that substitution in the 5-position would be the most
worthwhile modification to examine. Specifically, we chose
a phenyl substituent, since Mathey has shown that phosphole
3, available on a large scale through treatment of 2,3-
dimethyl-1,3-butadiene with Cl2PPh, reacts with t-BuOK to
furnish phospholide 4 (Figure 1).6 Complexation of 4 to
[Cp*FeCl]n provides phosphaferrocene 5, from which the
target phosphaferrocene-oxazoline ligands 7a-c and 7a′-
c′ can be generated via acylation and then oxazoline
formation.7
We were pleased to discover that ligand 7a, the 5-phenyl-
substituted derivative of ligand 2, affords improved enan-
tiomeric excess in the copper-catalyzed conjugate addition
of ZnEt2 to chalcone (62% ee f 79% ee; eq 3 vs eq 4). Of
course, the choice of oxazoline also influences the level of
stereoselection: of the three members of this new subclass
of phosphaferrocene-oxazoline ligands (7a-c), phenylgly-
cinol-derived 7b furnishes the lowest enantioselectivity (71%
ee), whereas aminoindanol-derived 7c provides the highest
(82% ee).8
scope of enones for which these phosphaferrocene-oxazoline
ligands are effective is fairly broad. Thus, we can achieve
catalytic enantioselective conjugate additions with good ee’s
for both electron-rich and electron-poor chalcone derivatives
(91 and 80% ees; entries 2 and 3). Interestingly, a â-fer-
rocene-substituted enone is also an excellent substrate for
this catalyst system (90% ee; entry 4).
The utility of these phosphaferrocene-oxazoline ligands
is not limited to 1,4-additions to chalcones and related
compounds. For example, â-alkyl-substituted enones are also
suitable reaction partners, although a relatively modest ee is
obtained if the â-substituent is unbranched (84 and 61% ees;
entries 5 and 6). Finally, alkyl ketones undergo conjugate
addition with good enantioselection (81% ee; entry 7).9,10
To gain some insight into the nature of the species that
are generated under our reaction conditions, we have
examined the relationship between product ee and ligand ee.11
As shown in Figure 2, in the presence of ligand 7b we
Additional optimization (e.g., Cu(OTf) instead of Cu-
(OTf)2) led to further enhancement in the stereoselection of
this process (87% ee; Table 1, entry 1). Importantly, the
Table 1. Copper-Catalyzed Enantioselective Conjugate
Addition of Diethylzinc to Acyclic Enones in the Presence of
Phosphaferrocene-Oxazoline Ligandsa
Figure 2. Negative nonlinear effect for the enantioselective
conjugate addition of diethylzinc to 4-chlorochalcone catalyzed by
Cu(OTf)/7b.
observe a clear, albeit small, negative nonlinear effect,
suggesting the presence of heterochiral bis- (or higher) ligated
complexes in the reaction mixture.
In conclusion, we have synthesized a new family of chiral
phosphaferrocene-oxazoline ligands and have applied them
to the copper-catalyzed asymmetric conjugate addition of
diethylzinc to a range of acyclic enones with generally high
(6) Holand, S.; Jeanjean, M.; Mathey, F. Angew. Chem., Int. Ed. Engl.
1997, 36, 98-100.
(7) The structures of 7a′, 7b, and 7c′ were determined by X-ray
crystallography (see Supporting Information for the structure of 7a′).
(8) Ligands 7a′, 7b′, and 7c′ furnish 26, 65, and 81% ees, respectively
(major enantiomer: S).
(9) Under identical conditions, Cu(OTf)/7c catalyzes the conjugate
addition of ZnEt2 to 2-cyclohexen-1-one in 78% ee and 83% yield.
(10) Under identical conditions, Cu(OTf)/7c catalyzes the conjugate
addition of ZnMe2 to chalcone in 89% ee in a very slow process (<10%
conversion after 18 h at 0 °C).
(11) For a review of nonlinear effects in asymmetric catalysis, see:
Kagan, H. B.; Luukas, T. O. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Chapter 4.1.
a All data are the average of two runs. Reaction conditions: enone (0.15
mmol, 1.0 equiv), ZnEt2 (0.23 mmol, 1.5 equiv), [Cu(OTf)]2‚C6H6 (3.8
µmol, 2.5%), ligand (9.0 µmol, 6%), toluene (2.5 mL), 0 °C, 24 h.
Org. Lett., Vol. 4, No. 21, 2002
3701
Shintani, Ryo
