Asymmetric catalysis of carbon-carbon bond forming reactions using amino acid-derived C1-symmetrical salen ligands

Article abstract of DOI:10.1016/j.tetasy.2008.11.037

Four amino acids (alanine, valine, phenylalanine and phenylglycine) have been converted into C₁-symmetrical salen ligands and complexed to titanium, vanadium, copper and cobalt. The resulting complexes have been used as asymmetric catalysts for asymmetric cyanohydrin synthesis, asymmetric Strecker reactions, asymmetric synthesis of α-methyl amino acids and asymmetric Darzens condensations. Satisfactory levels of asymmetric induction were obtained from reactions in which the (salen)metal complex acts as a chiral Lewis acid, but low levels of asymmetric induction were obtained from reactions carried out under solid-liquid phase-transfer conditions.

Full text of DOI:10.1016/j.tetasy.2008.11.037

Tetrahedron: Asymmetry 19 (2008) 2804–2815
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric catalysis of carbon–carbon bond forming reactions
using amino acid-derived C1-symmetrical salen ligands
b
Yuri N. Belokon0 , Jamie Hunt a, Michael North a,
*
a School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
b A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 119991 Moscow, Vavilov 28, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Four amino acids (alanine, valine, phenylalanine and phenylglycine) have been converted into C1-sym-
metrical salen ligands and complexed to titanium, vanadium, copper and cobalt. The resulting complexes
have been used as asymmetric catalysts for asymmetric cyanohydrin synthesis, asymmetric Strecker
Received 7 October 2008
Accepted 21 November 2008
Available online 24 January 2009
reactions, asymmetric synthesis of a-methyl amino acids and asymmetric Darzens condensations. Satis-
factory levels of asymmetric induction were obtained from reactions in which the (salen)metal complex
acts as a chiral Lewis acid, but low levels of asymmetric induction were obtained from reactions carried
out under solid–liquid phase-transfer conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Over the last 12 years,1 we have developed metal(salen) com-
plexes derived from cyclohexanediamine as highly effective cata-
tBu
tBu
lysts for
a range of carbon–carbon bond forming reactions.
TitaniumIV 1 and vanadiumV 2a,b complexes were found to cata-
lyze the asymmetric addition of trimethylsilyl cyanide,1,2 metal
cyanides1,3 (in the presence of an anhydride) and cyanoformates1,4
to aldehydes (Scheme 1). Complexes 1 and 2 are active at room
temperature with a substrate to catalyst ratio of up to 1000:1.
These complexes also afford products with ee0s >90% from a wide
range of aromatic aldehydes. Aliphatic aldehydes are also accept-
able substrates, although with reduced enantioselectivities (70–
90%), and complex 1 will also catalyze the asymmetric addition
of trimethylsilyl cyanide to ketones,1,5 whilst complex 2a will cat-
alyze the asymmetric addition of trimethylsilyl cyanide to imines.6
Complexes 1 and 2 have been commercialized7 by NPIL under the
trademark CACHy.
tBu tBu
O
O
N
N
O
O
N
N
O
Ti
Ti
O
tBu tBu
tBu
tBu
1
Whilst titanium and vanadium (salen) complexes were found to
form effective Lewis acid-based catalysts, copperII and cobaltII(sa-
len) complexes 3a,b and 4 were found to function as asymmetric
phase-transfer catalysts.1,8 Thus, complexes 3a,b were found to
catalyze the asymmetric alkylation of amino ester enolates, leading
O
N
N
O
V+
tBu
O
tBu
-
X
to the asymmetric synthesis of
a,a-disubstituted amino acids
tBu
2a
tBu
(Scheme 2).9 In a preliminary study,10 complex 4 was found to cat-
alyze asymmetric Darzens condensations as shown in Scheme 3.
Catalysts 1–4 all possess C2-symmetry. Whilst C2-symmetrical
catalysts are often useful in reducing the number of possible tran-
: X = EtOSO3
2b: X = Cl
OX
O
1
2
or
+ XCN
H
R
CN
R
* Corresponding author. Tel.: +44 191 222 7128; fax: +44 191 222 6929.
E-mail address: michael.north@ncl.ac.uk (M. North).
Scheme 1. Asymmetric cyanohydrin synthesis using complexes 1 and 2.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.037

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2805
R
R
NH3 /
MeOH
H2N
CONH2
6a-d
HCl.H2N
CO2Me
5a-d
N
N
O
LiAlH4 / THF
Co
a: R = Me; stereochemistry = (S)
O
b: R = CH2Ph; stereochemistry= (S)
c: R = Ph; stereochemistry = (R)
d: R = CHMe2; stereochemistry = (S)
R
NH2
R
R
H2N
3a
: R = H; M = Cu
7a-d
3b: R = H; M = Co
4: R = OMe; M = Co
3,5-di-tert-butyl
salicylaldehyde /
Δ, 20-48 hours
(58-90%)
4-methoxy-salicylaldehyde
or salicylaldehyde /
Δ, 20-48 hours
NaOH (solid) /
3a,b (cat) /
R"X
R
R
R"
CO2R'
(48-100%)
Ar
N
CO2R'
Ar
N
tBu
R'
R
R"
CO2H
tBu
tBu
OH
OH
N
N
R
H2N
OH
OH
N
N
R
Scheme 2. Asymmetric amino acid synthesis using complexes 3a,b.
O
NPh2
R'
R
MOH (solid)
/ 4 ( cat)
9a-d
; R' = OMe
10a-d; R' = H
O
tBu
8a-d
RCHO + XCH2CONPh2
X = Cl, Br, I
M = Na, K, Rb
O
Scheme 4. Synthesis of ligands 8a–d, 9a–d and 10a–d.
NPh2
R
derivative.17,18 In the case of diamine 7b which was isolated as
the free amine, this was achieved by refluxing a mixture of diamine
and 2 equiv of aldehyde in ethanol for 20 h. Shorter reaction times
resulted in formation of variable amounts of the mono-imine,
where only the less hindered of the two amino groups had reacted.
Salen ligand formation from diamines 7a,c,d, which were isolated
as their hydrochloride salt, was achieved using a mixed solvent
system of methanol and ethanol to dissolve the hydrochloride salt
in the presence of sodium methoxide. For reactions involving dia-
mines 7a,c, a reaction time of 24 h was sufficient to obtain salen li-
gands 8a,c, 9a,c and 10a,c, but the more sterically hindered
diamine 7d required a reaction time of 48 h at reflux to form li-
gands 8–10d.
O
Scheme 3. Asymmetric Darzens condensations using complex 4.
sition states for a reaction,11 C2-symmetry is not always advanta-
geous in an asymmetric catalyst since it restricts the options for
optimizing the chiral environment around the catalyst.12
We have previously reported the use of C1-symmetrical salen-
derived catalysts related to complexes 1–4 in asymmetric cyano-
hydrin synthesis13 and asymmetric enolate alkylation.9a,c In this
manuscript, we give full details of our recent work in this area,14
focussing on the use of amino acid-derived salen ligands bearing
unfunctionalized sidechains as catalysts for asymmetric cyanohy-
drin synthesis, asymmetric Strecker reactions, asymmetric amino
acid synthesis and asymmetric Darzens condensations.
Ligands 8a–d were used to prepare both titaniumIV and vana-
diumV complexes. Treatment of ligands 8a–d with titaniumIV chlo-
ride gave complexes 11a–d in a quantitative yield (Scheme 5). All
attempts to convert complexes 11a–d into the corresponding bis-
2. Results and discussion
2.1. Synthesis of catalysts
l
-oxo-bridged bimetallic complexes analogous to complex 1 were
unsuccessful, and resulted in decomposition back to ligands 8a–d
and/or diamines 7a–d. In light of this, complexes 11a–d were used
as precatalysts for asymmetric cyanohydrin synthesis, since it is
known that related C2-symmetrical complexes hydrolyze to the
bimetallic complexes in situ.2a,19
The amino acids (S)-alanine, (S)-phenylalanine, (R)-phenylgly-
cine and (S)-valine were selected as chiral starting materials for
the synthesis of the salen ligands on the basis of the different steric
environments associated with their unfunctionalized sidechains.
The synthesis of the C1-symmetrical salen ligands was achieved
as outlined in Scheme 4. Amino acid methyl ester hydrochlorides
5a–d were each converted into the corresponding amino amides
6a–d by treatment with a saturated solution of ammonia in meth-
anol.15 The resulting amino amides were then reduced by lithium
aluminium hydride in refluxing THF to give diamines 7a–d.16 Dia-
mines 7a,c,d were purified at this stage by formation and precipi-
tation of the corresponding dihydrochloride salts. This procedure
was not effective for diamine 7b, therefore it was used as the free
diamine.
Two routes were developed for the synthesis of vanadiumV com-
plexes 12a–d of ligands 8a–d. For asymmetric cyanohydrin synthe-
sis it was importantthat thecomplex possess a chloride ligand, as we
have recently shown that the nature of the counterion/sixth ligand
has a major effect on the rate of catalysis, though not on the enanti-
oselectivity.2d Thus, complex 2b is more reactive than complex 2a.
Complexes12a–c were prepared by a two-step synthesisin which li-
gands 8a–c were first treated with vanadyl sulfate to give a mixture
of vanadiumIV and vanadiumV(salen) complexes (Scheme 5). Treat-
ment of this mixture with ceric ammonium nitrate followed by
hydrochloric acid accomplished complete oxidation and counterion
exchange to form complexes 12a–c.20 For the synthesis of complex
12d, however, a more direct route involving treatment of ligand
10d with vanadiumV oxychloride was found to be effective.
