Discovery of a new efficient chiral ligand for copper-catalyzed enantioselective Michael additions by high-throughput screening of a parallel library

Article abstract of DOI:10.1002/(SICI)1521-3773(20000303)39:5<916::AID-ANIE916>3.0.CO;2-M

The optimal ligand 1 for the enantioselective copper-catalyzed 1,4- addition of Et₂Zn to cyclic enones [Eq. (1)] was established by multisubstrate (high-throughput) screening of a parallel library of chiral Schiff base ligands. The screening data show how the ligand structure is finely tuned by mutual influences of stereogenic center a (which controls the absolute configuration of the reaction product), stereogenic center b, and the substitution pattern of the aromatic ring.

Full text of DOI:10.1002/(SICI)1521-3773(20000303)39:5<916::AID-ANIE916>3.0.CO;2-M

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Bastida, A. de Blas, D. E. Fenton, A. Macías, A. Rodríguez, T.
Discovery of a New Efficient Chiral Ligand for
Copper-Catalyzed Enantioselective Michael
Additions by High-Throughput Screening of a
Parallel Library**
Â
Rodríguez-Blas, S. García-Granda, R. Corzo-Suarez, J. Chem. Soc.
Dalton Trans. 1997, 409; i) K. K. Nanda, A. W. Addison, N. Paterson,
E. Sinn, L. K. Thompson, U. Sakaguchi, Inorg. Chem. 1998, 37, 1028;
k) S. K. Dutta, U. Flörke, S. Mohanta, K. Nag, Inorg. Chem. 1998, 37,
5029; l) Yunqi Tian, Jian Tong, G. Frenzen, Jin-Yu Sun, J. Org. Chem.
1999, 64, 1442; m) Zheng Wang, A. E. Martell, R. J. Motekaitis, J.
Reibenspies, J. Chem. Soc. Dalton Trans. 1999, 2441.
Isabelle Chataigner, Cesare Gennari,*
Umberto Piarulli,* and Simona Ceccarelli
[5] J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, 1995.
The 1,4-addition of organometallic reagents to a,b-unsatu-
rated carbonyl compounds is an important process for C C
bond formation in organic synthesis.[1] A number of chiral
stoichiometric reagents have been described during the last
few years which allow enantioselective additions,[2] while the
development of chiral catalysts has been comparably slower.
A prominent position in this rapidly expanding field is
occupied by the copper-catalyzed, chiral-ligand-accelerated,
1,4-addition of organozinc reagents.[3] In particular, chiral
phosphoramidites,[3b] phosphites,[3c±f] and aminophosphanes[3g]
were used as ligands in the addition to cyclic enones with very
good enantioselectivities (up to 98% ee).[3b] On the other hand,
chiral sulfonamides, which have proved effective in various
catalytic asymmetric processes, were reported to catalyze the
conjugate addition of organozinc reagents to cyclic enones[4a]
only with marginal enantioselectivity (up to 31% ee).[4b]
We have developed a new family of chiral Schiff base
ligands of general structure 5, which contain a set of different
metal binding sites (a phenol, an imine, and a secondary
sulfonamide), with the expectation that such a multidentate
array would favor the formation of organometallic complexes
with well-organized spatial arrangements, and with the goal of
obtaining ligands for asymmetric catalysis capable of broad
applicability. Ligands 5 were easily obtained (Scheme 1) by
condensation of salicylaldehydes with enantiomerically pure
b-amino sulfonamides. Sulfonamides 3 were in turn synthe-
sized by coupling different primary amines with sulfonyl
chlorides 1, prepared in high yields from l-a-amino acids by a
straightforward synthetic protocol.[5] At the beginning of this
work, a few model ligands 5 were prepared and tested, which
proved effective in accelerating the copper-catalyzed (5%
Cu(OTf)2; Tf ˆ F3CSO2) conjugate addition of diethylzinc to
[6] S. R. Korupoju, P. S. Zacharias, Chem. Commun. 1998, 1267.
