Increasing enantioselectivities and reactivities by stereochemical tuning: Fenchone-based catalysts in dialkylzinc additions to benzaldehyde

Article abstract of DOI:10.1002/(SICI)1099-0690(200005)2000:9<1785::AID-EJOC1785>3.0.CO;2-0

Trimethylsilyl substitutions of the fenchyl alcohols [(1R,2R,4S)-exo-(2- Ar)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol, Ar = 2-methoxyphenyl (1) and Ar = 2-(dimethylaminomethyl)phenyl (2)] yield the chiral ligands 3 [Ar = 2- methoxy-3(trimethylsilyl)phenyl

Full text of DOI:10.1002/(SICI)1099-0690(200005)2000:9<1785::AID-EJOC1785>3.0.CO;2-0

FULL PAPER
Increasing Enantioselectivities and Reactivities by Stereochemical Tuning:
Fenchone-Based Catalysts in Dialkylzinc Additions to Benzaldehyde
[
a]
[a]
[°]
Bernd Goldfuss,* Melanie Steigelmann, and Frank Rominger
Dedicated to Professor Paul von Ragu e´ Schleyer on the occasion of his 70th birthday
Keywords: Asymmetric synthesis / Zinc / Transition structures / QM/MM computations
Trimethylsilyl substitutions of the fenchyl alcohols
(1R,2R,4S)-exo-(2-Ar)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-
ol, Ar = 2-methoxyphenyl (1) and Ar = 2-(dimethylaminome-
thyl)phenyl (2)] yield the chiral ligands 3 [Ar = 2-methoxy-3-
(26% ee S) and 2 (73% ee S). X-ray crystal structures of 3
and of its methylzinc complex 3-Zn reveal out-of-plane
bending of the methoxy groups as major geometrical con-
sequences of the trimethylsilyl substitutions. Analyses of
QM/MM ONIOM µ-O transition-structure models for 1, 2, 3,
and 4 show that trimethylsilyl-induced distortions of methoxy
and of dimethylaminomethyl groups explain the observed in-
creased enantioselectivities.
[
(trimethylsilyl)phenyl] and 4 [Ar = 2-(dimethylaminomethyl)-
3-(trimethylsilyl)phenyl]. Increased reactivities and enantio-
selectivities in diethylzinc additions to benzaldehyde are
obtained from 3 (63% ee R) and 4 (93% ee S), relative to 1
Introduction
[
1]
Enantioselective 1,2-additions of organozinc reagents
to prochiral carbonyl[ and imino systems are funda-
2]
[3]
mental tools for the synthesis of optically active com-
[
4]
pounds, and the design of chiral promoters for these pro-
[5]
cesses is of central interest. A huge number of chiral li-
gands has been applied in enantioselective additions of or-
[5,6]
ganozinc compounds to aldehydes,
but efficient ligands
with short synthetic routes are still desirable. The underly-
ing origins for directions and relative degrees of enantiose-
lectivities in dialkylzinc additions to aldehydes are puzz-
[
7]
Scheme 1. Enantioselective dialkylzinc addition to benzaldehyde
via anti- and syn-µ-O transition structures; the OʜD units desig-
nate chiral, donor (D) functionalized chelate ligands
ling.
Qualitative mechanistic understanding and quantitative
rationalization of enantioselection processes can provide a
basis for rational catalyst design. We have recently shown
that µ-O transition-structure models can be successfully em-
ployed to understand enantioselectivities of dialkylzinc ad-
ditions to benzaldehyde (Scheme 1), catalyzed by chiral β-
amino alcohols, e. g., proline and 1,2-diphenylethane deriv-
lectivities and reactivities in diethylzinc additions to benzal-
dehyde were investigated. Significantly improved enantiose-
lectivities and increased reactivities were obtained by
stereochemical tuning. X-ray crystal structures and compu-
tational analyses were employed to interpret and rationalize
the results of the catalytic reactions.
[
8]
atives.
Bicyclic terpenes (e.g., camphor and fenchone) are valu-
able sources for the construction of chiral ligands and cata-
[
9]
lysts, and Noyori et al. have proven that 3-exo-(dimethyl- Results and Discussion
[10]
amino)isonorborneol (DAIB) is among the best. Chelat-
ing fenchyl alcohols are readily accessible by organolithium Synthesis and Structural Characterization of the Ligands
additions to fenchone, but only moderate enantioselectivi-
Modular ligand systems are highly appreciated in enantio-
ties (up to 64% ee) were reported for catalyzed diethylzinc
selective catalysis, due to their high degree of variabil-
additions to benzaldehyde.[
9b]
[6,11]
ity.
