol % 1g). The activity is restored by the addi-
tion of extra PPh3, but the enantioselectivity remains nil (41% conv.
with 1 mol % (CuOTf)2ꢀC7H8, 1 mol % 1g and 1 mol % Ph3P). This
demonstrates that the P atom is important to have not only a high
activity, but also an appropriate organization in the enantiodeter-
mining step. From all these results, a proposal of mechanism was
1H (400 MHz), 13C (100 MHz), 19F (376.5 MHz), and 31P
(162 MHz) NMR spectra were recorded on a Bruker ARX400 spec-
trometer with complete proton decoupling for nucleus other than
1H. Chemical shifts are reported in ppm with the solvent resonance
as the internal standard (MeOD, 1H: d 3.31 ppm, 13C: d 49.05 ppm).
Data are reported as follows: chemical shift (d in ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quadruplet, sept = septuplet,
m = multiplet), coupling constants (Hz), integration and attribu-
tion. Optical rotations were recorded using a polarimeter Perkin–
Elmer 341. Elemental analyses were performed at Service centrale
d’analyse S.C.A.—U.S.R.—59/C.N.R.S. Solaize, France, and at the
Centre Régional de Mesures Physiques de l’Ouest (CRMPO), Univer-
sité de Rennes 1. The conversions and enantiomeric excesses of

J. Wencel et al. / Tetrahedron: Asymmetry 19 (2008) 1804–1809
1807
conjugate additions were measured using gas chromatography
(capillary column—Chiraldex GTA, 0.12 m, 30 m, 0.25 mm) with
159.85 (d, J (C,P) = 25.60 Hz, 1C, CN), 141.09 (d, J (C,P) = 17.58 Hz,
1C, Car), 138.73 (d, (C,P) = 18.21 Hz, 1C, Car), 137.72 (d,
l
J
J
cyclododecane as internal standard. The products of conjugate
additions were identified according to the literature.
(C,P) = 9.49 Hz, 1C, Car), 137.39 (d, J (C,P) = 10.33 Hz, 1C, Car),
135.27 (d, J (C,P) = 5.40 Hz, 2C, Car), 135.07 (d, J (C,P) = 5.36 Hz,
2C, Car), 133.97 (s, 1C, Car), 131.26 (s, 1C, Car), 130.17 (s, 2C, Car),
130.04 (s,1C, Car), 129.82 (d, J (C,P) = 6.97 Hz, 4C, Car), 128.85 (d, J
(C,P) = 4.34 Hz, 1C, Car), 88.90 (s, 1C, NC), 35.30 (s, 1C, C(CH3)3),
4.2. Materials
All non-aqueous reactions were performed under an argon
atmosphere using oven-dried glassware. Toluene was distilled
from sodium metal under nitrogen. Methanol was distilled from
sodium metal under argon. Tetrahydrofuran and diethyl ether
were desiccated on alumina column under nitrogen. Ethyl acetate
was distilled from calcium hydride under nitrogen. All other chem-
ical reagents and solvents were obtained from commercial sources
and used without further purification.
27.91 (s, 3C, CH3). ½a D20
¼ ꢁ7:4 (c 1, methanol). Anal. Calcd for
ꢂ
C
25H25NCsO2P: C, 56.09; H, 4.71; N, 2.62. Found: C, 56.52; H,
5.01; N, 2.56.