Diamines 7a–d were converted into salen ligands 8a–d, 9a–d
and 10a–d by condensation with the appropriate salicylaldehyde

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Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
R
N
O
R
N
O
Cl
Ti
N
O
N
O
Cu
tBu
tBu
Cl
13a-d
tBu
tBu
11a-d
Cu(OAc)2
/
(42-65%)
R
EtOH, H2O, Δ
(100%) TiCl4 / CH2Cl2
R
N
N
N
N
OH
HO
tBu
OH HO
tBu
R'
R'
9a-d
; R' = OMe
10a-d; R' = H
tBu
tBu
8a-d
Co(OAc)2 / EtOH, N2, 70 oC
or
1) VOSO4, EtOH, Δ
2) (NH4)2Ce(NO3)6
3) HCl (aq.)
Co(OAc)2 / THF, N2, 60 oC
(40-87%)
R
(50-90%)
R
or VOCl3
N
N
O
R'
Co
O
N
O
N
O
V
R'
tBu
O
tBu
Cl
14a-d
15a-d; R' = OMe
; R' = H
tBu
tBu
Scheme 6. Synthesis of copper(salen) complexes 13a–d and cobalt(salen) com-
plexes 14a–d and 15a–d.
12a-d
Scheme 5. Synthesis of titaniumIV complexes 11a–d and vanadiumV complexes
12a–d.
Each catalyst was tested at three different concentrations since
(especially for titanium-based catalysts) it is known2a,19 that
enantioselectivity can increase as the catalyst loading is decreased
due to residual water in the solvent being needed to convert the
Both copperII and cobaltII(salen) complexes form effective
asymmetric phase-transfer catalysts. For the asymmetric alkyl-
ation of amino ester enolates,1,8 both metals are equally effective,
and the optimal ligand contains unsubstituted aromatic rings. In
contrast, for the asymmetric Darzens condensation only cobaltII
complexes were found to be catalytically active, and the optimal li-
gand structure contains methoxy substituents.10 Therefore, ligands
10a–d were complexed to both copper and cobalt (Scheme 6) to
give complexes 13a–d and 14a–d, respectively, and ligands 9a–d
were complexed to cobalt to give complexes 15a–d. The copper
complexes were prepared from copper acetate in an ethanol and
water solvent system. The preparation of the cobalt complexes
was also achieved from the metal acetate, but required anhydrous
reaction conditions and an inert atmosphere to avoid oxidation to
the corresponding cobaltIII complexes. In most cases, the cobalt
complexes were conveniently formed in ethanolic solution, but
complex 14d had to be formed in tetrahydrofuran due to the lack
of solubility of ligand 10d.
dichloride precatalysts into catalytically active di-l-oxo-bridged
dimers. However, the titanium-based C1-symmetrical catalysts
11a–d proved to be inferior to the C2-symmetrical titanium and
vanadium complexes 1 and 2a at all concentrations. Only complex
11d gave reasonable levels of conversion and asymmetric induc-
tion, but at best these were just over half the values obtained using
catalyst 1. One mechanistically interesting observation was appar-
ent from these data, whereas catalysts 1, 11a and 11c induced pref-
erential formation of the enantiomer of the cyanohydrin with
opposite absolute configuration to that of the salen ligand, cata-
lysts 11b and 11d induced preferential formation of the cyanohy-
drin enantiomer with the same absolute configuration as the
salen ligand. This suggests that catalysts 1 and 11d may operate
by fundamentally different mechanisms. Further support for
this hypothesis comes from the fact that for catalyst 11d, the
2.2. Asymmetric cyanohydrin synthesis
catalyst / CH2Cl2,
O
16 hours, RT
OSiMe3
+ Me3SiCN
The standard test reaction for asymmetric cyanohydrin synthe-
sis used the addition of trimethylsilyl cyanide to benzaldehyde
(Scheme 7).21 The cyanohydrin trimethylsilyl ether 16 can be con-
verted into the corresponding acetate 17 without racemization,22
and the enantiomeric excess of acetate 17 can be determined by
chiral GC.2 Catalysts 11a–d and 12a–d were screened for this reac-
tion, since our previous work has shown that both titaniumIV and
vanadiumV(salen) complexes are catalytically active and that opti-
mal asymmetric induction is obtained with tert-butyl groups on
the aromatic rings of the salen ligand.1,2 The results obtained are
summarized in Table 1.
(85-100%)
Ph
H
Ph
CN
16
Ac2O / Sc(OTf)3 (1 mol%),
MeCN, RT, 20 minutes
OAc
CN
Ph
17
Scheme 7. Asymmetric synthesis of mandelonitrile trimethylsilyl ether 16 and
acetate 17.

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2807
Table 1
obtained using complex 2a. With the exception of electron-rich 4-
methoxybenzaldehyde and sterically hindered pivaldehyde, the
enantioselectivities with complex 12d were relatively independent
of the aldehyde structure. In particular, there was no significant
difference between the enantioselectivities observed with aro-
matic and aliphatic substrates.
Use of complexes 11a–d and 12a–d as catalysts for the asymmetric addition of
trimethylsilyl cyanide to benzaldehyde
Catalyst (mol %)
Conversiona (%)
ee (%) (configuration)b
(R,R,R,R)-1 (0.1)c
(R,R)-2a (0.1)c
(S,S)-11a (0.1)
(S,S)-11a (1.0)
(S,S)-11a (2.0)
(S,S)-11b (0.1)
(S,S)-11b (1.0)
(S,S)-11b (2.0)
(R,R)-11c (0.1)
(R,R)-11c (1.0)
(R,R)-11c (2.0)
(S,S)-11d (0.1)
(S,S)-11d (1.0)
(S,S)-11d (2.0)
(S,S)-12a (0.1)
(S,S)-12a (1.0)
(S,S)-12a (2.0)
(S,S)-12b (0.1)
(S,S)-12b (1.0)
(S,S)-12b (2.0)
(R,R)-12c (0.1)
(R,R)-12c (1.0)
(R,R)-12c (2.0)
(S,S)-12d (0.1)
(S,S)-12d (1.0)
(S,S)-12d (2.0)
100
87
9
88 (S)
95 (S)
30 (R)
22 (R)
20 (R)
4 (S)
12 (S)
11 (S)
20 (S)
22 (S)
20 (S)
46 (S)
48 (S)
54 (S)
4 (S)
The results obtained with catalysts 11a–d and 12a–d can be ex-
plained on the basis of the conformation of the salen ligand in octa-
hedral complexes.2e,14 For catalysts 1 and 2, the cyclohexyl unit can
only adopt a pseudo-equatorial orientation with respect to the
salen ligand/metal plane (Fig. 1), and this also locks the five-mem-
bered metal chelate ring into a single conformation (k for an RR-li-
gand). In the case of catalysts 11 and 12, however, the single
substituent can adopt either a pseudo-equatorial or a pseudo-axial
position and this allows the five-membered metal chelate ring to
adopt either a d- or k-conformation. For metal complexes with a
variety of geometries, examples of complexes with substituents
in both pseudo-equatorial and pseudo-axial positions are known.23
For octahedral complexes (as formed by coordination of the alde-
hyde to complexes 11 and 12), interactions between the single
substituent on the salen ligand and the axially coordinated groups
will be dominant, especially when the axially coordinated groups
are large.24 For small substituents (especially the methyl group in
11a and 12a), there is likely to be little preference for the substitu-
ent to adopt a pseudo-axial or pseudo-equatorial position and hence
little preference for the chelate ring to adopt a d or k-conformation.
Thus, little or no asymmetric induction would be expected from
catalysts 11a and 12a. As the size of the substituent increases,
however, it is increasingly likely to adopt a pseudo-equatorial posi-
tion to avoid steric interactions with the axially coordinated
groups. This pseudo-equatorial preference will be especially fa-
voured by the absence of a substituent on the other sp3-hybridized
carbon of the salen ligand. Thus, the valine-derived complexes 11d
and 12d will have a strong preference for the isopropyl group to
adopt the same conformation, which is imposed upon the cyclo-
hexyl group in complexes 1 and 2, and this explains why com-
plexes 11d and 12d give the highest levels of asymmetric
induction.
14
31
20
73
49
27
56
67
31
36
61
57
33
29
24
82
81
53
62
64
100
100
100
1 (S)
2 (S)
62 (S)
62 (S)
64 (S)
32 (S)
30 (S)
64 (S)
81 (S)
77 (S)
75 (S)
a
Conversion of benzaldehyde to mandelonitrile trimethylsilyl ether 16 under the
conditions shown in Scheme 7, determined by 1H NMR spectroscopy.
b
Enantiomeric excess of mandelonitrile acetate determined by chiral GC. Abso-
lute configuration is based on the known order of elution of the two enantiomers.
c
Data taken from Ref. 2.
conversion and enantioselectivity both increased as the catalyst
loading increased, whereas previous work has shown that for the
titanium dichloride precatalyst of complex 1, the enantioselectivity
increases as the catalyst loading is reduced to 0.1 mol %.2a,19
The C1-symmetrical vanadium complexes 12a–d gave more
encouraging results. Whilst complex 12a gave essentially racemic
product, complexes 12b and 12c gave enantioselectivities up to
64%. However, the best results were obtained with valine-derived
complex 12d, which gave complete conversion of benzaldehyde
to compound 16 at the lowest catalyst loading and an enantiose-
lectivity up to 81%. This enantioselectivity was still lower than that
obtained using catalyst 2a, but merited further investigation.
Therefore, the use of 0.1 mol % of this complex to catalyze the
asymmetric addition of trimethylsilyl cyanide to 10 other alde-
hydes was investigated, giving the results presented in Table 2.
Where a direct comparison could be made,2c the enantioselec-
tivities obtained using complex 12d were always lower than those
The absolute configuration of the product produced by catalysts
11 and 12 will be determined by a combination of the orientation
of the salen substituent, the conformation of the salen chelate ring
and the coordination positions of the aldehyde and trimethylsilyl
cyanide in the stereodetermining transition state. In particular,
since the complexes lack C2-symmetry, the apical coordination
positions (represented by X in Fig. 1) are non-equivalent and the
absolute configuration of the product is likely to be determined lar-
gely by which of these sites the aldehyde coordinates too. This can
account for the changes in product absolute configuration relative
to catalyst configuration observed for catalysts 11a–d and 12a–d.
