Chiral aminophosphine-oxazoline auxiliaries applied to copper-catalysed enantioselective 1,4-additions to enones

Article abstract of DOI:10.1016/j.tetasy.2004.01.002

A series of chiral aminophosphine-oxazoline auxiliaries has been prepared and applied in the copper-catalysed 1,4-addition of diethylzinc to enones. The addition products are obtained quantitatively in up to 67% ee. The most efficient ligand of the series is based on L-indoline carboxylic acid and L-valinol.

Full text of DOI:10.1016/j.tetasy.2004.01.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 757–761
Chiral aminophosphine–oxazoline auxiliaries applied to
copper-catalysed enantioselective 1,4-additions to enones
Catherine Blanc and Francine Agbossou-Niedercorn*
Laboratoire de Catalyse de Lille, UMR CNRS 8010, ENSCL, BP 108, 59652 Villeneuve d’Ascq Cedex, France
Received 2 December 2003; revised 19 December 2003; accepted 6 January 2004
Abstract—A series of chiral aminophosphine–oxazoline auxiliaries has been prepared and applied in the copper-catalysed 1,4-
addition of diethylzinc to enones. The addition products are obtained quantitatively in up to 67% ee. The most efficient ligand of the
series is based on L-indoline carboxylic acid and L-valinol.
Ó 2004 Elsevier Ltd. All rights reserved.
The catalytic asymmetric conjugate addition to a,b-
unsaturated systems is one of the most important
organic synthetic methodologies allowing a stereoselec-
tive formation of C–C bonds.1;2 Several chiral catalysts
have been developed to promote such transformations.2
Previously, the enantioselective conjugate addition of
organometallic reagents (Grignard reagents, organo-
lithium derivatives, and dialkylzinc species) has been
assisted more or less efficiently by chiral copper3 and
nickel catalysts.4
applied them with success in the enantioselective copper-
catalysed additions of alkylzinc to acyclic aliphatic
enones.12
During our continuing search for new chiral auxiliaries
based on the chiral pool,13 we have prepared a new
family of aminophosphine–oxazolines and reported on
their successful use in asymmetric allylic alkylation.14
Here, we report on the synthesis of new ligands of that
family and on their use in copper-catalysed conjugate
additions to enones.
The catalytic system introduced originally by Alexakis
et al., which is composed of an organozinc reagent and a
copper complex modified by a trivalent chiral phos-
phorus based auxiliary,5 has undergone a noteworthy
development. Actually, the various phosphorus based
chiral auxiliaries designed afterwards for that catalytic
reaction were based either on monodentate or on
bidentate ligands. As such, Feringa and co-workers has
introduced phosphoramidites as chiral ligands in cop-
per-catalysed 1,4-additions of dialkylzinc reagents.6
Additional phosphoramidites7 and other monodentate
phosphorus based auxiliaries have been designed based
on TADDOL, binaphthol or tartrate and used with
success.7–9 Phosphorus based bidentate ligands have also
been used, that is, diphosphite10 and phosphite–oxazo-
lines.11 For the synthesis of new chiral auxiliaries, the
use of the chiral pool as the source constitutes an
interesting alternative. As such, Hoveyda and co-work-
ers prepared phosphorus ligands based on peptides and
The aminophosphine–oxazoline ligands 1a and 1b
(Scheme 1) based on (S)-indoline carboxylic acid have
been prepared following the synthesis reported previ-
ously for ligands 2a and 2b based on proline and 3a and
3b based on tetrahydroisoquinoline carboxylic acid.14
Thus, the two new ligands have been synthesized fol-
lowing the route depicted in Scheme 2.14 Commercial
(S)-indoline carboxylic acid 4 was first converted into its
methyl ester 5. Then, the reaction of 5 with chloro-
diphenylphosphine in the presence of triethylamine in
THF provided the intermediate aminophosphine deriv-
ative, which was protected as a thiophosphine in the
presence of sulfur in toluene. The aminothiophosphine 6
was isolated after work-up in 65% yield for the two
steps. The acid 7 was obtained through hydrolysis of the
ester 6. Then, in separate experiments, a standard pep-
tide coupling between 7 and both isomers of valinol
provided the two diastereomeric aminothiophosphines
8a and 8b, quantitatively after work-up. The oxazolines
9a and 9b were obtained easily via cyclisation of the
corresponding amidoalcohols 8a and 8b in the presence
of p-tosylchloride under basic conditions and isolated in
* Corresponding author. Tel.: +33-03-20-43-49-27; fax: + 33-03-20-43-
65-85; e-mail: francine.agbossou@ensc-lille.fr
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.002

758
C. Blanc, F. Agbossou-Niedercorn / Tetrahedron: Asymmetry 15 (2004) 757–761
O
O
O
O
Cu(OTf)2
(cat)
N
N
Et2Zn
+
N
chiral aux.
