Copper-catalysed asymmetric 1,4-addition of organometallic reagents to 2-cyclohexenone using novel phosphine-phosphite ligands

Article abstract of DOI:10.1016/S0957-4166(00)00262-7

A series of novel non-symmetrical phosphine-phosphite ligands 1-10 have been tested in the copper-catalysed asymmetric addition of diethylzinc and triethylaluminium to 2-cyclohexenone. In all cases, excellent conversion and regioselectivities for the 1,4-product were found. Good enantiomeric excesses (up to 62%) were obtained when triethylaluminium was used as the alkylating reagent. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00262-7

Tetrahedron: Asymmetry 11 (2000) 3161±3166
Copper-catalysed asymmetric 1,4-addition of organometallic
reagents to 2-cyclohexenone using novel phosphine-phosphite
ligands
Montserrat Dieguez,a,* Sirik Deerenberg,b Oscar Pamies,a Carmen Claver,a P. W. N. M.
van Leeuwenb,* and Paul Kamerb
a
Â
Departament de Quõmica Fõsica i Inorganica, Universitat Rovira i Virgili, Pl. Imperial Tarraco 1,
Â
Á
43005 Tarragona, Spain
Á
bInstitute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 166,
1018 WV Amsterdam, The Netherlands
Received 22 June 2000; accepted 5 July 2000
Abstract
A series of novel non-symmetrical phosphine-phosphite ligands 1±10 have been tested in the copper-
catalysed asymmetric addition of diethylzinc and triethylaluminium to 2-cyclohexenone. In all cases,
excellent conversion and regioselectivities for the 1,4-product were found. Good enantiomeric excesses
(up to 62%) were obtained when triethylaluminium was used as the alkylating reagent. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Catalytic asymmetric synthesis using organometallic reagents has become one of the most
active areas of research in modern organic synthesis.1 In this area, enantioselective conjugate
addition of organometallic reagents to a,b-unsaturated compounds is a powerful tool to form
carbon±carbon bonds and simultaneously introduce a new stereogenic centre in an organic
molecule.2 In most of these reactions, the addition of organolithium, Grignard and diorganozincs
to enones is catalysed by copper complexes.2 Although stoichiometric enantioselective additions
have been widely studied,2b only a few catalytic systems have provided high enantioselectivities.2
Excellent enantioselectivities have been obtained in the copper-catalysed Michael addition of
Grignard and diorganozinc reagents to enones and other a,b-unsaturated carbonyl compounds
using phosphorus ligands3 14 such as phosphorus amidites,3 7 oxazoline±phosphite8 and
* Corresponding authors. Tel: 34-977558046; fax: 34-977559563; e-mail: dieguez@quimica.urv.es; tel: 31-0-20 5255419;
fax: 31-0-20 5256456, pwnm@anorg.chem.uva.nl.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00262-7

Â
M. Dieguez et al. / Tetrahedron: Asymmetry 11 (2000) 3161±3166
3162
phosphite ligands.9 13 However, further investigations are required in order to understand how to
obtain an ecient enantiocontrol in this reaction.
Van Leeuwen et al. have recently described the synthesis of a new class of chiral phosphine-
phosphite ligands15 and their successful use in asymmetric palladium-catalysed allylic alkylations
(ee's up to 83%)16 and rhodium-catalysed hydrogenations (ee's up to 99%).17 It has also been
shown that the use of these ligands, which contain di€erent donor atoms viz. an electron-donating
phosphine, an electron-withdrawing phosphite, a€ects the reactivity and selectivity of the
catalyst.15 17 Herein we report the use of this new class of phosphine-phosphite ligands (Fig. 1) in
the enantioselective 1,4-addition of organocuprates to 2-cyclohexenone.
Figure 1.
This type of ligand has the advantage that many structural variations can be made that can
provide information about the e€ects of the di€erent stereocentres on the enantioselectivity. This
study may give some insight into the origin of the stereochemistry of the reaction. The e€ect of
the stereogenic phosphine moiety has been investigated by introducing di€erent substituents at
the phosphorus atom. The in¯uence of the group attached to the stereogenic carbon next to the
phosphite moiety and the size of the substituent have also been studied. Furthermore, we
investigated the e€ect of the chain length using ligands 9 and 10. To the best of our knowledge,
this is the ®rst example of the use of phosphine-phosphite ligands in the 1,4-addition of
organocuprates to enones.
2. Results and discussion
We tested ligands 1±10 in the copper-catalysed conjugate addition of diethylzinc to 2-cyclo-
hexenone: results are shown in Table 1. The catalytic system was generated in situ by adding 1
equivalent of the corresponding ligand to a dichloromethane solution of Cu(OTf)2. Total
conversions and excellent regioselectivities for the 1,4-product were found for all ligands. No 1,2-
product was observed by gas chromatography.