Table 2
Use of complex 12d to catalyze the asymmetric addition of trimethylsilyl cyanide to
aldehydes
X
Conversiona (%)
ee (%) (configuration)b
H
Aldehyde
O
O
N
N
R
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
3-MeOC6H4CHO
4-MeOC6H4CHO
4-F3CC6H4CHO
C8H17CHO
Me2CHCHO
CyCHO
Me3CCHO
93
86
90
98
100
100
93
85
91
66 (S)
81 (S)
78 (S)
66 (S)
45 (S)
77 (S)
73 (S)
73 (S)
73 (S)
45 (S)
M
R
H
X
pseudo-equatorial
X
M
X
X
M
X
H
H
H
O
O
H
N
H
R
N
N
O
N
O
H
100
R
a
Conversion of aldehyde to cyanohydrin trimethylsilyl ether under the condi-
tions shown in Scheme 7, determined by 1H NMR spectroscopy.
pseudo-axial
pseudo-equatorial
b
Enantiomeric excess of cyanohydrin acetate determined by chiral GC. Absolute
configuration is based on the known order of elution of the two enantiomers.
Figure 1. Conformations of salen ligands.

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Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2.3. Asymmetric Strecker reactions
2.4. Asymmetric alkylation of amino ester enolates
Whilst asymmetric cyanohydrin synthesis has been known for
over a century,21 the closely related asymmetric addition of cya-
nide to imines has been known for only the last decade.25 Since
complex 2a was known to catalyze the asymmetric addition of cya-
nide to imines,6 the use of vanadiumV(salen) complexes 12a–d to
catalyze the same reaction was investigated. The test reaction is
shown in Scheme 8. Thus, addition of hydrogen cyanide (generated
in situ from trimethylsilyl cyanide and methanol26) to imine 18
generates amino nitrile 19. The enantiomeric excess of 19 can
readily be determined by 1H NMR analysis of its diastereomeric
camphor sulfonate salts.27
Asymmetric phase-transfer catalysis is usually carried out using
organocatalysts such as cinchona alkaloid derivatives28 or spiro-
ammonium salts.29 However, we have previously developed
C2-symmetrical salen complexes 3a,b as the first transition me-
tal-based catalysts for the asymmetric alkylation of enolates under
solid–liquid phase-transfer conditions.1,8,9 Therefore, it was of
interest to investigate the use of C1-symmetrical complexes 13a–
d and 14a–d as catalysts for the same reaction.
The standard test reaction used to compare catalysts for asym-
metric enolate alkylation is shown in Scheme 9. This has the
advantage that alanine derivative 20 is readily available, and prod-
uct 21 is not susceptible to racemization. In addition, the enantio-
meric excess of product 21 is readily determined by 1H NMR
analysis after derivatization with (S)-1-phenylethylisocyanate to
give diastereomeric ureas 22. We have previously shown that no
kinetic resolution occurs during this derivatization.9 The results
obtained using catalysts 13a–d and 14a–d are given in Table 4.
1) MeOH (1.2 eqiv.), toluene
2) 12a-d (10 mol%)
NBn
NHBn
+ Me3SiCN
(100%)
Ph
Ph
CN
18
19
Scheme 8. Asymmetric addition of cyanide to imine 18.
Me
There are significant differences between the optimal reaction
conditions required for asymmetric cyanohydrin synthesis and
asymmetric amino nitrile synthesis. Thus, whilst asymmetric cya-
nohydrin synthesis can be achieved using just 0.1 mol % of catalyst
at room temperature in dichloromethane (Section 2.2), asymmetric
Strecker reactions require the use of 10 mol % of catalyst at ꢀ40 °C
in toluene in the presence of methanol. The results obtained using
catalysts 12a–d are presented in Table 3.
N
CO2Me
Cl
20
1) NaOH (solid) / PhCH2Br,
13a-d or 14a-d (2 mol%) /
toluene, argon, 16 hours
2) MeOH / AcCl, argon, 4 hours
3) SiO2
(66-91%)
Table 3
Me
Ph
Use of complexes 12a–d as catalysts for the asymmetric addition of cyanide to imine
18
H2N
CO2Me
Catalysta
Conversion (%)
ee (%) (configuration)b
21
Me
(R,R)-2ac
(S,S)-12a
(S,S)-12b
(R,R)-12c
(S,S)-12d
100
100
100
100
100
75 (S)
10 (S)
90 (S)
9 (R)
Ph
N=C=O
Me
O
Me
Ph
81 (S)
a
Ph
N
N
CO2Me
All reactions were carried out using 10 mol % of catalyst under the conditions
shown in Scheme 8.
H
H
22
b
Enantiomeric excess and absolute configuration determined from the 1H NMR
spectra of the camphor sulfonate salts.
Scheme 9. Use of complexes 13a–d and 14a–d as catalysts for enolate alkylation
under solid–liquid phase transfer conditions.
c
Result taken from Ref. 6.
The results show a remarkable variation of enantioselectivity
with the structure of the catalyst. Whereas catalysts 12a,c derived
from alanine and phenylglycine gave negligible levels of asymmet-
ric induction, catalysts 12b,d derived from phenylalanine and va-
line gave >80% asymmetric induction, and were more effective
catalysts than the C2-symmetrical catalyst 2a. All the reactions
gave complete conversion of imine 18 into amino nitrile 19. The
complete conversion may be due to a facile uncatalyzed reaction
occurring during the work-up. The low levels of asymmetric induc-
tion observed with complexes 12a,c could be due to a very slow
but highly enantioselective reaction, rather than a non-stereoselec-
tive reaction. The same effect may also be responsible for the
apparent difference in enantioselectivity between complexes 12b
and 12d. For all the four catalysts 12a–d, amino nitrile 19 had
the same absolute configuration as the catalyst. In contrast, the
(R,R)-enantiomer of catalyst 2a formed the (S)-enantiomer of ami-
no nitrile 19. This is consistent with the mono-substituted ligands
adopting a structure with a different substituent location and/or
chelate ring conformation to the cyclohexanediamine-derived li-
gand. Further work is underway to investigate the mechanistic
and stereochemical aspects of this reaction and to extend it to
other substrates, and will be reported in due course.
Table 4
Use of complexes 13a–d and 14a–d as catalysts for the asymmetric alkylation of
alanine derivative 20a
Catalyst
Yield of 21 (%)
ee (%) (configuration)b
(R,R)-3ac
(R,R)-3bc
(S,S)-13a
(S,S)-13b
(R,R)-13c
(S,S)-13d
(S,S)-14a
(S,S)-14b
(R,R)-14c
(S,S)-14d
91
83
72
79
69
67
70
84
73
66
81 (R)
80 (R)
27 (S)
27 (S)
6 (S)
0
24 (S)
29 (S)
9 (S)
0
a
All reactions carried out using 2 mol % of catalyst under the conditions shown in
Scheme 9.
b
Enantiomeric excess and absolute configuration determined from the 1H NMR
spectra of ureas 22.
c
Data taken from Ref. 9b.
It is apparent that all catalysts 13a–d and 14a–d were signifi-
cantly inferior to the C2-symmetrical catalysts 3a,b. In contrast to
asymmetric cyanohydrin and amino nitrile synthesis, the highest

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2809
levels of asymmetric induction were obtained with complexes de-
rived from alanine and phenylalanine rather than valine. Interest-
ingly, in this case the relationship between the absolute
configuration of the catalyst and the product did not vary between
the C2- and C1-symmetrical catalysts. Thus, for catalysts 3a,b, 13a,b
and 14a,b the product had the same absolute configuration as the
catalyst. Only in the case of phenylglycine-derived catalysts 13c
and 14c was this trend not followed, and the enantiomeric ex-
cesses were very low (<10%) in this case. In view of the low enanti-
oselectivities obtained in this reaction, the use of catalysts 13a–d
nine showed any significant asymmetric induction. For the major
diastereomer of the epoxide product, the observed enantiomeric
excess was still less than half that obtained using catalyst 4.
The results also show that when bromoamide 24 was used, the
diastereoselectivity was independent of the catalyst used and in-
deed stayed the same if no catalyst was employed. In every case,
the cis-epoxide 25 was the major product, and the cis/trans ratio
was approximately 2.4:1. In contrast, for reactions carried out on
chloroamide 23, the observed diastereoselectivity was catalyst
dependent. In every case, trans-epoxide 26 was the major product,
but the cis/trans ratio changed from 1:1.8 (64% trans) when no cat-
alyst was used to 1:3.8 (79% trans) in the presence of catalysts
15c,d. Exactly how the catalysts are able to influence the diastere-
oselectivity of reactions involving substrate 23 without inducing
asymmetry into the reaction is not clear. The Darzens reaction is
mechanistically complex involving enolate formation, an aldol
reaction and intramolecular substitution, and under the reaction
conditions all of these steps may be reversible.30 We have previ-
ously analyzed Darzens reactions on substrates 23 and 24 in terms
of 24 giving epoxide 25 via a kinetically controlled, non-chelated
aldol reaction, whilst chloroamide 23 reacts via a thermodynami-
cally controlled chelated aldol reaction due to the lower leaving
group ability of chloride compared to bromide.10 Thus, it may be
that complexes 15a-d also coordinate to the chelated aldol inter-
mediate and do so in such a way as to enhance the preference
for all substituents to adopt equatorial positions in the six-mem-
bered chelate, whilst being too remote to influence the absolute
configuration of the newly formed stereocentres. One possible
structure for such an intermediate is shown in Figure 2, but the
heterogeneous nature of these reactions has prevented experimen-
tal confirmation of this type of intermediate.
and 14a–d for the asymmetric synthesis of
a-methyl a-amino
acids was not pursued further.
