Copper-catalyzed enantioselective conjugate addition of dialkylzinc reagents to enones with new peptidyl phosphane ligands

Article abstract of DOI:10.1016/j.tetasy.2003.10.002

Copper catalysts based on new peptidyl phosphane ligands have been developed for enantioselective conjugate additions of dialkylzinc reagents to cyclic enones. Enantioselectivities greater than 97% ee have been observed.

Full text of DOI:10.1016/j.tetasy.2003.10.002

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3823–3826
Copper-catalyzed enantioselective conjugate addition of
dialkylzinc reagents to enones with new peptidyl phosphane
ligands
Bernhard Breit* and Andy Ch. Laungani
Institut fu¨r Organische Chemie und Biochemie, Albert-Ludwigs-Universita¨t Freiburg i. Br., 79104 Freiburg i. Br., Germany
Received 27 August 2003; accepted 2 October 2003
Abstract—Copper catalysts based on new peptidyl phosphane ligands have been developed for enantioselective conjugate
additions of dialkylzinc reagents to cyclic enones. Enantioselectivities greater than 97% ee have been observed.
© 2003 Elsevier Ltd. All rights reserved.
Copper-mediated and catalyzed conjugate addition of
carbon nucleophiles to Michael acceptors is one of the
fundamental C/C-bond forming transformations in
organic synthesis.1 In the course of this reaction stereo-
chemistry can be controlled either by the reagent/cata-
lyst or by the substrate.2 The latter case becomes
particularly powerful if substrate bound reagent-direct-
ing groups (RDG) are employed, as we have shown
recently.3 In particular ortho-diphenylphosphanylben-
zoate (o-DPPB) has been identified as an ideal RDG.4
However, a more efficient approach would rely on a
non-covalent attachment of the RDG through either
hydrogen bonding, Lewis acid base interactions, salt
bridges or attractive van der Waals interactions, since
this would allow to use substoichiometric amounts of a
RDG. Furthermore, if one would add chiral informa-
tion to such a non-covalent RDG system, a transition
from substrate to reagent control and hence, to asym-
metric catalysis would be realized (Fig. 1). We envi-
sioned peptidyl-modified o-DPPB systems as interesting
Figure 1. Concept from substrate direction with substrate bound reagent-directing groups (RDG) to asymmetric catalysis with
non-covalent bound RDG’s for conjugate addition with organocopper reagents.
* Corresponding author. Tel.: +49-761-203-6051; fax: +49-761-203-8715; e-mail: bernhard.breit@organik.chemie.uni-freiburg.de
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.002

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B. Breit, A. Ch. Laungani / Tetrahedron: Asymmetry 14 (2003) 3823–3826
candidates for this approach.5 Dependent on the
selected amino acids and their corresponding side
chains different sorts of attractive substrate ligand
interactions may be initiated.
and a promising ee of 83% were observed (Table 1,
entry 1). Changing the copper salt to CuTC, which was
reported recently as a superior copper(I) source for
these type of reactions,11 increased reactivity and enan-
tioselectivity of the catalyst to 88% ee (Table 1, entries
2 and 3). However, the best results were observed when
CuBr·SMe2 was employed in diethyl ether at −30°C to
give the (R)-configured conjugate adduct in quantita-
tive yields and an ee of 93% (Table 1, entries 6 and 7).12
Even better results were found when going to the
dipeptide ligand L,L-2. Thus, under identical conditions
(compare entries 7 and 12, Table 1) the reaction was
faster (2 h at −30°C) and gave the (R)-configured
conjugate adduct in quantitative yield and an ee of
>97%. To explore the role of the second amino acid,
the test reaction with ligand D,L-4 was studied. As
expected the (S)-configured adduct was obtained with
an ee of 89%. Hence, the amino acid, coupled to the
o-DPPB unit directly, is most important for the enan-
tiodiscriminating step, and its absolute configuration
determines the absolute configuration of the new
stereogenic center of the product. However, the second
amino acid provides a fine tuning, which can either lead
to an increase [matched case for L,L-2] or decrease
[mismatched case D,L-4] of enantioinduction. In order
to study the effect of a third amino acid ligands L,L,L-3
and D,D,L-5 were examined. The copper catalysts
derived from these ligands showed significantly reduced
ee’s, with 70 and 74%, respectively (Table 1, entries 14
As a first test reaction, copper-catalyzed conjugate
additions of dialkylzinc reagents to cyclic enones were
studied.6 For these type of substrates attractive sub-
strate/ligand interactions may have to rely on van der
Waals forces. Thus, we chose valine for the construc-
tion of o-DPPB-peptidyl ligands. Gennari et al.7 and
Hoveyda et al.8 have reported a similar class of ligands
for conjugate additions to cyclic and acyclic enones.
Ligands 1–5 (Fig. 2) were prepared as depicted in
Scheme 1. Thus, valine methylester was coupled with
N-Z-protected valine employing DCC/NEt3.9 Depro-
tection of the Z-group through hydrogenolysis9 was
followed by coupling with the third amino acid or by
coupling with the ortho-diphenylphosphanyl benzoic
acid.10 The tert-butyl-amide ligands 6 and 7 were pre-
pared following similar procedures.
In a first screening we looked at the copper-catalyzed
conjugate addition of diethylzinc to cyclohexenone,
which is a well-studied prototype for this class of
reactions (Table 1).6 The first experiments were done
with the monopeptide ligand L-1 and with
(CuOTf)2·PhMe as the copper(I) source. Good yields
Figure 2. New chiral peptidyl-o-DPPB ligands synthesized and examined in this study.
Scheme 1. Preparation of peptidyl-o-DPPB phosphanes. Reagents and conditions: (a) N-Z-Valine, DCC, NEt3, CH2Cl2, rt
(62–91%); (b) H2 (1 atm) Pd/C, MeOH, rt (95–99%); (c) N-Z-valine, DCC, DMAP, CH2Cl2, rt (28–66%); (d) o-DPPBA, DCC,
DMAP, CH2Cl2, rt (29–85%).