4.3.4. Lithium tert-leucine phosphinoazomethinylate 1a-Li
1H NMR (400 MHz, MeOD): d 8.89 (d, J (H,P) = 5.35 Hz, 1H,
CHN), 8.22 (ddd, J (H,H) = 7.79, 4.04, 1.31 Hz, 1H, CHCCHN), 7.35–
7.15 (m, 12H, Har), 6.80 (ddd, J (H,H) = 7.74, 4.74, 0.87 Hz, 1H,
CHCP), 3.36 (s, 1H, CH), 0.83 (s, 9H, CH3). 31P NMR (162 MHz,
MeOD): d ꢁ15.60 (s, 1P). 13C NMR (101 MHz, MeOD): d 179.35 (s,
1C, COO), 160.27 (d, J (C,P) = 25.91 Hz, 1C, CN), 140.93 (d, J
(C,P) = 17.57 Hz, 1C, Car), 138.86 (d, J (C,P) = 18.50 Hz, 1C, Car),
137.66 (d, J (C,P) = 9.52 Hz, 1C, Car), 137.31 (d, J (C,P) = 10.13 Hz,
4.3. General experimental procedure for ligand’s synthesis 1a–g
A flame-dried Schlenk tube was charged with amino acid 2
(1 mmol, 1 equiv), metal hydroxide (1 mmol, 1 equiv), molecular
sieves 4 Å, and 5 mL of MeOH. The mixture was stirred under an ar-
gon atmosphere at room temperature for 15 min. 2-(Diphenyl-
1C, Car), 135.27 (d,
J (C,P) = 5.13 Hz, 2C, Car), 135.07 (d, J
(C,P) = 5.39 Hz, 2C, Car), 134.04 (s, 1 C, Car), 131.40 (s, 1C, Car),
130.20 (s, 2C, Car), 130.08 (s, 1C, Car), 129.83 (d, J (C,P) = 7.07 Hz,
4C, Car), 128.83 (d, J (C,P) = 4.34 Hz, 1C, Car), 88.75 (s, 1C, CH),
phosphino)-benzaldehyde
3 (297 mg, 1 mmol, 1 equiv) was
added to the resulting solution. The reaction was allowed to stir
at 40 °C for 3 h. Filtration of molecular sieves and removal of vola-
tiles in vacuo left behind a yellow solid.
35.34 (s, 1C, C(CH3)3), 27.90 (s, 3C, CH3). ½a D20
¼ ꢁ11:5 (c 1, meth-
ꢂ
anol). Anal. Calcd for C25H25NCsO2P, H2O: C, 70.25; H, 6.37; N,
3.28. Found: C, 70.37; H, 6.31; N, 3.32.
4.3.1. Sodium tert-leucine phosphinoazomethinylate 1a-Na
1H NMR (400 MHz, MeOD): d 8.86 (d, J (H,P) = 5.19 Hz, 1H, CHN),
8.25–8.19 (m, 1H, CHarCCHN), 7.36–7.02 (m, 12H, CHar), 6.78–6.72
(m, 1H, CHarCP), 3.33 (s, 1H, CH), 0,79 (s, 9H, CH3). 31P NMR
(162 MHz, MeOD): d ꢁ15.63 (s, 1P). 13C NMR (101 MHz, MeOD):
d 179.13 (s, 1C, COO), 159.84 (d, J (C,P) = 25.92 Hz, 1C, CHN),
140.83 (d, J (C,P) = 17.90 Hz, 1C, Car), 138.53 (d, J (C,P) = 18.61 Hz,