2.5. Asymmetric Darzens condensations
The Darzens condensation of
a-haloamides 23 and 24 with
benzaldehyde is catalyzed by C2-symmetrical complex 4.10 The
diastereoselectivity of the reaction is dependent on the halide
present in substrate 23/24, with chloroamide 23 giving predomi-
nantly trans-epoxide 26, whilst bromoamide 24 gives predomi-
nantly cis-epoxide 25. Therefore, the ability of the corresponding
C1-symmetrical cobaltII(salen) complexes 15a–d to influence both
the enantio- and diastereoselectivity of this reaction was studied.
The standard conditions used to study this reaction are shown in
Scheme 10. The enantiomeric excess of epoxides 25 and 26 could
be determined by chiral HPLC. The results obtained using catalysts
15a–d are presented in Table 5.
O
KOH (solid) /
15a-d (2 mol%),
Ph
CONPh2
CONPh2
CH2Cl2, RT, 4 hours
25
26
PhCHO + XCH2CONPh2
+
O
R
(72-97%)
23
: X = Cl
24: X = Br
Ph
N
O
N
O
Co
Scheme 10. Use of complexes 15a–d to catalyze asymmetric Darzens
condensations.
Cl
O
MeO
OMe
NPh2
Ph
K
Table 5
O
Use of complexes 15a–d as catalysts for the asymmetric Darzens condensation of
substrates 23 and 24a
Figure 2. Possible chelated intermediate to explain the diastereoselectivity of
reactions involving substrate 23 and catalysts 15a–d.
Catalyst
Substrate
25/26b
ee 25c
ee 26c
Yieldd (%)
Nonee
23
24
23
24
23
24
23
24
23
24
23
24
1:1.8
2.4:1
1:2.7
2.4:1
1:2.3
2.6:1
1:2.9
2.4:1
1:3.8
2.2:1
1:3.8
2.3:1
73
78
84
93
97
83
86
79
72
79
80
79
3. Conclusions
Nonee
(R,R)-4f
3
42
4
18
5
2
3
12
2
29
44
11
21
5
0
8
11
8
2
(R,R)-4f
C1-symmetrical salen ligands derived from four different amino
acids have been prepared and complexed to four different metal
ions to give catalysts for four different carbon–carbon bond form-
ing reactions. Application of titaniumIV and vanadiumV complexes
to asymmetric cyanohydrin synthesis gave satisfactory levels of
asymmetric induction in some cases (especially with complex
12d), though in no case were the enantioselectivities as high as
those obtained using the corresponding C2-symmetrical catalysts
1 and 2. In contrast, use of the same vanadiumV complexes to cat-
alyze asymmetric Strecker reactions did, in two cases, give higher
levels of asymmetric induction than those obtained using C2-sym-
metrical complex 2a.
(S,S)-15a
(S,S)-15a
(S,S)-15b
(S,S)-15b
(R,R)-15c
(R,R)-15c
(S,S)-15d
(S,S)-15d
0
a
All reactions carried out using 2 mol % of catalyst under the conditions shown in
Scheme 10.
b
c
d
e
f
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC.
Combined yield of epoxides 25 and 26.
Data taken from Ref. 10a.
The use of C1-symmetrical salen complexes as asymmetric cat-
alysts for enolate reactions conducted under phase-transfer condi-
tions was also investigated. Complexes 13a,b and 14a,b did show
Data taken from Ref. 10b
enantioselectivities of 20–30% in the asymmetric synthesis of
a-
None of the C1-symmetrical catalysts came close to matching
the enantioselectivities achieved with C2-symmetrical catalyst 4
with either substrate 23 or 24. Only complex 15a derived from ala-
methyl-phenylalanine methyl ester, but these were far lower than
the 80–81% enantiomeric excess achievable using C2-symmetrical
catalysts 3a,b. The use of complexes 15a–d as asymmetric cata-

2810
Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
lysts for the Darzens condensation was also studied under phase-
transfer conditions. Again, no significant levels of asymmetric
induction were achieved, though the catalysts were able to en-
hance the diastereoselectivity of reactions involving chloroamide
substrate 23.
dried (Na2SO4), filtered and concentrated in vacuo to give ligands
8a,c,d, 9a,c,d and 10a,c,d.
4.2.1. (2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzylidene)]-1,2-
diaminopropane 8a17a,b
Obtained as a yellow gel (80%). ½a D20
¼ þ173:0 (c 0.1, CHCl3).
ꢂ
mmax 3584 (br), 2960 (s), 2908 (s), 2869 (s), 1630 (s) and
1597 cmꢀ1 (m). dH 1.19 (18H, s), 1.29 (3H, d, J 5.9 Hz), 1.34 (9H,
s), 1.35 (9H, s), 3.5–3.7 (2H, m), 3.7–3.8 (1H, m), 6.9–7.0 (2H, m),
7.2–7.3 (2H, m), 8.25 (1H, s), 8.29 (1H, s), 13.70 (2H, br s). dc
20.4, 29.4, 29.6, 29.7, 31.3, 31.4, 31.5, 34.1, 35.1, 63.9, 64.9,
118.0, 118.1, 126.0, 126.1, 126.9, 127.0, 136.8, 136.9, 140.1,
140.2, 158.1, 158.2, 165.6, 167.5. m/z (ESI) 529.3 (M+Na+, 100),
507.3 (MH+, 18), 64.0 (46). Found (ESI) 507.3948 (MH+,
C33H51N2O2 requires 507.3945).
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded in CDCl3 using Bruker
Avance spectrometers. 1H NMR spectra were recorded at 300 or
360 MHz. 13C NMR spectra were recorded at 75 or 90 MHz. All
chemical shifts (d) are quoted in parts per million (ppm) relative
to tetramethylsilane using the residual solvent peak as an internal
standard, and all coupling constants (J) are quoted in Hertz. Multi-
plicities are reported as singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m) or a combination of these. Low and high resolu-
tion mass spectra were recorded by the EPSRC national service, or
by King0s College London using electron ionization (EI), chemical
ionization (CI) or electrospray ionization (ESI). IR spectra of solids
were recorded on a Thermo electron corporation Nicolet Avatar
370 DTGS: Smart Orbit Diamond ATR 30,000–200 cmꢀ1. IR spectra
of liquids and oils were recorded as a thin film between NaCl plates
4.2.2. (1R)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzylidene)]-1-
phenyl-1,2-diaminoethane 8c17c
Obtained as a yellow gel (72%) after purification by column
chromatography on silica gel using dichloromethane as eluent.
½
a 2D0
ꢂ
¼ ꢀ27:2 (c 0.25, CHCl3). mmax 3434 (br), 2958 (s), 2869 (m)
and 1629 cmꢀ1 (s). dH 1.33–1.35 (18H, m), 1.50–1.54 (18H, m),
3.9–4.1 (1H, m), 4.2–4.3 (1H, m), 4.7–4.8 (1H, m), 7.1–7.2 (2H,
m), 7.4–7.5 (5H, m), 7.5–7.6 (2H, m), 8.52 (1H, s), 8.62 (1H, s),
13.66 (2H, br s). dc 29.5, 29.6, 31.4, 31.5, 34.4, 35.4, 66.8, 74.4,
117.1, 118.1, 126.1, 126.4, 127.1, 127.2, 127.3, 127.7, 128.8,
136.7, 136.8, 140.1, 140.3, 141.0, 158.1, 158.2, 167.1, 167.9. m/z
(ESI) 583.4 (MH+, 100), 367.2 (25), 234.0 (18), 79.0 (41). Found
(ESI) 583.4258 (MH+, C39H55N2O2 requires 583.4258).
on
a Perkin–Elmer Spectrum One FT-IR spectrometer. The
strengths of the vibrations are quoted as broad (br), strong (s),
medium (m) or weak (w). Optical rotation measurements were
undertaken using an Optical Activity POLAAR 2001 polarimeter,
and melting points were recorded using Barnstead Electrothermal
9100 melting point apparatus.
Gas chromatography was carried out using a Hewlett Packard
5890 Series II Plus instrument fitted with a TCD detector using a
Supelco Gamma DEX 120 fused silica capillary column
(30 m ꢁ 0.25 mm) with hydrogen as the carrier gas. High perfor-
mance liquid chromatography was conducted on a Varian Pro Star
410 system using a Daicel Chiralpak ADH column with UV detec-
tion at 254 nm and a solvent system of hexane/isopropanol (4:1)
with a flow rate of 1 mL/min. All silica gel chromatography was
performed using either Merck Silica Gel 60 (0.04–0.063 mm) or
4.2.3. (2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzylidene)]-3-
methyl-1,2-diaminobutane 8d
Obtained as a yellow gel (62%) after purification by column
chromatography on silica gel using hexane as eluent.
½
a 2D0
ꢂ
¼ þ84:0 (c 0.1, CHCl3). mmax 3435 (br), 2960 (s), 2871 (m)
and 1630 cmꢀ1 (s). dH 0.92 (3H, d, J 3.9 Hz), 0.94 (3H, d, JH
3.9 Hz), 1.17 (9H, s), 1.19 (9H, s), 1.32 (9H, s), 1.35 (9H, s), 1.9–
2.0 (1H, m), 3.1–3.2 (1H, m), 3.56 (1H, dd, J 12.2, 8.4 Hz), 3.86
(1H, dd, J 12.2, 2.9 Hz), 6.9–7.0 (2H, m), 7.2–7.3 (2H, m), 8.22
(1H, s), 8.23 (1H, s), 13.60 (2H, br s). dc 18.4, 19.9, 29.5, 29.6,
29.7, 29.8, 31.4, 31.5, 34.1, 35.1, 62.5, 76.1, 118.0, 118.1, 126.0,
126.2, 127.0, 136.7, 136.8, 140.1, 140.2, 158.2, 158.3, 166.6,
167.5. m/z (CI) 535.4 (MH+, 53), 88.1 (23), 86.0 (68), 74.0 (100).
