Copper-catalyzed enantioselective conjugate addition of diethylzinc to α,β-unsaturated carbonyl compounds using diphosphonites as chiral ligands

Article abstract of DOI:10.1016/S0040-4039(01)02355-3

BINOL-based diphosphonites in which ferrocene functions as the achiral backbone are excellent chiral ligands in the Cu(OTf)₂-catalyzed conjugate addition of Et₂Zn to enones, enantioselectivities of up to 99% being observed.

Full text of DOI:10.1016/S0040-4039(01)02355-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1189–1191
Copper-catalyzed enantioselective conjugate addition of
diethylzinc to a,b-unsaturated carbonyl compounds using
diphosphonites as chiral ligands†
Manfred T. Reetz,* Andreas Gosberg and Dominique Moulin
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim/Ruhr, Germany
Received 12 December 2001; accepted 13 December 2001
Abstract—BINOL-based diphosphonites in which ferrocene functions as the achiral backbone are excellent chiral ligands in the
Cu(OTf)2-catalyzed conjugate addition of Et2Zn to enones, enantioselectivities of up to 99% being observed. © 2002 Elsevier
Science Ltd. All rights reserved.
We have previously shown that BINOL-based diphos-
phonites of type 1 and 2 are excellent bidentate ligands
in the asymmetric Rh-catalyzed hydrogenation of prochi-
ral olefins, enantioselectivity typically being in the range
of 97–99% ee.1 Since these results constitute the first cases
of high asymmetric induction in catalytic hydrogenation
using chiral diphosphonites as ligands,2 it was of interest
to study the behavior of 1 and 2 in other types of transition
metal-catalyzed reactions. We now show that these
ligands are also well suited for asymmetric conjugate
addition of Et2Zn to prochiral enones.3–5
Upon adding Et2Zn to a cooled (−30°C) mixture of
cyclohexenone (3a) and catalytic amounts of Cu(OTf)2
(1 mol%) in the presence of the chiral ligand 1a
(Cu:ligand=1:2) and allowing the mixture to react for 20
h, an excellent conversion to the product 4a was observed,
enantioselectivity amounting to 95% ee (Table 1, entry
R
O
P
R
O
O
Fe
O
O
P
R
P
P
O
O
O
R
1
a
b
c
2
R = H
R = CH3
R = C6H5
O
O
1 mol-% Cu(OTf)2
+
Et2Zn
2 mol-% ligand
THF/-30 °C/20 h
( )n
( )n
3
a
b
4
a
b
n = 1
n = 2
n = 1
n = 2
Keywords: catalysis; enones; zinc and compounds; addition reactions; asymmetric synthesis.
* Corresponding author. Tel.: +49 208 306 2000; fax: +49 208 306 2985; e-mail: reetz@mpi-muelheim.mpg.de
† Dedicated to Professor Dr. Bernhard Lu¨cke on the occasion of his 65th birthday.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02355-3