4.3.5. Sodium valine-phosphinoazomethinylate 1b
1H NMR (400 MHz, MeOD): d 8.93 (d, J (H,P) = 5.38 Hz, 1H, CHN),
8.12 (ddd, J (H,H) = 7.79, 4.04, 1.30 Hz, 1H, CHCCHN), 7.38–7.14 (m,
12H, Har), 6.81 (ddd, J (H,H) = 7.72, 4.66, 0.93 Hz, 1H, CHCP), 3.33 (s,
0.5H, NCH), 3.27 (s, 0.5H, NCH), 2.18–2.06 (m, 1H, CH(CH3)2), 0.79
(d, J = 6.76 Hz, 3H, CH3), 0.51 (d, J = 6.72 Hz, 3H, CH3). 31P NMR
(162 MHz, MeOD): d ꢁ15.73 (s, 1P). 13C NMR (101 MHz, MeOD) :
d 179.93 (s, 1C, COO), 160.86 (d, J (C,P) = 25.99 Hz, 1C, CN),
140.89 (d, J (C,P) = 17.61 Hz, 1C, Car), 139.01 (d, J (C,P) = 18.65 Hz,
1C, Car), 137.46 (d,
J (C,P) = 9.46 Hz, 1C, Car), 137.13 (d, J
(C,P) = 10.11 Hz, 1C, Car), 135.05 (d, J (C,P) = 2.97 Hz, 2C, Car),
134.85 (d, J (C,P) = 3.35 Hz, 2C, Car), 133.77 (s, 1C, Car), 131.08 (s,
1C, Car), 129.96 (s, 2C, Car), 129.84 (s, 1C, Car), 129.60 (d, J (C,P)
= 7.17 Hz, 4C, Car), 128.64 (d, J (C,P) = 4.34 Hz, 1C, Car), 88.72 (s,
1C, Car), 137.61 (d,
J (C,P) = 9.40 Hz, 1C, Car), 137.28 (d, J
(C,P) = 10.11 Hz, 1C, Car), 135.30 (d, J (C,P) = 3.58 Hz, 2C, Car),
135.10 (d, J (C,P) = 3.65 Hz, 2C, Car), 134.01 (s, 1C, Car), 131.42 (s,
1C, Car), 130.21 (s, 2C, Car), 130.06 (s, 1C, Car), 129.84 (d, J
(C,P) = 7.06 Hz, 4C, Car), 128.74 (d, J (C,P) = 4.30 Hz, 1C, Car), 86.68
(s, 1C, NCH), 32.75 (s, 1C, CH), 20.34 (s, 1C, CH3), 19.33 (s, 1C,
1C, NC), 35.07 (s, 1C, C(CH3)3), 27.66 (s,3C, CH3). ½a D20
¼ ꢁ11:4 (c
ꢂ
1, methanol). Anal. Calcd for C25H27NNaO3P: C, 67.71; H, 6.14; N,
3.16. Found: C, 67.74; H, 5.95; N, 3.15.
4.3.2. Potassium tert-leucine phosphinoazomethinylate 1a-K
1H NMR (400 MHz, MeOD): d 8.92 (d, J (H,P) = 5.20 Hz, 1H, CHN),
8.30 (ddd, J (H,H) = 7.78, 4.03, 1.28 Hz, 1H, CHarCCHN), 7.37–7.18
(m, 12H, Har), 6.81 (ddd, J (H,H) = 7.73, 4.79, 0.93 Hz, 1H, CHarCP),
3.38 (s, 1H, CH), 0.85 (s, 9H, CH3). 31P NMR (162 MHz, MeOD): d
ꢁ15.60 (s, 1P). 13C NMR (101 MHz, MeOD) : d 179.12 (s, 1C,
CH3). ½a 2D0
¼ ꢁ11:7 (c 1, methanol). Anal. Calcd for C24H23NNaO2P,
ꢂ
H2O: C, 67.13; H, 5.87; N, 3.26. Found: C, 66.63; H, 5.70; N, 3.46.