With chelating fenchyl alcohols, variations of coor-
We here present a combined experimental and computa-
tional study of fenchone-based catalysts, whose enantiose-
dination donor functions (e.g., OMe, CH NMe , Scheme 2)
2
2
[12]
are easily accessible;
this enables tuning of the stereo-
chemical outcome of enantioselective diethylzinc addi-
[
a]
Organisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
E-mail: Bernd.Goldfuss@urz.uni-heidelberg.de
X-ray analyses.
[13]
tions.
Substituents (X, e.g., SiMe ) in ortho positions of
3
the aryl moieties (Scheme 2) should even further influence
[
°]
[14]
reactivities and enantioselectivities of the catalysts.
Eur. J. Org. Chem. 2000, 1785Ϫ1792
 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0509Ϫ1785 $ 17.50ϩ.50/0
1785

B. Goldfuss, M. Steigelmann, F. Rominger
FULL PAPER
Scheme 2. Chelating fenchyl alcohols
Figure 2. X-ray crystal structure of 4
A comparison of the X-ray crystal structures of 2 (X ϭ
H) and 4 (X ϭ SiMe , Scheme 2, Figure 2) shows a small
3
decrease of the C4–C5–C6 angle (126° in 2, 121° in 4) and
a slight increase of the C6–C5–C8 angle (116° in 2 and 118°
in 4) upon trimethylsilyl substitution (Table 2). The O2–C3–
C4–C5 segment is less coplanar in 4 (49°) than in 2 (43°).
The N7–C6–C5–C8 dihedral angle of 4 is not larger than
that of 2 (both 110°, Table 2).[
15]
Figure 1. X-ray crystal structure of 3
Reactivity and Enantioselectivity of the Catalysts
Geometrical effects of the ortho-trimethylsilyl substitu-
ents are indeed apparent from comparisons of X-ray crystal
The chiral 1,3,3-trimethylbicyclo[2.2.1]heptane moieties,
structures of the ligands 1 (X ϭ H) and 3 (X ϭ SiMe3, the heteroatom donor groups and the chelate ring sizes[
Scheme 2, Figure 1). While the methoxy group is aligned are all identical for the pair 1 and 3 and the pair 2 and 4
coplanar with the aryl moiety in 1 (C7–O6–C5–C8: –3°, (Scheme 2). The trimethylsilyl substituents of 3 and 4 make
Table 1), trimethylsilyl substitution forces the methyl group them more reactive (increased chemical yield) than 1 and 2,
to bend out of the aryl plane in 3 (C7–O6–C5–C8: –72°, respectively (Table 3). Furthermore, the degrees of enanti-
Table 1). This alignment reduces repulsion between C7 and oselectivity of 3 and 4 are greater than those of 1 and 2,
16]
˚
˚
C8 (2.81 A in 1, 3.05 A in 3) and hence results in a smaller respectively (Table ). Even the direction of enantioselectiv-
O6–C5–C8 angle in 3 (118°) than in 1 (123°, Table 1). How- ity of 3 (R product) and 1 (S product) differ.
ever, repulsive interactions arise from close contacts be-
Why do trimethylsilyl substituents in the remote ortho
tween the geminal dimethyl unit (C10, Scheme 2) of the bi- position of 3 increase the reactivity relative to 1 (Scheme 2)?
cycloheptane moiety and the out-of-plane bent C7 in 3 Elaborate investigations by Noyori et al. on DAIB-cata-
˚
˚
(
3.66 A) relative to 1 (4.29 A). This results, by rotation of lyzed dialkylzinc additions to benzaldehyde revealed that
the C3–C4 axis, in a more coplanar arrangement of the O2– monomeric zinc chelate complexes are the active catalysts
C3–C4–C5 unit (33° in 3, 47° in 1, Table 1). Hence, trime- for dialkylzinc additions to aldehydes, while the dimers are
thylsilyl substitution of 1 significantly alters the HOʜOMe unreactive.[ The monomer–dimer equilibrium of zinc che-
17]
alignment in 3.
late complexes determines the appearance of the mono-
Table 1. X-ray crystal structural data of chelating fenchyl alcohols 1[13] and 3 (see Scheme 2); distances in A, angles in °
˚
H1–O6
O2–O6
O2–C3–C4
C4–C5–O6
O6–C5–C8
C5–C8–X9
O2–C3–C4–C5
C7–O6–C5–C8
[
a]
1
3
1.94
1.86
2.62
2.60
108
109
116
119
123
118
120
127
47
33
–3
–72
[
a]
Average values of four independent molecules of 1.
