Dramatic improvement of the enantiomeric excess in the asymmetric conjugate addition reaction using new experimental conditions

Article abstract of DOI:10.1021/ja025598k

The asymmetric conjugate addition of dialkylzincs is usually performed with Cu(OTf)₂ in toluene. We show that by using a copper carboxylate in Et₂O, THF, or EtOAc, we strongly improve the enantioselectivity with a given ligand. Ee va

Full text of DOI:10.1021/ja025598k

Published on Web 04/18/2002
Dramatic Improvement of the Enantiomeric Excess in the Asymmetric
Conjugate Addition Reaction Using New Experimental Conditions
A. Alexakis,* C. Benhaim, S. Rosset, and M. Humam
Department of Organic Chemistry, UniVersity of GeneVa, 30, Quai Ernest Ansermet, 1211 GeneVa 2, Switzerland
Received January 15, 2002
Scheme 1
The formation of chiral carbon-carbon bonds by using the
asymmetric conjugate addition reaction has been widely investi-
gated.1 Conditions have been developed, using a catalytic quantity
of copper(II) triflate and chiral ligands associated to an organozinc
reagent,2 to perform this reaction in high yield and good to excellent
enantioselectivity.3 Our current objective is to generalize the
experimental conditions for a variety of different Michael acceptors.4
Table 1. Asymmetric Conjugate Addition with L1 on
Cyclohexenone with Selected Copper Salts8
a
a
entry copper salts
Tol.a
Et2O
CH Cl2a
THF
EtOAca
2
The optimization of the asymmetric conjugate addition reaction
has been realized essentially by examining two parameters: the
solvent and the nature of the copper salt, which appear to be crucial
to obtain good enantiomeric excess. For example, Sewald reported
the use of different copper(I) salts using chiral sulfonamides as
ligands and found divergent enantioselectivities according to the
Cu source.5 Using [Cu(CH3CN)4BF4], Woodward6 obtained his best
results on trans-nonenone with THF as solvent instead of toluene.
In the course of our studies on the asymmetric 1-4 addition with
new ligands, based on the induced atropoisomerism of a simple
biphenol unit,7 we found that new experimental conditions greatly
improve the enantiomeric excesses. Moreover, these new conditions
also improve many results with known ligands.
1
2
3
4
5
6
7
8
9
10
11
12
13
Cu(OTf)2
Cu(acac)2
Cu(OCOCF3)2
Cu(OAc)2
Cu(OAc)2‚H2O
Cu(O2CR)2
CuTCc
Cu(ClO4)2‚6H2O
Cu(BF4)2‚6H2O
CuSO4‚5H2O
CuCl
CuCN
CuSPh
>99%, 82% >99%, 90% >99%, 72% 87%, 90%
>99%, 80% >99%, 90% >99%, 82% 22%, 60%
92%, 90%
82%, 85%
93%, 90%
60%, 90%
27%, 88%
>99%, 91% >99%, 92%
95%, 89% >99%, 92%
92%, 91% >99%,93%
92%, 84% 80%, 95%
94%, 84% 60%, 90%
90%, 84% 70%, 90%
b
>99%, 91% >99%,94% >99%, 90% 40%, 80% >99%, 93%
90%, 93% >99%,96% >99%, 90% 83%, 90% >99%, 94%
65%, 73% >99%, 86% >99%, 58% 98%, 90%
81%, 85%
63%, 85%
72%, 80%
23%, 43%
70%, 76%
19%, 43%
92%, 60% 84%, 90%
35%, 20%
>99%, 80% >99%, 82% >99%, 76%
50%, 0% >99%, 79%
>99%, 10%
97%, 65%
a Conversion, ee. b Cu(naphthenate)2. c CuTC: copper(I) thiophene-2-
carboxylate.
Scheme 2
The new ligands L1, L2, and L3 (eq 1) were designed upon
hypothesizing that the induced atropoisomerism of the flexible
biphenol unit will adopt the configuration of the matched binaph-
thol-related ligand L4. These ligands were in many cases as good
or even better than the parent ligand L4.7 However, we felt that
there was still room for improvement. Thus, we have tested the
basic ligand L1 (Scheme 1), the least efficient one, with different
copper sources, and in various solvents (Table 1).
