Rational design of chiral 1,1′-binaphthylazepine-based ligands for the enantioselective addition of ZnEt2 to aromatic aldehydes

Article abstract of DOI:10.1016/S0957-4166(02)00323-3

By rational design, novel atropisomeric 1,1-binaphthylazepine-based 1,2-amino alcohols 1f and 1g have been prepared in enantiopure form and tested as catalytic precursors in the enantioselective addition of diethylzinc to aromatic aldehydes: the correspon

Full text of DOI:10.1016/S0957-4166(02)00323-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1385–1391
Rational design of chiral 1,1%-binaphthylazepine-based ligands for
the enantioselective addition of ZnEt2 to aromatic aldehydes
Stefano Superchi, Egidio Giorgio, Patrizia Scafato and Carlo Rosini*
Dipartimento di Chimica, Universita` della Basilicata, Via Nazario Sauro 85, 85100 Potenza, Italy
Received 5 June 2002; accepted 14 June 2002
Abstract—By rational design, novel atropisomeric 1,1-binaphthylazepine-based 1,2-amino alcohols 1f and 1g have been prepared
in enantiopure form and tested as catalytic precursors in the enantioselective addition of diethylzinc to aromatic aldehydes: the
corresponding (S)-1-arylpropanols have been obtained in quantitative yields and e.e.s up to 95%. A rationale explaining the
stereochemical outcome of the reaction, as well as the influence of structural features of the ligands on the enantioselectivity of
the addition, is also provided. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ethylation of arylaldehydes. We observed that, in all
cases, (S)-binaphthyl moieties induced the formation of
the (S)-alcohol and that, by simply increasing the size
of the R groups, with no changes to the chiral back-
bone of such molecules, it was possible to dramatically
increase the enantioselectivity.
In recent years enantiopure 1,1%-binaphthylazepines
have been successfully employed as catalytic chiral lig-
ands in several asymmetric processes.1 However, an
interpretation of their efficiency in these processes has
never been provided and the rational design of chiral
auxiliaries of this type for a specific reaction has never
been approached. Therefore, in order to determine the
structural features which affect the efficiency of such
ligands and to improve their performance we recently
decided to start an investigation aimed at evaluating the
behavior, as chiral catalysts, of some binapthylazepine-
based 1,2-amino alcohols (Fig. 1).2,3 The enantioselec-
tive addition of ZnEt2 to arylaldehydes was taken as a
benchmark reaction.4 As a matter of fact, only a single
previous study was reported by Noyori and co-workers
who, using the simplest amino alcohol of this series,
(S)-1a, in the addition of ZnEt2 to benzaldehyde,
In fact, with ligand 1b the enantioselectivity in the
ethylation of benzaldehyde increased to 64% e.e. from
the 49% e.e. of Noyori’s ligand 1a. Increasing the size
of the R group in 1c, substituted with a spirocyclohexyl
moiety, and in 1d led to even higher e.e.s of 81 and
87%, respectively. Interestingly, a further increase in the
OH
1 (0.08 equiv)
Ar CHO
Ar
H
Et
*
ZnEt2 (2 equiv)
toluene, RT
obtained
a moderate 49% e.e. of (S)-1-phenyl-
propanol.1d Furthermore, on the basis of computa-
tional studies, Goldfuss and Houk5 suggested that the
low enantioselectivity of 1a was due to the lack of a
substituent at the oxygen bearing carbon atom C(2).
With the aim of determining if the introduction of
substituents of increasing size on C(2) really would
afford better results, we prepared2 some new enantio-
pure binaphthylazepine 1,2-amino alcohols and tested3
them as catalytic precursors in the enantioselective
R
R
R
R
N
OH
N
OH
1a R = H
1b R = Me
1f R = Me
1g R = Ph
1c R, R = -(CH2)5-
1d R = Ph
1e R = t-Bu
* Corresponding author. Tel.: +39-0971-202241; fax: +39-0971-
202223; e-mail: rosini@unibas.it
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00323-3

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S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
steric hindrance at C(2) in 1e, with introduction of two
tert-butyl moieties, led, on the contrary, to a drop in
the enantioselectivity to 64% e.e. An analogous
decrease occurred with the introduction of a stereogenic
center at C(2).3 Ligand 1d, having a diphenylhydroxy-
methyl moiety6 (the so called ‘magic group’), was also
tested in the addition of ZnEt2 to a number of arylalde-
hydes, affording the corresponding 1-arylpropanols
quickly and rapidly in e.e.s ranging from 70 to 87%.