Table 2. X-ray crystal structural data of fenchyl alcohols 2[13] and 4 (see Scheme 2); distances in A, angles in °
˚
H1–N7
O2–N7
O2–C3–C4
C5–C8–H9
C4–C5–C6
C6–C5–C8
O2–C3–C4–C5
N7–C6–C5–C8
2
4
1.69
1.80
2.66
2.64
108
111
120
129
126
121
116
118
43
49
110
110
1786
Eur. J. Org. Chem. 2000, 1785Ϫ1792

Fenchone-Based Catalysts in Dialkylzinc Additions to Benzaldehyde
FULL PAPER
Table 3. Enantioselective additions of diethylzinc to benzaldehyde; in hexanes, 3 mol-% ligand was employed
Ligand
T [°C]
Reaction time [h]
Chemical yield[a]
Enantiomer[b]
%ee [c]
[
[
d]
d]
1
2
3
4
–30
ϩ6
–30
ϩ6
24
24
24
24
56%
57%
66%
79%
S
S
R
S
26
73
63
93
[
a]
[b]
Major enantiomer of the 1-phenyl-1-propanol product. – [c] Enantio-
The completion of reaction was monitored by GC analysis. –
meric excess, chiral HPLC analyses. – [ See ref.
d]
[13]
Scheme 3. Synthesis and monomer–dimer equilibrium of methylzinc chelate complexes
meric species and hence influences the reactivity. This equi- smaller than for 1-Zn (32.3 kcal/mol). The increased tend-
librium (shown in Scheme 3 for methylzinc complexes of 1 ency of (3-Zn) towards dissociation is apparently geomet-
2
and 3) is also crucial for asymmetric amplification phenom- rically determined, and is shown by larger external (dimer-
[
18]
˚
˚
ena.
forming) Zn–O distances [2.21 A in (3-Zn) vs. 2.13 A in (1-
2
Zn) ] of the central Zn O rings, shorter internal Zn–O
2
2
2
˚
˚
bonds [1.88 A in (3-Zn) vs. 1.91 A in (1-Zn) ] and longer
aryl–aryl distances [3.72 A in (1-Zn) vs. 5.09 A in (3-Zn) ]
2
2
˚
˚
2
2
(
Figure 4, 5).
[19]
Scheme 4. Structures of (1-Zn)
2
and (3-Zn)
2
We recently reported the X-ray crystal structure of the
dimeric methylzinc chelate complex (1-Zn) (Scheme 4, Fig-
2
[
19]
ure 3),
which is the methyl analog of the ethylzinc cata-
lyst of 1 (employed for the catalytic experiments, Table 3).
Complex (1-Zn) has syn-aligned methylzinc moieties (Fig-
2
ure 3), analogous to Noyori’s homochiral syn-methylzinc
[
18b]
DAIB complex.
Figure 4. ONIOM (RHF/LanL2DZ:UFF) optimized structure of
1-Zn)
(
2
Synthesis and X-ray crystal analysis of trimethylsilyl-sub-
stituted 3-Zn reveals the formation of dimeric (3-Zn) (Fig-
2
ure 6), in analogy to dimeric (1-Zn) (Scheme 4). Significant
2
geometrical differences are, however, apparent in (3-Zn)2
relative to (1-Zn) . In contrast to the syn alignments of
2
methylzinc groups in the X-ray crystal structure of (1-
Zn)2,[ anti orientations of methylzinc groups are apparent
19]
in (3-Zn) (Figure 6).
2
Complex (1-Zn) exhibits short Zn–O(Me) contacts of
2
˚
[19]
˚
2.19 A. In (3-Zn) , the Zn–O(Me) distance (2.40 A) is long
2
[19]
Figure 3. X-ray crystal structure of (1-Zn)
2
due to repulsion between synperiplanar aligned methyl
˚
Computational evaluations assess the degree of dimer groups at oxygen and zinc (C–O–Zn–C: 2°, C–C: 3.41 A),
˚
formation in the monomer–dimer equilibria of the methyl- while a shorter Zn–O(Me) contact (2.27 A) arises from an
zinc catalysts 1-Zn and 3-Zn (Scheme 3).[20] In agreement antiperiplanar methoxy and methylzinc group arrangement
with the higher reactivity of 3-Zn (Table 3), the dimeriz- (C–O–Zn–C: 173°). The aryl–methoxy group coplanarity
ation energy for 3-Zn (21.0 kcal/mol) is 11.3 kcal/mol (measured by the C7–O6–C5–C8 dihedral angle, Scheme 2)
Eur. J. Org. Chem. 2000, 1785Ϫ1792
1787

B. Goldfuss, M. Steigelmann, F. Rominger
FULL PAPER
methylzinc groups, yielding R- and S-configured products
(
Scheme 5), are used.