Found (ESI) 535.4252 (MH+ C35H55N2O2 requires 535.4258).
Fluorochem Silica Gel 40–63
l 60 A.
4.2. General procedure for the synthesis of ligands 8a,c,d, 9a,c,d
and 10a,c,d
Amino amides15 6a–d (1.0 equiv) and lithium aluminium hy-
dride (3.0 equiv) were dissolved in dry THF at 0 °C under a nitrogen
atmosphere. The reaction mixture was then refluxed under nitro-
gen for 16–72 h, and was then allowed to cool to room tempera-
ture. The reaction mixture was then cooled to 0 °C, and 1%
aqueous potassium hydroxide solution was slowly added. The
resulting precipitate was filtered and washed with toluene. The
toluene washings were dried (Na2CO3), filtered, and methanol
and acetyl chloride (3.0 equiv) were added. The mixture was then
left to stir at room temperature overnight, at which time the dia-
mine dihydrochloride salt precipitated as a white solid. The precip-
itate was filtered and air dried. Diethyl ether was added to the
filtrate and left to stir for another 20 min resulting in the precipi-
tation of a second batch of dihydrochloride salt, which was filtered
and air dried. The combined crops of the diamine dihydrochloride
salt were then dissolved in methanol and ethanol (1:1), and so-
dium methoxide (3.0 equiv) and the appropriate salicylaldehyde
derivative (2.0 equiv) were added. The solution was then refluxed
overnight, cooled to room temperature, filtered and concentrated
in vacuo. The residue was taken up in CH2Cl2, filtered, washed suc-
cessively with distilled water (2 ꢁ 30 mL) and brine (1 ꢁ 30 mL),
4.2.4. (2S)-[N,N0-Bis-(20-hydroxy-40-methoxy benzylidene)]-1,2-
diaminopropane 9a
Obtained as a yellow gel (65%). ½a D20
¼ þ425:0 (c 0.04, CHCl3).
ꢂ
mmax 2967 (m), 1623 (s) and 1515 cmꢀ1 (m). dH 1.28 (3H, d, J
6.2 Hz), 3.4–3.6 (2H, m), 3.70 (3H, s), 3.71 (3H, s), 3.73 (1H, br s),
6.2–6.4 (4H, m), 6.9–7.0 (2H, m), 8.06 (1H, s), 8.12 (1H, s), 13.70
(2H, br s). dc 20.5, 55.3, 55.6, 64.5, 65.4, 101.4, 106.3, 106.4,
106.5, 108.3, 112.9, 121.0, 129.3, 133.0, 135.1, 163.5, 163.6,
164.7, 165.7. m/z (ESI) 343.3 (MH+, 100%). Found (ESI) 343.1651
(MH+, C19H23N2O4 requires 343.1652).
4.2.5. (1R)-[N,N0-Bis-(20-hydroxy-40-methoxy benzylidene)]-1-
phenyl-1,2-diaminoethane 9c
Obtained as a yellow gel (53%) after purification by column
chromatography on silica gel using diethyl ether as eluent.
½
a 2D0
ꢂ
¼ ꢀ60:0 (c 0.06, CHCl3). mmax 3428, 1623 and 1514 cmꢀ1
(m). dH 3.68 (3H, s), 3.69 (3H, s), 3.7–3.8 (1H, m), 3.9–4.0 (1H,
m), 4.48 (1H, dd, J 8.2, 4.5 Hz), 6.2–6.4 (4H, m), 6.9–7.0 (2H, m),
7.1–7.4 (5H, m), 8.01 (1H, s), 8.18 (1H, s), 13.74 (2H, br s). dc
55.2, 55.3, 65.9, 73.5, 101.3, 101.4, 106.4, 106.5, 112.6, 112.7,
127.0, 127.3, 127.6, 128.6, 128.7, 132.7, 133.0, 140.8, 163.7,

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2811
163.8, 164.8, 165.7. m/z (ESI) 405.2 (MH+, 100), 242.0 (10). Found
4.3.1. (2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzylidene)]-3-
(ESI) 405.1807 (MH+ C24H25N2O4 requires 405.1809).
phenyl-1,2-diaminopropane 8b17c
Obtained as yellow crystals (58%) after purification by column
chromatography on silica gel using dichloromethane as eluent. Mp
4.2.6. (2S)-[N,N0-Bis-(20-hydroxy-40-methoxy benzylidene)]-3-
methyl-1,2-diaminobutane 9d
Obtained as a yellow gel (61%) after purification by column
chromatography on silica gel using hexane as eluent.
165.2–166.5 °C (decomp.). ½a D20
¼ þ63:5 (c 0.052, CHCl3). mmax
ꢂ
3411 (br), 2958 (s), 2868 (m) and 1629 cmꢀ1 (s). dH 1.15 (9H, s),
1.17 (9H, s), 1.32 (9H, s), 1.33 (9H, s), 2.9–3.0 (2H, m), 3.5–3.7 (2H,
m), 3.82 (1H, dd, J 11.1, 2.1 Hz), 6.84 (1H, d, J 2.4 Hz), 6.94 (1H, d, J
2.4 Hz), 7.01–7.2 (1H, m), 7.25 (1H, t, J 2.2 Hz), 8.04 (1H, s), 8.23
(1H, s), 13.69 (2H, br s). dc 29.5, 29.6, 31.4, 31.5, 34.1, 34.2, 35.1,
41.1, 64.0, 71.4, 117.9, 118.0, 126.0, 126.2, 126.5, 127.0, 127.1,
128.5, 129.6, 136.7, 136.8, 138.2, 140.1, 140.2, 158.1, 158.2, 166.6,
167.8. m/z (CI) 569.5 (MH+, 38), 234.2 (100), 106.0 (52), 52.2 (73).
Found (ESI) 569.4104 (MH+ C38H53N2O2 requires 569.4102).
½
a 2D0
ꢂ
¼ þ78:6 (c 0.5, CHCl3). mmax 3467 (br), 2962 (m), 1626 (s),
1579 (m) and 1515 cmꢀ1 (m). dH 0.99 (3H, d, J 3.2 Hz), 1.01 (3H,
d, J 3.2 Hz), 1.9–2.1 (1H, m), 3.1–3.3 (1H, m), 3.55 (1H, dd, J 12.3,
8.5 Hz), 3.77 (3H, s), 3.78 (3H, s), 3.87 (1H, dd, J 12.4, 2.8 Hz),
6.3–6.4 (4H, m), 7.0–7.1 (2H, m), 8.10 (1H, s), 8.12 (1H, s), 13.86
(2H, br s). dc 18.0, 19.7, 31.2, 55.1, 55.2, 61.6, 75.1, 101.3, 106.2,
106.3, 112.4, 112.5, 132.5, 132.6, 132.7, 132.8, 163.5, 164.3,
164.5, 165.3. m/z (ESI) 371.3 (MH+, 47), 151.9 (63), 139.0 (85),
125.1 (60), 103.0 (36), 86.0 (100), 72.0 (42). Found (ESI)
371.1966 (MH+ C21H27N2O4 requires 371.1965).
4.3.2. (2S)-[N,N0-Bis-(20-hydroxy-40-methoxy benzylidene)]-
3-phenyl-1,2-diaminopropane 9b
Obtained as a yellow gel (48%) after purification by column chro-
4.2.7. (2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-1,2-diaminopropane
10a
matography on silica gel using diethyl ether as eluent. ½a D20
¼ þ67:0
ꢂ
(c 0.06, CHCl3). m
max 3434 (br), 1623 (s) and 1514 cmꢀ1 (m). dH 2.83
Obtained as
a
yellow solid (100%). Mp 51.7–51.9 °C.
(1H, dd, J 13.4, 7.5 Hz), 2.97 (1H, dd, J 13.6, 4.5 Hz), 3.5–3.6 (2H,
m), 3.70 (6H, s), 3.7–3.8 (1H, m), 6.2–6.4 (4H, m), 6.8–6.9 (1H, m),
6.9–7.0 (1H, m), 7.0–7.3 (5H, m), 7.81 (1H, s), 8.06 (1H, s), 13.63
(2H, br s). dc 41.3, 55.6, 63.7, 63.8, 71.3, 101.7, 106.8, 112.9, 125.8,
128.8, 129.9, 133.1, 138.3, 164.0, 164.4, 164.8, 166.0. m/z (ESI)
419.3 (MH+, 6), 307.2 (17), 285.2 (100), 152.0 (98). Found (ESI)
419.1962 (MH+ C25H27N2O4 requires 419.1965).
½
a 2D0
ꢂ
¼ þ332:0 (c 0.05, CHCl3). mmax 3400 (br), 2971 (m), 2883 (m),
1631 (s) and 1581 cmꢀ1 (m). dH 1.29 (3H, d, J 6.1 Hz), 3.5–3.7 (2H,
m), 3.7–3.8 (1H, m), 6.7–6.9 (4H, m), 7.1–7.2 (4H, m), 8.21 (1H, s),
8.25 (1H, s), 12.62 (2H, br s). dc 20.6, 65.3, 66.3, 116.9, 117.0, 118.5,
118.6, 118.8, 129.0, 131.4, 131.5, 132.3, 132.4, 161.1, 161.2, 164.4,
166.4. m/z (ESI) 283.2 (MH+, 100), 179.1 (19), 122.0 (5). Found
283.1439 (MH+ C17H19N2O2 requires 283.1441).