We thought that possible improvement in the enan-
tioselectivity could also be achieved by introduction of
substituents on the C(N) of the amino ethanol moiety.
These groups could in fact give rise to steric interac-
tions with both the chiral binaphthyl moiety and the
phenyl groups at C(2), thus affording better chirality
transfer. Herein, we therefore describe the preparation
of the two new binaphthylazepine-based ligands 1f and
1g and the results achieved in their use as catalytic
precursors in the enantioselective ethylation of
arylaldehydes.
It is generally accepted that the active catalytic species
in the asymmetric ethylation of aldehydes with ZnEt2 in
the presence of an amino alcohol ligand is the chelated
ethylzinc alkoxide (A), formed by reaction between the
amino alcohol and a molecule of diethylzinc (Scheme
1).4a This species, coordinating both the aldehyde and a
second molecule of ZnEt2, then promotes the stereose-
lective ethylation of the carbonyl. Taking this mecha-
nistic rationale into account we can suppose that in the
amino alcohols 1b–e the chirality of the binaphthyl
moiety affects the reaction center in some way, thus
leading to asymmetric induction. Chirality transmission
from the binaphthyl moiety to the NꢀZnꢀO fragment
must therefore occur and, reasonably, this transmission
is mediated by the groups linked to the C(2) carbon
bearing the oxygen atom.
2. Results and discussion
Both amino alcohols 1f and 1g were easily prepared
(Scheme 2) by addition of excess of MeLi or PhLi,
respectively, to the binaphthylazepine amino ester
(S)-3. The latter was, in turn, obtained in 83%
yield by reaction of (S)-2,2%-bis(bromomethyl)-1,1%-
binaphthalene2,7 with the p-toluenesulfonate salt of
methyl-2-amino-2-methylpropanoate 2, in the presence
of triethylamine in THF. Reaction of (S)-3 with MeLi
in THF at −78°C then afforded (S)-1f in 44% yield
while reaction of (S)-3 with PhLi in THF at −78°C
provided (S)-1g in 74% yield.
H
N
N
Zn
RCHO, ZnEt2
Et
*
HO
Zn Et
O
H
R
O
R
O
Et
Zn
(A)
Et
Et
Scheme 1.
1f
O
Br
Br
2
N
OMe
Et3N, THF, reflux
1g
3
Scheme 2.
Table 1. Enantioselective addition of ZnEt2 to benzaldehyde mediated by ligands (S)-1b, d, f and g
Run
Liganda
Time (min)
Temp. (°C)
Yield (%)b
E.e. (%)c (ac)d
1e
2e
3
4
5
(S)-1b
(S)-1d
(S)-1dg
(S)-1f
840
30
40
120
60
70
20
20
20
20
20
20
97f
99
99
98
99
99
64 (S)
87 (S)
84 (S)
62 (S)
95 (S)
94 (S)
(S)-1g
6
(S)-1gg
a 8 mol% of ligand was used.
b Chromatographic (GLC) yield. No traces of benzyl alcohol were detected.
c Determined by HPLC on a Chiralcel OD column.
d Determined by elution order on a Chiralcel OD column.4d
e See Ref. 3.
f About 1 mol% of benzyl alcohol was detected.
g 3 mol% of ligand was used.

S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
1387
The most efficient ligand of the tetrasubstituted family,
1g, was compared with the best disubstituted one, 1d3
in the ethylation of a number of different aromatic
aldehydes (Table 2). Both ligands afforded high e.e.
values, almost irrespective of the steric and electronic
nature of the substrates (a moderate detrimental effect
on both the reaction rate and enantioselectivity was
observed when the aldehyde contained an electron-
donating methoxy group in the para-phenyl position)
(runs 3 and 4). With all aldehydes the tetrasubstituted
ligand 1g afforded higher e.e.s than the parent 1d,
confirming the result obtained in the case of benzalde-
hyde, and also confirming our expectations about the
best efficiency of chirality transfer in this type of ligand.
In particular, with ligand 1g e.e.s in the range 87–95%
were obtained, which is, with any substrate, about
7–10% higher8 than those afforded using 1d.