N
PPh2
PPh2
10
12
1a
2a
1b
O
O
Cu(OTf)2
(cat)
O
O
N
N
+
Et2Zn
N
N
chiral aux.
Ph
Ph
Ph
Ph
PPh2
PPh2
11
Scheme 3.
2b
13
O
O
N
N
In order to investigate the influence of the chiral
aminophosphine and oxazoline moieties, the ligands
were next applied in copper-catalysed enantioselective
additions to enones.16 Two model substrates have been
investigated, that is, the cyclic 2-cyclohexenone 10 and
the acyclic chalcone 11 (Scheme 3). The results are
summarised in Table 1. For our first attempts, we con-
sidered the reaction between 10 and ZnEt2 in the pres-
ence of either Cu(OTf)2-1a or Cu(OTf)2-1b in toluene
(entries 1 and 2). The precatalysts Cu(OTf)2-1a and
Cu(OTf)2-1b were prepared ex situ through reaction of
N
N
PPh2
PPh2
3b
3a
Scheme 1.
52–60% yields.15 Finally, the aminophosphine residues
were recovered from 9a and 9b through reduction with
Ni-Raney in THF providing 1a and 1b in ca. 95% yield.
O
O
1) Ph2PCl, NEt3
MeOH
OH
THF
OMe
SOCl2
2) S8, Toluene
N
N
H
H
5
4
O
O
LiOH
MeOH
OMe
OH
N
N
PPh2
PPh2
S
S
6
7
O
p-TsCl
OH
(R)-valinol
N
H
DMAP
CH2Cl2
BOP, NEt3
CH3CN
N
PPh2
8a
S
O
O
Ni Raney
THF
N
N
N
N
PPh2
PPh2
S
1a
9a
Scheme 2.

C. Blanc, F. Agbossou-Niedercorn / Tetrahedron: Asymmetry 15 (2004) 757–761
Table 1. Cu catalysed conjugate addition of diethylzinc to enonesa
759
Entry
Enone
Ligand
Solvent
Temp. (°C)
Conv. (%)b
Ee (%) (config.)c
1
10
1a
1b
2a
2b
3a
3b
1a
1a
1a
1a
1b
2b
3b
2b
2b
1b
2b
3b
Toluene
Toluene
)20
)20
)20
)20
)20
)20
)20
)20
)20
20
100
100
100
100
100
100
100
99
47 (S)
62 (S)
35 (S)
63 (S)
34 (S)
29 (S)
43 (S)
24 (S)
27 (S)
41 (S)
32 (S)
37 (S)
37 (S)
67 (S)
61 (S)
30 (S)
6 (S)
2
3
Toluene
Toluene
Toluene
4
5
6
Toluene
7
Toluene/hexaned
THF/hexaned
Toluene/hexane
Toluene
8
9e
10
11
12
13
14f
15g
16
17
18
88
100
100
100
100
100
100
100
100
100
Toluene
Toluene
20
20
Toluene
Toluene
20
)20
)20
)20
)20
)20
Toluene
Toluene
11
Toluene
Toluene
11 (S)
a The catalytic reactions were carried out in the presence of a ligand/Cu initial ratio of 1.2 unless otherwise stated. Substrate/Cu: 100.
b The conversions were determined by 1H NMR on the crude reaction mixture through integration of allyl and ethyl groups.
c Enantiomeric excesses were determined by chiral GC analysis using a Lipodex E column. The configurations were determined by comparison with
literature data.18
d The hexane corresponds to the amount introduced while adding ZnEt2 1.1 M in hexane to the precatalyst in solution in the mentioned solvent
(actual mixture: 1/1).
e Using Cu(MeCN)PF6 as catalyst.
f 0.5 mol % initial copper amount.
g 2.5% initial copper amount.
Cu(OTf)2 with the corresponding auxiliary 1a or 1b
(ligand to copper ratio: 1.2) in toluene at room tem-
perature for 2 h. Then, after lowering the temperature to
)20 °C, ZnEt2 (in solution in toluene 1.1 M) was added
to the homogeneous solution followed by the enone. In
the presence of 1 mol % of an initial copper complex
amount, the two reactions went to completion within,
nonoptimised, 15 h and provided selectively the 1,4-
addition product 12 in 47% and 62% ee, respectively
(entries 1 and 2). It has to be noticed that the reaction
went also to completion within 30 min at )20 °C. This
experimental procedure was perfectly reproducible.