4.3.6. Sodium iso-leucine-phosphinoazomethinylate 1c
1H NMR (400 MHz, MeOD): d 8.90 (d, J (H,P) = 5.45 Hz, 1H, CHN),
8.07 (ddd, J (H,H) = 7.69, 4.02, 1.18 Hz, 1H, CHCCHN), 7.33–7.08 (m,
12H, Har), 6.76 (ddd, J (H,H) = 7.71, 4.68, 0.86 Hz, 1H, CHCP), 3.33
(d, J (H,H) = 8.33 Hz, 1H, NCH), 1.93–1.82 (m, 1H, CH(CH3)(CH2)),
1.04–0.97 (m, 1H, CH2), 0.75 (d, J (H,H) = 6.77 Hz, 3H, CH3), 0.59
(dd, J (H,H) = 6.62, 3.54 Hz, 4H, CH3, CH2). 31P NMR (162 MHz,
MeOD): d ꢁ15.76 (s, 1P). 13C NMR (101 MHz, MeOD): d 179.89 (s,
1C, COO), 160.92 (d, J (C,P) = 26.03 Hz, 1C, CHN), 140.94 (d, J
(C,P) = 17.94 Hz, 1C, Car), 138.97 (d, J (C,P) = 18.37 Hz, 1C, Car),
137.68 (d, J (C,P) = 9.41 Hz, 1C, Car), 137.29 (d, J (C,P) = 10.26 Hz,
COO), 159.71 (d,
J (C,P) = 25.75 Hz, 1C, CN), 140.87 (d, J
(C,P) = 17.56 Hz, 1C, Car), 138.51 (d, J (C,P) = 18.59 Hz, 1C, Car),
137.48 (d, J (C,P) = 9.49 Hz, 1C, Car), 137.16 (d, J (C,P) = 10.14 Hz,
1C, Car), 135.03 (d,
J (C,P) = 4.31 Hz, 2C, Car), 134.85 (d, J
(C,P) = 4.31 Hz, 2C, Car), 133.76 (s, 1C, Car), 131.06 (s, 1C, Car),
129.96 (s, 2C, Car), 129.83 (s, 1C, Car), 129.56 (d, J (C,P) = 7.20 Hz,
4C, Car), 128.63 (d, J (C,P) = 4.36 Hz, 1C, Car), 88.70 (s, 1C, NC),
35.07 (s, 1C, C(CH3)3), 27.67 (s, 3C, CH3). ½a D20
¼ ꢁ11:0 (c 1, meth-
ꢂ
anol). Anal. Calcd for 2C25H25NKO2P, H2O: C, 66.64; H, 5.82; N,
3.11. Found: C, 66.56; H, 5.72; N, 3.06.
1C, Car), 135.30 (d, J (C,P) = 8.71 Hz, 2C, Car), 135.10 (d, J
(C,P) = 8.89 Hz, 2C, Car), 133.96 (s, 1C, Car), 131.41 (s, 1C, Car),
130.22 (s, 1C, Car), 130.19 (s, 1C, Car), 130.06 (s, 1C, Car), 129.86
(d, J (C,P) = 1.16 Hz, 2C, Car), 129.79 (d, J (C,P) = 1.25 Hz, 2C, Car),
128.75 (d, J (C,P) = 4.29 Hz, 1C, Car), 85.63 (s, 1C, NCH), 38.90 (s,
1C, CH(CH3)(CH2)), 26.07 (s, 1C, CH2), 16.30 (s, 1C, CHCH3), 11.31
4.3.3. Cesium tert-leucine phosphinoazomethinylate 1a-Cs
1H NMR (400 MHz, MeOD): d 8.88 (d, J (H,P) = 5.20 Hz, 1H, CHN),
8.23 (ddd, J (H,H) = 7.78, 4.03, 1.21 Hz, 1H, CHarCCHN), 7.31–7.19
(m, 12H, Har), 6.78 (ddd, J (H,H) = 7.71, 4.74, 0.92 Hz, 1H, CHCP),
3.34 (s, 1H, CH), 0.81 (s, 9H, CH3). 31P NMR (162 MHz, MeOD): d
ꢁ15.59 (s, 1P). 13C NMR (101 MHz, MeOD): d 179.31 (s, 1C, COO),
(s, 1C, CH2CH3). ½a D20
¼ ꢁ15:0 (c 1, methanol). Anal. Calcd for
ꢂ
C
25H25NNaO2P, 0.5H2O: C, 69.12; H, 6.03; N, 3.22. Found: C,
68.67; H, 6.02; N, 3.32.