[7] To our knowledge, only one such [2‡4] condensation has been
reported. It employs an inverse (tetraaldehyde/diamine) combination
of reagents, with no structural similarities to the reagents used in the
present work: B. P. Clark, J. R. Harris, G. H. Timms, J. L. Olkowski,
Tetrahedron Lett. 1995, 36, 3889.
[8] B. Dietrich, P. Viout, J.-M. Lehn, Macrocyclic ChemistryÐAspects of
Organic and Inorganic Supramolecular Chemistry, VCH, Weinheim,
1993, p. 268.
[9] A. J. Atkins, A. J. Blake, M. Schröder, J. Chem. Soc. Chem. Commun.
1993, 353.
[10] X-ray structure data for [LH6]Br2(PF6)4 ´ 7MeOH: Mr ˆ 2492.91,
Å
triclinic, space group Pl, a ˆ 18.071(3), b ˆ 18.184(2), c ˆ
20.081(2) Š, a ˆ 78.67(1), b ˆ 81.87(1), g ˆ 62.49(1)8, Vˆ 5729(2) Š3,
l ˆ 0.71073 Š, Tˆ 200(2) K, Z ˆ 2, 1calcd ˆ 1.445 gcm 3, m(MoKa) ˆ
0.867 mm 1. Red block (0.84 Â 0.52 Â 0.44 mm). No absorption cor-
rection; number of measured/unique/observed (Fo ꢀ 4.0s(F)) reflec-
tions: 22115/20018/7798 (Rint ˆ 0.0535); 3.58 ꢁ 2q ꢁ 50.08; w-scan;
structure solution/refinement: direct methods, full-matrix least-
squares, SHELXTL NT 5.10 (Bruker AXS, 1998); refined parameters:
1502. The crystal deteriorated during measurement, and the intensity
of three standard reflections (measured every 100 reflections) de-
creased 28%. The crystal diffracted poorly despite its size; conse-
quently, the data set was measured only up to an angle q ˆ 258. One of
the PF6 ions shows positional disorder which could be resolved. All H
atoms were calculated in geometrically optimized positions. R1 ˆ
0.1086, wR2 ˆ 0.2781; 1fin (max./min.): 1.364/ 1.020 eŠ 3. Crystallo-
graphic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-135908. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
[11] a) W. Bauer, unpublished results; b) S. Braun, H.-O. Kalinowski, S.
Berger, 100 and More Basic NMR Experiments, VCH, Weinheim,
1996, p. 120.
[12] N. L. Allinger, Young H. Yuh, Jenn-Huei Lii, J. Am. Chem. Soc. 1989,
111, 8551.
[13] a) R. Menif, A. E. Martell, P. J. Squattrito, A. Clearfield, Inorg. Chem.
1990, 29, 4723; b) L. F. Lindoy, S. Mahendran, K. E. Krakowiak,
Haoyun An, J. S. Bradshaw, J. Heterocycl. Chem. 1992, 29, 141; c) see
also ref. [7].
[*] Prof. Dr. C. Gennari, Dr. I. Chataigner, M.Sc. S. Ceccarelli
Dipartimento di Chimica Organica e Industriale
[14] C. Dietz, A. Grohmann, unpublished results.
Á
Universita di Milano
Centro CNR per lo Studio delle Sostanze Organiche Naturali
via G. Venezian 21, 20133 Milano (Italy)
Fax : (‡ 39)02-236-4369
E-mail: cesare@iumchx.chimorg.unimi.it
Dr. U. Piarulli
Dipartimento di Scienze Mat. Fis. e Chimiche
Á
Universita dellꢁInsubria
via Lucini 3, 22100 Como (Italy)
E-mail: umberto@iumchx.chimorg.unimi.it
[**] We thank the Commission of the European Union (TMR Network
grant ªCombinatorial catalystsº ERB-FMR XCT 96-0011) for finan-
cial support and a postdoctoral fellowship to I. Chataigner. We are
Á
grateful to Mr. Andrea Stevenazzi and Ms. Chiara Monti (Universita
di Milano) for technical assistance. Part of this work was presented as
a plenary lecture (C. Gennari) at 11th European Symposium on
Organic Chemistry (ESOC 11, Göteborg, Sweden, July 23 ± 28, 1999).