Both copper(I) and copper(II) species were tested. Copper(II)
salts usually have the advantage of being cheaper and easier to
handle. The reduction to the true catalytic species Cu(I) is done in
situ by Et2Zn (Scheme 2). All the experiments in Table 18 were
run under the same experimental conditions, whatever the copper
source or the solvent (Cu/ligand ratio 1/2, temperature -30 °C,
reaction time 3 h), then quenched with dilute HCl. Some general
trends may be readily drawn. First, acetonitrile is not an adequate
solvent for the conjugate addition, most conversions being very
low.2a Second, with the exception of CuCl, CuSPh, and Cu(ClO4)‚
6H2O, most mineral salts gave low conversion and/or low to
moderate ee values. All comparisons are made with the previous
standard conditions (toluene, Cu(OTf)2), which gave complete
conversion and 82% ee (Entry 1).
The solvent study shows that several solvents may be used in
this reaction. THF and EtOAc afford high levels of enantioselec-
tivity. However, with both these solvents, the rate of the reaction
is slower, although longer reaction time brings the reaction to
completion.2b Entry 1, with Cu(OTf)2, clearly demonstrates that as
far the enantioselectivity is concerned, higher ee values are obtained
in ethereal solvents (Ether, THF, and EtOAc). This result contrasts
to the usual belief that a noncoordinating solvent, such as toluene,
is the most appropriate for the Cu-catalyzed conjugate addition of
dialkyl zincs.2
In view of previous studies, it was believed that Cu(OTf)2 was
the most efficient Cu salt for this reaction.2,3c,e This effect has been
ascribed to the higher Lewis acidity of this salt as compared to
* Corresponding author. E-mail: alexandre.alexakis@chiorg.unige.ch.
9
5262
J. AM. CHEM. SOC. 2002, 124, 5262-5263
10.1021/ja025598k CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Conjugate Addition with L1 to L4
With the exception of chalcone (Entry 4), acyclic enones gave spec-
tacular improvements of the enantioselectivity. Thus, benzalacetone
(Entry 3) gave 93% ee with L2 (from 53% under the previous con-
ditions) and 93% with L4 (from 80% ee). trans-Nonenone (Entry
5) gave 81% ee with L1. It should be pointed out that ligand L5
also gave an improved result with 70% ee, from 57% on the trans-
nonenone with CuTC.4a The ee of 5-methyl-3-hexen-2-one (Entry
6) went up to 80% (L4), instead of 31% under the previous
conditions.4a
Similar improvements were noticed with nitro-olefins. Nitrosty-
rene (Entry 7) gave up to 82% ee with L2, a slightly better result
than with our previous best ligand L6,4b whereas nitrocyclohexene
(Entry 8) gave 95% ee with both L2 and L4, the best reported ee
for this substrate.
In conclusion, we have shown that the new experimental condi-
tions greatly improve the enantioselectivity of the conjugate addition
of dialkyl zincs to several Michael acceptors, and specifically >99%
ee for 2-cyclohexenone. Cu(OTf)2 as the copper source could be
advantageously replaced by much cheaper copper carboxylates. In
addition, we demonstrated that other solvents than toluene are toler-
ated, a result that may solve the problem of the poor solubility of
some substrates. Finally, we have shown that the Lewis acidity of
the copper salt, previously believed to play an important role, is
not a significant factor.
Acknowledgment. The authors thank the Swiss National
Research Foundation No. 20-61891.00 and COST action D12/0022/
99 for financial support, and Frontier Scientific Ltd for a generous
gift of CuTC.
a Reaction in toluene. b New reactions in ether. c 98% ee with Bu2Zn.
Supporting Information Available: Full results on all copper salts,
experimental procedures, and analytical data of the conjugate adduct
(Chiral GC, SFC, HPLC) (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
most other Cu salts. We found that Cu carboxylates, either Cu(I)
or Cu(II), are even more efficient (entries 2-7). It is clear that the
Lewis acid effect is not involved in the degree of enantioselectivity,
nor on the reaction rate. A more careful look on the various Cu
carboxylates shows that the best Cu salts are Cu(OCOCF3)2, in THF
(Entry 3), Cu(OAc)2‚H2O9 in ether (Entry 5), and copper thiophene-
2-carboxylate (CuTC)10 in either toluene, ether, or ethyl acetate
(Entry 7). The degree of lipophilicity of the Cu salt seems to play
some role: copper thiophene-2-carboxylate (CuTC) and Cu naph-
thenate perform better than Cu(OAc)2. Cu naphthenate is a
particularly interesting salt, as it is soluble even in hydrocarbon
solvents. It is also interesting to note that Cu(OAc)2‚H2O is slightly
better than Cu(OAc)2. Whether the water molecule plays any role
is still an open question.11 Finally, a comparison of the cost of the
Cu salt is worth noting: Cu(OAc)2‚H2O and Cu naphthenate, the
cheapest salts, are also among the best.