4.3.3. (2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-phenyl-1,2-
diaminopropane 10b
4.2.8. (1R)-[N,N0-Bis-(20-hydroxybenzylidene)]-1-phenyl-1,2-
diaminoethane 10c
This ligand was unstable to chromatography on silica gel and
could not be purified. Therefore, the impure ligand was used for
complex preparation without characterization.
Obtained as yellow crystals (51%) after recrystallization from
hexane. Mp 97.1–97.3 °C. ½a D20
¼ þ88:0 (c 0.05, CHCl3). mmax 3250
ꢂ
(br), 3055 (w), 3023 (w), 2912 (w), 1627 (s), 1609 (m) and
1578 cmꢀ1 (m). dH 2.9–3.0 (1H, m), 3.1–3.2 (1H, m), 3.7–3.8 (2H,
m), 4.0–4.1 (1H, m), 6.7–6.9 (2H, m), 6.9–7.0 (2H, m), 7.08 (1H,
dd, J 7.6, 1.6 Hz), 7.1–7.3 (8H, m), 8.00 (1H, s), 8.29 (1H, s), 13.17
(2H, s). dc 41.3, 64.5, 71.9, 117.4, 119.0, 127.0, 128.9, 129.9,
131.8, 131.9, 132.7, 138.1, 161.5, 165.8, 167.1. m/z (ESI) 359.3
(MH+, 68), 255.2 (33), 122.0 (100), 105.0 (20). Found 359.1753
(MH+ C23H23N2O2 requires 359.1754).
4.2.9. (2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-methyl-1,2-
diaminobutane 10d
Obtained as a yellow gel (50%) after purification by column
chromatography on silica gel using Et2O as eluent. ½a D20
¼ þ250:0
ꢂ
(c 0.03, CHCl3). mmax 3376 (br), 3051 (m), 2959 (m), 2872 (m),
1631 (s) and 1580 cmꢀ1 (m). dH 0.8–0.9 (6H, m), 1.8–2.0 (1H, m),
3.1–3.2 (1H, m), 3.24 (1H, dd, J 6.5, 1.2 Hz), 3.80 (1H, ddd, J 12.3,
3.7, 1.2 Hz), 6.6–6.8 (2H, m), 6.8–6.9 (2H, m), 7.0–7.1 (2H, m),
7.1–7.2 (2H, m), 8.10 (1H, s), 8.12 (1H, s). dc 19.7, 20.1, 31.5, 62.9,
76.2, 117.7, 119.8, 120.9, 128.3, 128.4, 130.1, 130.2, 133.6, 136.8,
155.8, 161.6, 165.1, 165.7, 166.8. m/z (ESI) 311.2 (MH+, 100),
207.1 (43), 178.1 (26), 122.0 (10), 74.2 (20). Found (ESI)
311.1752 (MH+ C19H23N2O2 requires 311.1754).
4.4. General procedure for the synthesis of titanium dichloride
complexes 11a–d
A mixture of ligands 8a–d (1 equiv) and TiCl4 (1 M solution in
CH2Cl2; 1 equiv) was stirred at room temperature under an argon
atmosphere in dry CH2Cl2 for 3 h. The reaction was concentrated
in vacuo, and the residue was washed with Et2O and with 1:1
Et2O/petroleum ether to give complexes 11a–d.
4.3. General procedure for the synthesis of ligands 8–10b
4.4.1. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzylidene)]-
1,2-diaminopropanato] titaniumIV chloride 11a
Amino amide15b 6b (1.0 equiv) and lithium aluminium hydride
(3.0 equiv) were dissolved in dry THF at 0 °C under a nitrogen
atmosphere. The reaction mixture was then refluxed under nitro-
gen for 16–72 h, and was then allowed to cool to room tempera-
ture. The reaction mixture was then cooled to 0 °C and 1%
aqueous potassium hydroxide solution was slowly added. The
resulting precipitate was filtered and washed with toluene. The
toluene washings were dried (Na2CO3), filtered and evaporated to
give diamine 7b, which was immediately dissolved in ethanol,
and the appropriate substituted salicylaldehyde (2.0 equiv) was
added. The solution was refluxed for 20 h, cooled to room temper-
ature, filtered and concentrated in vacuo. The residue was then ta-
ken up in CH2Cl2, filtered, washed successively with distilled water
(2 ꢁ 30 mL) and brine (1 ꢁ 30 mL), dried (Na2SO4), filtered and
concentrated in vacuo to give ligands 8–10b.
Obtained as a red/brown solid (100%). Mp 351.1–352.0 °C (de-
comp.). ½a 2D0
¼ þ800:0 (c 0.003, CHCl3). mmax 2953 (m), 2906 (m),
ꢂ
2868 (m), 1615 (s) and 1562 cmꢀ1 (m). dH 1.22 (9H, s), 1.24 (9H, s),
1.42 (18H, s), 1.46 (3H, d, J 6.4 Hz), 3.9–4.0 (2H, m), 4.4–4.5 (1H,
m), 7.2–7.3 (2H, m), 7.5–7.6 (2H, m), 8.20 (1H, s), 8.21 (1H, s). dc
16.7, 17.3, 30.0, 30.9, 31.3, 31.4, 34.5, 34.6, 35.6, 61.5, 65.6, 125.4,
125.9, 129.4, 129.9, 131.3, 131.5, 135.2, 137.2, 144.6, 144.7, 159.7,
160.4, 162.4, 164.3. m/z (EI) 622.3 (M+, 13), 587.3 (MꢀCl+, 100).
Found (EI) 622.2565 (M+ C33H48N2O248Ti35Cl2 requires 622.2567).
4.4.2. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
dene)]-3-phenyl-1,2-diaminopropanato] titaniumIV chloride 11b
Obtained as a red/brown solid (100%). Mp 291.0–291.4 °C (de-
comp.). ½a 2D0
¼ ꢀ266:7 (c 0.006, CHCl3). mmax 2953 (s), 2866 (m),
ꢂ

2812
Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
1608 (s), 1559 (s) and 1546 cmꢀ1 (s). dH 1.20 (9H, s), 1.22 (9H, s),
1.43 (9H, s), 1.45 (9H, s), 2.97 (1H, dd, J 13.2, 6.5 Hz), 3.47 (1H,
dd, J 13.1, 8.6 Hz), 3.7–3.8 (1H, m), 4.1–4.2 (1H, m), 4.40 (1H, dd,
J 13.1, 5.4 Hz), 6.85 (1H, d, J 2.2 Hz), 7.2–7.3 (1H, m), 7.4–7.5 (2H,
m), 7.59 (1H, s), 8.23 (1H, s). dc 29.4, 30.0, 31.2, 31.3, 34.4, 34.5,
35.5, 35.6, 41.2, 63.7, 69.8, 125.3, 127.1, 127.7, 128.0, 129.0,
129.5, 129.8, 131.4, 131.7, 137.1, 137.2, 137.4, 144.5, 144.6,
159.9, 160.9, 164.5, 165.2. m/z (EI) 663.4 (MꢀCl+, 26), 234.3 (20),
219.2 (100), 86.1 (31), 84.1 (48), 48.9 (26). Found (EI) 698.2879
(M+ C39H52N2O248Ti35Cl2 requires 698.2880).
4.5.2. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
dene)]-3-phenyl-1,2-diaminopropanato] vanadiumV chloride 12b
Obtained as
a
green solid (82%). Mp 130.1–130.6 °C.
½
a 2D0
ꢂ
¼ ꢀ690:0 (c 0.02, CHCl3). mmax 2955 (s), 2869 (m), 1611 (s)
and 1548 cmꢀ1 (s). dH 1.22 (9H, s), 1.25 (9H, s), 1.34 (9H, s), 1.44
(9H, s), 3.0–3.2 (2H, m), 4.0–4.1 (1H, m), 4.3–4.4 (1H, m), 4.6–4.7
(1H, m), 7.0–7.3 (6H, m), 7.57 (1H, s), 7.66 (1H, s), 7.78 (1H, s),
8.01 (1H, s), 8.75 (1H, s). dc 14.5, 14.7, 24.3, 28.9, 29.4, 31.2, 31.3,
31.4, 31.5, 34.6, 51.2, 127.2, 127.5, 128.1, 128.5, 128.8, 129.0,
129.3, 129.6, 129.7, 130.0, 132.1, 132.5, 159.1, 169.7. m/z (ESI)
647.4 (MꢀCl+, 100). Found (ESI) 647.3414 (MꢀCl+ C39H52N2O3V re-
quires 647.3412).
4.4.3. [(1R)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
dene)]-1-phenyl-1,2-diaminoethanato] titaniumIV chloride 11c
Obtained as a red/brown solid (100%). Mp 368.2–369.0 °C (de-
4.5.3. [(1R)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
comp.). ½a 2D0
ꢂ
¼ þ1300:0 (c 0.004, CHCl3). mmax 2956 (s), 2868 (m),
dene)]-1-phenyl-1,2-diaminoethanato] vanadiumV chloride 12c
1614 (s), 1560 (m) and 1547 cmꢀ1 (m). dH 1.18 (9H, s), 1.26 (9H,
s), 1.45 (9H, s), 1.47 (9H, s), 3.86 (1H, dd, J 13.6, 5.3 Hz), 4.7–4.8
(1H, m), 5.3–5.4 (1H, m), 6.92 (1H, d, J 2.3 Hz), 7.26 (1H, d, J
2.3 Hz), 7.3–7.4 (2H, m), 7.4–7.5 (3H, m), 7.48 (1H, d, J 2.3 Hz),
7.5–7.6 (1H, m), 7.71 (1H, d, J 2.1 Hz), 8.25 (1H, d, J 1.5 Hz). dc
30.1, 31.3, 31.4, 34.5, 34.6, 35.6, 35.7, 65.8, 70.0, 125.5, 125.6,
125.9, 126.0, 129.5, 129.7, 129.8, 130.0, 131.4, 131.5, 135.4,
137.2, 137.3, 144.7, 144.8, 159.6, 164.0, 164.2. m/z (EI) 684.2 (M+,
100), 630.3 (20), 126.9 (20). Found (EI) 684.2723 (M+
C38H50N2O248Ti35Cl2 requires 684.2723).