Â
M. Dieguez et al. / Tetrahedron: Asymmetry 11 (2000) 3161±3166
3163
Table 1
Catalytic conjugate addition reactions of ZnEt2 to 2-cyclohexenonea
The e€ect of the temperature and catalyst loading were studied using ligand 1. Increasing the
catalyst loadings increased the conversion but the regioselectivity for the 1,4-product and
enantioselectivity were not a€ected (entries 1 and 2). In contrast to Cu±diphosphite catalysts,13
better enantioselectivities were obtained at low temperature (entries 1, 3±5). Within the accuracy
of these experiments, there was no change in the enantioselectivities over time. This agrees with
the presence of the same aggregates during the reaction time.
By comparing the results obtained with the di€erent substituted ligands 1±6, we can conclude
that the introduction of sterically demanding groups on the phosphine moiety has a negative

Â
M. Dieguez et al. / Tetrahedron: Asymmetry 11 (2000) 3161±3166
3164
in¯uence on activities (TOF) (entries 1, 6±10). Using the (RP,SC) ligand 1 the (S)-product was
obtained with 17% ee, whereas the diastereoisomeric (RP,RC) ligand 2 gave the opposite
enantiomer in only 7% ee (entries 1 and 6). Apparently, both the con®guration of the phosphine
moiety and the con®guration of the carbon next to the phosphite moiety are essential for
enantiocontrol.
Changing the substituent of the stereogenic centre next to the phosphite in¯uences both
conversion and enantioselectivity. Ligands 7 and 8, which contain a methyl substituent, gave
lower conversions and enantioselectivities than ligands 1 and 5 with a phenyl substituent (entries
11 and 12 versus 1 and 9).
The in¯uence of the chain length was also investigated with ligands 9 and 10. Better
conversions and enantioselectivities were observed for the more rigid ligands 9 and 10 (entries 13
and 14). Unexpectedly, and unlike the observed co-operative e€ect between phosphine and
carbon next to the phosphite observed with related ligands 1 and 2, changing the con®guration of
this stereocentre does not a€ect the enantioselectivity.
Although Michael additions of organolithium, Grignard and diorganozinc reagents to enones
have been widely studied in the last decade,2 very little attention has been paid to
trialkylaluminium reagents.18 20 Table 2 shows the results of the copper-catalysed conjugate
addition of triethylaluminium to 2-cyclohexenone. It is noteworthy that better results have been
obtained using [Cu(MeCN)4]BF4 instead of Cu(OTf)2 as a catalyst precursor.
Table 2
Catalytic conjugate addition reactions of AlEt3 to 2-cyclohexenonea
Using the (RP,RC) phosphine-phosphite ligand 10 excellent conversion and good enantio-
selectivity (up to 62%) were obtained (entry 1), whereas for the diastereoisomeric ligand 9 and
related (RP,SC) ligand 1, with one more carbon atom in the backbone, much lower