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
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dichloromethane in the presence of methyl trimethylsilyl
dimethylketene acetal (MTDA, 6) (2.0 equiv)[5] and a cata-
lytic amount (0.2 equiv) of polymer-bound ª4-dimethylami-
nopyridineº[10] (7) to catalyze the coupling reaction and
scavenge the liberated HCl. Apart from the polymer, which is
removed by filtration, the only by-products were trimethyl-
silyl chloride and methyl isobutyrate. These are volatile and
are removed with the solvent. After all the amine had been
consumed, the excess sulfonyl chloride was removed by
reaction with solid-phase-bound [tris(2-aminoethyl)amine][9c]
(8) (3.0 equiv) and subsequent filtration. The tert-butyloxy-
carbonyl (Boc) protecting group was then cleaved with 25%
CF3CO2H (TFA) in CH2Cl2, and the resulting amine trifluor-
oacetate salts (1.0 equiv) were treated in MeOH with
aldehydes 4 (0.9 equiv) in the presence of 7[10] (3.0 equiv) to
yield the target Schiff bases 5 in 76% overall yield (average);
these were pure enough to be used in the ligand-catalyzed
reactions.
A multisubstrate[8, 11] high-throughput screening of the
library was realized by performing the conjugate addition
reactions on an equimolar mixture of 2-cyclohexenone (9) and
2-cycloheptenone (10, each 0.1 mmol), using 5.5 mol% ligand
5 (0.011 mmol) and 5 mol% Cu(OTf)2 (0.010 mmol) in
toluene at 208C. The reactions were quenched after 5 h,
and the crude reaction mixtures were directly analyzed for
conversion and enantiomeric excess by gas chromatography
using a chiral capillary column, under conditions where the
four peaks of the two enantiomeric pairs show baseline
separation (time for each analysis: 15 min).
R1
R1
a
R2NH2
+
SO2NHR2
SO2Cl
HNBoc
BocNH
1
2
3
1a; R1 = Me
1b; R1 = iPr
1c; R1 = iBu
2f; R2 = CH2Ph
2g; R2 = (R)-CH(Me)Cy
2h; R2 = (S)-CH(Me)Cy
2i; R2 = iPr
1d; R1 = CH2Ph
1e; R1 = tBu
2j; R2 = CHPh2
2k; R2 = tBu
2l; R2 = (R)-CH(iPr)CH2OH
2m; R2 = (S)-CH(iPr)CH2OH
2n; R2 = (R)-CH(Me)Ph
2o; R2 = (S)-CH(Me)Ph
R1
O
O
b
S
N
NHR2
CHO
OH
OH
R3
5
R3
4
4p; R3 = H
4q; R3 = 3,5-tBu2
4r; R3 = 3,5-Cl2
4s; R3 = 5,6-(CH)4
4t; R3 = 3-OMe
4u; R3 = 5-NO2
Scheme 1. Synthesis of the library of ligands 5. a) 1 (1.2 equiv),
(1.0 equiv), (2.0 equiv), (0.2 equiv), CH2Cl2, 208C, 3 h; then
(3.0 equiv), 3 h, 86%; b) 3 (1.0 equiv), TFA:CH2Cl2 (1:3), 208C, 30 min;
evaporation; 4 (0.9 equiv), 7 (3.0 equiv), CH3OH, 208C, 24 h, 88%.
