shown that a tetrahydrosalen-derived and a sulfonyldiamino
Cu(I) complex, respectively, catalyze the nitroaldol reaction
of a variety of aromatic substrates with good to high yields
and ee’s. The latter catalyst also generates aliphatic nitroaldol
products with high asymmetric induction but at the cost of
long reaction times (up to 120 h) unless a large excess of
pyridine is employed.
We recently reported the synthesis of the first diketone-
derived C2-symmetric bisoxazolidine (not to be confused with
structurally quite different bisoxazolines) and showed several
applications of this new class of chiral ligands in asymmetric
catalysis. The aminoindanol-derived bisoxazolidine 1 (Figure
1) has been proven to be broadly useful for a variety of
Initial screening of several metal salts using ethanol as solvent
revealed that copper acetate complexes afford the most promis-
ing results. We found that the use of 10 mol % of 1 and Cu(I)
acetate at room temperature allows smooth reaction between
nitromethane and benzaldehyde toward 2-nitro-1-phenylethanol
in 96% yield and 68% ee within 1.5 h. The replacement of
Cu(I) by Cu(II) acetate gave the Henry reaction product in
similar ee’s but at only 50% conversion after 24 h. Further
optimization of catalyst loading, solvents, additives such as
pyridine, temperature, and substrate concentration showed that
the best results can be obtained with 10 mol % of 1 and 9 mol
% of CuOAc in ethanol at -15 °C. Under these conditions,
we obtained 2-nitro-1-phenylethanol from benzaldehyde in 93%
yield and 89% ee after 16 h (Scheme 1).
Scheme 1. Bisoxazolidine-CuOAc-Catalyzed Henry Reaction
Figure 1. Structure of bisoxazolidine 1.
dialkylzinc promoted reactions.13 We found that this ligand
catalyzes the enantioselective alkynylation of aromatic and
aliphatic aldehydes, generating chiral propargylic alcohols
in high yield and ee.14 We also obtained excellent results
when this catalyst was applied in the alkylation of aldehydes
with Me2Zn and Et2Zn.15 We have most recently developed
a synthetic protocol for the asymmetric nitroaldol reaction
utilizing bisoxazolidine 1, nitromethane, and dimethylzinc
to generate the reactive zinc nitronate in situ.16 Although
the Henry reaction products were obtained in high yields
and ee’s, a remaining drawback of this procedure is that 3
equiv of expensive, pyrophoric dimethylzinc is required. We
therefore decided to explore the possibility of a dimethylzinc-
free bisoxazolidine-catalyzed nitroaldol reaction.
We then decided to explore other aromatic substrates
(Table 1). In general, the bisoxazolidine-CuOAc-catalyzed
Table 1. Enantioselective Henry Reaction of Aromatic
Aldehydesa
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a All reactions were performed on a 1 mmol scale using 10 mol % of
1, 9 mol % of CuOAc, and 10 equiv of nitromethane in 2.4 mL of EtOH.
b Isolated yields. c The ee’s and absolute configurations were determined
by chiral HPLC analysis using Chiralcel OD and Chiralpak AD as described
in the literature.10c,17
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