Asymmetric conjugate addition of metal alkyl reagents catalyzed by copper complexes with BINPO: A hemilabile P,O-heterobidentate axially chiral ligand

Article abstract of DOI:10.1016/j.tetasy.2005.08.041

We herein report the use of a new class of P,O-bidentate arylphosphine ligand for the asymmetric copper catalyzed conjugate addition of dialkylzinc and trialkylaluminium with the enantiomeric excesses reaching 91% while (R)-muscone was obtained with 77% ee.

Full text of DOI:10.1016/j.tetasy.2005.08.041

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3143–3146
Asymmetric conjugate addition of metal alkyl reagents
catalyzed by copper complexes with BINPO: a hemilabile
P,O-heterobidentate axially chiral ligand
a
a
a
a,
*
Nicolas Fuchs, Magali dꢀAugustin, Munir Humam, Alexandre Alexakis,
b
b,
*
Rossana Taras and Serafino Gladiali
a
D e´ partement de chimie organique, Universit e´ de Gen e` ve, 30 Quai Ernest-Ansermet, CH-1211 Gen e` ve 4, Switzerland
b
Dipartimento di Chimica, Universita di Sassari, Via Vienna 2, 07100 Sassari, Italy
Received 22 August 2005; accepted 25 August 2005
Available online 28 September 2005
Abstract—We herein report the use of a new class of P,O-bidentate arylphosphine ligand for the asymmetric copper catalyzed con-
jugate addition of dialkylzinc and trialkylaluminium with the enantiomeric excesses reaching 91% while (R)-muscone was obtained
with 77% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
In this context, we were interested to have an insight
into the potential of hemilabile bidentate ligands in this
reaction and for this reason we have addressed our
The formation of carbon–carbon bonds is one of the
most important synthetic reactions in organic chemistry.
In this context, the transition metal catalyzed conjugate
addition is an excellent way to introduce hard nucleo-
philes to Michael acceptors. In addition, it allows
asymmetry to be induced in the formation of this new
bond.
0
attention towards 2-diphenylphosphinyl-2 -diphenyl-
0
phosphino-1,1 -binaphtalene [(R)-BINPO] L1, a new
5
type of ligand developed by Gladiali et al. (Fig. 1). Due
1
to the presence of a hard oxygen and a soft phosphorus
as the donors, BINPO displays a pronounced propensity
6
to act as a hemilabile ligand, even if it can also bind
the metal by chelate coordination. BINPO has been
successfully employed as a chiral inducer in the Pd-
For this process, two metals hold a prominent position
2
3
7
as catalysts, copper and rhodium. These systems
provide complementary methods for the preparation
of 1,4-adducts through alkyl or aryl/alkenyl group
additions.
catalyzed allylic alkylation and in a range of addition
5
reactions to styrene covering hydrosilylation, hydro-
8
9
formylation and Rh-catalyzed hydroboration.
In the copper-catalyzed version, dialkylzinc reagents
2
d
were the most frequently used. However, trialkylalu-
minium reagents were also reported to afford good
PPh2
L1
4
P(O)Ph2
results. Amongst the >300 ligands screened in this
2
d
reaction, quite a few were bidentate, however, the best
results were consistently obtained with monodentate
derivatives. Amongst these, phosphites and phospho-
ramidites perform better than phosphines.
Figure 1.
2. Results and discussion
*
Corresponding authors. Tel.: +41 22 379 65 22; fax: +41 22 379 32
5; e-mail addresses: alexandre.alexakis@chiorg.unige.ch; gladiali@
ssmain.uniss.it
It was our hope that coordination of the soft phospho-
rus and of the hard oxygen to the copper and to the
other metal (Zn or Al), respectively, could occur in a
1
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.041