Scheme 5. Computed anti- and syn-µ-O transition structures; the
OʜD unit denotes the chelating ligand with an OMe donor group
(
2 2
D) for 1 and 3 and a CH NMe donor (D) for 2 and 4
S-Configured 1-phenyl-1-ethanol (as model for the ex-
perimental 1-phenyl-1-propanol) is produced by ligands 1
and 2 via the lowest-energy transition structures 1-syn (S)
and 2-anti (S) (Table 4). The computed direction and the
lower enantioselectivity for 1 [0.4 kcal/mol energy differ-
ence, ∆E, between 1-syn (S) and 1-anti (R)] relative to 2
Figure 5. ONIOM (RHF/LanL2DZ:UFF) optimized structure of
[
20]
(3-Zn)
2
[
∆E ϭ 2.5 kcal/mol between 2-anti (S) and 2-syn (R)] corre-
spond with the experimental results (Table 3).
Table 4. Computed (RHF/LanL2DZ:UFF) total (a.u.) and relative
(
(
kcal/mol) energies of µ-O-syn and -anti transition structures
Scheme 5); transition structure optimizations and frequency ana-
lyses were performed by ONIOM (RHF/LanL2DZ:UFF) compu-
tations; a single imaginary frequency corresponds in all cases to
methyl transfer from zinc to the aldehyde carbon atom; the lowest
energy transition structure (in bold and italics typeface) determines
the configuration of the product and the energy difference to the
next stable transition structure (bold typeface) is used as a measure
for enantioselectivity
Ligand
anti (R)
anti (S)
syn (R)
syn (S)
1
–434.91175
0.4
–434.89675
9.8
–434.88393
17.8
–434.91230
0.0
rel.
2
–434.89222
3.0
–434.89707
0.0
–434.89304
2.5
–434.88370
8.4
rel.
3
–434.89995
0.0
–434.87761
6.2
–434.88229
11.1
434.88745
0.0
–434.87976
12.7
–434.88217
3.3
–434.89822
1.1
–434.87086
10.4
rel.
4
Figure 6. X-ray crystal structure of (3-Zn)
2
rel.
in (3-Zn) is –101° for the methoxy group with the larger
Trimethylsilyl substitution of 1 changes the direction of
2
˚
(
2.40 A) Zn–O distance and –56° for the methoxy group enantioselectivity for 3, both experimentally (Table 3) and
˚
with the shorter (2.27 A) contact to Zn. As in the X-ray computationally (Table 4): the most stable transition struc-
crystal structure of 3 (Figure 1), close distances between the ture changes from 1-syn (S) to 3-anti (R). Formation of (R)-
methoxy methyl groups and the geminal dimethyl moiety of 1-phenyl-1-ethanol via 3-anti (R) is more favorable (∆E ϭ
the bicycloheptane unit are apparent in (3-Zn) (C–C: 3.55 1.1 kcal/mol) for 3 than generation of the S product via 3-
2
˚
[19]
A). The in-plane aligned methoxy group in (1-Zn)
rise to much longer distances (C–C: 3.85 A). The internal ence of 3 for the R product is in agreement with experi-
Zn–O bonds of the central Zn O rings of (1-Zn) (1.97 A) mental enantioselectivities (Table 3).
and (3-Zn) (1.95, 1.98 A) are similar, while the external
gives syn (S) (∆E ϭ 0.4 kcal/mol, Table 4). This increased prefer-
2
˚
˚
2
2
2
˚
Superpositions show how trimethylsilyl substitutions sta-
2
(
dimer-forming) Zn–O bonds are shorter in (1-Zn) (2.01 bilize 3-anti (R) and destabilize 3-syn (S) relative to the ana-
2
˚
˚
A) than in (3-Zn) (2.02, 2.04 A). This reflects the greater logous structures of 1 (Figure 7 and Figure 8). The trans-
2
tendency of (3-Zn) to dissociate more readily into reactive ition structures reveal distortions of 3-syn (S) and of 3-anti
2
monomers 3-Zn, and agrees with the higher reactivity of 3 (R) relative to 1-syn (S) and 1-anti (R).