B. Breit, A. Ch. Laungani / Tetrahedron: Asymmetry 14 (2003) 3823–3826
3825
Table 1. Enantioselective copper-L* catalyzed conjugate addition of diethylzinc to cyclohexenone. Screening for optimal
reaction parameters
Entry
Ligand
Cu-salt
Solvent
T (°C)
t (h)
Conversion (%)a
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L,L-2
L,L-2
L,L-2
L,L-2
L,L-2
D,L-4
L,L,L-3
D,D,L-5
L-6
(CuOTf)2·PhMe
CuTC
CuTC
Toluene
Toluene
Ether
THF
Ether
Toluene
Ether
Toluene
Toluene
Toluene
Ether
Ether
Ether
Ether
Ether
Ether
Ether
−30
−30
−30
−30
−50 to −30
−50 to −30
−30
−50 to −30
−50 to −30
−50 to −30
−50 to −30
−30
6
2
5
19
5
3
4
6
5
4
4
2
2
20
21
3
100
99
100
97
94
95
96
85
95
92
97
95
95
89
95
98
89
97
82
94
96
83 (R)
88 (R)
84 (R)
62 (R)
85 (R)
89 (R)
93 (R)
84 (R)
82 (R)
93 (R)
95 (R)
>97 (R)
89 (S)
70 (R)
74 (S)
72 (R)
76 (R)
CuTC
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
(CuOTf)2·PhMe
CuTC
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
99
100
100
100
100
100
100
100
98
98
99
96
100
9
10
11
12
13
14
15
16
17
−30
−30
−30
−30
L,L-7
−30
<20
a Determined by GC analysis.
b Isolated yield after chromatographic work-up.
c Determined by chiral GC (GT-A).
Table 2. Enantioselective copper-catalyzed conjugate addi-
tion of dialkylzinc to cycloalkenones with L,L-2
and 15). Thus, attachment of a third amino acid,
irrespective of its configuration, is inferior for the lig-
ands ability to induce enantioselectivity. In a final stage
of ligand investigation, we examined the role of the
ester termination of the peptide chain. For this reason,
ligands L-6 and L,L-7 which possess a secondary amide
chain termination were explored. Interestingly, the cata-
lysts derived from these ligands gave significantly lower
stereoinduction (Table 1, entries 16 and 17). Hence, the
ester chain termination plays, for yet unknown reasons,
an important role for enantioinduction.
Entry
n
R
t (h)
Conv.a
Yieldb
ee (%)c
1
2
1
1
1
1
2
0
Et
2
2.5
23
23
4
100
100
91
95
76
98
96
n.d.
n.d.
75
>97 (R)
94 (R)
31 (R)
49 (R)
82 (R)
91 (R)e
n-Bu
Me
Me
Et
3
4d
5
Having identified the copper complex derived from
dipeptide ligand L,L-1 as the best catalyst, a small
survey of this catalysts’ scope with respect to substrate
structure and organozinc reagents was undertaken
(Table 2).
6
Et
1.5
100
77
a Determined by GC analysis.
b Isolated yield after chromatographic work-up.
c Determined by chiral GC (GT-A).
Thus, addition of the dibutyl zinc reagent to cyclo-
hexenone occurred with similar efficiency as observed
for diethyl zinc (see Table 2, entries 1 and 2). However,
addition of dimethyl zinc to cyclohexenone proved to
be problematic in both ether and toluene as the solvent
(Table 2, entries 3 and 4). When going from cyclo-
hexenone to cycloheptenone the ee dropped to 82%
(entry 5) for diethylzinc addition. However, for the
cylcopentenone system, which is generally regarded as a
difficult case for these reactions,8c good enantioselection
of 91% ee was detected (entry 6).
d Reaction was performed in toluene at −30°C.
e Determined by chiral HPLC (Chiralcel OB-H).
system to a non-covalent attractive interaction, has led
us to peptidyl-o-DPPB esters, which by nature are
chiral and hence, represent attractive ligands for asym-
metric catalysis.
This study has shown that for conjugate addition of
dialkylzinc reagents to enones the peptidyl-o-DPPB
systems provide efficient catalysts, which combine high
reactivity with high enantioselectivity. Furthermore,
these systems should offer a much broader potential,
In summary, starting with the idea of changing the
covalent connection of an RDG based on the o-DPPB