While applying the same catalytic conditions for reac-
tions carried out in the presence of the ligands 2a, 2b, 3a
and 3b, total conversions are also obtained and the
addition product 12 was isolated in 29–63% ee (entries
3–6). The two auxiliaries 1b and 2b exhibit identical
selectivities (entries 2 and 4). Interestingly, the same
enantiomer (S) of the product 12 is formed with the
three pairs of diastereomeric chiral auxiliaries (1a/1b, 2a/
2b, 3a/3b). For ligands 1a/1b and 2a/2b the (S,R) ligands
are providing the highest eeÕs (entries 2 and 4), whereas
the opposite is true for the pair 3a/3b where the (S,S)
ligand 3b is leading to a higher ee value (entry 5). Thus,
there is no obvious trend observed within this ligand
series in correlation with the level and sense of asym-
metric induction for the 1,4-addition reaction.
selectivity (Dee ¼ )23%). This important decrease is
attributed to the THF solvent used. Indeed, in our case,
a noncoordinating solvent seems the most appropri-
ate.5;6;17
When the copper(I) complex [Cu(MeCN)]PF6 was
employed to prepare the catalyst instead of Cu(OTf)2,
the reaction was slightly slower as a conversion of 88%
was reached and the addition product 12 was obtained
in only 27% ee (entry 9 vs 7) (Dee ¼ )16%). Thus, cop-
per(II) precatalysts are preferably used over copper(I)
species, the former being also easier to handle.
On the other side, the reaction is quite sensitive to the
temperature. Indeed, a reaction carried out at room
temperature is leading to a slightly lower selectivity in
the presence of ligand 1a (Dee ¼ )6%) (entry 10 vs 1)
whereas a more significant decrease is observed with
ligands 1b (Dee ¼ )30%) (entry 11 vs 2), and 2b
(Dee ¼ )26%) (entry 12 vs 4). On the contrary, an
opposite variation is observed with ligand 3b
(Dee ¼ +9%) (entry 13 vs 6).
The overall conformational rigidity presented by the
auxiliaries 1a/1b and 2a/2b due to the presence of the
five-membered ring skeleton bearing the aminophos-
phine residue is probably very similar as close asym-
metric inductions are achieved with the corresponding
copper catalysts. The flexibility of the six-membered
cycle of 3a and 3b prevents the preferential formation of
a single well defined complex in solution and leads to
several less selective conformations. Such a behaviour
can explain the opposite impact on the selectivity
observed with the diastereomeric auxiliaries 3a and 3b.
The addition was also carried out with ZnEt2 in solution
in hexane while the precatalyst was prepared either in
toluene (entry 7) or in THF (entry 8). The presence of
hexane is slightly detrimental to the enantioselectivity
(Dee ¼ )4%) when associated to toluene. The mixture
THF/hexane led to a more significant decrease of the

760
C. Blanc, F. Agbossou-Niedercorn / Tetrahedron: Asymmetry 15 (2004) 757–761
Chapter 31.1; (c) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994; (d) Hayashi,
T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829; Review on
copper catalyzed organozinc additions: Feringa, B. L.;
Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organo-
copper Chemistry; Krause, N., Ed.; Wiley-VCH GmbH:
Weinheim, 2002; p 224, Chapter 7; (e) Alexakis, A.;
Benhaim, C.. Eur. J. Org. Chem. 2002, 3221; (f) Sibi, M.
P.; Manyem, S.. Tetrahedron 2000, 56, 8033; (g) Krause,
N.; Hoffmann-Roder, A.. Synthesis 2001, 171.
By lowering the initial concentration of the chiral cata-
lyst to 0.5 mol %, the ee of the addition product 12
increased slightly to 67% (Dee ¼ +4%) (entry 14 vs 4),
whereas, an increase of the concentration to 2.5% led to
a little drop of the ee was observed (Dee ¼ )2%) (entry
15 vs 4). As mentioned by Feringa and co-workers,
copper complexes at different concentrations may form
different catalytic species leading to different selectivi-
ties.6
3. (a) Ahn, K. H.; Klassen, R. B.; Lippard, S. J. Organomet-
allics 1990, 9, 3178; (b) Villacorta, G. M.; Rao, C. P.;
Lippard, S. J. J. Am. Chem. Soc. 1988, 110, 3175; (c) Van
Klaveren, M.; Lambert, F.; Eijkelkamp, D. J. F. M.; Grove,
D. M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135; (d)
Van Koten, G. Pure Appl. Chem. 1994, 66, 1455; (e)
Spescha, M.; Rihs, G. Helv. Chim. Acta 1993, 76, 1219; (f)
Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275;
(g) Tanaka, K.; Matsui, J.; Suzuki, H. J. Chem. Soc., Perkin
Trans. I 1993; 153; (h) Zhou, Q.-L.; Pfaltz, A Tetrahedron
1994, 50, 4467; (i) Feringa, B. L.; de Vries, A. H. M. In
Advances in Catalytic Processes; Doyle, M. D., Ed.; Jai:
Connecticut, USA, 1995, Vol. 1, p 151; (j) Jansen, J. F. G.