2
8
6
7
In the construction of the library, the choice of the building
blocks (sulfonyl chlorides, amines, and aldehydes) is crucial. A
test library of 60 compounds (one sulfonyl chloride 1d, ten
amines 2 f ± o, and six aldehydes 4p ± u) was built to study the
role of R2 and R3 by maximizing their diversity. This first set of
ligands was screened under the conditions described above,
and the results revealed some interesting features. 1) Poor
enantioselectivities (ꢁ40%ee) were obtained with amines
2k ± m (irrespective of the aldehyde), and with aldehydes 4t
and 4u (irrespective of the amine). 2) Enantioselectivities
with amines 2n and 2o were lower than those obtained with
amines 2g and 2h. 3) The stereocenter bearing R1 controls the
absolute configuration of the reaction product, while the
stereocenter on R2 (when present) tunes the selectivity.
From this analysis a new library of 100 terms was designed,
containing five sulfonyl chlorides (1a ± e), five amines (2 f ± j),
and four aldehydes (4p ± s). From the screening of this library,
5bhr (R1 ˆ iPr; R2 ˆ (S)-CH(Me)Cy; R3 ˆ 3,5-Cl2) was iden-
tified as the best ligand for 2-cyclohexenone (82%ee) and
2-cycloheptenone (81%ee). These results confirm the value
of the combinatorial approach: it would have been very
difficult to identify this ligand for the two different substrates
if a ªrationalº or a ªpositional scanningº[12] approach were
followed. The data in Table 1 clearly show the importance of
the mutual influences of the substituents R1 ± R3 in the fine
tuning of the ligand structure.
cyclohexenone (9). The enantiomeric excesses were only
moderate or poor, ranging from 28% with catalytic (5.5%)
5dfp (R1 ˆ CH2Ph, R2 ˆ CH2Ph, R3 ˆ H) to 48% with 5dfq
(R1 ˆ CH2Ph, R2 ˆ CH2Ph, R3 ˆ 3,5-tBu2) (Scheme 2).[6] At
this stage, we considered a combinatorial approach for tuning
the ligand structure and improving the results,[7, 8] taking
advantage of the ligand synthesis scheme, a sequence of
coupling steps with different monomers (Scheme 1), which is
well-suited for the generation of diversity.
O
O
Cu(OTf)2 (cat.); 5 (cat.)
+
Et2Zn
n
C6H5CH3, -20°C
n
12 n = 1
13 n = 2
14 n = 0
9 n = 1
10 n = 2
11 n = 0
Scheme 2. Enantioselective conjugate addition of Et2Zn to enones 9 ± 11
catalyzed by Cu(OTf)2/5. Screening of the library of ligands 5.
For the synthesis of the ligand library, we used solution-
phase parallel synthesis and solid-phase extraction (SPE)
techniques to scavenge excess reagents and reaction by-
products, and avoid chromatography.[8, 9] For the formation of
sulfonamides 3 (Scheme 1), the reaction of excess sulfonyl
chlorides 1 (1.2 equiv) with amines 2 (1.0 equiv) was run in
Optimization of the reaction conditions was performed on
the single enones 9 ± 11 using the best ten ligands shown in
Table 1, and taking into consideration the catalyst loading, the
concentration, the reaction temperature, and the solvent.
Angew. Chem. Int. Ed. 2000, 39, No. 5
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Table 1. High-throughput screening of the library of ligands 5: best ten
results.
[4] a) M. Kitamura, T. Miki, K. Nakano, R. Noyori, Tetrahedron Lett.
1996, 37, 5141 ± 5144; b) V. Wendisch, N. Sewald, Tetrahedron:
Asymmetry 1997, 8, 1253 ± 1257.
[5] a) M. Gude, U. Piarulli, D. Potenza, B. Salom, C. Gennari, Tetrahedron
Lett. 1996, 37, 8589 ± 8592; b) C. Gennari, M. Gude, D. Potenza, U.
Piarulli, Chem. Eur. J. 1998, 4, 1924 ± 1931.