relative to 1 in diethylzinc additions to benzaldehyde.[
21]
These distortions move the aldehyde carbon atom away
How do the trimethylsilyl substituents of 3 and 4 influ- from the transferring methyl group in 3-syn (S), but com-
ence the enantioselectivities in diethylzinc additions to press electrophilic and nucleophilic parts in 3-anti (R). The
benzaldehyde? The experimental enantioselectivities methyl transfer is favored more on the side of the Zn O2
2
22]
(
Table 1) can be reproduced[ and can be explained com- ring which is opposite to the trimethylsilyl group in 3-anti
[8,23]
putationally by µ-O transition-structure models,
if four (R). As in the X-ray crystal structures of 3 and of (3-Zn)2
µ-O transition-structure types with anti- and syn-aligned (Figure 1 and Figure 6), the distortions arise from trime-
1788
Eur. J. Org. Chem. 2000, 1785Ϫ1792

Fenchone-Based Catalysts in Dialkylzinc Additions to Benzaldehyde
FULL PAPER
on the side of the Zn O core which is opposite to the tri-
2
2
methylsilyl group.
Figure 9. Superposition of 2-anti (S) (black) and 4-anti (S) (gray)
transition structures; zinc atoms are eclipsed and hydrogen atoms
are omitted for clarity
Figure 7. Superposition of 1-syn (S) (black) and 3-syn (S) (gray)
transition structures; zinc atoms are eclipsed and hydrogen atoms
are omitted for clarity
Figure 10. Superposition of 2-syn (R) (black) and 4-syn (R) (gray)
transition structures; zinc atoms are eclipsed and hydrogen atoms
are omitted for clarity
The trimethylsilyl-induced distortions originate from in-
creased N7–C6–C5–C8 dihedral angles [Scheme 2, 105° in
4
-anti (S) vs. 97° in 2-anti (S); 105° 4-syn (R) vs. 95° in 2-
[15]
syn (R)], and give rise to the observed increased enantio-
Figure 8. Superposition of 1-anti (R) (black) and 3-anti (R) (gray) selectivity of the S product by 4 relative to 2 (Table 3).
transition structures; zinc atoms are eclipsed and hydrogen atoms
are omitted for clarity
Conclusions
thylsilyl-induced out-of-plane bending of methoxy groups
and repulsion with geminal dimethyl units of the bicyclo-
The introduction of trimethylsilyl groups in the ortho po-
˚
˚
heptane moieties [C–C: 3-syn (S) 3.96 A, 1-syn (S) 4.54 A; sitions of the fenchyl alcohols 1 and 2 alters the direction
˚
˚
3
-anti (R) 3.95 A, 1-anti (R) 4.59 A] and explain the ob- (for 3) and increases the degree of enantioselectivity as well
served enantioselectivities (Table 3). as the reactivity (for 3 and 4) in diethylzinc additions to
Trimethylsilyl substitution of 2 increases the enantioselec- benzaldehyde. X-ray crystal structure analysis shows that
tivity of the R product for 4, both experimentally (73 to trimethylsilyl substitution induces reorientation of the me-
9
3% ee, Table 3) and computationally. The energy difference thoxy group in 3. Computational analyses of dimeric
is increased from 2.5 kcal/mol between 2-anti (S) and 2-syn methylzinc chelate complexes of 1 and 3 show that 3-Zn has
R) to 3.3 kcal/mol in the analogous anti (S) and syn (R) a greater tendency to dissociate into reactive monomers
transition structures of 4 upon trimethylsilyl substitution than 1-Zn has; this agrees with the higher experimental re-
Table 4). activity of 3 relative to 1. The different natures of 1 and 3
Superpositions of 2,4-anti (S) and of 2,4-syn (R) show are also apparent from the geometries of the X-ray crystal
distortions upon trimethylsilyl substitution (Figure 9 and structures of (3-Zn) and (1-Zn) . The experimental trends
(
(
2
2
Figure 10). Similar to transition structures of 1 and 3 (Fig- of the enantioselectivities in diethylzinc additions to benzal-
ure 7 and Figure 8), methyl transfer becomes more favored dehyde are reproduced by µ-O transition structure models.
Eur. J. Org. Chem. 2000, 1785Ϫ1792
1789

B. Goldfuss, M. Steigelmann, F. Rominger
FULL PAPER
Analyses of the transition structures show that trimethylsi- pared from n-butyllithium (0.15 mol, 1.59 , 94.3 mL) in hexanes
and N,N-dimethylbenzylamine (0.15 mol, 22.53 mL).[ Chlorotri-
24]
lyl substitutions induce reorientations of methoxy and of
dimethylaminomethyl groups. The observed enantioselec-
tivities arise from these distinct stereochemical effects.
