Salicylaldehyde Schiff bases derived from 2-ferrocenyl-2-amino alcohols. Part 2: Stereochemical divergence in the titanium-promoted enantioselective diketene addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2006.03.017

Chiral Schiff bases arising from the condensation of a set of diversely substituted (S)-2-amino-2-ferrocenyl ethanol derivatives 1a-e with salicylaldehydes 2A-B have been tested in the asymmetric, titanium-promoted diketene addition to benzaldehyde. This

Full text of DOI:10.1016/j.tetasy.2006.03.017

Tetrahedron: Asymmetry 17 (2006) 1104–1110
Salicylaldehyde Schiff bases derived from 2-ferrocenyl-2-amino
alcohols. Part 2: Stereochemical divergence in the titanium-promoted
enantioselective diketene addition to benzaldehyde
Rosa Ma Moreno and Albert Moyano*
` `
´
Unitat de Recerca en Sı´ntesi Asimetrica, Departament de Quımica Organica, Universitat de Barcelona, Facultat de Quımica,
C. Martı´ i Franques 1-11, 08028 Barcelona, Spain
´
`
Received 6 March 2006; accepted 15 March 2006
Available online 27 April 2006
Abstract—Chiral Schiff bases arising from the condensation of a set of diversely substituted (S)-2-amino-2-ferrocenyl ethanol derivatives
1a–e with salicylaldehydes 2A–B have been tested in the asymmetric, titanium-promoted diketene addition to benzaldehyde. This study
has revealed that the enantiofacial selectivity of this reaction depends strongly on the substitution pattern of the amino alcohol compo-
nent. Molecular mechanics calculations have led to the identification of a transition state model that explains these observations.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
alyze the enantioselective reaction of trimethylsilyl cyanide
with aldehydes. Herein, we report on their use as chiral
controllers in another important enantioselective transfor-
mation: the asymmetric synthesis of 5-hydroxy-3-keto
esters by the titanium-promoted addition of diketene to
aldehydes.
Chiral Schiff bases derived from the condensation of sali-
cylaldehydes with 2-amino alcohols have found widespread
use as ligands in asymmetric synthesis. These compounds
act as tridentate O,N,O ligands, and a great number of
metallic complexes derived from them have been described
in the literature. Depending upon the nature of the metal
centre, these chiral complexes are able to promote a variety
of enantioselective transformations.1 Up till now, a rela-
tively small number of 2-amino alcohols, most of which
derived from a-amino acids, have been used for their
preparation.
2. Results and discussion
2.1. Enantioselective reaction of diketene with benzaldehyde
Building upon a reaction previously reported by Mukai-
yama,4 Oguni et al. disclosed in 19945 that the reaction
of diketene with aldehydes in the presence of chiral Schiff
base–titanium alkoxide complexes proceeded with moder-
ate to good enantioselectivity to afford the corresponding
5-hydroxy-3-oxoesters (Scheme 1). In their initial studies,5,6
these workers found that the enantioselectivity of the reac-
tion depended on the nature of the Schiff base used: on the
one hand, the existence of a tert-butyl group at the 3-posi-
tion of the salicylaldehyde moiety was essential for achiev-
ing sizable asymmetric induction, and on the other best
results were obtained with monosubstituted 2-amino alco-
hols such as valinol or tert-leucinol. In order to obtain a
satisfactory yield, equimolar, or at least more than
50 mol % amounts of titanium complexes were necessary.
Subsequently, Oguni found that the replacement of the
salicylaldehyde component by a 2-hydroxybenzophenone
In connection with a research program devoted to the
development of new chiral auxiliaries and ligands based
on 2-amino-2-ferrocenylalkanols,2 we have prepared a set
of salicylaldehyde Schiff base ligands 3aA–dB derived from
2-amino-2-ferrocenylethanols 1a–e,3 with different degrees
of substitution both at the C1 and C2 positions, and from
aldehydes 2A–B (see Fig. 1), in order to investigate the cat-
alytic efficiency of their titanium alkoxide complexes in
asymmetric additions to aldehydes. In the preceding paper
in this issue, we have described the synthesis of these novel
chiral complexes, and have shown that they are able to cat-
*
Corresponding author. Tel.: +34 93 4021245; fax: +34 93 3397878;
e-mail: amoyano@ub.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.017

R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
1105
NH2
OH
NH2
OH
NH2
OH
NH2
OH
NH2
OH
Fe
Fe
Fe
Fe
Fe
Me
Me
Ph
Me Me
1b
1e
1c
1a
1d
H
R2
tBu
2A
O
OH
H
H
1a-e
tBu
R1
N
N
OH
OH
OH
Me
OH
OH
R5
H
Fe
R3
R4
H
2B
O
3aA, R1=tBu, R2,R3,R4,R5=H
(R)-4
3bA, R1=tBu, R2,R3,R4=H, R5=Me
3cA, R1=tBu, R2,R4,R5=H, R3=Me
3dA, R1=tBu, R2,R3=H, R4,R5=Me
3eA, R1=tBu, R2,R3,R4=H, R5=Ph
3bB, R1=Ad, R3,R4=H, R2,R5=Me
3cB, R1=Ad, R4,R5=H, R2,R3=Me
Figure 1. Chiral salicylaldehyde Schiff base ligands used in this work.