The 1,2-amino alcohols 1f and 1g were tested (Table 1)
in the enantioselective addition of diethylzinc to benz-
aldehyde and the results compared with those of the
parent disubstituted amino alcohols 1b and 1d (Table
1).3 The reactions were carried out in dry toluene at
20°C in the presence of 8 mol% of chiral ligand and
monitored by TLC and GC–MS analysis. When com-
plete conversion of the aldehyde was detected, the
mixture was quenched by addition of 10% aqueous
HCl. After extraction with Et2O, drying, and evapora-
tion of solvent, the product ratio was directly deter-
mined on the crude mixture by GC–MS and the e.e. of
the product 1-phenyl-1-propanol was measured by
HPLC on a chiral stationary phase.
The results in Table 1 show that in the presence of
catalytic amounts of compounds 1f and 1g, diethylzinc
adds smoothly and cleanly to benzaldehyde providing
(S)-1-phenyl-1-propanol with complete conversion and
no traces of benzyl alcohol. It is worth noting that
while the tetramethyl derivative 1f (run 4) affords a
moderate 62% e.e., i.e. with almost the same enantiose-
lectivity as that induced by the dimethyl compound 1b
(run 1), the dimethyldiphenyl azepine 1g induces the
formation of the alcohol (run 5) with 95% e.e., a value
significantly higher than that observed using the corre-
sponding diphenyl precursor 1d (run 2). This result
confirms the positive effect of the diphenylhydroxy-
methyl portion in inducing higher enantioselectivity and
points out the significant effect of the gem-dimethyl
moiety in allowing better transfer of chirality to the
C(2) carbon. In order to further test the efficiency of 1d
and 1g, two trials using only 3 mol% of these ligands
were performed (runs 3 and 6), obtaining in both cases
enantioselectivities comparable with those obtained
with 8 mol% of ligand, even though slightly longer
reaction times were required. This result is a further
indication of the efficiency and suitability of this type of
binaphthylazepine-based ligands for asymmetric
catalysis.
A great number of experimental4,9 and theoretical5,10
studies on the mechanism of the asymmetric addition of
diethylzinc to aldehydes have been reported, defining
the intermediates of the reaction and providing some
proposals about the possible transition states. Much of
the evidence points out that the complexation of the
ethylzinc aminoalkoxide (A) (Scheme 1)4a with both the
aldehyde and a second molecule of diethylzinc, pro-
motes the migration of an ethyl moiety to the carbonyl
group through a tricyclic transition state like those
depicted in Fig. 2.10a The energy differences between
the transition states which lead to opposite enan-
tiomers, calculated at ab initio or semiempirical levels,
have been employed to explain the stereochemical out-
come and the enantioselectivity displayed by different
catalysts.5,10 By means of semiempirical PM3 calcula-
tions Goldfuss and Houk5 reported that in the addition
of diethylzinc to benzaldehyde catalyzed by 1a, the four
possible transition states (Fig. 2),11 exhibit an anti-(S)<
anti-(R)<syn-(R)<syn-(S) order of relative energies. A
small energy difference is present between the anti and
syn structures, with the anti-(S) transition state being of
slightly lower energy than the anti-(R). On the basis of
Table 2. Addition of ZnEt2 to arylaldehydes mediated by ligands (S)-1d and (S)-1ga
Run
Ligand
Ar
Time (min)
Yield (%)b
E.e. (%)c (ac)d
1e
2
1d
1g
1d
1g
1d
1g
1d
1g
C6H5
C6H5
30
45
90
90
10
10
20
20
99
99
99
99
99
99
99
99
87 (S)
95 (S)
80 (S)
87 (S)
3e
4
4-CH3OC6H4
4-CH3OC6H4
4-CNC6H4
4-CNC6H4
4-CF3C6H4
4-CF3C6H4
5e
6
84f (S)g
95f (S)g
85i (S)g
94i (S)g
7e,h
8
a 8 mol% of amino alcohol was used.
b Chromatographic (GLC) yield. No traces of benzyl alcohol were detected.
c Determined by HPLC on a Chiralcel OD column.
d Determined by elution order on a Chiralcel OD column.4d
e See Ref. 3.
f Determined by HPLC on a Chiralcel OJ column.
g Determined by comparison of [h]D with literature values.16
h Experiment reported in Ref. 3 was repeated and a more accurate e.e. value was determined by HPLC analysis of alcohol acetate.
i Determined by HPLC of its acetate derivative on a Chiralcel OJ column.