3144
N. Fuchs et al. / Tetrahedron: Asymmetry 16 (2005) 3143–3146
cooperative mode so as to build up a transition state of
highly organized asymmetry.
Table 2. Temperature optimization
O
O
2
mol% Cu(CH CN) PF
3
4
6
4
mol% L1
The first attempts were done with diethylzinc on 2-
cyclohexenone but the results were not promising with
only 40% ee (Scheme 1).
Et O; T ˚C
.5 eq. Me Al
3
2
1
a
Entry
Temp. (°C)
Conv. (%)
ee (%)
1
2
3
4
ꢀ10
ꢀ30
ꢀ45
ꢀ65
>99
>99
>99
91
66
77
89
91
O
O
2
mol% CuTC
mol% L1
Et O, -30˚C
4
yield = 96%
ee = 40%
2
1
.4 eq. Et Zn
2
a
GC conversions.
Scheme 1.
In contrast, when the reaction was carried out with tri-
methylaluminium the results were quite encouraging.
A short list of copper salts was tested under the condi-
3
Table 3. Screening of enones with Me Al
Entry
Substrates
Conv. (%)
Isolated
yield (%)
ee (%)
89 (R)
89 (R)
tions we developed for other ligands and R Al reagents
3
O
(
Table 1). From this screening, Cu(CH CN) PF turned
3 4 6
1
2
>99
61
57
out to be the best suited catalyst for the enantioselectiv-
ity of the reaction. This result is quite interesting because
so far Cu(CH CN) BF was consistently reported to be
O
3
4
4
4
b,e
>99
the best performer in this reaction.
O
Table 1. Copper salt optimization
3
>99
60
77 (R)
O
O
2
mol% Copper salt
mol% L1
Et O, -30˚C
4
2
O
1
.5 eq. Me Al
3
4
5
6
>99
>99
>99
31
50
15
71 (S)
25 (R)
74 (R)
a
Entry
Copper salt
Conv. (%)
ee (%)
72
O
O
1
2
3
4
5
6
7
CuCl
CuBr
>99
nd
b
nd
Cu(OAc)
Cu(OTf)
CuTC
2
Æ2H
2
O
>99
>99
>99
>99
>99
70
29
69
65
77
2
Bu
Cu(CH
Cu(CH
3
CN)
CN)
4
BF
PF
4
3
4
6
a
GC conversions.
Too many by-products.
b
Michael addition to the starting material of the alumi-
nium enolate of 3-methyl cyclohexanone produced in the
first Cu-catalyzed conjugate addition. Cycloheptenone
gave similar results (entry 2) with 57% isolated yield
and 89% ee.
In the Cu-catalyzed conjugate addition, it is known that
the lowest reaction temperature is not always the best
one for enantioselectivity. Therefore, this parameter
was checked (Table 2) and we observed that working
at ꢀ45 °C, was the best temperature for the enantio-
selectivity.
1
0
Due to its ring size (15 membered) 2-cyclopentadece-
none is generally considered to react like an acyclic en-
1
2
one. The conjugate addition of the methyl group to
this substrate (entry 3) affords the well-known fragrance
Although at ꢀ65 °C we were able reach 91% ee, the
conversion was incomplete. Therefore, we decided to
perform the next screening at ꢀ45 °C, where a quanti-
tative conversion of 2-cyclohexenone was obtained at
the expense of a modest decrease of ee (89%).
1
3
(R)-Muscone with 77% ee, one of the best reported for
1
4
the asymmetric synthesis of this compound. With the
exception of chalcone (entry 5), which was a poor sub-
strate for this reaction (25% ee), the two other tested
acyclic enones (entries 4 and 6) gave comparable levels
of enantioselectivity (71% and 74%, respectively).
A range of cyclic and acyclic enones were tested under
standard conditions (Table 3). Cyclohexenone afforded
3
-methyl cyclohexanone in 61% isolated yield (entry 1)
For the sake of comparison, the same work was carried
out with triethylaluminium. Screening of the copper salt
showed that, this time, Cu(CH CN) BF was the best
salt. Optimization of the temperature revealed, again,
that ꢀ45 °C was the most favourable. Finally, the con-
in spite of the complete conversion. This result shows
the importance of the competing polymerization that
plagues the reaction of 2-cyclohexenone with organo-
3
4
4
1
1
aluminium reagents. The polymer is produced via a

N. Fuchs et al. / Tetrahedron: Asymmetry 16 (2005) 3143–3146
3145
jugate addition to the various cyclic and acyclic enones
was performed (Table 4).
up to 86% ee. From these results, it follows that phos-
phine ligands should no more be neglected in this reac-
tion. Our results also demonstrate that the
heterobidentate nature of the P,O-ligand is essential
for high stereoselections to be pursued in the conjugate
addition. For instance, BINAP, the homobidentate
close relative of BINPO, is a very poor chiral inducer
3
Table 4. Screening of enones with Et Al
Entry
Substrates
Conv. (%)
Isolated
ee (%)
yield (%)
1
5
in this process. Whether the good performances of
BINPO may be related or not to the hemilabile behav-
iour of this ligand currently remains a matter of
O
1
>99
61
66
86 (R)
1
6
speculation.
O
2
3
>99
>99
75 (R)
41 (R)
O
Acknowledgements
n.d.
The authors thank the Swiss National Research Foun-
dation (no. 200020-105368) and COST action D24/
0
003/01 (OFES contract no. C02.0027) for financial
O
support.
4
5
6
>99
>99
>99
40
25
27
20 (S)
16 (R)
51 (R)
O
O
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2
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4
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7
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1
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4
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3146
N. Fuchs et al. / Tetrahedron: Asymmetry 16 (2005) 3143–3146
1
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4
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1
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afford the crude product. Purification by flash chroma-
tography over silica gel afforded the pure product.