3826
B. Breit, A. Ch. Laungani / Tetrahedron: Asymmetry 14 (2003) 3823–3826
since their modular construction in combination with
the possibilities of solid phase peptide synthesis should
allow the adjustment of the ligands architecture and the
nature of its attractive interactions to the substrate by
changing the nature of the peptide side chain. Hence,
the peptidyl-o-DPPB systems have a great potential as
interesting ligands for many transition metal catalyzed
processes.
Imamoto, T. J. Am. Chem. Soc. 1999, 64, 2988–2989; (g)
Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879–2888.
7. For a similar combinatorial approach to chiral sulfon-
amide ligands, see: (a) Ongeri, S.; Piarulli, U.; Roux, M.;
Monti, C.; Gennari, C. Helv. Chim. Acta 2002, 85, 3388;
(b) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli, U.;
Ceccarelli, S. Chem. Eur. J. 2001, 7, 2628; (c) Chataigner,
I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 916–918.
8. (a) Hird, W.; Hoveyda, A. H. Angew. Chem. 2003, 115,
1314; Angew. Chem., Int. Ed. Engl. 2003, 42, 1276; (b)
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779–780; (c) Degrado, S. J.; Mizu-
tani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,
755–756.
9. Valine methylester and N-Z-valine are commercially
available. For the coupling with DCC/NEt3 and the
Z-deprotection, see: Ueda, T.; Saito, M.; Kato, T.; Izu-
miya, N. Bull. Chem. Soc. Jpn. 1983, 56, 568–572.
10. Typical procedure for the preparation of the best ligand:
Acknowledgements
We thank DFG, the Fonds of the Chemical Industry
and Krupp Foundation (Krupp Award for young uni-
versity teachers to B.B.) for financial support.
References
2-(diphenylphospanyl)-benzamido-L-valyl-L-valine
methylester L,L-2:
1. General reviews: (a) Posner, G. H. Org. React. 1972, 19,
1; (b) Yamamoto, Y. Angew. Chem. 1986, 98, 945; (c)
Lipshutz, B. H.; Sengupta, Z. Org. React. 1992, 41, 135;
(d) Organocopper Reagents—A Practical Approach, Tay-
lor, R. J. K., Ed.; Oxford University Press: New York,
1994; (e) Krause, N.; Gerold, A. Angew. Chem. 1997, 109,
194; Angew. Chem., Int. Ed. Engl. 1997, 36, 186. Conju-
gate addition: (f) Kozlowski, J. A. Comp. Org. Synth.
1991, 4, 169; (g) Rossiter, B. E.; Swingle, N. M. Chem.
Rev. 1992, 92, 771; (h) Krause, N. Kontakte (Darmstadt),
1993, 1, 3; (i) Yamamoto, Y. In Houben-Weyl, Methods
for Organic Synthesis, 1995; Vol. E21b, 2041. For appli-
cations towards total synthesis of prostaglandines: (j)
Noyori, R.; Suzuki, M. Angew. Chem. 1984, 96, 854–882;
Angew. Chem., Int. Ed. Engl. 1984, 23, 847–875.
2. Substrate control: (a) Breit, B.; Demel, P. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, 2002; Chapter 6, p. 188. Reagent control: Ref.
1g; (b) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L.
A. In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, 2002; Chapter 7, p. 224.
3. (a) Breit, B.; Demel, P. Tetrahedron 2000, 56, 2833; (b)
Breit, B. Angew. Chem. 1998, 110, 535; Angew. Chem.,
Int. Ed. Engl. 1998, 37, 525.