A.; Feringa, B. L. J. Chem. Soc., Chem. Commun. 1989, 741;
(k) Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem. 1990,
55, 4168; (l) Seebach, D.; Jeache, G.; Pichoto, A.; Auder-
gon, L. Helv. Chim. Acta 1997, 80, 2515; (m) Stangeland, E.
L.; Sammakia, T. Tetrahedron 1997, 53, 16503.
4. (a) Soai, K.; Hayasaka, T.; Ugajin, S.; Yokoyama, S.
Chem. Lett. 1988, 1571; (b) Soai, K.; Okuda, M.;
Okamoto, M. Tetrahedron Lett. 1991, 32, 95; (c) Soai,
K.; Yokoma, S.; Hayasaka, T.; Ebihara, K. J. Org. Chem.
1988, 53, 4148; (d) Soai, K.; Hayasaka, T.; Ugajin, S.
Chem. Commun. 1989, 516; (e) Bolm, C.; Ewald, M.
Tetrahedron Lett. 1990, 31, 5011; (f) Bolm, C.; Ewald, M.;
Felder, M. Chem. Ber. 1992, 125, 1205; (g) De Vries, A. H.
M.; Imbos, R.; Feringa, B. L. Tetrahedron: Asymmetry
1997, 8, 1467; (h) Jansen, J. F. G. A.; Feringa, B. L.
Tetrahedron: Asymmetry 1992, 3, 581; (i) Fujisawa, T.;
Itoh, S.; Shimizu, M. Chem. Lett. 1994, 297.
The results show that both the chiral oxazoline and the
chiral aminophosphine units have an influence on the
enantioselectivity of the process. The stereochemical
outcome of the reaction seems however to be essentially
related to the configuration of the aminophosphine
residue as the chirality is imposed by the aminophos-
phine framework alone. Indeed, the absolute stereo-
chemistry of the addition product is the same in all cases
where homochiral aminophosphine skeletons have been
used.
Under similar catalytic conditions, the conjugate addi-
tion of diethyl zinc to chalcone 11 provided the addition
product 13 with overall lower selectivities, up to 30% ee
in the presence of 1b (entries 16–18). This feature is
frequently observed while comparing the selectivities of
the addition to this two substrates 10 and 11.
In summary, we have described the easy preparation of
new aminophosphine–oxazolines and their use in cop-
per-catalysed conjugate additions to enones. The selec-
tivities induced by these new chiral auxiliaries are in line
with the behaviour of other bidentate auxiliaries con-
taining a phosphine. The potential of the reported
auxiliaries in other asymmetric transformations is under
investigation in our laboratory.
5. Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron:
Asymmetry 1993, 4, 2427.
6. De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2374.
7. Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
Acknowledgements
8. Keller, E.; Maurer, J.; Naasz, R.; Schader, T.; Meetsma,
A.; Feringa, B. L. Tetrahedron: Asymmetry 1998, 9, 2409.
9. Arnold, L. A.; Imbos, R.; Maudoli, A.; De Vries, A.;
Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
10. (a) Yan, M.; Chan, A. Tetrahedron Lett. 1999, 40, 6645;
We thank CNRS and MEN (grant to C.B.) for financial
support.
ꢀ
(b) Pamies, O.; Dieguez, M.; Net, G.; Ruiz, A.; Claver, C.
Tetrahedron: Asymmetry 2000, 11, 4377.
References and notes
11. Knochel, A.; Escher, I.; Pfaltz, A. Synlett 1997, 1429.
12. (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 755; (b) Mizutani, H.; Degrado,
S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 779.
13. Agbossou-Niedercorn, F.; Suisse, I. Coord. Chem. Rev.
2003, 242, 145.