1808
J. Wencel et al. / Tetrahedron: Asymmetry 19 (2008) 1804–1809
4.3.7. Sodium leucine-phosphinoazomethinylate 1d
4.4. General experimental procedure for complex syntheses
1H NMR (400 MHz, MeOD): d 8.91 (d, J (H,P) = 5.48 Hz, 1H,
CHN), 8.07 (ddd, J (H,H) = 7.78, 4.03, 1.31 Hz, 1H, CHCCN), 7.33–
7.05 (m, 12H, Har), 6.74 (ddd, J (H,H) = 7.72, 4.71, 0.85 Hz, 1H,
CHCP), 3.71 (dd, J (H,H) = 9.70, 4.39 Hz, 1H, NCH), 1.63–1.44 (m,
2H, CH2), 0.88 (m, 1H, CH), 0.65 (d, J (H,H) = 6.66 Hz, 3H, CH3),
0.53 (d, J (H,H) = 6.51 Hz, 3H, CH3). 31P NMR (162 MHz, MeOD): d
ꢁ15.81 (s, 1P). 13C NMR (101 MHz, MeOD) : d 180.35 (s, 1C,
A flame-dried Schlenk tube was charged with (CuOTf)2ꢀC7H8
(52.8 mg, 0.1 mmol, 0.1 equiv) and ligand 1a-Na (42.5 mg,
0.1 mmol, 0.1 equiv). Dry ethyl acetate (20 mL) was added and
the resulting green mixture was stirred at room temperature for
30 min. The resulting solution was concentrated in vacuo to afford
a green powder in quantitative yield. ½a D20
¼ þ10:5 (c 1 in metha-
ꢂ
COO), 160.93 (d,
J
(C,P) = 26.02 Hz, 1C), 140.72 (d,
J
nol). Anal. Calcd for C27H25Cu2F6NNaO8PS2: C, 38.12; H, 2.96; N,
1.65. Found: C, 37.85; H, 3.18; N, 1.44.
(C,P) = 17.68 Hz, 1C, Car), 138.66 (d, J (C,P) = 18.21 Hz, 1C, Car),
137.34 (d, J (C,P) = 9.21 Hz, 1C, Car), 137.06 (d, J (C,P) = 10.15 Hz,
1C, Car), 135.09 (d,
J
(C,P) = 20.24 Hz, 2C, Car), 134.82 (d,
J
4.5. Representative experimental proceudre for Cu-catalyzed
conjugate addition of dialkylzinc reagents to cyclic and acyclic
enones
(C,P) = 20.18 Hz, 2C, Car), 133.77 (s, 1C, Car), 131.31 (s, 1C, Car),
130.07 (s, 1C, Car), 129.94 (d, J (C,P) = 5.67 Hz, 2C, Car), 129.66 (d,
J (C,P) = 2.75 Hz, 2C, Car), 129.59 (d, J (C,P) = 2.87 Hz, 2C, Car),
128.53 (d, J (C,P) = 3.96 Hz, 1C, Car), 76.40 (s, 1C, NCH), 43.99 (s,
1C, CH), 25.14 (s, 1C, CH2), 23.76 (s, 1C, CH3), 21.36 (s, 1C, CH3).
A flame-dried Schlenk tube was charged with copper source
(0.02 mmol, 0.02 equiv) and ligand (0.01 mmol, 0.01 equiv). Next
3 mL of an ethyl acetate solution containing cyclododecane
(33.6 mg, 0.2 mmol, 0.2 equiv) was added and the resulting green
mixture was stirred at room temperature for 15 min, after which
Et2Zn (1.5–3 mmol) was added dropwise. Finally, cyclic or acyclic
enone (1 mmol, 1 equiv) was added at required temperature. The
resulting brown solution was allowed to stir at the required tem-
perature for 6–14 h and the reaction was quenched by the addi-
tion of 5 mL of a 1 N HCl solution. The product was extracted
with 5 mL of Et2O. The organic phase was washed with water
and brine, dried over MgSO4, filtrated, and concentrated under
vacuo.
½
a 2D0
ꢂ
¼ ꢁ12:3 (c 1 in methanol). Anal. Calcd for C25H25NNaO2P,
0.5H2O: C, 69.12; H, 6.03; N, 3.22. Found: C, 69.19; H, 6.00; N,
3.36.