H
tBu
N
OH
OH
Me
Me
(S)
Ti(OiPr)4
OH
O
O
O
R
+
OiPr
O
R
H
O
CH2Cl2, -20 ºC
69-92% yield, 80:20-92:8 er
R = aryl, alkenyl, alkyl
Scheme 1. Oguni’s enantioselective approach to 5-hydroxy-3-oxoesters (Ref. 6a).
allowed the reaction to be performed with a 20 mol %
amount of the Schiff base.7 The diketene addition was
assumed to proceed through an aldol type reaction of the
aldehyde with a titanium enolate formed from diketene
and the titanium alkoxide complex. When Schiff bases
derived from (S)-valinol were used, the aldehydes were
attacked from the si face by this enolate: a stereochemical
outcome that was rationalized6a by the putative transition
state depicted in Figure 2A. In this model, the octahedral
titanium(IV) is coordinated in the same plane by the triden-
tate Schiff base and the enolate arising from diketene. The
aldehyde is coordinated below this plane, syn to the isopro-
pyl group of valinol, and oriented in such a way that the
formyl hydrogen points towards the phenolic oxygen. In
this way, the si face of benzaldehyde is attacked intramo-
lecularly by the titanium enolate, leading to the predomi-
nant formation of the (S)-configured 5-hydroxy-3-
oxoester. Shortly thereafter, Corey8 suggested an alterna-
tive model for this reaction, based on the formation of a
CH–O hydrogen bond. In the transition state model pro-
posed by Corey (Fig. 2B), the octahedral titanium(IV) is
also coordinated in the same plane by the tridentate Schiff
base and the enolate. The benzaldehyde molecule occupies
an apical position, now anti to the isopropyl substituent.
The formation of an intramolecular hydrogen bond be-
tween the formyl hydrogen and the valinol oxygen orien-
tates the aldehyde in order to expose its si face to the
titanium enolate.
Optically active 5-hydroxy-3-oxoesters are useful interme-
diates in the synthesis of inhibitors of HMG–CoA reduc-
tase.9 Over the past few years a number of other
approaches to their enantioselective preparation have ap-
peared in the literature;10 Oguni’s method, however, still
stands out for the ready availability of both the reagents
and the chiral ligand, as well as for the simplicity of the
experimental procedure. We therefore felt that a re-exami-
nation of this reaction with Schiff bases derived from 2-

1106
R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
iPr
H
H
O
si
N
O
H
iPr
H
H
O
Ti
Me
Me
O
O
Ti
N
O
O
Me
O
Me
O
O
H
Me
O
si
O
Me
O
Me
Me
O
iPr
Pri
Me
Me
B
A
Figure 2. Transition state models for the enantioselective titanium-promoted diketene addition to benzaldehyde according to Oguni (A, Ref. 6a) and to
Corey (B, Ref. 8).
ferrocenyl-2-amino alcohols would be worthwhile. More-
over, we reasoned that an investigation of the influence
of the substitution of the amino alcohol moiety on the ste-
reochemical outcome of the reaction could offer some clues
on the mechanism of the reaction, by testing the predictive
ability of both Oguni’s6a and Corey’s8 models.
inspection of the transition state models depicted in Figure
2, that the major enantiomer of our product would have an
(R)-configuration, resulting from the addition to the re-face
of the aldehyde with a ligand of configuration opposite to
that of (S)-valinol. We were surprised to find, however, that
both polarimetric and chromatographic data clearly
showed that, in fact, the (S)-enantiomer of 5 was predomi-
nant in our mixture. This gave us a first indication of the
fact that the predictive power of the transition state models
previously proposed for this reaction6a,8 was very limited.