1388
S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
H
H3C
N
N
Et
N
N
Ph
H
H
H H
H H
H H
Et
Et
Zn
Zn
Zn
O
Zn
O
O
O
H
H
O
O
Zn
H
Ph
H
Zn
Et
H
H
H
Et
CH3
H
O
O
H
Et
Zn
Zn
H
Et
Ph
Et
H
CH3
Ph
H3C
anti (S)
anti (R)
syn (R)
syn (S)
Figure 2.
this observation the preferential formation of the (S)-1-
phenylpropanol and the low enantioselectivity achieved
with 1a could be explained. Taking these studies into
account we can attempt to provide a qualitative ratio-
nale for the stereochemical outcome of the reaction
with 1d and 1g, as well as of the influence of the
substituents present on the amino alcoholic moiety. We
can in fact reasonably suppose that also in 1d and 1g
the two most stable transition states are anti-(S) and
anti-(R) (Fig. 3) and therefore that the enantioselectiv-
ity of the reaction is primarily determined by the energy
difference of the transition states.12 In the anti-(S) and
anti-(R)-transition states of 1d and 1g the steric influ-
ence of the benzylic CH2 forces the groups on the
carbon bearing the nitrogen (hydrogens in 1d and
methyl groups in 1g) to adopt a pseudo-equatorial and
pseudo-axial position, in turn forcing one of the phenyl
groups (Ph*) on C(2) to be in an axial position and
over the plane of the five-membered Zn aminoalkoxide
ring. From Fig. 3 we can see that in anti-(R) the axial
phenyl Ph* and the ethyl group on zinc (Et*) are on the
same side of the ring, while in anti-(S) the Ph* and Et*
moieties are on opposite sides. Therefore, greater desta-
bilization of the anti-(R) with respect to the anti-(S)
transition state results, giving rise to a greater energy
difference between the two transition states, and lead-
ing to the higher enantioselectivity observed experimen-
tally for 1d and 1g with respect to 1a. The introduction
of two more methyl groups on the nitrogen bearing
carbon in 1g gives rise to stronger steric interaction
with both the benzylic CH2 on one side and the C(2)
phenyl groups on the other, forcing the Ph* group even
closer to the Et* group. Enhancement of the energy
difference between the anti-(S) and anti-(R) transition
states results, leading to a higher enantioselectivity. In
summary, in ligand 1d, and even more in 1g, by simple
steric interactions, efficient chirality transfer from the
atropisomeric chiral binaphthyl backbone to the achiral
amino alcohol moiety can occur, generating a chiral
environment around the zinc atom in the zinc
aminoalkoxide complex.13,14 Chirality transfer from
these compounds is so efficient that even if no stereo-
genic center is present close to the complexing zinc
atom, high enantiodiscrimination in the ethylation step
is achieved. These results show, once more, how simple
and rational modifications of the amino alcohol chain
of these atropisomeric ligands without introducing
stereogenic carbons can allow significant improvement
of the efficiency and asymmetric induction properties of
such ligands in the asymmetric ethylation of
arylaldehydes.
3. Conclusions
By means of a rational analysis of the structural fea-
tures affecting the efficiency of the 1,1%-binaphthyl-
azepine-based amino alcohols and making therefore
suitable modifications to their structure it was possible
to markedly improve the enantioselectivity of such lig-
ands in the addition of ZnEt2 to aryl aldehydes. The
results obtained in this reaction with ligand 1g are
among the highest displayed by a catalytic precursor
having only axial chirality.15 This fact may stimulate
further theoretical investigations to quantitatively and
more rigorously clarify the correlation between struc-
ture and catalytic activity of these ligands. As shown
here and in our previous work2 1,1-binaphthylazepine
amino alcohols can be easily prepared in both enan-
tiomeric forms starting from commercially available
enantiopure 1,1%-binaphthol. The marked improvement
in the performance of the ligands obtained here as a
result of simple structural modifications makes this type
of compound promising precursors for preparing tailor-
made ligands for asymmetric catalysis. Work is now in
N
Ph*
R
Et
N
Et*
Zn
Ph*
R
O
Ph
Zn
R
H
O
O
O
Ph
Zn
Zn
Ph
R
Et
CH3
Ph
Et*
H
CH3
anti (S)
anti (R)
Figure 3.

S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
1389
progress on the use of these compounds as catalytic
precursors for other enantioselective transformations.
