Table 1 The Cu-catalysed addition of diethylzinc to unsaturated ketones with ligands 3–7 (Scheme 1)a
Substrate
1a
1b
1c
Entry
Ligand
Yield (%)b
Ee (%)c
Yield (%)b
Ee (%)c
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
3a
4a
4b
4c
4d
5
6
4ad
7
61
84
92
86
77
89
91
—
—
62 (S)-(2)
60 (S)-(2)
83 (S)-(2)
81 (S)-(2)
66 (S)-(2)
19 (R)-(+)
7 (S)-(2)
—
77
82
90
81
75
90
76
—
—
55 (2)
68 (2)
86 (2)
87 (2)
80 (2)
23 (+)
7 (+)
82
78
86
84
78
52
90
13
39
30 (S)-(+)
71 (R)-(2)
81 (R)-(2)
41 (R)-(2)
78 (R)-(2)
3 (S)-(+)
29 (R)-(2)
8 (S)-(+)
26 (S)-(+)
—
—
—
a The reactions were carried out at 1.0 mmol scale with 1.1 equiv of Et2Zn in CH2Cl2, in the presence of the catalyst generated in situ from Cu(OTf)2 (2 mol%)
and the ligand (3 mol%), at 220 °C. b Isolated yield. c The enantioselectivity was determined by chiral GC or HPLC. The absolute configuration of the
products was determined by comparison of their optical rotation and their GC and HPLC behaviour with the literature data and with the behaviour of the
authentic samples (for details see ESI†). d The reaction was carried out in the absence of the Cu salt.
isopropyl group lost the enantioselectivity (Table 1, entry 6).
The importance of the conformational twist introduced by the
N–Me group about the bond linking it to the stereogenic centre
can be illustrated with ligand 6, based on proline, where such a
twist cannot be achieved as the alkyl substituents are tied up in
the cycle. The use of ligand 6 resulted in a dramatic decrease in
enantioselectivity (Table 1, entry 7). A possible structure of the
complex CuCl2·4a, as predicted by molecular modelling, is
shown in Fig. 1.
In conclusion, we have demonstrated that the tertiary amide
group in new amino acid-based ligands 4a–d can relay the chiral
information to the metal coordinated. It controls the level and
the sense of asymmetric induction in the Cu-catalysed conjugate
addition of Et2Zn to enones with 587% ee. Extension of this
principle is currently being pursued in this Laboratory.
We thank the University of Glasgow for financial support and
Degussa AG for a gift of
L
-valine and -valinol.
L
A set of experiments was performed to provide a better
insight into the structure of the active catalyst. Thus, in the
absence of a copper salt, 1c was converted into (S)-(+)-2c in a
very low yield and poor enantioselectivity (13% and 8%,
respectively; entry 8), confirming the crucial involvement of
copper in the catalysis.‡ The role of the pyridine unit was
investigated with the aid of ligand 7 lacking the pyridine
nitrogen. Again, (S)-(+)-2c was formed in low yield and
enantioselectivity (39% and 26%, respectively; entry 9).
Notes and references
‡ Note that Et2Zn is inert even to aldehydes and can be activated by a
suitable ligand, which distorts its stable, rod-shape geometry.9
1 For recent reviews on catalytic asymmetric processes, see: (a) H. Tye, J.
Chem. Soc., Perkin Trans. 1, 2000, 275; (b) S. T. Handy, Curr. Org.
Chem., 2000, 4, 363; (c) F. Fache, E. Schulz, M. L. Tommasino and M.
Lemaire, Chem. Rev., 2000, 100, 2159; (d) I. Ojima, Catalytic
Asymmetric Synthesis, 2nd edn., J. Wiley and Sons, New York, 2000.
2 For a recent review on chiral relay effect, see: (a) O. Corminboeuf, L.
Quaranta, P. Renaud, M. Liu, C. P. Jasperse and M. P. Sibi, Chem. Eur.