We began our study by performing the addition of diketene
to benzaldehyde with the Schiff base ligand (R)-4, since we
have previously observed that the degree of asymmetric
induction exerted by the ferrocenyl group in chiral auxilia-
ries or ligands derived from amino alcohol 1a is very sim-
ilar to that of a phenyl group.2f According to the general
protocol developed by Oguni,6 a preformed dichlorometh-
ane solution of the titanium di(isopropoxide) complex of
the Schiff base was stirred at ꢀ20 ꢁC with an equimolar
amount of benzaldehyde and two molar equivalents of
diketene for 60–65 h. After the hydrolysis of the complex,
isopropyl 5-hydroxy-5-phenyl-3-oxopropanoate 5 was iso-
lated in 54% yield and with a 61:39 er (Table 1, entry 1).
The result described by Oguni for this reaction, with the
ligand (S)-4, was 56% yield and 55:45 er.6a,b Although
Oguni did not specify the absolute configuration of oxoester
5 obtained under these conditions, it could be assumed, by
In the presence of imine 3aA (Table 1, entry 2), (S)-5 was
again obtained, in practically the same yield (53%) and
enantiomeric purity (60:40 er). This result emphasizes the
steric similarity of the ferrocenyl and the phenyl groups
in the absence of conformational control of the former.2f
According to the results reported in the preceding paper
in this issue, the introduction of additional substituents at
C1 should modify the conformational preferences of the
ferrocenyl group, bringing about significant changes in
the stereochemical outcome of the product. In effect, the
use of the Schiff base 3bA (entry 3) reversed the enantio-
facial selectivity of the addition, leading to the formation
of (R)-5 with increased enantioselectivity (85:15 er).
Table 1. Asymmetric addition of diketene to benzaldehyde promoted by chiral Schiff base (3,4)–titanium isopropoxide complexes
OH
*
O
O
Ligand, Ti(OiPr)4
O
H
OiPr
+
O
CH2Cl2, -20 ºC, 60-65 h
O
5
Entry
Ligand
Yielda (%)
erb
Configurationc
1
2
3
4
5
6
7
8
(R)-4
3aA
3bA
3cA
3dA
3eAd
3bB
3cB
54
53
51
69
18
34
50
45
61:39
60:40
15:85
77:23
0
30:70
17:83
75:25
(S)
(S)
(R)
(S)
—
(R)
(R)
(S)
a Yield of isolated product 5 after chromatographic purification.
b By HPLC (Chiral PAK AD).
c By comparison of the sign of specific rotation values with those in the literature.6a
d Generated in situ by condensation of 2A with 1e before the addition of titanium tetra(isopropoxide).

R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
1107
A smaller increase in enantioselectivity with regard to 3aA
2.2. Molecular modelling of intermediate complexes
(up to 70:30 er) was observed in the case of ligand 3eA
(entry 6). Rather unexpectedly,2f the presence of a gem-
dimethyl moiety at C1 (ligand 3dA, entry 5) produced race-
mic 5 in very low yield. Since the formation of the titanium
alkoxide complex was also complete in this case, we specu-
lated that the increased steric hindrance of this complex
prevented the coordination of the aldehyde and/or the
generation of the titanium enolate from diketene. The
adamantyl-substituted Schiff base 3bB (entry 7) behaved
analogously to 3bA (83:17 er in (R)-5). The presence of a
methyl substituent at C2 in amino alcohol 1c did not bring
about a reversal of the enantioface selectivity of the reac-
tion with respect to ligands derived from 1a; when using
both 3cA (entry 4) and 3cB (entry 8) as chiral ligands,
the (S)-enantiomer of 5 was again the major product of
the diketene addition. On the other hand, the enantiomeric
purity of the product was substantially increased (up to
77:23 er; 80:20 er when corrected for the enantiomeric
purity of 1c2g) with respect to that obtained with 3aA. In
summary, even if the best ligand identified in this study
(3bA) afforded the addition product 5 in moderate yield
and enantioselectivity, the intriguing trends observed in
the variation of the stereochemical outcome of the reaction
with the substitution pattern of the Schiff base ligands
were not easily accommodated with current mechanistic
models, and we concluded that a more detailed investi-
gation of this issue was warranted.
