Table 1 Comparison of polymer-bound and corresponding soluble
ligands
modulating N-substituent identified in the first screening round,
i.e. the 4-tosyl-group B20 did not emerge as the substituent of
choice after the second round. Rather, the pivaloyl amide B3
which reached only rank four in the first round turned out to be
most advantageous after appropriate combination with the right
binaphthyl unit. Thus, if we had followed the frequently used
strategy of ‘positional scanning’,2a,b optimising each sub-
stituent independently and subsequently carrying only the best
candidate through (instead of several ones as done here), the
most efficient ligand A1–B3–C2 would not have been identi-
fied. This finding is of general relevance to combinatorial ligand
and catalyst development. It shows that the concept of
‘positional scanning’ may not be general and should be applied
with care.
BINOL-
Entrya Ligand type substituent eeb [%] (ligand)
Heterogeneousa
Homogeneousa
eeb [%] (ligand)
1
2
3
4
5
6
Oxa-
Bispidine
N-
Pivaloyl-
N-Toluene
4-Sulfonyl
H
Me
H
Me
H
Me
39 (A2–C1)
45 (A2–C2)
44 (A1–B3–C1)
67 (A1–B3–C2)
56 (A1–B20–C1) 56 (24)
46 (A1–B20–C2) 51 (26)
43 (1)
47 (27, 1 mol%)
Not determined
64 (25)
a Conversion in all cases > 95%; isolated yields > 90%; b Determined by
means of gas chromatography (Lipodex E, Macherey&Nagel); the (R)-
enantiomer was formed predominantly in all cases.
In order to validate the screening of the solid-phase bound
ligands and to compare the recorded results with the corre-
sponding reactions in homogeneous solution, ligands 24–27
were synthesized as shown in Scheme 4.
combinatorial ligand development and screening system em-
ploying immobilized heterogeneous catalysts provides a correct
picture of the corresponding situation for the enantioselective
conjugate addition reactions in homogeneous solution.
This research was supported by the Fonds der Chemischen
Industrie. E. L. is grateful to the Alexander-von-Humboldt
Foundation for a fellowship.
Notes and references
1 Reviews: (a) M. T. Reetz, Angew. Chem., 2001, 113, 292; Angew.
Chem., Int. Ed. Engl., 2001, 40, 284; (b) B. Jandeleit, D. J. Schäfer, T.
S. Powers, H. W. Turner and W. H. Weinberg, Angew. Chem., 1999,
111, 2648; Angew. Chem., Int. Ed. Engl., 1999, 38, 2494; (c) S. Dahmen
and S. Bräse, Synthesis, 2001, 1431.
2 (a) B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A. Harrity, M. L.
Snapper and A. H. Hoveyda, Angew. Chem., 1996, 108, 1776; Angew.
Chem., Int. Ed. Engl., 1996, 35, 1668; (b) K. D. Shimizu, B. M. Cole, C.
A. Krueger, K. W. Kuntz, M. L. Snapper and A. H. Hoveyda, Angew.
Chem., 1997, 109, 1782; Angew.Chem., Int. Ed. Engl., 1997, 36, 1704;
(c) M. S. Sigman and E. N. Jacobsen, J. Am. Chem. Soc., 1998, 110,
4901; (d) M. B. Francis and E. N. Jacobsen, Angew.Chem., 1999, 111,
987; Angew. Chem., Int. Ed. Engl., 1999, 38, 937.
3 (a) S. Orlandi, A. Mandoli, D. Pini and P. Salvadori, Angew. Chem.,
2001, 113, 2587; Angew. Chem., Int. Ed. Engl., 2001, 40, 2519; (b) L.
Canali, E. Cowan, H. Deluze, C. L. Gibson and D. C. Sherrington, J.
Chem. Soc., Perkin Trans. 1, 2000, 2055; (c) A. J. Brouwer, H. J. van der
Linden and R. M. J. Liskamp, J. Org. Chem., 2000, 65, 1750.
4 N. Krause and A. Hoffmann-Röder, Synthesis, 2001, 171.
5 A. Alexakis, J. C. Frutos and P. Mangeney, Tetrahedron: Asymmetry,
1993, 4, 2427.
Scheme 4 Synthesis of ligands 24–27: (a) TosNHNH2, TosOH, NaCNBH3,
DMF, 2 h, 100 °C, 48%; (b) H2, Pd/C, EtOH, 12 h, rt; (c) Piv2O, DMAP,
pyridine, 12 h, rt, 71% (21, 2 steps); (d) TosCl, DMAP, pyridine, 12 h, rt,
72% (22, 2 steps); (e) TFA, CH2Cl2, 30 min, rt; (f) ClP(BINOL) 10, Et3N,
toluene, 12 h, rt, 51% (24); (g) PCl3, Et3N, THF, 1 h, 0 °C; then 3,3A-
dimethyl-2,2A-dihydroxy[1,1A]binaphthyl, Et3N, THF, 12 h, rt, 30% (25),
12% (26) and 3% (27), respectively; Piv = pivaloyl, Tos = toluene-
4-sulfonyl.
To this end, bispidinones 19 and 20 were converted into Boc-
protected intermediates 21–23. After removal of the Boc group
the liberated secondary amine was phosphitylated. Phosphor-
amidite 24 was obtained readily by reaction with chlor-
ophosphite 10. In the cases of methyl-substituted phosphor-
amidites 25–27 subsequent treatment of the secondary amine
with PCl3 and the dimethyl-substituted binaphthol gave better
results.
In Table 1 the enantioselectivity recorded in the Cu-catalyzed
conjugate addition of diethylzinc to cyclohexenone in the
presence of soluble ligands 24–27 and 1 is compared with the
values determined in the presence of the corresponding
polymer-bound ligands. In all cases the ee-values are very
similar, the maximum deviation reaching only 5% ee. Thus, the
6 B. L. Feringa, Acc. Chem. Res., 2000, 33, 346.
7 I. Chataigner, C. Gennari, U. Piarulli and S. Ceccarelli, Angew.Chem.,
2000, 112, 953; Angew. Chem., Int. Ed. Engl., 2000, 39, 916.
8 O. Huttenloch, J. Spieler and H. Waldmann, Chem. Eur. J., 2001, 7,
671.
9 P. Arjunan, K. D. Berlin, C. L. Barnes and D. van der Helm, J. Org.
Chem., 1981, 46, 3196.
10 J. Scherer, G. Huttner, M. Büchner and J. Bakos, J. Organomet. Chem.,
1996, 520, 45.
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