4.3. (S)-(+)-2,2%-[2-(Methoxycarbonyl-(1,1-dimethyl)-
ethyl)2-azapropane-1,3-diyl]-1,1%-binaphthalen, 3
To a solution of (S)-2,2%-bis(bromomethyl)-1,1%-binaph-
thalene (660 mg, 1.5 mmol) in anhydrous THF (45
mL), under nitrogen, was added 2 (694 mg, 2.4 mmol)
followed by triethylamine (1.6 mL, 11.4 mmol). The
mixture was stirred under reflux for 6 days, then cooled
to rt. The resulting suspension was filtered, the solid
washed with THF and the collected organic phases
were evaporated to dryness. The recovered solid residue
was dissolved in CHCl3 and washed with saturated
NH4Cl, water and brine, then dried over anhydrous
Na2SO4. After evaporation of solvent the crude was
purified by column chromatography (SiO2; CHCl3/ethyl-
acetate 95:5) recovering (S)-3 (495 mg, 83%) as a
4. Experimental
4.1. General procedures
Melting points were determined with a Kofler hot-stage
1
apparatus and are uncorrected. H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded in
CDCl3 on a Bruker Aspect 300 spectrometer. Optical
rotations were measured with a JASCO DIP-370 digital
polarimeter. THF was freshly distilled prior its use on
sodium benzophenone ketyl and stored under nitrogen
atmosphere. Enantiopure (S)-2,2%-bis(bromomethyl)-
1,1%-binaphthalene was prepared as previously
described.2 2-Methyl-2-aminopropanoic acid (a-amino
isobutyrric acid) (Aldrich) was used as purchased. Tri-
ethylamine was distilled over CaH2 and stored under
nitrogen on KOH. Methyllithium (Aldrich) was used as
1
slightly yellow glass. [h]2D0=+301.5 (c 1.0, CHCl3); H
NMR (300 MHz, CDCl3): l 1.45 (s, 3H), 1.46 (s, 3H),
3.49 (d, 2H, J=12.5 Hz), 3.52 (s, 3H), 3.93 (d, 2H,
J=12.5 Hz), 7.20–7.26 (m, 2H), 7.39–7.46 (m, 4H), 7.54
(d, 2H, J=8.3 Hz), 7.92 (d, 4H, J=8.2 Hz); 13C NMR
(75 MHz, CDCl3): l 176.1, 135.1, 134.2, 133.0, 131.3,
128.4, 128.3, 128.2, 127.5, 125.6, 125.3, 62.9, 51.5, 49.8,
24.9. Anal. calcd for C27H25NO2:C, 82.00; H, 6.37; N,
3.54; O, 8.09. Found: C, 82.05; H, 6.30; N, 3.46; O,
8.19%.
a
1.6 M solution in diethylether, phenyllithium
(Aldrich) was used as a 1.8 M solution in cyclohexane/
diethylether (7:3). Addition of organometallics were
performed using syringe–septum cap technique under
nitrogen atmosphere. Toluene was freshly distilled prior
its use on sodium benzophenone ketyl under nitrogen
atmosphere. Diethylzinc was used as a 1.0 M solution
in hexane (Aldrich) and was used as purchased. Com-
mercially available (Aldrich) benzaldehyde, 4-anisalde-
hyde, and 4-trifluoromethylbenzaldehyde were distilled
prior their use and stored under nitrogen atmosphere.
Commercially available (Aldrich) 4-cyanobenzaldehyde
was used as purchased. All the 1-aryl-1-propanols
obtained by addition of diethylzinc to arylaldehydes
showed NMR spectra in full agreement with literature
data. Enantiomeric excesses of the optically active 1-
aryl-1-propanols were determined by HPLC analysis
performed on a JASCO PU-1580 pump with a Varian
2550 UV detector and Daicel Chiralcel OD or OJ
columns. Analytical TLC was performed on 0.2 mm
silica gel plate Merck 60 F-254. Mixture composition
was determined by GLC–MS on a Hewlett–Packard
6890 chromatograph equipped with a HP-5973 mass
detector.