References
(1) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033. Alexakis in Transition Metal
Catalysed Reaction; Murahashi, S.-I., Davies, S. G., Eds.; IUPAC
Blackwell Science: Oxford, 1999; p 303.
(2) (a) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993,
4, 2427. (b) Alexakis, A.; Vastra, J.; Mangeney P. Tetrahedron Lett. 1997,
38, 7745 (c) De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2374.
(3) (a) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988. (b) Morimoto,
T.; Yamagushi, Y.; Suzuki, M.; Saitoh, A. Tetrahedron Lett. 2000, 41,
10025. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (d) Escher, I.
H.; Pfaltz, A. Tetrahedron 2000, 56, 2879. (e) Yan, M.; Zhou, Z. Y.;
Chan, A. S. C. Chem. Commun. 2000, 2, 115. (f) Alexakis, A.; Vastra, J.;
Burton, J.; Benhaim, C.; Fournioux, X.; Van den Heuvel, A.; Leveˆque,
J.-M.; Maze´, F.; Rosset, S. Eur. J. Org. Chem. 2000, 24, 4011. (g)
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755.
(4) (a) Alexakis, A.; Benhaim, C.; Fournioux, X.; van denHeuvel, A.; Leveˆque,
J.-M.; March, S.; Rosset, S. Synlett 1999, 11, 1811. (b) Alexakis, A.;
Benhaim, C. Org. Lett. 2000, 2, 2579. (c) Alexakis, A.; Benhaim, C.
Tetrahedron: Asymmetry 2001, 12, 1151.
We believe that, by analogy to copper sulfonamide,12 Cu-
carboxylates serve as efficient bridge for a mixed zinc cuprate
complex, the active nucleophilic species (Scheme 2).
(5) Wendisch, V.; Sewald, N. Tetrahedron: Asymmetry 1997, 8, 1253.
(6) Bo¨rner, C.; Denis, M. R.; Sinn, E.; Woodward, S. Eur. J. Org. Chem.
2001, 2435.
(7) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim,
C. Synlett 2001, 9, 1375.
(8) The full list of the tested Cu-salts is available in the Supporting
Information.
Having established the most appropriate experimental conditions
for cyclohexenone, we examined the behavior of other Michael
acceptors. The experiments were performed with Cu(OAc)2‚H2O,
Cu naphthenate (the cheapest), and copper thiophene-2-carboxylate
(CuTC) (the most efficient), in Et2O solvent, and with all three
ligands L1, L2, and L3. In addition, the parent ligand L4 was also
tested under the same conditions. All reactions were carried out
until complete conversion, and the results are shown in Table 2.
Cyclohexenone is usually the standard substrate for testing the
asymmetric conjugate addition. Ligands L2 and L3 gave greatly
improved results with the highest reported ee of 99.1%, thus sur-
passing the parent ligand L4 (Entry 1). Although cycloheptenone
followed the same trend, the best ee was 95%, with L1 (Entry 2).
(9) Christoffers has reported the use of Cu(OAc)2H2O to perform Michael
reactions with very good results: Christoffers, J. Synlett 2001, 6, 723.
(10) This salt has been shown to be very efficient in the cross-coupling
reaction: Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91.
(11) (a) Keller, E.; Maurer, J.; Naasz, R.; Schader, T.; Meetsma, A.; Feringa,
B. L. Tetrahedron: Asymmetry 1998, 9, 2409. (b) Delapierre, G.;
Constantineux, T.; Brunel, J. M.; Buono, G. Eur. J. Org. Chem. 2000,
2507.
(12) Kitamura, M.; Miki T.; Nakano, K.; Noyori, R. Bull. Chem. Soc. Jpn.
2000, 73, 999.
JA025598K
9
J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002 5263