Since imines 3bA and 3cA led to the formation of 5 with the
highest enantiomeric purities, albeit with opposite absolute
configuration (Table 1, entries 3 and 4), we selected these
ligands to build a transition state model that could account
for these results. Thus, we proposed that the reaction could
take place via the titanium(IV) complexes depicted in Fig-
ure 3. In these complexes, the titanium atom has an
approximately octahedral geometry and is coordinated by
the O,N,O atoms of the Schiff base. The remaining three
coordination sites are occupied by an isopropoxide ligand,
benzaldehyde and the enolate derived from diketene,
respectively. In this way, there are four possible geometri-
cal isomers for each complex, depending on the position
occupied by the enolate (fac or mer with respect to the
Schiff base) and on the relative disposition of the isoprop-
oxide and the ferrocenyl moieties (syn or anti). In each of
these geometrical isomers, the coordinated benzaldehyde
is oriented so as to minimize the steric interactions of the
phenyl group with the rest of the complex. With this
nomenclature, Oguni’s model (Fig. 2A) corresponds to a
mer-anti isomer, and Corey’s model (Fig. 2B) is of the
mer-syn type. As it can be seen in Figure 3, only the fac-
syn isomer would lead to the predominant formation of
(R)-5, by attack of the enolate to the re face of benzalde-
hyde; in the other three isomers, the (S)-enantiomer of 5
should be produced preferentially.
Fe
Fe
si
iPr
R4
H
R4
O
H
H
R3
R3
O
O
R5
O
O
R5
N
O
N
O
Ti
Ti
O
O
O
iPr
O
si
H
Me
Me
O
O
O
iPr
Me
Me
iPr
Me
Me
mer-anti
mer-syn
iPr
Fe
O
iPr
O
R4
H
O
Fe
R3
O
N
O
R5
Ti
O
H
re
O
Ti
R4
O
R3
H
O
R5
O
N
O
si
Me
H
Me
Me
Me
O
O
iPr
Me
Me
O
iPr
fac-anti
fac-syn
Figure 3. Geometrical isomers for the transition state complexes.

1108
R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
For both imines 3bA and 3cA, we optimized the geometries
of these isomers by means of the SYBYL force-field11 as
Fe
12
implemented in the SPARTAN
package of programs.
Fe
R4
Two energetic minima were located for each isomer, corre-
sponding to two different conformational arrangements of
the ferrocenyl group:2f IN (when oriented towards the
metallic centre) and OUT (when directed away from it).
The calculated relative energies of the optimized structures
are shown in Table 2. In all instances, the OUT conformer
is less stable than the IN, due to the unfavourable interac-
tions of the ferrocenyl group with the aromatic fragment
(Fig. 4). Inspection of the molecular models shows that if
the R4 substituent is different from hydrogen, then the IN
conformers are also destabilized, by repulsive interactions
of this substituent with the ferrocenyl group. This could
explain the low reactivity associated with the disubstituted
R4
L1
Ti
L1
Ti
R3
R3
H
H
O
R5
O
R5
N
O
N
O
L2
L2
Me
Me
L3
L3
Me
Me
Me
Me
OUT
IN
Figure 4. Limiting conformations of the ferrocenyl group in octahedral
Schiff base titanium(IV) complexes. The OUT conformers are destabilized
by repulsive interactions of the ferrocenyl group with the salicylaldehyde
fragment. When R4 is different from hydrogen, the IN conformers are also
destabilized, by repulsive interactions of this substituent with the
ferrocenyl group.
Table 2. Calculated relative energies (in kcal molꢀ1) of the transition state
models for the asymmetric addition of diketene to benzaldehyde promoted
by the chiral Schiff base (3bA,3cA)–titanium isopropoxide complexes
ligand 3dA (Table 1, entry 5). Finally, it is worth noting
that the fac-anti isomers are much less stable than the other
ones, because of the repulsion between the large enolate
and the ferrocenyl fragments.
Entry
Ligand
Isomera
Rel. energyb
Configurationc
1
2
3
4
5
6
7
8
3bA
3bA
3bA
3bA
3bA
3bA
3bA
3bA
mer-syn-IN
mer-syn-OUT
mer-anti-IN
mer-anti-OUT
fac-syn-IN
fac-syn-OUT
fac-anti-IN
fac-anti-OUT
3.8
4.9
3.9
4.4
2.9
4.5
11.2
11.7
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
The two most stable isomers for imine 3cA are the mer-syn-
IN (Table 2, entry 9) and the mer-anti-IN (Table 2, entry
11); both lead to the predominant formation of product
(S)-5. In Figure 5, we show the evolution of the mer-syn-
IN transition state complex corresponding to 3cA into
the addition complex of (S) configuration.