Larger substituents than trimethylsilyl (e.g., triphenylsilyl or
triisopropylsilyl) might lead to even stronger effects and re-
sult in higher reactivities and enantioselectivities in dial-
kylzinc additions to aldehydes.
methylsilane (0.15 mol, 19.04 mL) was slowly added at 0 °C and
the reaction mixture was stirred at room temperature for 6 h. Hy-
drolytic work up (NaHCO solution), washing, drying (Na SO )
3 2 4
and distillation (0.11 mbar, 52 °C) yielded 11.5 g (37%) of N,N-
dimethyl-2-(trimethylsilyl)benzylamine, which was added to a mix-
ture of n-butyllithium (55.7 mmol, 35 mL) in hexanes. The solution
was stirred 1 h at 60 °C. (–)-Fenchone (55.7 mmol, 9.0 mL) was
added at 0 °C and the mixture was stirred for 12 h at room temper-
2 4
ature. Hydrolytic workup, washing, drying (Na SO ) and crystal-
lization at –30 °C yielded a crude product, which was recrystallized
from pentane. White crystals of 4 were obtained (12.8 g, 36 mmol,
Experimental Section
2
3
1
2
(
1
2
4%). M.p.: 115 °C. – [α]
300 MHz, CDCl ): δ ϭ 0.32 [s, 9 H, (Si) CH
), 1.18 (s, 3 H, CH ), 2.18 [s, 6 H, (N)CH
D
ϭ –130.0 (c ϭ 2.0, hexanes). – H NMR
], 0.33 (s, 3 H, CH ),
], 0.09–
], 4.03 [d, 1
2
], 7.16 (t, 1 H, J ϭ 7.7 Hz, ar), 7.32 (d, 1
General: The reactions were carried out under argon (Schlenk and
needle-septum techniques) with dried and degassed solvents. – X-
ray crystal analyses were performed with a Bruker Smart CCD
diffractometer. – NMR spectra were recorded with a Bruker
AMX300 spectrometer. – IR spectra were run with a Bruker Equi-
nox 55 FT-IR spectrometer. – Optical rotations were measured with
a Perkin–Elmer P241 machine. – GC analyses were carried out with
a Chrompack (CP9001) and HPLC analyses on a HP-1100 machine
with a Chiracel OB-H column. – For the synthesis of 1 and 2, see
3
3
3
.14 (s, 3 H, CH
.50 [m, 7 H, CH(2)], 3.56 [d, 1 H, J ϭ 12 Hz, (N)CH
3
3
3
2
2
2
3
H, J ϭ 12 Hz, (N)CH
3
3
13
H, J ϭ 6.1 Hz, ar), 7.71 (d, 1 H, J ϭ 8.2 Hz, ar). – C NMR
CDCl ): δ ϭ 2.1, 18.4, 23.6, 24.0, 29.6, 34.5, 41.4, 44.3, 46.7, 50.3,
4.5, 62.8, 86.1, 124.7, 132.1, 132.1, 141.0, 142.7, 144.6. – IR (KBr,
(
5
3
–
1
cm ): ν˜ ϭ 3429, 3050, 2995, 2873, 2750, 1007. – C22
H37NOSi
[
13]
(359.63): calcd. C 73.48, H 10.37, N 3.89; found: C 73.45, H 10.36,
ref. – Crystallographic data (excluding structure factors) for the
structures reported in this paper were deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
nos. CCDC-135946 to -135948. Copies of the data can be obtained
free of charge on application to: CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (int.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
N 3.91. – X-ray crystal data of 4: C22
H
37NOSi; M ϭ 359.63; space
˚
˚
˚
group P2
1
; a ϭ 9.9810(5) A, b ϭ 9.9875(5) A, c ϭ 11.3068(6) A,
˚
3
β ϭ 107.886(1)°; V ϭ 1072.65(9) A ; Z ϭ 2; T ϭ 200(2) K; µϭ
–
1
0
.119 mm ; reflections total: 6840, unique: 3492, observed: 3345
[
I Ͼ 2σ(I)]; parameters refined: 236; R ϭ 0.044; wR ϭ 0.114;
1
2
GOFallϭ 1.03.