Obtained as a green solid (90%). Mp 163.2–163.4 °C. ½a D20
¼ þ320:0 (c
ꢂ
0.02, CHCl3). m
max 2956 (m), 2921 (s), 2852 (m), 1614 (s) and 1584 cmꢀ1
(m). dH 1.16 (9H, s), 1.18 (9H, s), 1.33 (9H, s), 1.35 (9H, s), 3.8–3.9 (1H,
m), 4.0–4.2 (1H, m), 4.95 (1H, dd, J 8.2, 3.6 Hz), 6.9–7.0 (2H, m), 7.2–7.5
(5H, m), 7.6–7.7 (2H, m), 8.25 (1H, s), 8.34 (1H, s). dc 24.6, 28.8, 29.2,
31.4, 31.7, 34.5, 34.8, 51.1, 51.5, 72.7, 127.5, 128.8, 128.9, 129.0, 129.3,
129.6, 129.7, 129.9, 130.0, 130.2, 132.1, 132.5, 132.7, 136.2, 144.7, 164.3,
169.4, 169.8. m/z (ESI) 633.2 (MꢀCl+, 100), 611.1 (28), 116.0 (13). Found
633.3254 (MꢀCl+ C38H50N2O2V requires 633.3261).
4.6. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
4.4.4. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
dene)]-3-methyl-1,2-diaminobutanato] titaniumIV chloride 11d
Obtained as a red/brown solid (100%). Mp 163.6–163.8 °C (de-
dene)]-3-methyl-1,2-diaminobutanato] vanadiumV chloride 12d
Ligand 8d (560 mg, 1.05 mmol) was dissolved in dry THF
(35 mL), and vanadiumV oxychloride (0.15 mL, 1.58 mmol,
1.5 equiv) was added with stirring. The solution was stirred at
room temperature for 30 min, then the solvent was removed in va-
cuo. The residue was purified by column chromatography on silica
gel using first EtOAc/hexane (3:1), then EtOAc/hexane/MeOH
(1:1:1) as eluents. Collection of the dark green fractions and re-
moval of the solvent in vacuo gave complex 12d (599 mg, 90%)
comp.). ½a 2D0
¼ ꢀ240:0 (c 0.005, CHCl3). mmax 2955 (s), 2869 (m),
ꢂ
1606 (s) and 1543 cmꢀ1 (s). dH 0.92 (3H, d, J 6.7 Hz), 0.94 (3H, d,
J 6.7 Hz), 1.23 (9H, s), 1.25 (9H, s), 1.42 (9H, s), 1.44 (9H, s), 2.3–
2.5 (1H, m), 3.6–3.7 (1H, m), 3.95 (1H, dd, J 13.5, 3.4 Hz), 4.32
(1H, dd, J 12.7, 5.0 Hz), 7.2–7.3 (2H, m), 7.5–7.6 (2H, m), 8.23
(1H, s), 8.29 (1H, s). dc 18.8, 19.5, 20.2, 26.7, 29.6, 29.7, 31.1,
31.3, 34.4, 34.6, 35.5, 60.9, 74.6, 125.2, 125.3, 129.4, 129.8, 131.4,
131.5, 137.0, 137.1, 144.3, 144.4, 160.0, 160.7, 164.7, 165.0. m/z
(EI) 615.3 (MꢀCl+, 10), 234.2 (21), 219.2 (100), 57 (9). Found (EI)
648.2928 (M+ C35H52N2O246Ti35Cl2 requires 648.2927).
as a green solid. Mp 184.7–184.9 °C. ½a D20
¼ ꢀ3600:0 (c 0.0033,
ꢂ
CHCl3). mmax 2955 (m), 2869 (m), 1614 (s) and 1557 cmꢀ1 (m). dH
0.88 (3H, d, J 6.6 Hz), 1.02 (3H, d, J 6.6 Hz), 1.28 (9H, s), 1.30 (9H,
s), 1.43 (9H, s), 1.45 (9H, s), 2.0–2.1 (1H, m), 3.70 (1H, dd, J 9.8,
3.5 Hz), 4.18 (1H, d, J 13.0 Hz), 4.97 (1H, d, J 8.0 Hz), 7.4–7.5 (2H,
m), 7.6–7.7 (2H, m), 8.63 (1H, s), 8.72 (1H, s). dc 19.6, 20.0, 20.1,
29.8, 29.9, 30.1, 30.4, 31.3, 31.7, 34.8, 35.9, 36.1, 63.4, 120.9,
121.3, 121.8, 128.2, 129.7, 132.2, 132.6, 135.9, 136.5, 144.5,
162.2, 164.8, 165.7, 166.5. m/z (ESI) 599.3 (MꢀCl+, 100). Found
599.3415 (MꢀCl+ C35H52N2O3V requires 599.3412).
4.5. General procedure for the synthesis of vanadium oxychloride
complexes 12a–c
Ligands 8a–c (1.0 equiv) and vanadyl sulfate hydrate (1.8 equiv)
were dissolved in dry ethanol with gentle warming. Dry THF was
added and the solution was refluxed for 3 h. The solution was then
allowed to cool to room temperature, and the solvent was removed
in vacuo. The residue was taken up in acetonitrile, and ceric ammo-
nium nitrate (1.2 equiv) was added. The mixture was stirred at
room temperature for 10 min, then the solvent was removed in va-
cuo. The residue was taken up in dichloromethane, washed with
1M aqueous hydrochloric acid and brine, dried (Na2SO4), filtered
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using first CH2Cl2, then EtOAc/MeOH
(2:1) as eluents to give complexes 12a–c.
4.7. General procedure forthe synthesis of copperII(salen) complexes
13a–d
To a solution of ligands 10a–d (1.0 equiv) in ethanol/water
(8:1) was added copperII acetate monohydrate (1.0 equiv). The
mixture was then heated at reflux with vigorous stirring for
2 h, after which the solution was allowed to cool to room tem-
perature. The solvent was removed in vacuo, and Et2O was
added to the residue causing a purple solid to precipitate. The
solid was filtered, washed with Et2O and hexane and air dried
to give complexes 13a–d.
4.5.1. [(2S)-[N,N0-Bis-(20-hydroxy-30,50-di-tert-butyl benzyli-
dene)]-1,2-diaminopropanato] vanadiumV chloride 12a
Obtained as
a
green solid (50%). Mp 164.1–164.4 °C.
½
a 2D0
ꢂ
¼ þ1050:0 (c 0.002, CHCl3). mmax 2955 (m), 2868 (m), 1615
4.7.1. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-1,2-diamino-
(s) and 1549 cmꢀ1 (m). dH 1.28 (9H, s), 1.30 (9H, s), 1.4–1.5 (21H,
m), 3.9–4.0 (2H, m), 4.5–4.7 (1H, m), 7.4–7.5 (2H, m), 7.6–7.7
(2H, m), 8.27 (1H, s), 8.31 (1H, s). dc 19.5, 29.7, 30.2, 31.6, 31.7,
34.8, 36.1, 121.5, 121.9, 128.4, 129.1, 132.3, 134.1, 164.3, 164.9.
m/z (ESI) 571.4 (MꢀCl+, 100), 102.1 (77). Found (ESI) 571.3098
(MꢀCl+ C33H48N2O3V requires 571.3099).
propanato] copperII 13a
Obtained as
a purple solid (60%). Mp 237.6–238.0 °C.
½
a 2D0
ꢂ
¼ ꢀ140:0 (c 0.02, CHCl3). mmax 2970 (m), 2912 (m), 1622 (s),
1599 (s), 1536 (s) and 1469 cmꢀ1 (m). m/z (EI) 343.1 (M+, 83),
146.0 (100), 132.0 (94), 49.1 (88). Found (ESI) 344.0582 (MH+
C17H17N2O2Cu requires 344.0581).

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2813
4.7.2. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-phenyl-1,2-
diaminopropanato] copperII 13b
1588 (s), 1558 (m), 1519 (m), 1485 (m) and 1217 (s). m/z (EI)
399.2 (M+, 19), 235.0 (100), 220.0 (13). Found (EI) 399.0755 (M+
C19H20N2O4Co requires 399.0750).
Obtained as a purple solid (57%). Mp 195.8–196.4 °C (decomp.).
½
a 2D0
ꢂ
¼ ꢀ320:0 (c 0.01, CHCl3). mmax 3024 (w), 2938 (w), 1621 (s),
1598 (s), 1558 (s), 1495 (m) and 1468 cmꢀ1 (m). m/z (EI) 419.2
(M+, 56), 330.1 (43), 328.1 (100), 132.0 (22). Found (EI) 419.0811
(M+ C23H20N2O2Cu requires 419.0815).
4.8.5. [(2S)-[N,N0-Bis-(20-hydroxy-40-methoxybenzyl-idene)]-3-
phenyl-1,2-diaminopropanato] cobaltII 15b
Obtained as a bright orange solid (40%). Mp 288.8–289.0 °C (de-
comp.). ½a 2D0
ꢂ
¼ ꢀ1500:0 (c 0.02, CHCl3).
mmax 2904 (m), 1587 (s), 1519
4.7.3. [(1R)-[N,N0-Bis-(20-hydroxybenzylidene)]-1-phenyl-1,2-
diaminoethanato] copperII 13c
(s), 1494 (m), 1449 (m) and 1218 cmꢀ1 (s). m/z (EI) 475.2 (M+, 93),
384.1 (100). Found (EI) 475.1065 (M+ C25H24N2O4Co requires 475.1063).