Entry Ligand R1 R2
R3
ee (12) [%] ee (13) [%]
1
2
3
4
5
6
7
8
9
5bhr
5ehq
5biq
5ejq
5chr
5chq
5aiq
5ehs
5bjq
5ehr
iPr (S)-CH(Me)Cy 3,5-Cl2 82
tBu (S)-CH(Me)Cy 3,5-tBu2 80
81
79
72
75
74
71
76
71
69
67
[6] The absolute configuration shown in Scheme 2 for 12 (3S) was
determined by 13C NMR spectroscopy after derivatization with
(1R,2R) 1,2-diphenylethylenediamine (A. Alexakis, J. C. Frutos, P.
Mangeney, Tetrahedron: Asymmetry 1993, 4, 2431 ± 2434). The
absolute configuration of 13 is unknown. The absolute configuration
of 14 (3S) was determined by optical rotation: G. H. Posner, M. Hulce,
Tetrahedron Lett. 1984, 25, 379 ± 382.
[7] For reviews on the combinatorial development of new catalysts, see:
a) C. Gennari, H. P. Nestler, U. Piarulli, B. Salom, Liebigs Ann. 1997,
637 ± 647; b) K. D. Shimizu, M. L. Snapper, A. H. Hoveyda, Chem.
Eur. J. 1998, 4, 1885 ± 1889; c) B. Jandeleit, D. J. Schaefer, T. S. Powers,
H. W. Turner, W. H. Weinberg, Angew. Chem. 1999, 111, 2648 ± 2689;
Angew. Chem. Int. Ed. 1999, 38, 2494 ± 2532, and references therein.
[8] C. Gennari, S. Ceccarelli, U. Piarulli, C. A. G. N. Montalbetti, R. F. W.
Jackson, J. Org. Chem. 1998, 63, 5312 ± 5313.
iPr iPr
tBu CHPh2
3,5-tBu2 76
3,5-tBu2 74
iBu (S)-CH(Me)Cy 3,5-Cl2 73
iBu (S)-CH(Me)Cy 3,5-tBu2 72
Me iPr
tBu (S)-CH(Me)Cy (CH)4
iPr CHPh2 3,5-tBu2 70
tBu (S)-CH(Me)Cy 3,5-Cl2 71
3,5-tBu2 69
71
10
Under the best conditions (2.75 mol% 5, 2.5 mol%
Cu(OTf)2, toluene/hexane 80/20, 5 h), 5bhr was identified as
the best ligand for cyclohexenone 9 and cycloheptenone 10
[9] a) R. M. Lawrence, S. A. Biller, O. M. Fryszman, M. A. Poss, Synthesis
1997, 553 ± 558; b) D. L. Flynn, J. Z. Crich, R. V. Devraj, S. L. Hocker-
man, J. J. Parlow, M. S. South, S. Woodard, J. Am. Chem. Soc. 1997,
119, 4874 ± 4881; c) R. J. Booth, J. C. Hodges, J. Am. Chem. Soc. 1997,
119, 4882 ± 4886; d) J. J. Parlow, D. A. Mischke, S. S. Woodard, J. Org.
Chem. 1997, 62, 5908 ± 5919; e) J. J. Parlow, D. L. Flynn, Tetrahedron
1998, 54, 4013 ± 4031.
O
O
S
O
S
O
N
HN
N
HN
Cl
OH
tBu
OH
[10] Polymer-bound ªdimethylaminopyridineº (4-(N-benzyl-N-methyla-
mino)pyridine on polystyrene) is commercially available from the
Aldrich Chemical Company.
Cl
tBu
5chq
5bhr
[11] X. Gao, H. B. Kagan, Chirality 1998, 10, 120 ± 124.
[12] B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A. Harrity, M. L.
Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108, 1776 ± 1779;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1668 ± 1671.