9
10
11
12
13
14
15
16
3cA
3cA
3cA
3cA
3cA
3cA
3cA
3cA
mer-syn-IN
mer-syn-OUT
mer-anti-IN
mer-anti-OUT
fac-syn-IN
fac-syn-OUT
fac-anti-IN
fac-anti-OUT
0.5
2.7
0.0
3.7
0.7
4.7
7.4
7.5
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
In the case of imine 3bA, the mer-syn and the mer-anti com-
plexes are relatively destabilized with respect to the analo-
gous ones in 3cA (compare entries 1 and 3 with entries 9
and 11 in Table 2) because of steric repulsion between
the methyl substituent at C1 with the aldehyde (see Fig. 6
for an example). For this ligand, then, the most stable tran-
sition state complex is the fac-syn-IN (Table 2, entry 5),
leading to the formation of (R)-5 (see Fig. 7). Moreover,
the energy difference between the fac-syn-IN complex and
a See Figures 3 and 4.
b Relative final strain energies (in kcal molꢀ1).
c Absolute configuration of the product obtained by intramolecular attack
of the titanium enolate to the less hindered face of benzaldehyde.
Figure 5. For imine 3cA, the mer-syn-IN isomer of the transition state complex leads to the formation of (S)-5.

R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
1109
complexes of Schiff bases derived from (1S,2R)-1-amino-
1-ferrocenyl-2-propanol 1b and from (S)-2-amino-2-ferro-
cenyl-1-propanol 1c exhibit strongly divergent enantio-
facial selectivities in the reaction of benzaldehyde with
diketene (preferential re-face addition and preferential
si-face addition, respectively), a result for which no prece-
dent can be found in the literature. Molecular mechanics
calculations on the transition state complexes have led to
a mechanistic model that is more comprehensive than those
previously proposed for this reaction.
4. Experimental
4.1. General materials and methods
Optical rotations were measured at room temperature
(23 ꢁC); concentrations are given in g 100 mlꢀ1. Infrared
spectra were recorded in a Fourier transform mode, using
NaCl film techniques. NMR spectra were recorded in
CDCl3 solution. The reactions were run in flame- or
oven-dried glassware under a N2 atmosphere. Commer-
cially available reagents (with the exception of benzalde-
hyde, which was distilled prior to use) were employed as
received. Dichloromethane was distilled from calcium hy-
dride. The preparation of Schiff bases 3aA–cB is described
in the preceding paper in this issue.
Figure 6. mer-syn Isomer of the transition state complex for imine 3cA,
showing the destabilizing interaction between the methyl substituent at C1
and the coordinated aldehyde.
the most stable of the complexes leading to (S)-5 (mer-syn-
IN and mer-anti-IN, entries 1 and 3 of Table 2, respec-
tively) is of 0.9–1.0 kcal molꢀ1. In the case of 3cA, the min-
imum energy gap between the most stable of the complexes
leading to (R)-5 (fac-syn-IN, entry 13, Table 2) and a com-
plex leading to (S)-product (mer-syn-IN, entry 9, Table 2) is
of 0.2 kcal molꢀ1 only; this is a fact that correlates well
with the smaller enantioselectivity observed for this ligand.
4.2. General procedure for the asymmetric addition of
diketene to benzaldehyde mediated by Schiff base–
titanium isopropoxide complexes
3. Conclusions
To a stirred solution of the Schiff base (1.0 mmol) in anhy-
drous dichloromethane (5.5 ml), under an argon atmo-
sphere, titanium tetra(isopropoxide) (0.27 ml, 0.91 mmol)
was added with the aid of a syringe and the resulting red-
coloured solution was stirred at room temperature for
1 h. After cooling to ꢀ20 ꢁC, freshly distilled benzaldehyde
(92 ll, 0.91 mmol) and diketene (0.14 ml, 1.82 mmol) were
sequentially added via a syringe and stirring was main-
tained for 60–65 h at the same temperature. After the addi-
In conclusion, the incorporation of 2-amino-2-ferro-
cenylalkanols 1a–e into salicylaldehyde Schiff bases gives
rise to a new class of chiral ligands whose titanium alkoxide
complexes are able to promote the asymmetric addition of
diketene to benzaldehydes. Both the enantioselectivity and
the stereochemical outcome of these processes are con-
trolled by the positioning of substituents in the 2-amino-
2-ferrocenylethanol moiety. In particular, the titanium
Figure 7. For imine 3bA, the fac-syn-IN isomer of the transition state complex leads to the formation of (R)-5.