To a solution of
L-valyl-L-valine methylester (0.900 g,
3.91 mmol), 2-(diphenylphosphino)-benzoic acid (1.33 g,
4.34 mmol) and DMAP (0.480 g, 3.93 mmol) in anhy-
drous dichloromethane (20 ml) was added at room tem-
perature DCC (0.910 g, 4.41 mmol). The resultant yellow,
chalky mixture was stirred at room temperature for fur-
ther 20 h. The mixture was filtered through a 2-cm pad of
Celite (wetted with dichloromethane), and the filter cake
was washed with dichloromethane (2×20 ml). After con-
centration in vacuo, the residue was chromatographed on
silica gel (petrolether/ethyl acetate, 2:1) to give ligand
L,L-2 as a glass foam (1.74 g, 85%, Rf 0.49). Mp 65–
67°C; [h]2D6=−22.6 (c 0.975, CHCl3); 1H NMR (300
MHz, CDCl3): l=0.84 (d, J=6.9 Hz, 3H), 0.87–0.97 (3d,
J=7.3 Hz, J=7.1 Hz, J=7.0 Hz, 9H), 2.05–2.22 (m, 2H),
3.73 (s, 3H), 4.38 (dd, J=8.2, 6.3 Hz, 1H), 4.52 (dd,
J=8.6, 5.0 Hz, 1H), 6.46 (bd, J=8.5 Hz, 1H), 6.54 (bd,
J=8.2 Hz, 1H), 6.96–7.02 (m, 1H), 7.21–7.44 (m, 12H),
7.60–7.67 (m, 1H); 13C NMR (100 MHz, CDCl3): l=
18.1, 18.2, 19.1, 19.2, 30.9, 31.2, 57.5, 59.4, 60.5, 127.9,
128.7 (d, J=5.8 Hz, 4C), 128.8, 128.9 (d, J=5.8 Hz, 2C),
129.0, 130.6, 132.1 (d, J=10.2 Hz), 132.4 (d, J=8.7 Hz),
132.6, 133.7 (d, J=20.3 Hz, 2C), 133.9 (d, J=20.3 Hz,
2C), 134.6, 169.0, 170.9, 172.0; 31P NMR (121 MHz,
CDCl3): l=−10.3. Anal. calcd for C30H35N2O4P: C,
69.48; H, 6.80; N, 5.40. Found: C, 69.22; H, 6.67; N,
5.14.
4. Breit, B. Chem. Eur. J. 2000, 6, 1519.
5. For other types of peptidyl modified phosphane ligands
for asymmetric catalysis, see: (a) Gilbertson, S. R.; Col-
libee, S. E.; Agarkov, A. J. Am. Chem. Soc. 2000, 122,
6522–6523; (b) Agarkov, A.; Uffman, E. W.; Gilbertson,
S. R. Org. Lett. 2003, 5, 2091–2094.
6. For reviews, see: (a) Alexakis, A. Eur. J. Org. Chem.
2002, 3221; Krause, N.; Hoffmann-Ro¨der, A. Synthesis
2001, 171. See also: Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2620–2623; (b) Strangeland, E. L.;
Sammakia, T. Tetrahedron 1997, 53, 16503–16510; (c)
Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.;
Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104–1105;
(d) Alexakis, A.; Benhaim, C.; Fournioux, X.; van den
Heuvel, A.; Leveque, J.-M.; March, S.; Rosset, S. Synlett
1999, 1811–1813; (e) Hu, X.; Chen, H.; Zhang, X. Angew.
Chem., Int. Ed. 1999, 38, 3518–3521; (f) Yamanoi, Y.;
11. Alexakis, A.; Benhaim, C. B.; Rosset, S.; Humam, M. J.
Am. Chem. Soc. 2002, 124, 5262.
12. General procedure for the catalytic conjugate addition of
dialkylzinc to enones:
A solution of CuBr·SMe2 (2.1 mg, 0.01 mmol) and chiral
ligand L,L-2 (12.5 mg, 0.024 mmol) in diethyl ether (1.5
ml) was stirred for 30 min. The pale green solution was
cooled to −30°C and dialkylzinc reagent (3.0 equiv.) was
added followed by addition of a solution of enone (1.0
equiv.) in diethyl ether (0.5 ml) after 1 h at −30°C. The
reaction was monitored by TLC and quenched with 1N
aqueous HCl. The crude product was filtered and dried
over silica gel/MgSO4 to give the 1,4-addition products.