for the discovery of new asymmetric catalysis using a
combinatorial library of polymer-supported chiral ligands,
we envision that the HTS would enable the rapid optimiza-
tion of asymmetric catalysis even for a single polymer-
supported chiral ligand.
supported Nb-imidazoline (2). The construction of 2 was
confirmed by the analysis of 13C-PST/MAS NMR5 and IR
spectra.
With the polymer-supported Nb-imidazoline ligands in
hand, we studied the Cu-catalyzed enantioselective monoben-
zoylation of meso-1,2-diols. The importance of asymmetric
desymmetrization of diols in obtaining biologically important
products has promoted recent advances, but the catalytic and
nonenzymatic asymmetric desymmetrization of meso-diols
is still limited.6 In the first screening to find the lead catalyst,
various kinds of metal salts were examined as in Scheme 2.
In recent efforts to create new chiral ligands, we have
succeeded in developing the N-tethered bis(imidazoline)
ligand 1 (Figure 2).3 For example, the 1-Cu(OTf)2 catalyst
Scheme 2. Polymer-Supported Nb-Imidazoline (2)-Metal Salt
Catalyzed Asymmetric Benzoylation of meso-2,3-Butanediol
Figure 2. N-Tethered bis(imidazoline) ligands: Nb-imidazoline
(1) and polymer-supported Nb-imidazoline (2).
showed activity in promoting the monobenzoylation of
racemic 1,2-diol. Although the enantiomeric excess (ee) of
the product was moderate, this preliminary result prompted
us to further explore the potential of the Nb-imidazoline
ligand.4
To perform the new reaction optimization, we prepared
polymer-supported Nb-imidazoline (2) as shown in Scheme
1. After immobilization of chloromethyl imidazoline onto
Direct monitoring of the asymmetric reaction using CD
detection clearly indicated that the most effective catalyst
was the 2-CuCl catalyst. The efficiency of the asymmetric
catalyst was found to decrease somewhat in the order [Cu]
> [Pd] ∼ [Ni] > [Co]. Despite the fact that recent reports
based on Matsumura’s pioneering work6c have focused on
the Cu(II) catalysis, the HTS results show that the Cu(I)
complex has high catalytic activity. Conventional purification
by silica gel column chromatography and analysis using
chiral stationary phase HPLC revealed that the 2-CuCl
catalyst provided the adduct in 64% yield with 61% ee. Thus,
the asymmetric conversion yield (ACY),2 given as the square
root of the chemical yield multiplied by the enantiomeric
excess, was 62%. This result is better than that obtained using
2-CuCl2 (29% yield, 52% ee, ACY 39%).
Scheme 1. Synthesis of Polymer-Supported Nb-Imidazoline (2)
the polystyrylsulfonyl chloride, a nucleophilic substitution
using aminomethyl imidazoline provided the polymer-
(2) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa,
A. Angew. Chem., Int. Ed. 2006, 45, 5978-5981.
(3) Arai, T.; Mizukami, T.; Yokoyama, N.; Nakazato, D.; Yanagisawa,
A. Synlett 2005, 2670-2672.
The optimization in Scheme 3 indicated that CHCl3 and
CH2Cl2 were appropriate solvents. Conventional analysis
revealed that the reaction in CH2Cl2 provided the adduct in
60% yield with 60% ee; the adduct was provided in CHCl3
(4) Recent progresses on chiral ligands containing the imidazoline
motif: (a) Morimoto, T.; Tachibana, K.; Achiwa, K. Synlett 1997, 783-
785. (b) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Russell, D. R. J. Chem.
Soc., Perkin. Trans. 1 2001, 1500-1503. (c) Manges, F.; Neuburger, M.;
Pfaltz, A. Org. Lett. 2002, 4, 4713-4716. (d) Busacca, C. A.; Grossbach,
D.; So, R. C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett. 2003, 5, 595-
598. (e) Casey, M.; Smyth, M. P. Synlett 2003, 102-106. (f) Guiu, E.;
Claver, C.; Benet-Buchholz, J.; Castillo´n, S. Tetrahedron: Asymmetry 2004,
15, 3365-3373. (g) Bastero, A.; Claver, C.; Ruiz, A.; Castillo´n, S.; Daura,
E.; Bo, C.; Zangrando, E. Chem. Eur. J. 2004, 10, 3747-3760. (h) Bhor,
S.; Anilkumar, G.; Tse, M. K.; Klawonn, M.; Do¨bler, C.; Bitterlich, B.;
Grotevendt, A.; Beller. M. Org. Lett, 2005, 7, 3393-3396. (i) Weiss, M.
E.; Fischer, D. F.; Xin, Z.-q.; Jautze, S.; Schweizer, W. B.; Peters, R. Angew.
Chem., Int. Ed. 2006, 45, 5694-5698.
(5) Arai, T.; Fujiwara, A.; Watanabe, M.; Yokoyama, N.; Fujito, T.;
Deguchi, K.; Yanagisawa, A. Tetrahedron Lett. 2006, 47, 1673-1677.
(6) Several impressive examples of nonenzymatic asymmetric benzoy-
lation of meso-1,2-diol have been described: (a) Oriyama, T.; Imai, K.;
Hosoya, T.; Sano, T. Tetrahedron Lett. 1998, 39, 397-400. (b) Oriyama,
T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron Lett. 1998, 39, 3529-3532.
(c) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am. Chem.
Soc. 2003, 125, 2052-2053. (d) Mizuta, S.; Sadamori, M.; Fujimoto, T.;
Yamamoto, I. Angew. Chem., Int. Ed. 2003, 42, 3383-3385. (e) Mazet,
C.; Ko¨hler, V.; Pfaltz, A. Angew. Chem., Int. Ed. 2005, 44, 4888-4891.
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Org. Lett., Vol. 9, No. 6, 2007