alcohols, was based on a novel Cu(OTf)2-phosporamide
catalyst discovered by Feringa et al.8 We subsequently
examined other racemic vinyloxiranes and screened potential
phosphoroamidite ligands for this new catalytic enantio-
selective reaction. In the present paper, we report that the
chiral Cu(II) complex with ligand 1 (Figure 1) is a highly
(Table 1), was obtained with an increased regio- and
enantioselectivity with respect to 2. Encouraged by these
preliminary results, we were intrigued by the possibility of
the addition of dialkylzinc reagents to the enantiotopic faces
of a prochiral symmetrical epoxide, thus avoiding the
inherent limitations of a kinetic resolution process.
The unknown epoxides 6-10, bearing enantiotopic meth-
ylidene moieties in an allylic position with respect to the
endocyclic oxirane ring, were therefore synthesized (Scheme
1). Vinyloxiranes 6-10 were prepared from the correspond-
Scheme 1. Synthesis of Substratesa
Figure 1. Phosphoroamidites 1 and 2 used as chiral ligands.
effective catalyst for the addition of diethylzinc to both
racemic and meso-methylidenecycloalkane epoxides.
Initial experiments revealed that the addition of Et2Zn to
racemic methylidene cycloalkane epoxide 3 was greatly
accelerated9 by the presence of a catalytic amount (1.5 mol
%) of Cu(OTf)2 and phosphoramidites 1 or 2 (3 mol %) (see
Figure 1 and Table 1).
Table 1. Enantioselective Conjugate Addition of Diethylzinc to
Racemic Epoxide 3 Catalyzed by Cu(OTf)2/L* (Kinetic
Resolution Protocol)a
a Reagents and conditions: (a) Zn dust, CH3COOH, H2O, rt, 1
h, 82%; (b) pyrolysis at 1 mmHg, 45-90%; (c) H2O2 (30%v/v),
Na2CO3 (20% in H2O), acetone, 0 °C to rt, 2 h, 70-90%; (d) LDA,
MePPh3Br, THF, 0 °C to rt, 0-45-1.5 h, 39-77%; (e) KOH, CH3I,
dioxane-H2O, 18 h, 51%; (f) NBS, CCl4, hν, 74%.
entry
L*
yieldb (%)
eec (%)
SN2′/SN2d
ing enediones 12-1412 and 16 by oxidation with H2O2 in
the presence of Na2CO3 and subsequent Wittig olefination
with MePPh3Br in LDA/THF. The synthesis of conjugate
triene epoxide 6 was similarly obtained after vacuum
pyrolysis of the corresponding Diels-Alder adduct 12,
previously treated with alkaline H2O2.13
We began our study with symmetrical epoxide 8, which
was treated with Et2Zn in the presence of a catalytic amount
of chiral ligand 2 (3 mol %) and Cu(OTf)2 (1.5 mol %) to
1
2
1
2
89 (4)
76 (4)
88 [S-(4)]
85 [S-(4)]
97/3
85/15
a All reactions were run as described in ref 10 (0.50 equiv of Et2Zn).
b Isolated yield of allylic alcohol 4 based on the reacted substrate (substrate
conversion 50% ( 5). c Determined by GC analysis of the crude reaction
mixture using a chiral column. For the determination of the absolute
configuration of the major enantiomer, see the Supporting Information.
d Composition determined by NMR and GC capillary analysis of the crude
reaction mixture.
The so-called mismatched ligand11 1, derived from (S)-
Binol and (S)-bis-phenylethylamine and, therefore, diaster-
eomeric with respect to 2, was superior to the latter in terms
of enantioselectivity and efficiency when methylidenecy-
cloalkane epoxide 3 was employed: the corresponding allylic
alcohol 4, derived from a conjugate addition pathway (SN2′)
(8) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374. (b) Feringa, B. L.; Pineschi, M.; Arnold, L.
A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36,
2620. (c) Krause, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 283. (d) Imbos,
R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1,
623. (e) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L.
J. Am. Chem. Soc. 1999, 121, 1104.
(9) The corresponding blank reactions performed without the chiral
ligands gave a complex reaction mixture containing adducts 4 and 5 in a
1:1 ratio. For a review of ligand-accelerated catalysis, see: Berrisford, D.
J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.
(7) Badalassi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
Feringa, B. L. Tetrahedron Lett. 1998, 39, 7795.
934
Org. Lett., Vol. 2, No. 7, 2000