Â
M. Dieguez et al. / Tetrahedron: Asymmetry 11 (2000) 3161±3166
3165
enantioselectivities were obtained (entries 3 and 4). Moreover, by comparing the enantio-
selectivities from ligand 10 by using ZnEt2 and Cu(OTf)2 (Table 1, entry 14) and AlEt3 and
[Cu(MeCN)4]BF4 (Table 2, entry 1) we can conclude that for phosphine-phosphite ligands not
only the con®guration of the phosphine and the sterogenic centre next to the phosphite in¯uence
enantioselectivities, but that the catalyst precursor and the nature of the alkylating reagent are
also important in determining enantioselectivity.
Encouraged by the promising behaviour using ligand 10, further studies directed towards the
development of an ecient ligand are in progress.
3. Experimental
3.1. Typical procedure for the catalytic conjugate addition of diethylzinc 2-cyclohexenone
In a typical procedure a solution of Cu(OTf)2 (9 mg, 0.025 mmol) and phosphine-phosphite
(0.025 mmol) in dichloromethane (3 mL) was stirred for 30 min at room temperature. After
cooling to 273 K, diethylzinc (1 M sol. in hexanes, 3.5 mL, 3.5 mmol) was added. A solution of
2-cyclohexenone (0.24 mL, 2.5 mmol) and undecane as GC internal standard (0.25 mL) in
dichloromethane (3 mL) was then added. The reaction was monitored by GC. The reaction was
quenched with HCl (2 M) and ®ltered twice through ¯ash silica gel. The conversion and enantiomeric
excesses were measured by GC using a Lipodex-A column.
3.2. Typical procedure for the catalytic conjugate addition of triethylaluminium to 2-cyclo-
hexenone
In a typical procedure triethylaluminium (1 M sol., 3.5 mL, 3.5 mmol) and enone (0.6 M sol. in
CH2Cl2, 3.5 mL, 2.5 mmol) were introduced sequentially and in a dropwise manner over 10 min
to
a
CH2Cl2 solution (3 mL) containing phosphine-phosphite (0.025 mmol) and
[Cu(MeCN)4]BF4 (7.8 mg, 0.025 mmol) at 253 K. After 5 min the reaction was quenched with
HCl (2 M) and undecane as GC internal standard (50 mL) was added. The organic layer was
®ltered twice through ¯ash silica gel. The conversion and ee's were measured by GC using a
Lipodex-A column.
Acknowledgements
We thank the Spanish Ministerio de Educacion y Cultura and the Generalitat de Catalunya
(CIRIT) for ®nancial support (PB97-0407-CO5-01). Financial support from CW/STW is also
gratefully acknowledged (project no. 349-3590).
References
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J. Wiley & Sons: New York, 1994. (b) Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. (c) Halpern, J. Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: New York, 1985; Vol. 5. (d) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A; Yamamoto, H., Eds.; Springer: Berlin, 1999.

Â
M. Dieguez et al. / Tetrahedron: Asymmetry 11 (2000) 3161±3166
3166
2. For reviews, see: (a) Lipshutz, B. H. Synthesis 1987, 325. (b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771. (c) Alexakis, A. Organocopper Reagents, A Practical Approach; Taylor, R. J. K., Ed.; Oxford University
Press, 1994; Chapter 8. (d) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (e) Krause, N.
Angew. Chem., Int. Ed. Engl. 1998, 37, 283. (f) Alexakis, A. in Transition Metal Catalysed Reactions; Murahashi,
S.-I.; Davies, S. G., Eds.; IUPAC Blackwell Science: Oxford, 1999; 303.
3. de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374.
4. Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9, 1341.
5. Zhang, F. Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1998, 9, 1179.
6. Mori, T.; Kosaka, K.; Nakagawa, Y.; Nagaoka, Y.; Tomioka, K. Tetrahedron: Asymmetry 1998, 9, 3175.
7. Naasz, R; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104.
8. Knobel, A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 9, 1429.
9. Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney, P. Tetrahedron Lett. 1998, 39, 7869.
10. Yan, M.; Yang, L. W.; Wong, K. Y.; Chan, A. S. C. Chem. Commun. 1999, 1, 11.
11. Yan, M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645.
12. Yan, M.; Zhou, Z. Y.; Chan, A. S. C. Chem. Commun. 2000, 115.
13. Pamies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 1999, 10, 2007.
14. Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 3518.
15. Deerenberg, S.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organometallics 2000, 19, 2065.
16. Deerenberg, S.; Schrekker, H. S.; van Strijdonck, G. P. F.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Fraanje,
J.; Goubitz, K. J. Org. Chem., in press.
17. Deerenberg, S.; Pamies, O.; Dieguez, M.; Claver, C.; Kamer, P. C. J.; van Leeuwen, manuscript in preparation.
18. Bennett, S. M. W.; Brown, S. M.; Muxworthy, J. P.; Woodward, S. Tetrahedron Lett. 1999, 40, 1767.
19. Pamies, O.; Net, G.; Ruiz, A.; Claver, C.; Woodward, S. Tetrahedron: Asymmetry 2000, 11, 871.
20. Bennett, S. M. W.; Brown, S. M.; Cunningham, A.; Dennis, M. R.; Muxworthy, J. P.; Oakley, M. A.; Woodward,
S. Tetrahedron 2000, 56, 2847.