Synthesis and Characterization of 3-Zn: A solution of dimethylzinc
0.4 mmol, 2.0 , 0.2 mL) in toluene was added to 3 (0.4 mmol,
.13 g) at 0 °C. The mixture was stirred for 1 h at room temperature
methane evolved). Colorless crystals of 3-Zn were obtained by
Synthesis and Characterization of (1R,2R,4S)-exo-(2-Methoxy-3-
trimethylsilylphenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (3): A
solution of ortho-lithioanisole in TMEDA/hexanes was prepared
(
0
(
from n-butyllithium (0.11 mol, 1.59 , 63 mL) in hexanes, TMEDA
1
slow cooling of this solution to 0 °C. – – H NMR (300 MHz,
]toluene): δ ϭ –0.16 [s, 3 H, (Zn)CH ], 0.29 [s, 9 H, (Si)CH ],
.61 (s, 3 H, CH ), 1.11–2.04 [m, 13 H, CH(2,3)], 3.99 [s, 3 H,
O)CH ], 6.82–7.60 (m, 3 H, ar). – C NMR ([D
.7, 1.4, 24.8, 25.0, 31.7, 35.4, 43.2, 48.1, 50.4, 56.4, 65.2, 91.5,
5.2, 122.7, 131.9, 133.6, 135.1, 139.3, 164.0. – C42 Si Zn
24]
(
0.11 mol, 16.5 mL) and anisole (0.10 mol, 10.9 mL).[ Chlorotri-
[D
8
3
3
methylsilane (0.11 mol, 14.0 mL) was slowly added at 0 °C, and the
reaction mixture was stirred at room temperature for 6 h. Hydro-
lytic workup (NaHCO solution), washing, drying (Na SO ), and
3 2 4
distillation (1.0 mbar, 41 °C) yielded 12.8 g (71%) of 2-trimethylsi-
lylanisole, which was added to a mixture of 45.7 mL n-butyllithium
0
(
3
1
3
3
8
]toluene): δ ϭ –
6
9
H
68
O
4
2
2
(
823.88): calcd. C 62.03, H 8.52; found C 62.06, H 8.50. – X-ray
(
(
80 mmol) in hexanes and 12.0 mL TMEDA (80 mmol) at 0 °C.
–)-Fenchone (70 mmol, 11.3 mL) was added at 0 °C and the mix-
crystal data of (3-Zn) : C42
˚ ˚ ˚
1 1 1
P2 2 2 ; a ϭ 10.8060(1) A, b ϭ 16.0068(2) A, c ϭ 24.0982(3) A;
2
68 4 2 2
H O Si Zn ; M ϭ 823.88; space group
ture was stirred for 12 h at room temperature. Hydrolytic workup,
washing, drying (Na SO ) and crystallization at 6 °C yielded a
˚
3
–1
V ϭ 4168.25(8) A ; Z ϭ 4; T ϭ 200(2) K; µ ϭ 1.247 mm ;
reflections total: 31055, unique:7277, observed: 6900 [I Ͼ 2σ(I)];
2
4
crude product, which was recrystallized from pentane. White crys-
tals of 3 were obtained (8.4 g, 25 mmol, 25%). M.p.: 104 °C. –
1 2
parameters refined: 467; R ϭ 0.021; wR ϭ 0.051; GOFall ϭ 1.05.