4.3.8. Sodium phenylglycine-phosphinoazomethinylate 1e
1H NMR (400 MHz, MeOD): d 8.95 (d, J (H,P) = 5.41 Hz, 1H, CHN),
8.16 (ddd, J (H,H) = 7.74, 3.94, 1.13 Hz, 1H, CHCCHN), 7.31–7.08 (m,
17H, Har), 6.77 (ddd, J (H,H) = 7.71, 4.80, 0.91 Hz, 1H, CHCP), 4.83 (s,
1H, NCH). 31P NMR (162 MHz, MeOD): d ꢁ15.31 (s, 1P). 13C NMR
(101 MHz, MeOD):
d
178.55 (s, 1C, COO), 161.34 (d,
J
J
(C,P) = 25.80 Hz, 1C, CHN), 141.90 (s, 1C, Car), 140.77 (d,
(C,P) = 17.25 Hz, 1C, Car), 139.30 (d, J (C,P) = 18.40 Hz, 1C, Car),
137.51 (d, J (C,P) = 9.42 Hz, 1C, Car), 137.22 (d, J (C,P) = 9.99 Hz,
Conversions and enantiomeric purities of the products were ob-
tained from GLC analysis (Chiraldex-GTA column).
1C, Car), 135.26 (d,
J (C,P) = 9.42 Hz, 2C, Car), 135.06 (d, J
(C,P) = 9.51 Hz, 2C, Car), 133.95 (s, 1C, Car), 131.58 (s, 1C, Car),
130.20 (d, J (C,P) = 2.84 Hz, 2C, Car), 130.08 (s, 1C, Car), 129.83 (d,
4.6. Determination of the enantiomeric excesses
J
(C,P) = 7.23 Hz, 2C, Car), 129.43 (s, 1C, Car), 129.14 (d, J
4.6.1. 3-Ethylcyclohexanone
(C,P) = 13.87 Hz, 2C, Car), 128.80 (s, 1C, Car), 128.77 (s, 1C, Car),
Capillary
column
Chiraldex
GTA,
(0.12
l
m,
30 m,
128.26 (s, 1C, Car), 127.98 (s, 2C, Car), 81.80 (s, 1C, NCH).
0.25 mm), pression 104 kPa, total He flow 9.2 mL/min; 90 °C
(30 min)–15 °C/min–160 °C (10 min); RT(R) = 23.2 min; RT(S) =
25.1 min; RT(2-cyclohexen-1-one) = 16.4 min; RT(cyclododecane) =
26.7 min.
½
a 2D0
ꢂ
¼ þ4:5 (c 1, methanol). Anal. Calcd for C27H21NNaO2P,
0.25H2O: C, 72.08; H, 4.82; N, 3.11. Found: C, 72.11; H, 4.79; N,
3.20.
4.3.9. Valine-phosphinoazomethinylate methyl ester 1f
4.6.2. 3-Ethylcycloheptanone
1H NMR (400 MHz, MeOD): d 8.85 (d, J (H,P) = 5.27 Hz, 1H, CHN),
7.92 (dd, J (H,H) = 7.09, 3.53 Hz, 1H, CHCCHN), 7.35–7.12 (m, 12H,
Har), 6.81 (dd, J (H,H) = 7.16, 4.79 Hz, 1H, CHCP), 3.57 (s, 3H, OCH3),
3.47 (d, J (H,H) = 7.39 Hz, 1H, NCH), 2.09 (qd, J (H,H) = 13.68, 6.77,
6.77, 6.75 Hz, 1H, CH), 0.72 (d, J (H,H) = 6.77 Hz, 3H, CH3), 0.60
(d, J (H,H) = 6.75 Hz, 3H, CH3). 31P NMR (162 MHz, MeOD): d
ꢁ14.64 (s, 1P). 13C NMR (101 MHz, MeOD): d 173.43 (s, 1C, COO),
Capillary column Chiraldex GTA, (0.12
pression 98.1 kPa, total He flow
(45 min)–1 °C/min–110 °C–15 °C/min–160 °C (10 min); RT(S) =
45.5 min; RT(R) = 46.8 min. RT(2-cyclohepten-1-one) = 34.6 min;
RT(cyclododecane) = 27.0 min.