4.4. (S)-(+)-2,2%-[2-(1,1,2,2-Tetramethyl-2-hydroxy-
ethyl)-2-azapropane-1,3-diyl]-1,1%-binaphthalene, 1f
To a solution of (S)-3 (158 mg, 0.4 mmol) in anhydrous
THF (3 mL), under nitrogen at −78°C, was added
dropwise a solution of MeLi in diethyl ether (1.6 M, 1.5
mL, 2.4 mmol). The mixture was stirred at −78°C for
90 min, then quenched with water and the solvent
evaporated under reduced pressure. The recovered
residue was dissolved in CHCl3 and washed sequen-
tially with saturated NH4Cl, water, and brine. The
organic phase was then dried over anhydrous Na2SO4
and concentrated to dryness. The recovered residue was
purified by column chromatography (SiO2; CHCl3/ethyl-
acetate 1:1) yielding (S)-1f as a glassy colorless solid (70
mg, 44%) and the corresponding ketone (60 mg) formed
from single addition of MeLi to (S)-3. [h]2D0=+245 (c
1
1.0, CHCl3); H NMR (300 MHz, CDCl3): l 1.19 (s,
3H), 1.23 (s, 3H), 1.26 (s, 3H), 1.41 (s, 3H), 3.42 (d, 2H,
J=12.4 Hz), 4.13 (d, 2H, J=12.4 Hz), 5.4–5.8 (br s,
1H), 7.2–7.3 (m, 2H), 7.4–7.5 (m, 4H), 7.58 (d, 2H,
J=8.3 Hz), 7.94 (dd, 4H, J=5.2, 7.9 Hz). Anal. calcd
for C28H29NO: C, 85.02; H, 7.39; N, 3.54; O, 4.04.
Found: C, 84.96; H, 7.44; N, 3.49; O, 4.11%.
4.2. Methyl 2-methyl-2-aminopropanoate p-toluenesulf-
onate, 2
A solution of 2-methyl-2-aminopropanoic acid (5.17 g,
50 mmol) and p-toluenesulfonic acid monohydrate
(19.0 g, 100 mmol) in methanol (250 mL) was stirred
under reflux for 40 h. After evaporation of the solvent
under reduced pressure, the oily residue was submitted
to lyophilization for 2 h. The residue was triturated
with Et2O (500 mL) and then filtered. The recovered
solid was recrystallized from acetone to afford 2 as a
white solid (7.36 g, 51%). Evaporation of the mother
liquor afforded a further 2.6 g of slightly impure 2. Mp
147–148°C; 1H NMR (300 MHz, CDCl3): l 1.51 (s,
6H), 2.35 (s, 3H), 3.71 (s, 3H), 7.16 (d, 2H, J=8.05
Hz), 7.76 (d, 2H, J=8.05 Hz), 8.32 (br s, 3H).
4.5. (S)-(+)-2,2%-[2-(1,1-Dimethyl-2,2-diphenyl-2-hydroxy-
ethyl)-2-azapropane-1,3-diyl]-1,1%-binaphthalene, 1g
To a solution of (S)-3 (198 mg, 0.5 mmol) in anhydrous
THF (4 mL), under nitrogen at −78°C, was added
dropwise a solution of PhLi (1.8 M in cyclohexane/
diethylether 7:3, 1.7 mL, 3.0 mmol). The resulting
mixture was stirred at −78°C for 12 h, then quenched
with water and the solvent evaporated to dryness. The
recovered residue was dissolved in Et2O (40 mL) and

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S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
washed sequentially with saturated NH4Cl, and brine.
The organic layer was dried over anhydrous Na2SO4
and concentrated under vacuum. The recovered residue
was purified by column chromatography (SiO2;
petroleum ether/Et2O 95/5) affording pure (S)-1g as a
glassy white solid (193 mg, 74%). [h]2D0=+154 (c 1.0,
Maruoka, K. Org. Lett. 2001, 3, 1273; (q) Stranne, R.;
Vasse, J.-L.; Moberg, C. Org. Lett. 2001, 3, 2525; (r) Lu,
G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2147; (s) Ma, J.-A.;
Wang, L.-X.; Zhang, W.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2001, 12, 2801; (t) Widhalm, M.; Nettekoven,
U.; Kalchhauser, H.; Mereiter, K.; Calhorda, M. J.;
Felix, V. Organometallics 2002, 21, 315; (u) Ooi, T.;
Uematsu, Y.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 1551.
1
CHCl3); H NMR (300 MHz, CDCl3): l 1.26 (s, 3H),
1.63 (s, 3H), 3.14 (d, 2H, J=12.6 Hz), 3.54 (d, 2H,
J=12.6 Hz), 6.3–6.7 (br s, 1H), 7.1–7.5 (m, 14H),
7.8–8.0 (m, 8H). Anal. calcd for C38H33NO: C, 87.83;
H, 6.40; N, 2.70; O, 3.08. Found: C, 87.68; H, 6.49; N,
2.66; O, 3.17%.