1. (a) General reviews on 1,4-conjugate addition: Perlmutter,
P. In Conjugate Addition Reactions in Organic Synthesis;
Baldwin, J. E.; Magnus, P. D., Eds.; Tetrahedron Organic
Chemistry Series no. 9; Pergamon: Oxford; 1992; (b)
Schmalz, H.-G. In Comprehenvise Organic Synthesis;
Trost, B. M., Flemming, I., Eds.; Pergamon: Oxford,
1991; (c)Yamamoto, Y. In Stereoselective Synthesis;
Methods Org. Chem. (Houben-Weyl); Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schauman, E., Eds.;
Thieme: Stuttgart–New York, 1995; Vol. 4, p 2041; (d)
Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
2. (a) General reviews on asymmetric 1,4-conjugate addition:
Ojima, I. Catalytic Asymmetric Synthesis II; Wiley-VCH:
New York, 2000; (b) Tomioka, K.; Nagaoka, Y. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999,
14. Blanc, C.; Hannedouche, J.; Agbossou-Niedercorn, F.
Tetrahedron Lett. 2003, 44, 6469.
15. 9a: RMN 1H (300 MHz, CDCl3): d 0.76 (d, J ¼ 6:8 Hz,
3H, CH3); 0.87 (d, J ¼ 6:8 Hz, 3H, CH3); 1.55 (sext,
J ¼ 6:8 Hz, 1H, CH(CH3)2); 3.08 (dapp, J ¼ 16:2 Hz, 1H,
CHH0); 3.57 (dd, 1H, J ¼ 16:0 and 10.4 Hz, CHH0); 3.67
(dd, J ¼ 17:0 and 8.8 Hz, 1H, N–CH); 3.77 (tapp, 1H,
J ¼ 8:5 Hz, CHH0–O); 4.06 (dd, J ¼ 9:8 and 8.4 Hz,
1H, CHH0–O); 4.89 (m, 1H, CH); 6.38 (d, J ¼ 7:5 Hz,
1H, Harom); 6.85 (m, 1H, Harom); 7.15 (m, 1H, Harom); 7.32
(m, 1H, Harom); 7.45–7.54 (m, 6H, Harom); 7.80–7.97 (m,

C. Blanc, F. Agbossou-Niedercorn / Tetrahedron: Asymmetry 15 (2004) 757–761
761
4H, Harom). RMN 31P (121.5 MHz, CDCl3): d 60.4 (s).
RMN 13C (50 MHz, CDCl3): d 18.5 (s, CH3); 19.2 (s,
CH3); 32.7 (s, CH(CH3)2); 35.0 (d, J ¼ 4:9 Hz, CH2); 58.3
(d, J ¼ 3:9 Hz, CH–N); 70.9 (s, CH2–O); 72.3 (d,
J ¼ 2:0 Hz, CH); 114.8 (d, J ¼ 2:5 Hz, Carom); 121.7–
132.8 (m, Carom); 144.9 (d, J ¼ 3:7 Hz, Carom); 166.6 (d,
J ¼ 2:5 Hz, C@O.). Anal. Calcd for C26H27N2OPS: C,
69.95; H, 6.01; N, 6.27. Found: C, 69.69; H, 6.20; N, 6.48.
1a: RMN 31P (121.5 MHz, CDCl3): d 43.1 (s).
2.7 mmol) was added. The reaction mixture was stirred at
)20 °C for 15 h and then quenched with a saturated
solution of NaHCO3. The organic phase was separated,
washed with brine, dried over MgSO4, and evaporated
under reduced pressure. Purification by flash chromato-
graphy gave 3-ethylcyclohexanone 12 in quantitative yield.
The enantiomeric excess was determined by chiral GC
using Lipodex E (carrier: H2 60 kPa; oven temperature:
90 °C; tR(R): 8.3 min; tR(S): 8.9 min).
16. Under nitrogen atmosphere, 1a (13.2 mg, 0.034 mmol,
1.2 mol %) was dissolved in dry degassed toluene (2 mL).
The solution was added to Cu(OTf)2 (10 mg, 0.027 mmol,
1 mol %) and the resulting solution was stirred at room
temperature for at least 2 h. The solution was transferred
via canula to a Schlenk tube cooled to )20 °C containing
Et2Zn (3.8 mL 1.1 M in toluene). The enone 10 (0.26 mL,
17. (a) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron
Lett. 1997, 38, 7745; (b) Yan, M.; Yang, L.-W.; Wong,
K.-Y.; Chan, A. S. C. Chem. Commun. 2001, 11; (c) Mori,
T.; Kosaka, Y.; Nakagawa, Y.; Nagaoka, Y.; Tomioka,
K. Tetrahedron: Asymmetry 1998, 9, 3175.
18. Alexakis, A.; Benhaim, C.; Rosset, S.; Human, M. J. Am.
Chem. Soc. 2002, 124, 5262.