1190
M. T. Reetz et al. / Tetrahedron Letters 43 (2002) 1189–1191
O
O
1 mol-% Cu(OTf)2
+
Et2Zn
O
O
2 mol-% ligand
THF/-30 °C/20 h
6
5
O
O
1 mol-% Cu(OTf)2
+
Et2Zn
Ph
2 mol-% ligand
Ph
THF/-30 °C/20 h
Ph
Ph
7
8
Table 1. Cu(OTf)2-catalyzed conjugate addition of Et2Zn in the presence of chiral diphosphonites
Entry
Substrate
Ligand
Temperature (°C)
Conversion (%)
% ee (abs. config.)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
5
5
5
7
7
1a
1a
1b
1b
1c
2
1a
1a
1a
1b
1a
1a
1a
1b
1c
−30
−20
−30
−20
−20
−30
−30
−30
−20
−30
−30
22
89–94
100
72–88
100
95 (R) (+)
92–94 (R) (+)
93–99 (R) (+)
95 (R) (+)
38 (R) (+)
29–46 (R) (+)
90–93 (+)
87a
100
53–65
86–92
100
100
87
29–37
91–92
100
100
100
9
84a
10
11
12
13
14
15
88a
69–71 (R) (−)
8 (R) (−)
55 (R) (−)
64 (R) (−)
24 (S) (+)
7
7
7
0
0
0
a Absolute configuration not determined.
1).6 At −20°C enantioselectivity turned out to be a little
lower (entry 2). The use of the dimethyl-analog 1b led
to an increase in enantioselectivity, whereas the phenyl
derivative 1c resulted in only 38% ee (Table 1, entry 5).
Surprisingly, the ethano-bridged diphosphonite 2 failed
to afford acceptable results (Table 1, entry 6), which
means that the nature of the achiral backbone is cru-
cial.
References
1. Reetz, M. T.; Gosberg, A.; Goddard, R.; Kyung, S.-H.
Chem. Commun. (Cambridge) 1998, 2077–2078.
2. (a) Nifant’ev, I. E.; Manzhukova, L. F.; Antipin, M. Y.;
Struchkov, Y. T.; Nifant’ev, E. E. Russ. J. Gen. Chem.
1995, 65, 682–685; (b) Ni-catalyzed hydrocyanation using
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2001, 7, 1614–1618; (c) Rh-catalyzed hydrosilylation of
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Similar results were observed in the case of the pyra-
none 5, enantioselectivity comparing well with the best
results previously reported by Chan who used a chiral
diphosphite7 (Table 1, entries 8–10). In contrast, chal-
cone 7 reacted with considerably lower asymmetric
induction (ee=64–71%; Table 1, entries 11–15). Thus,
the general trend that a given ligand system seldom
works well for both cyclic and for acyclic substrates3–5
seems to pertain in our system as well.
3. For general reviews of enantioselective conjugate addi-
tions, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033–8061; (b) Krause, N.; Hoffmann-Roder, A. Syn-
thesis 2001, 2, 171–196.
4. For early representative papers concerning the conjugate
addition of diethylzinc using various catalysts, see: (a)
Bolm, C.; Ewald, M. Tetrahedron Lett. 1990, 35, 5011–
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The ligands described herein are easy to prepare and
belong to the best systems currently available, although
the chiral phosphoramidites described by Feringa5b
result in slightly higher enantioselectivities. The study
of other transition metal-catalyzed reactions using our
ligands is in progress.

M. T. Reetz et al. / Tetrahedron Letters 43 (2002) 1189–1191
1191
5. For the copper-catalyzed conjugate addition of diethyl-
zinc, see: (a) Alexakis, A.; Frutos, J.; Mangeney, P. Tetra-
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6. Typical experimental procedure: In a 30 mL Schlenk tube,
1 mL of a 10 mM solution of Cu(OTf)2 in THF and 2 mL
of a 10 mM solution of a chiral ligand (e.g. 1a) in THF
were added at room temperature. A green coloration was
immediately observed. After 20 min of stirring the solution
turned yellow and 0.5 mL of a 2 [M] solution of cyclo-
hexenone (3a) in THF was added. 50 mL of n-decane was
added as an internal standard for the determination of
conversion. The temperature was cooled down to −30°C
and after 20 min 0.5 mL of a 3 [M] solution of Et2Zn in
THF was added. The mixture is stirred at −30°C for 20 h.
Then 10 mL of a 1.2 [M] solution of HCl are added at
−30°C, the Schlenk tube was warmed up to room temper-
ature and 20 mL of water and 30 mL of CH2Cl2 were
added. The water phase was extracted three times with
CH2Cl2. The organic phase was dried over MgSO4. After
evaporation of THF the crude product was purified on
silica gel with a 9:1 mixture of hexane and ether as an
eluant.
7. Yan, M.; Zhou, Z.-Y.; Chan, A. S. C. Chem. Commun.
(Cambridge) 2000, 115–116.