2
3
1
[
α]
D
ϭ –88.2 (c ϭ 2.0, hexanes). – H NMR (300 MHz, CDCl
], 0.49 (s, 3 H, CH ), 1.11 (s, 3 H, CH
), 1.10–2.45 (m, 7 H, CH(2)), 3.82 (s, 3 H, (O)CH
3
3
3
):
Catalysis: Catalysis was performed with ligands 1 to 4 according
), to the following general procedure: The ligand (0.07 mmol, 3 mol-
), % with respect to benzaldehyde) was treated with diethylzinc in
δ ϭ 0.32 [s, 9 H, (Si)CH
.16 (s, 3 H, CH
3
3
1
7
(
3
3
3
.01 (t, J ϭ 7.6 Hz, 1 H, ar), 7.30 (d, J ϭ 7.2 Hz, 1 H, ar), 7.54
hexanes (3.3 mL, 3 mmol, 0.9 ) at 0 °C for 15 min. To this mix-
): δ ϭ 0.6, 18.1, 21.7, ture, benzaldehyde (0.24 mL, 0.25 g, 2.4 mmol) was added at the
3
13
d, J ϭ 8.0 Hz, 1 H, ar). – C NMR (CDCl
3
2
1
2
4.1, 29.7, 33.5, 41.6, 46.0, 49.6, 53.9, 64.4, 86.0, 122.0, 131.3,
temperature specified for each ligand (Table 3). After the reaction
time (24 h), the mixture was quenched with water and hydrolyzed
with hydrochloric acid. The organic layer was separated, washed,
–1
32.8, 134.4, 135.4, 164.7. – IR (KBr, cm ): ν˜ ϭ 3465, 3045, 2954,
866, 1012. – C20 Si (332.56): calcd. C 72.23, H 9.70; found
32 2
H O
C 72.25, H 9.80. – X-ray crystal data of 3: C20
H
32
O
2
Si; M ϭ neutralized (NaHCO ), dried (Na SO ) and 1-phenyl-1-propanol
3
2
4
˚
˚
3
1
32.56; space group P2
1
; a ϭ 7.6729(1) A, b ϭ 11.0159(2) A, c ϭ
was distilled. The optical purity was measured by polarimetry and
the enantiomeric excess was analyzed by chiral HPLC [Chiracel
OB-H, 99.2:0.8 hexanes: iPrOH, 25 °C, 254 nm, 1-phenyl-1-pro-
˚
˚
3
1.4503(2) A, β ϭ 98.647(1)°; V ϭ 956.82(3) A ; Z ϭ 2; T ϭ 200(2)
–1
K; µ ϭ 0.131 mm ; reflections total: 7169, unique: 3178, observed:
001 [I Ͼ 2σ(I)]; parameters refined: 219; R ϭ 0.029; wR
GOFall ϭ 1.04.
3
1
2
ϭ 0.073; panol: 18.5 min (S), 25.6 min (R)].
Computational Details: The complexes and the transition structures
Synthesis and Characterization of (1R,2R,4S)-exo-(2-Dimethyl-
aminomethyl-3-trimethylsilylphenyl)-1,3,3-trimethylbicyclo[2.2.1]-
heptan-2-ol (4): ortho-Lithio-N,N-dimethylbenzylamine was pre-
were fully optimized without constraints with Morokuma’s
ONIOM[ method implemented in GAUSSIAN98, combining
25]
[26]
ab initio levels (RHF/LanL2DZ) with Rappe’s universal force field
1790
Eur. J. Org. Chem. 2000, 1785Ϫ1792

Fenchone-Based Catalysts in Dialkylzinc Additions to Benzaldehyde
UFF, Scheme 6).[27] LanL2DZ denotes Los Alamos ECP and
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[
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[
28]
1869–1876. –
Y. Suzuki, Y. Ogata, K. Hiroi, Tetrahedron:
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[
29]
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transition structures were analyzed by frequency computations and
showed one imaginary frequency of the methyl transfer mode.
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[
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14]
Scheme 6. ONIOM (RHF/LANL2DZ:UFF) layers of computed
transition structures
B. Goldfuss, M. Steigelmann, S. I. Kahn, K. N. Houk, J. Org.
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J. M. Brown, M. Pearson, J. T. B.
Acknowledgments
1
We thank the Fonds der Chemischen Industrie (Liebig grant for B.
G.), the Deutsche Forschungsgemeinschaft and the Research Pool
Foundation (University Heidelberg) for financial support and the
Degussa-Hüls AG for generous gifts of chemicals. B. G. is espe-
cially grateful to Prof. Dr. P. Hofmann for generous support at Hei-
delberg.
[15]
The N7–C6–C5–C8 angle in the X-ray crystal structure of 4
(110°) is not increased relative to that in the X-ray crystal struc-
ture of 2 (110°) because close C6H–HCSi9 distances (H–H:
˚ ˚
.05 A, C–C: 3.48 A) favor a small N7–C6–C5–C8 dihedral
2
angle in 4. The repulsive C6H–HCSi9 contacts would decrease
even more if N7–C6–C5–C8 increased to over 110°. Trimethyl-
silyl conformations analogous to that in the X-ray crystal struc-
ture of 4 were examined in transition structures with 4, but
were found to be energetically unfavorable.
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anti aligned methyl groups at zinc centers, were computed to be
4.7 kcal/mol (1-Zn) and 3.4 kcal/mol (3-Zn) higher in energy.
Attempts to obtain X-ray crystal structures of analogous
methylzinc complexes of ligands 2 and 4 were not successful so
far. No stable dimeric methylzinc complexes were found com-
putationally for ligands 2 or 4.
Increased reactivity can lead to increased enantioselectivity,
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Eur. J. Org. Chem. 2000, 1785Ϫ1792