l
m, 30 m, 0.25 mm),
9.1 mL/min; 90 °C
4.6.3. 3-Isopropylcyclohexanon
164.07 (d,
J
(C,P) = 23.14 Hz, 1C, CHN), 139.79 (d,
J
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
(C,P) = 17.43 Hz, 1C, Car), 139.50 (d, J (C,P) = 19.44 Hz, 1C, Car),
137.28 (d, J (C,P) = 8.89 Hz, 1C, Car), 137.14 (d, J (C,P) = 9.48 Hz,
pression 99.6 kPa, total He flow 9.2 mL/min; 90 °C (40 min)–
15 °C/min–160 °C (10 min); RT (R) = 36.5 min; RT(S) = 41.5 min.
RT(2-cyclohexen-1-one) = 15.8 min; RT(cyclododecane) = 26.5 min.
1C, Car), 135.13 (d,
J (C,P) = 1.53 Hz, 2C, Car), 134.92 (d, J
(C,P) = 1.55 Hz, 2C, Car), 134.00 (s, 1C, Car), 131.85 (s, 1C, Car),
130.07 (d, J (C,P) = 3.76 Hz, 2C, Car), 129.92 (s, 1C, Car), 129.70 (d,
J (C,P) = 2.91 Hz, 2C, Car), 129.63 (d, J (C,P) = 2.90 Hz, 2C, Car),
128.85 (d, J (C,P) = 3.79 Hz, 1C, Car), 81.05 (s, 1C, NCH), 52.21 (s,
1C, OCH3), 32.49 (s, 1C, CH(CH3)2), 19.44 (s, 1C, CH3), 18.63 (s,
4.6.4. 3-Isopropylcyclopentanone
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
pression 98.0 kPa, total He flow 9.7 mL/min; 70 °C (50 min)–1 °C/
min–75 °C–15 °C/min–160 °C (10 min); RT(S) = 52.1 min; RT(R) =
54.5 min. RT(2-cyclopenten-1-one) = 18.9 min; RT(cyclododecane) =
58.2 min.
1C, CH3) ½a 2D0
¼ ꢁ9:1 (c 1, methanol).
ꢂ
4.3.10. Sodium tert-leucine azomethinylate 1g
1H NMR (400 MHz, MeOD): d 8.12 (s, 1H, CHN), 7.74–7.70 (m,
2H, Har), 7.32–7.29 (m, 1H, Har), 3.44 (s, 1H, NCH), 0.94 (s, 9H,
CH3). 13C NMR (101 MHz, MeOD): d 179.56 (s, 1C, COO), 162.16
(s, 1C, CHN), 137.98 (s, 1C, Car), 131.50 (s, 1C, Car), 129.57 (s, 2C,
Car), 129.54 (s, 2C, Car), 88.55 (s, 1C, NCH), 35.36 (s, 1C, C(CH3)3),
4.6.5. 4-Ethyl-5-methylhexan-2-one
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
pression 104.0 kPa, total He flow 9.9 mL/min; 80 °C
(30 min)–10 °C/min–160 °C (5 min); RT(R) = 16.5 min; RT(S) =
18.1 min. RT(5-methylhexan-2-one) = 11.6 min; RT(cyclododecane) =
33.9 min.
27.97 (s, 3C, CH3). ½a D20
¼ ꢁ3:2 (c 1, methanol).
ꢂ

J. Wencel et al. / Tetrahedron: Asymmetry 19 (2008) 1804–1809
1809
2. Selected reviews: (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236; (b) Krause, N.; Hoffman-Röder, A. Synthesis 2001, 171–196; (c) Ferringa,
B. L. Acc. Chem. Res. 2000, 33, 346–353.
3. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844.
4. For recent examples, see: (a) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779–781; (b) Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5,
3201–3203; (c) Clavier, H.; Coutable, L.; Guillemin, J. C.; Mauduit, M.
Tetrahedron: Asymmetry 2005, 16, 921–924.