(at 208C), giving 12 in 90%ee and 13 in 85%ee, with 100%
conversion in both cases and 93 ± 95% yield (isolated
product). Compound 5chq (Figure 1) was recognized as the
best ligand for cyclopentenone (11) (at 08C), giving 14 in
80%ee albeit in a low yield (25%).
The Melting Point Alternation in
a,w-Alkanediols and a,w-Alkanediamines:
Interplay between Hydrogen Bonding and
Hydrophobic Interactions**
In conclusion, we have developed a parallel library of new
Schiff base chiral ligands 5 and optimized their use in the
enantioselective conjugate addition of Et2Zn to cyclic enones
by a high-throughput screening approach. Work is in progress
to extend the scope of ligands 5 in other enantioselective
Venkat R. Thalladi, Roland Boese,* and
Hans-Christoph Weiss
reactions.
Received: October 14, 1999 [Z14150]
Dedicated to Professor Paul Rademacher
on the occasion of his 60th birthday
[1] a) P. Perlmutter in Conjugate Addition Reactions in Organic Synthesis,
Vol. 9 (Eds.: J. E. Baldwin, P. D. Magnus), Tetrahedron Organic
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en Org. Chem. (Houben-Weyl) 4th ed. 1995 ± , Vol. E21b, Vol. 4, 1995,
chap. 1.5.2.1.
[2] a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771 ± 806; b) N.
Krause, A. Gerold, Angew. Chem. 1997, 109, 194 ± 213; Angew. Chem.
Int. Ed. Engl. 1997, 36, 186 ± 204; c) B. L. Feringa, A. H. M. de Vries in
Advances in Catalytic Processes, Vol. 1 (Ed.: M. P. Doyle), JAI,
Greenwich, CT, 1995, pp. 151 ± 192.
[3] a) Although the mechanistic path for this reaction has not yet been
completely clarified, it is likely that mixed (Cu ± Zn) organometallic
species are involved in the catalytic step. For a brief review, see: N.
Krause, Angew. Chem. 1998, 110, 295 ± 297; Angew. Chem. Int. Ed.
1998, 37, 283 ± 285; b) R. Naasz, L. A. Arnold, M. Pineschi, E. Keller,
B. L. Feringa, J. Am. Chem. Soc. 1999, 121, 1104 ± 1105, and references
therein; c) A. K. H. Knöbel, I. H. Escher, A. Pfalz, Synlett 1997, 1429;
d) A. Alexakis, J. Vastra, J. Burton, C. Benhaim, P. Mangeney,
Tetrahedron Lett. 1998, 39, 7869 ± 7872, and references therein; e) O.
Pamies, G. Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 1999, 10,
2007 ± 2014; f) M. Yan, A. S. C. Chan, Tetrahedron Lett. 1999, 40,
6645 ± 6648; g) T. Mori, K. Kosaka, Y. Nakagawa, Y. Nagaoka, K.
Tomioka, Tetrahedron: Asymmetry 1998, 9, 3175 ± 3178.
Hydrogen bonding and hydrophobic interactions are ubiq-
uitous in biological structures, be they lipids, proteins, or
nucleic acids.[1] The interference between these two kinds of
interactions in such natural systems is obvious, but hard to
study and difficult to perceive owing to their inherent
complexity. An understanding of such interference has
important implications in biological and material phenom-
[*] Prof. Dr. R. Boese, Dr. V. R. Thalladi, Dipl.-Chem. H.-C. Weiss
Institut für Anorganische Chemie
Universität-GH Essen
Universitätsstrasse 5 ± 7, 45117 Essen (Germany)
Fax: (‡49)201-183-2535
E-mail: boese@structchem.uni-essen.de
[**] The Melting Point Alternation in n-Alkanes and Derivatives, Part 2.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. V.R.T. thanks the Alexander
von Humboldt Foundation for a postdoctoral fellowship. Part 1:
ref. [6].
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Angew. Chem. Int. Ed. 2000, 39, No. 5