2. Mecca, T.; Superchi, S.; Giorgio, E.; Rosini, C. Tetra-
hedron: Asymmetry 2001, 12, 1225.
3. Superchi, S.; Mecca, T.; Giorgio, E.; Rosini, C. Tetra-
hedron: Asymmetry 2001, 12, 1235.
4.6. Typical procedure for the addition of diethylzinc to
arylaldehydes
4. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49; (b) Soai, K.; Niwa, S. Chem. Rev.
1992, 92, 833; (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757; (d) Dai, W.-M.; Zhu, H.-J.; Hao, X.-J. Tetrahedron:
Asymmetry 2000, 11, 2315 and references cited therein.
5. Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998.
6. Braun, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 519.
7. (a) Gingras, M.; Dubois, F. Tetrahedron Lett. 1999, 40,
1309; (b) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999,
1, 1679.
8. An e.e. increase of about 10% could appear, at a first
glance, as a limited success. However, it has to be noted
that an e.e. enhancement from 85 to 95% requires (see,
for instance: Izumi, Y.; Tai, A. Stereodifferentiating
Reactions; Academic Press: New York, 1977; Chapter 7,
p. 178.) a DDG* gain of about 1 kcal/mol, i.e. a large
energy difference. The e.e.s experimentally observed in
the ethylation of benzaldehyde in fact correspond to a
DDG* of 0.62 kcal/mol for 1a, 1.55 kcal/mol for 1d, and
2.13 kcal/mol for 1g, respectively. This means that 1g
gives rise to TSs having larger differences, in energy and
structure, with respect to those given by 1d and 1a.
9. See, for example: Paleo, M. R.; Cabeza, I.; Sardina, F. J.
J. Org. Chem. 2000, 65, 2108.
To a solution of the ligand (0.05 mmol) in dry toluene
(3 mL) under a nitrogen atmosphere at rt, was added a
solution of ZnEt2 in hexane (1.0 M, 1.25 mL, 1.25
mmol). The mixture was stirred for 30 min, then a
solution of the arylaldehyde (0.62 mmol) in dry toluene
(1.3 mL) was added. The mixture was monitored by
GC–MS analysis and when no more traces of the
aldehyde were detected the reaction was quenched by
addition of 10% aqueous HCl. The mixture was
extracted with Et2O and the organic phase was washed
with brine, and dried over anhydrous Na2SO4. After
evaporation of the solvent the recovered solid residue
was directly analyzed by GC–MS and HPLC.
Acknowledgements
Financial support from MURST (COFIN2000) and
Universita` della Basilicata (Potenza) is gratefully
acknowledged.
10. (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 6327; (b) Yamakawa, M.; Noyori, R. Organometal-
lics 1999, 18, 128; (c) Goldfuss, B.; Steigelmann, M.;
Khan, S. I.; Houk, K. N. J. Org. Chem. 2000, 65, 77; (d)
Vazquez, J.; Pericas, M. A.; Maseras, F.; Lledos, A. J.
Org. Chem. 2000, 65, 7303; (e) Goldfuss, B.; Steigelmann,
M.; Rominger, F. Eur. J. Org. Chem. 2000, 1785; (f)
Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2001,
123, 2464.
11. The sketches in Figs. 2 and 3, although based upon the
transition states calculated in Ref. 5, are just pictorial
representations. For nomenclature of TS’s, see Ref. 5.
12. Inspection of Fig. 2 shows a high steric crowding in the
syn-(R) and syn-(S) transition states, thereby suggesting
a high energy level for these structures. Therefore, their
influence on the reaction path can be considered negligi-
ble and they can be reasonably ruled out from our
discussion.
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1
also obtained from the H NMR spectra of 1f and 1g. In
fact, in both of these amino alcohols, the diastereotopic
methyl groups on the nitrogen-bearing carbon display in
1
the H NMR spectrum a very large signal separation, of

S. Superchi et al. / Tetrahedron: Asymmetry 13 (2002) 1385–1391
1391
68 Hz in 1f and of 111 Hz in 1g. The diastereotopicity
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6.5 Hz, suggesting that also more remote groups on C(2)
are subject to the influence of the chiral binaphthyl
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