4.6.6. 4-Ethylnonan-2-one
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
pression 104.0 kPa, total He flow 9.9 mL/min; 80 °C (60 min)–
2 °C/min–100 °C–10 °C/min–160 °C (5 min); RT(S) = 50.0 min;
RT(R) = 54.3 min. RT(nonen-2-one) = 42.3 min; RT(cyclododecane) =
40.2 min.
5. For examples, see: (a) Diégez, S. M.; Deeremberg, O.; Claver, C.; Van Leeuwen, P.
W. N. M.; Kramer, P. Tetrahedron: Asymmetry 2000, 11, 3161–3166; (b) Fraser,
P. K.; Woodward, S. Chem. Eur. J. 2003, 9, 776–783; (c) D’Augustin, M.; Palais, L.;
Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376–1378.
6. For examples, see: (a) Lopez, F.; Harutyunyan, S. R.; Meetsma, A.; Minaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752–2756; (b) Lee, K.-S.; Brown,
M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182–7184; (c)
Martin, D.; Kehrli, S.; D’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am.
Chem. Soc. 2006, 128, 8416–8417.
4.6.7. 4-Phenylhexan-2-one
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
pression 108.0 kPa, total He flow 9.7 mL/min; 100 °C (60 min)–
2 °C/min–120 °C–10 °C/min–160 °C (5 min); RT(R) = 50.5 min;
RT(S) = 53.3 min. RT(phenylhexen-2-one) = 63.7 min; RT(cyclo-
dodecane) = 16.8 min.
7. Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579–5580.
8. (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755–
756; (b) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
13362–13363; (c) Kevin Brown, M.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2005, 44, 5306–5310; (d) Kacprzynski, M. A.; Kazane, S. A.; May, T. L.;
Hoveyda, A. H. Org. Lett. 2007, 9, 3187–3190.
4.6.8. 4-Isopropylnonan-2-one
Capillary column Chiraldex GTA, (0.12 lm, 30 m, 0.25 mm),
pression 109.9 kPa, total He flow 10.5 mL/min; 80 °C (90 min)–
10 °C/min–160 °C (10 min); RT (+) = 67.1 min; RT (ꢁ) = 69.9 min.
RT(nonen-2-one) = 40.9 min; RT(cyclododecane) = 38.4 min.
9. Soeta, T.; Selim, K.; Kuriyama, M.; Tomioka, K. Adv. Synth. Catal. 2007, 349, 629–
635.
10. Blaser, H.-U.; Pugin, B.; Spindler, F. J. Mol. Catal. A: Chem. 2005, 231, 1–20.
11. Selected recent papers: (a) Bernsmann, H.; van den Berg, M.; Hoen, R.;
Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem.
2005, 70, 943–951; (b) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.;
Falciola, C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.; Bernadinelli, G.; Alexakis,
A. Angew. Chem., Int. Ed. 2007, 46, 7462–7465.
12. Bradar, D. B.; Gau, H.-M. Tetahedron: Asymmetry 2008, 19, 733–738.
13. Knizhnikov, V. A.; Azizbekyan, O. P.; Prishchepenko, V. M. Russ. J. Gen. Chem.
2003, 73, 1445–1447.
Acknowledgements
This work was supported by the CNRS, the Region Bretagne and
the Ministère de la Recherche et de la Technologie (Grant to J.W.
and D.R.). M.M. and C.C. thank Bretagne-Valorisation for his finan-
cial support related to the development of chiral ligands for asym-
metric catalysis.
14. Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine,
H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10,
31–36.
15. Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
5262–5263.
References
16. Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153–4155.
17. Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2004, 126, 12784–12785.
18. (a) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269–279; (b)
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2209.
1. (a) Perlmutter, P. Conjugate Addition Reaction in Organic Synthesis. In
Tetrahedron Organic Chemistry Series; Pergamon Press: Oxford, 1992; Vol. 9;
(b) Yamamoto, Y. Methods Org. Chem. (Houben-Weyl), 1995, 4 (stereoselective
Synthesis), 2041–2057.