Planar-Chiral Heterocycles as Ligands in Metal-Catalyzed Processes: Enantioselective Addition of Organozinc Reagents to Aldehydes

Full text of DOI:10.1021/jo962156g

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J . Org. Chem. 1997, 62, 444-445
P la n a r -Ch ir a l Heter ocycles a s Liga n d s in
Meta l-Ca ta lyzed P r ocesses:
En a n tioselective Ad d ition of Or ga n ozin c
Rea gen ts to Ald eh yd es
Peter I. Dosa, J . Craig Ruble, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received November 19, 1996
As part of a program directed toward the development
of new families of chiral nucleophilic catalysts and new
classes of chiral ligands, we have begun to explore the
chemistry of 2-substituted heterocycles that are π-bound
to transition metals (e.g., 1).1 Such complexes are chiral
by virtue of the presence of MLn and the differentiation
of R from H, and the asymmetric environment around
the Lewis-basic heteroatom can readily be “tuned” by
varying the steric bulk either of the metal fragment or
of R. We recently demonstrated that enantiopure planar-
chiral heterocycles function as efficient nucleophilic acy-
lation catalysts for the kinetic resolution of secondary
alcohols.1 In this paper, we report that they also serve
as effective chiral ligands,2 catalyzing the enantioselec-
tive addition of organozinc reagents to aldehydes.
F igu r e 1. Product ee as a function of catalyst ee for the
reaction of benzaldehyde with ZnEt2 in the presence of 3 mol
% of 2b.
Alkylation of the potassium salt of 2a affords tridentate
ligand 2b (eq 2), which has indeed proved to be a more
effective asymmetric catalyst than 2a . Thus, reaction of
benzaldehyde with ZnEt2 in the presence of 3 mol % of
(-)-2b produces (S)-1-phenyl-1-propanol in 90% ee (eq
3; cf. eq 1).5,6 Several striking examples of asymmetric
amplification have been reported for amino alcohol-
catalyzed additions of organozinc reagents to aldehydes;7
in the case of 2b, however, the relationship between the
ee of the catalyst and the ee of the product is essentially
linear (Figure 1).
A study of the addition of ZnEt2 to 4-substituted
benzaldehydes reveals that catalyst 2b provides high
enantioselectivity regardless of the electronic character
of the aromatic ring (eq 48). However, consistent with
other amino alcohol-catalyzed ZnEt2 reactions,3c some-
Because an array of â-amino alcohols are known to
catalyze the asymmetric addition of diethylzinc to alde-
hydes,3 we focused our initial efforts in this area on
planar-chiral â-amino alcohol 2a . Treatment of benzal-
dehyde with 3 mol % of (-)-2a and 1.2 equiv of ZnEt2
results in the formation of (S)-1-phenyl-1-propanol with
modest enantioselectivity (51% ee; eq 1).
We next chose to follow the lead of Hoshino, who has
established that O-alkylation of a chiral â-amino alcohol
with 1,1-diphenyloxirane can enhance the stereoselec-
tivity observed for organozinc additions to aldehydes.4
(5) Representative procedure: ZnEt2 (31 µL, 0.30 mmol) was added
dropwise by syringe to a solution of (+)-2b (3.6 mg, 0.0074 mmol) and
benzaldehyde (26.5 mg, 0.25 mmol) in 3.0 mL of toluene. After being
stirred for 24 h at room temperature, the reaction was quenched by
the addition of 2.5 mL of 1 N HCl. The resulting mixture was extracted
with Et2O, and the organic layer was concentrated. Purification by
flash chromatography (20% Et2O/pentane) afforded 28.8 mg (92%) of
1-phenyl-1-propanol, which was acylated with acetic anhydride. Chiral
GC analysis of the acetate revealed a 90% ee of the R isomer. Note:
The data reported for eqs 1 and 3-7 are the average of two runs, one
with each enantiomer of the catalyst.
(1) (a) Ruble, J . C.; Fu, G. C. J . Org. Chem. 1996, 61, 7230-7231.
(b) Ruble, J . C.; Latham, H. A.; Fu, G. C., in press.
(2) (a) First report of N-coordination of an azaferrocene to a
transition metal: Pyshnograeva, N. I.; Setkina, V. N.; Kursanov, D.
N. Izv. Akad. Nauk SSSR, Ser. Khim. 1984, 2778-2780. (b) Review of
σ,π-complexes of five-membered monoheterocycles: Sadimenko, A. P.;
Garnovskii, A. D.; Retta, N. Coord. Chem. Rev. 1993, 126, 237-318.
(3) (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823-2824.
(b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem. Soc.
1986, 108, 6071-6072. (c) Comprehensive review of the enantioselec-
tive addition of organozinc reagents to aldehydes: Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833-856.
(6) Benzaldehyde is the only substrate for which optimization
studies have been performed. The enantioselectivity is not sensitive
to changes in catalyst loading, temperature, concentration, stoichiom-
etry of ZnEt2, or solvent (hexane, 1:1 toluene:hexane, Et2O, or PhCF3).
(7) (a) Oguni, N.; Matsuda, Y.; Kaneko, T. J . Am. Chem. Soc. 1988,
110, 7877-7878. (b) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.;
Kitamura, M. Pure Appl. Chem. 1988, 60, 1597-1606.
(4) Ishizaki, M.; Fujita, K.-i.; Shimamoto, M.; Hoshino, O. Tetrahe-
dron: Asymmetry 1994, 5, 411-424.
(8) The absolute configuration of 1-(4-fluorophenyl)propanol has not
been determined (no literature data are available).
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J . Org. Chem., Vol. 62, No. 3, 1997 445
what lower stereoselectivity is observed when the aro-
matic ring is replaced with an n-alkyl group (63% ee; eq
5).
to a metal serve as effective catalysts for the enantiose-
lective addition of organozinc reagents to aldehydes. To
the best of our knowledge, this is the first application of
this family of ligands in asymmetric catalysis, and our
current efforts are focused on extending their utility to
an array of transition metal-catalyzed reactions.
Ack n ow led gm en t. We thank the members of the
Buchwald group (MIT) for generously sharing their
equipment. Support has been provided by the American
Cancer Society, the Camille and Henry Dreyfus Foun-
dation, the National Science Foundation (predoctoral
fellowship to J .C.R.; Young Investigator Award to
G.C.F., with funding from Procter & Gamble, Merck,
Pfizer, DuPont, Rohm & Haas, and Pharmacia &
Upjohn), and the Research Corporation. Acknowledg-
ment is made to the donors of the Petroleum Research
Fund, administered by the American Chemical Society,
for partial support of this research.
We have also explored the reactions of ZnMe2 and
ZnPh2 with aldehydes in the presence of catalyst (-)-2b.
In the case of ZnMe2, addition to benzaldehyde provides
(S)-1-phenylethanol in good enantiomeric excess (83% ee;
eq 6), while the reaction of ZnPh2 with 4-chlorobenzal-
dehyde proceeds with moderate stereoselectivity (57% ee;
eq 7).9
In conclusion, we have established that 2-substituted
heterocycles that are chiral by virtue of π-complexation
(9) Crystalline ZnPh2 (Strem) was used in these reactions. To the
best of our knowledge, this is the first example of the catalytic
enantioselective addition of ZnPh2 to an aldehyde. The few previous
reports of asymmetric catalysis with “ZnPh2,” prepared by mixing
phenylmagnesium halide and zinc chloride, appear not to involve
ZnPh2. For a discussion, see ref 3c, pp 846-847.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (9 pages).
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