1110
R. Ma Moreno, A. Moyano / Tetrahedron: Asymmetry 17 (2006) 1104–1110
´
Rosol, M.; Moreno, R. M.; Lopez, C.; Maestro, M. A.
Angew. Chem., Int. Ed. 2005, 44, 1865–1869; (e) Rosol, M.;
Moyano, A. J. Organomet. Chem. 2005, 609, 2328–2333; (f)
Bueno, A.; Moreno, R. M.; Moyano, A. Tetrahedron:
Asymmetry 2005, 16, 1763–1778; (g) Moreno, R. M.; Bueno,
A.; Moyano, A. J. Org. Chem. 2006, 71, 2528–2531.
3. A few ferrocenyl imines derived from the condensation of
chiral ferrocenylamines with aromatic aldehydes have been
used as ligands in asymmetric synthesis. See: (a) Hayashi, T.;
Hayashi, C.; Uozomi, Y. Tetrahedron: Asymmetry 1995, 6,
2503–2506; (b) Kim, T.; Lee, H.; Ryu, E.; Park, D.-K.; Cho,
C.; Shim, S. C.; Jeong, J. H. J. Organomet. Chem. 2002, 649,
258–267; (c) Hu, X.; Chen, H.; Dai, H.; Zheng, Z. Tetra-
hedron: Asymmetry 2003, 14, 3415–3421.
tion of isopropyl alcohol (0.36 ml), the reaction mixture
was stirred at room temperature for 4 h, poured over a
mixture of aqueous 0.1 M HCl (12 ml) and diethyl ether
(12 ml) and stirred vigorously for 20–24 h at room temper-
ature. The mixture was then extracted with diethyl ether
(3 · 25 ml) and the combined extracts were washed with
saturated aqueous sodium bicarbonate (2 · 25 ml) and
with brine (2 · 25 ml), dried over magnesium sulfate and
evaporated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (eluent, hex-
ane–ethyl acetate mixtures of increasing polarity) to give
isopropyl 5-hydroxy-5-phenyl-3-oxopentanoate 5. The IR
and the 1H NMR spectra of this compound fully coincided
23
with those described in the literature.6a ½aꢁD [(R)-5, 85:15
24
4. Izawa, T.; Mukaiyama, T. Chem. Lett. 1975, 161–164.
5. Hayashi, M.; Inoue, T.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 341–342.
6. (a) Hayashi, M.; Inoue, T.; Miyamoto, Y.; Oguni, N.
Tetrahedron 1994, 50, 4385–4398; (b) Oguni, N.; Hayashi,
M.; Harada, M.; Matsushita, A. U.S. Patent 5,457,225; (c)
Hayashi, M.; Kaneda, H.; Oguni, N. Tetrahedron: Asymme-
try 1995, 6, 2511–2516.
er] = +42.4 (c 0.66, CHCl3) {lit.6a ½aꢁD [(S)-5, 92:8 er] =
ꢀ40.8 (c 1.0, CHCl3)}.
Conditions for the determination of the enantiomeric com-
position of 5: Chiral PAK AD column, 95% hexane–5%
isopropyl alcohol + 0.2% TFA, U = 1 ml minꢀ1
, T =
7. (a) Hayashi, M.; Tanaka, H.; Oguni, N. Tetrahedron:
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25 ꢁC, k = 254 nm, tR((+)-(R)-5) = 13.3 min, tR((ꢀ)-(S)-5)
21.8 min.
=
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Acknowledgements
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We gratefully acknowledge the financial support from
´
y Tecnologıa (DGI, project
Ministerio de Ciencia
BQU2003-03426). R.M. thanks the Generalitat de Catalu-
nya (DURSI) for a predoctoral fellowship. We are grateful
´
to Dr. Montserrat Alcon (Enantia, S.L.), for her assistance
in HPLC analyses and to Professor Varinder K. Aggarwal
(University of Bristol), for a generous gift of (1R,2S)-2-azi-
do-2-ferrocenyl-1-phenylethanol.
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