J . Org. Chem. 2000, 65, 77-82
77
Ra tion a liza tion of En a n tioselectivities in Dia lk ylzin c Ad d ition s to
Ben za ld eh yd e Ca ta lyzed by F en ch on e Der iva tives†
Bernd Goldfuss,*,‡ Melanie Steigelmann,‡ Saeed I. Khan,§,| and K. N. Houk§
Organisch-Chemisches Institut der Universita¨t Heidelberg, Im Neuenheimer Feld 270,
D-69120 Heidelberg, Germany, and Department of Chemistry and Biochemistry, University of California,
Los Angeles 405 Hilgard Avenue, Los Angeles, California 90095-1569
Received J uly 6, 1999
Three (-)-fenchyl alcohol derivatives, {(1R,2R,4S)-exo-(2-Ar)-1,3,3-trimethylbicyclo[2.2.1] heptan-
2-ol, Ar ) o-anisyl (2), 2-N-methylimidazolyl (3), 2-N,N-dimethylbenzylamine (4)} were synthesized,
characterized by X-ray analyses, and employed as precatalysts in diethyl zinc additions to
benzaldehyde. Directions and relative degrees of enantioselectivities are rationalized by QM/MM
ONIOM computations of µ-O transition structure models. Enantioselectivities arise from repulsive
interactions between “transferring” or “passive” alkyl groups at the zinc centers and the substituents
at donor groups or the bicyclo[2.2.1]heptane moieties. These results enable predictions for ligand-
tuning to improve catalyst efficiency of fenchone-based ligands in dialkylzinc additions to aldehydes.
In tr od u ction
isoborneol (DAIB) catalyzed dialkylzinc, ZnR2 (R ) Me,
Et), additions to benzaldehyde. The enantioselective step
was found to proceed through “anti” and “syn” µ-O
transition structures.5 We have recently shown that µ-O
transition structure models can be successfully employed
to understand enantioselectivities with other chiral
â-amino alcohols, e.g., proline and 1,2-diphenylethane
derivatives.6
Enantioselective 1,2-additions of organometallic re-
agents to prochiral carbonyl compounds are fundamental
in syntheses of optically active molecules.1 Hence, the
design of efficient chiral promoters for these processes
is of central interest.2 Combinatorial methods for syn-
theses and high throughput screening of catalysts are
being developed currently3 but hardly provide answers
for the puzzling questions regarding the origins of
enantioselectivities. This knowledge, however, is es-
sential for a rational catalyst design.
Noyori et al. reported profound experimental4 and
computational5 studies of (2S)-3-exo-(dimethylamino)-
† This article is dedicated to Prof. Paul von Rague´ Schleyer on the
occasion of his 70th birthday.
A large number of chiral chelating ligands has been
synthesized and applied in enantioselective additions of
organozincs7 to aldehydes,2,8 but ligands with short
synthetic routes are still desirable. Additions of donor-
functionalized organolithiums to fenchone provide ef-
ficient one-step routes to chiral chelating fenchyl alcohol
ligands (e.g. 1). For 1, however, only moderate enantio-
selectivities were reported (64% ee of (R)-1-phenylpro-
panol).9
* Corresponding author. E-mail: Bernd.Goldfuss@urz.uni-heidel-
berg.de.
‡ Organisch-Chemisches Institut der Universita¨t Heidelberg.
§ Department of Chemistry and Biochemistry, UCLA.
| Responsible for X-ray crystal analysis.
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To explore origins of the enantioselectivities, we syn-
thesized fenchone-based ligands with different coordina-
tion groups (D), 2-4, and employed them as precatalysts
in dialkylzinc additions to benzaldehyde. The stereo-
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10.1021/jo991070v CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999