A long-range chiral relay via tertiary amide group in asymmetric catalysis: new amino acid-derived N,P-ligands for copper-catalysed conjugate addition.

Article abstract of DOI:10.1039/b304131j

New N,P-ligands 4-6, derived from valinol and prolinol, respectively, have been developed for the asymmetric, copper(I)-catalysed conjugate addition of diethylzinc to unsaturated ketones; the tertiary amide group has been shown to effectively relay the chiral information from the ligand backbone to the active centre.

Full text of DOI:10.1039/b304131j

A long-range chiral relay via tertiary amide group in asymmetric
catalysis: new amino acid-derived N,P-ligands for copper-catalysed
conjugate addition†
Andrei V. Malkov,* John B. Hand and Pavel Kocˆovsky´*
Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ.
E-mail: amalkov@chem.gla.ac.uk. E-mail: P.Kocovsky@chem.gla.ac.uk
Received (in Cambridge, UK) 14th April 2003, Accepted 16th June 2003
First published as an Advance Article on the web 30th June 2003
New N,P-ligands 4–6, derived from valinol and prolinol,
axis.7 In this way, the chiral information from the amino acid
backbone would be relayed to the metal.
respectively, have been developed for the asymmetric,
copper(
I)-catalysed conjugate addition of diethylzinc to
To verify this hypothesis, the N-methyl amide 4a was
prepared and employed in the Cu-catalysed conjugate addition
of diethylzinc to a,b-unsaturated ketones (Scheme 1, Table 1).8
While in the case of cyclohexenone 1a, N-methylation did not
affect the enantioselectivity, a noticeable increase (from 55% to
68% ee; entries 1 and 2) was detected for cycloheptenone 1b.
However, the most dramatic change in the stereochemical
outcome was observed in the case of chalcone 1c as a substrate.
Here, the N-methylation of the ligand resulted in a substantial
improvement of enantioselectivity (from 30 to 71% ee; entries
1 and 2) and led to the formation of the opposite enantiomer!
Another difference between the N-methylated ligand and its
N–H analogue is that the enantioselectivity can be further
improved by tuning the steric bulk of the pyridine moiety.
Ligands 4b–d, prepared from the corresponding 6-methylpico-
linic, 6-phenylpicolinic and quinaldic acids, respectively, all
showed an increase in enantioselectivity compared to 4a
(entries 3–5). The best results in this series were obtained with
ligand 4b, which gave up to 86% ee (entry 3).
unsaturated ketones; the tertiary amide group has been
shown to effectively relay the chiral information from the
ligand backbone to the active centre.
Development of methods for asymmetric synthesis has become
one of the leading topics in the ongoing quest for new synthetic
methodologies. A vast number of catalytic processes allowing
conversion of prochiral substrates into chiral products of high
enantiomeric purity have been reported.1 Two complementary
approaches to the catalyst design can be identified: (i)
development of the structurally new chiral ligands and (ii)
seeking enhancement of the enantioselectivity by modification
of the known catalytic systems. In these efforts, exploitation of
the chiral relay effect represents an emerging new strategy.2
The term “chiral relay” was introduced by Davies for the
auxiliary-controlled enantioselective synthesis of chiral a-
amino acids.3 Here, the conformationally flexible tertiary amide
group placed in between the source of chirality and the reaction
centre has been shown to effectively convey the chiral
information which resulted in excellent diastereoselectivities. In
this model the chiral centre constitutes an integral part of the
molecule and hence serves as a stoichiometric chiral auxil-
iary.
The size of the N-alkyl group proved to be crucial, with
methyl being optimal. The N-methyl was sufficient to induce
the required conformational change but still small enough not to
overcrowd the system. On the other hand, ligand 5 with an N-
An extension to catalytic processes has been reported by Sibi4
and Renaud.5 In their approach, a conformationally flexible
non-chiral auxiliary is incorporated into the substrate to relay
the chiral environment created by a chiral Lewis acid. In this
case, the chiral information is conveyed from an external
source, namely the chiral catalyst, generated from a metal
precursor and a conventional chiral ligand.
Herein, we report on a different approach to the utilisation of
the chiral relay effect. Our strategy is based on the integration of
the chiral relay network into the ligand architecture. Morimoto6
has recently applied N,P-ligands 3a,b (Chart 1) to enantiose-
lective copper-catalysed conjugate addition of diethylzinc to
cyclohexenone 1a (Scheme 1). With ligand 3a, the product 2a
was obtained in 52% ee (toluene, 220 °C), while the
6-methylpyridine analogue 3b gave lower enantioselectivity
(40% ee). Assuming that the coordination to the metal occurs
through the pyridine and phosphine groups, it would result in
the formation of an eight-membered ring. The single chiral
centre in this complex is rather distant from the metal to be able
to effectively influence the new bond-forming process occur-
ring at the metal. As a result, low enantioselectivity was
attained. We reasoned that introduction of an additional alkyl
group at the amide nitrogen should add more bias to the chelate
by forcing the side-chain of the amino acid backbone and the N-
alkyl group away from each other. In turn, the resulting
arrangement should create an appropriate conformational twist
about the carbonyl–pyridine bond, thereby creating a chiral
Scheme 1
† Electronic supplementary information (ESI) available: synthesis and
characterisation of chiral ligands 4–7; experimental details of catalytic
Michael addition, characterisation of the products and enantioselectivity
determination. See http://www.rsc.org/suppdata/cc/b3/b304131j/
Chart 1 Chiral ligands.
1948
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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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