J., 2003, 9, 28. For a review on related asymmetric activation, see: (b) K.
Mikami, M. Terada, T. Korenaga, Y. Matsumoto, M. Ueki and R.
Angelaud, Angew. Chem., Int. Ed., 2000, 112, 3532. For an earlier
observation of chiral relay in Mo-catalysed allylic substitution, see: (c) A.
V. Malkov, P. Spoor, V. Vinader and P. Kocˆovsky´, Tetrahedron Lett.,
2001, 42, 509.
3 (a) S. D. Bull, S. G. Davies, S. W. Epstein and J. V. A. Ouzman, Chem.
Commun., 1998, 659; (b) S. D. Bull, S. G. Davies, D. J. Fox and T. G. R.
Sellers, Tetrahedron: Asymmetry, 1998, 9, 1483; (c) S. D. Bull, S. G.
Davies, S. W. Epstein, M. A. Leech and J. V. A. Ouzman, J. Chem. Soc.,
Perkin Trans. 1, 1998, 2321.
4 (a) M. P. Sibi, L. Venkatraman, M. Liu and C. P. Jasperse, J. Am. Chem.
Soc., 2001, 123, 8444; (b) M. P. Sibi and M. Liu, Org. Lett., 2001, 3,
4181.
1
In the H NMR spectrum of a 1 : 1 complex of AgOTf and
ligand 4a, generated as a model system, the amide (E/Z)-
isomers, present in the free ligand, collapsed into one. The
signals of the pyridine protons were shifted compared to the free
ligand and sharpened, which is consistent with the coordination
to the metal. Broadening of the signals in the amino acid
backbone suggests a certain degree of flexibility of the CH2
group; by contrast, signals for the N-Me and i-Pr groups
involved in the chiral relay remained sharp. In the 31P NMR
spectrum, free ligand exhibited two signals (at 222.1 and
224.2 ppm), while on coordination to AgOTf they coalesced
into one (at 21.0 ppm). The IR spectrum showed no difference
in the amide frequency of the free and coordinated ligand (1635
cm21), indicating that the amide group was not involved in the
coordination. Similar results were obtained with ligand 3a,
confirming that in both cases the bidentate coordination is
realised and the favourable change of conformation in the eight-
membered chelate CuCl2·4a is attributable to the tertiary amide
group. A weak negative non-linear effect was observed in the
catalytic reaction which implies either an aggregation of the
active complex or formation of a dimeric species.
5 L. Quaranta, O. Corminboeuf and P. Renaud, Org. Lett., 2002, 4, 39.
6 T. Morimoto, Y. Yamaguchi, M. Suzuki and A. Saitoh, Tetrahedron
Lett., 2000, 41, 10025.
7 (a) J. Clayden, J. H. Pink and S. A. Yasin, Tetrahedron Lett., 1998, 39,
105. For induction of atropoisomerism in flexible biphenylene ligands,
used in Cu-catalysed conjugate addition, see: (b) A. Alexakis, S. Rosset,
J. Allamand, S. March, F. Guillen and C. Benhaim, Synlett, 2001,
1375.
8 For a recent review on asymmetric Cu-catalysed addition of dialkyl zinc
reagents to enones, see: (a) A. Alexakis and C. Benhaim, Eur. J. Org.
Chem., 2002, 3221. For a recent review on enantioselective Michael
addition, see: (b) N. Krause and A. Hoffmann-Roder, Synthesis, 2001,
171. For a recent report on the use of peptide-derived phosphines as
ligands in the same reaction, see: (c) A. W. Hird and A. H. Hoveyda,
Angew. Chem., Int. Ed., 2003, 42, 1276 and papers cited therein.
9 For a review, see: R. Noyori and M. Kitamura, Angew. Chem., Int. Ed.
Engl., 1991, 30, 49.
Fig. 1 Proposed chelation in the Cu(II)–4a complex.
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