During the reaction, the product precipitated. The reaction mix-
ture was allowed to cool to room temperature, and the precipitate
was filtered and washed with distilled water, MeOH and Et2O to af-
ford compound 13c as a purple solid (65%). Mp 299.9–300.1 °C.
4.8.6. [(1R)-[N,N0-Bis-(20-hydroxy-40-methoxybenzyl-idene)]-1-
phenyl-1,2-diaminoethanato] cobaltII 15c
Obtained as an orange solid (53%). Mp 295.2–296.6 °C (de-
½
a 2D0
ꢂ
¼ ꢀ400:0 (c 0.01, CHCl3). mmax 3025 (w), 2903 (w), 1626 (s),
comp.). ½a 2D0
¼ þ440:0 (c 0.01, CHCl3). mmax 3033 (w), 2999 (w),
ꢂ
1600 (s), 1538 (s), 1506 (m), 1495 (m) and 1444 cmꢀ1 (s). m/z
(EI) 405.1 (M+, 100), 274.0 (38), 272.0 (91), 208.0 (57), 152.9
(27). Found (EI) 405.0655 (M+ C22H18N2O2Cu requires 405.0659).
2944 (w), 1587 (s), 1531 (m), 1494 (m), 1455 (m), 1441 (m) and
1210 cmꢀ1 (s). m/z (EI) 461.1 (M+, 100), 298.0 (21), 195.0 (10).
Found 461.0908 (M+ C24H22N2O4Co requires 461.0906).
4.7.4. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-methyl-1,2-
diaminobutanato] copperII 13d
4.8.7. [(2S)-[N,N0-Bis-(20-hydroxy-40-methoxybenzyl-idene)]-3-
methyl-1,2-diaminobutanato] cobaltII 15d
Obtained as a purple solid (42%). Mp 109.8–110.2 °C (decomp.).
Obtained as a bright orange solid (64%). Mp 250.6–251.0 °C (de-
½
a 2D0
ꢂ
¼ ꢀ160:0 (c 0.01, CHCl3).
mmax 3019 (m), 2959 (m), 1620 (s), 1599
comp.). ½a 2D0
ꢂ
¼ ꢀ160:0 (c 0.01, CHCl3).
mmax 3000 (w), 2989 (w), 2956
(s), 1531 (s), 1465 (m), 1443 (m) and 1387 cmꢀ1 (s). m/z (EI) 371.1
(M+, 11), 328.1 (11), 132.0 (44), 91.1 (27), 77.1 (24), 49.1 (27), 43.2
(100). Found (ESI) 372.0892 (MH+ C19H23N2O2Cu requires 372.0894).
(w), 2874 (w), 1607 (s), 1586 (m), 1519 (s), 1485 (m), 1463 (m) and
1218 cmꢀ1 (s). m/z (EI) 427.1 (M+, 100), 384.1 (75), 162.0 (24), 43.1
(60). Found (EI) 427.1066 (M+ C21H24N2O4Co requires 427.1063).
4.8. GeneralprocedureforthesynthesisofcobaltII(salen) complexes
14a–c and 15a–d
4.9. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-methyl-1,2-
diaminobutanato] cobaltII 14d
Ligands 9a–d or 10a–c (1.0 equiv) and anhydrous cobaltII ace-
tate (1.0 equiv) were stirred in dry ethanol at 70 °C for 1 h under
a nitrogen atmosphere. During this time a solid precipitated. The
mixture was allowed to cool to room temperature, filtered and
the solid was washed with hexane under a nitrogen atmosphere.
The residue was recrystallized from hot ethanol, followed by filtra-
tion and washing with hexane to give complexes 14a–c and 15a–d.
Ligand 10d (200 mg, 0.64 mmol) and anhydrous cobaltII acetate
(114 mg, 0.64 mmol, 1.0 equiv) were dissolved in dry THF (3 mL),
and the reaction mixture was stirred at 60 °C for 1.5–2 h under a
nitrogen atmosphere. The solution was then cooled to room tem-
perature, and hexane (ca. 10–12 mL) was added until an orange so-
lid precipitated. The precipitate was filtered under nitrogen,
washed with hexane and air dried to give complex 14d as an or-
ange solid (206 mg, 87%). Mp 186.2–186.6 °C (decomp.).
4.8.1. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-1,2-diamino-
propanato] cobaltII 14a
½
a 2D0
ꢂ
¼ ꢀ707:7 (c 0.013, CHCl3). mmax 2962 (m), 1636 (s), 1600 (s),
1564 (s), 1557 (s), 1530 (s) and 1471 cmꢀ1 (m). m/z (EI) 367.1
(M+, 53), 324.2 (36), 176.9 (45), 131.9 (41), 91.1 (54), 77.1 (54),
58.9 (65), 51.1 (78), 43.2 (100). Found (EI) 367.0854 (M+
C19H22N2O4Co requires 367.0851).
Obtained as a chocolate brown solid (42%). Mp 252.8–253.4 °C.
½
a 2D0
ꢂ
¼ ꢀ1180:0 (c 0.02, CHCl3). mmax 2913 (m), 1602 (s), 1591 (s),
1531 (s) and 1469 cmꢀ1 (s). m/z (EI) 339.1 (M+, 34), 84.0 (44),
51.1 (44), 49.0 (100). Found (ESI) 340.0603 (MH+ C17H17N2O2Co re-
quires 340.0617).
4.10. General procedure for the asymmetric synthesis of
cyanohydrin trimethylsilyl ethers and acetates
4.8.2. [(2S)-[N,N0-Bis-(20-hydroxybenzylidene)]-3-phenyl-1,2-
diaminopropanato] cobaltII 14b
The aldehyde (0.984 mmol) and catalysts 11a–d or 12a–d (0.1–
2.0 mol %) were dissolved in freshly distilled CH2Cl2 (5 mL). Tri-
methylsilyl cyanide (0.14 mL, 1.08 mmol, 1.1 equiv) was added,
and the reaction mixture was left to stir at room temperature over-
night. The solution was then filtered through a pad of silica gel
using CH2Cl2 as eluent. The solvent was removed in vacuo to leave
the cyanohydrin trimethylsilyl ether as a yellow oil, which was
analyzed by 1H NMR spectroscopy without further purification to
determine the conversion. A sample of the cyanohydrin trimethyl-
silyl ether and scandium triflate (1 mol %) was dissolved in aceto-
nitrile (5 mL), and Ac2O (2.0 equiv) was added. The reaction
mixture was stirred at room temperature for 20 min, before being
filtered through a pad of silica using CH2Cl2 as eluent. Removal of
the solvent in vacuo gave the cyanohydrin acetate (100% conver-
sion), which was analyzed by chiral GC.
Obtained as an orange/red solid (45%). Mp 279.8–280.0 °C (de-
comp.). ½a 2D0
¼ ꢀ720:0 (c 0.01, CHCl3). mmax 3016 (w), 2942 (w),
ꢂ
1599 (s), 1530 (s), 1494 (m), 1469 (m) and 1440 cmꢀ1 (m). m/z
(EI) 415.1 (M+, 44), 324.1 (82), 91.1 (50), 83.9 (55), 49.1 (100).
Found (EI) 415.0851 (M+ C23H20N2O2Co requires 415.0851).
4.8.3. [(1R)-[N,N0-Bis-(20-hydroxybenzylidene)]-1-phenyl-1,2-
diaminoethanato] cobaltII 14c
Obtained as an orange solid (42%). Mp 276.6–277.0 °C (de-
comp.). ½a 2D0
¼ þ640:0 (c 0.01, CHCl3). mmax 3028 (w), 2911 (w),
ꢂ
1603 (s), 1558(m), 1538 (s), 1495 (m), 1447 (m) and 1441 cmꢀ1
(s). m/z (EI) 401.1 (M+, 100), 268.0 (54). Found (EI) 401.0697 (M+
C22H18N2O2Co requires 401.0695).
4.8.4. [(2S)-[N,N0-Bis-(20-hydroxy-40-methoxy benzylidene)]-1,2-
diaminopropanato] cobaltII 15a
4.10.1. Phenyl-trimethylsilanoxy-acetonitrile 162c
Obtained as a bright red solid (51%). Mp 239.4–240.0 °C (de-
Obtained as a yellow oil (up to 100% conversion, and up to 81%
ee). dH 0.23 (9H, s), 5.48 (1H, s), 7.1–7.3 (5H, m). GC conditions: Ini-
comp.). ½a 2D0
¼ ꢀ560:0 (c 0.01, CHCl3). mmax 2961 (m), 2920 (m),
ꢂ

2814
Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
tial temperature 100 °C, hold for 2 min, ramp rate 5 °C/min. tR
enantiomer 15.7 min, tR S enantiomer 16.0 min.
R
4.11. General procedure for the asymmetric synthesis of amino
nitrile 19
VanadiumV(salen) complexes 12a–d (0.05 mmol, 10 mol %)
were dissolved in toluene (20 mL) under an argon atmosphere,
and the solution was cooled to ꢀ40 °C. Trimethylsilyl cyanide
(0.075 mL, 0.58 mmol, 1.2 equiv) and methanol (0.03 mL,
0.58 mmol, 1.2 equiv) were added, and the reaction mixture was
stirred at ꢀ40 °C for 1 h. Imine 18 (0.085 mL, 0.48 mmol, 1.0 equiv)
was then added, and the reaction mixture was stirred at ꢀ40 °C for
24 h. The reaction mixture was filtered through a pad of silica
using CH2Cl2 as eluent, and the solvent was removed in vacuo to
give amino nitrile 19 as a yellow oil (100% conversion, 690% ee).
dH 4.04 (1H, d, J 13.0 Hz), 4.15 (1H, d, J 13.0 Hz), 4.84 (1H, br s),
4.96 (1H, s), 7.3–7.4 (6H, m), 7.4–7.5 (4H, m). The enantiomeric ex-
cess of the product was determined by the reaction of amino nitrile
19 with (R)-camphor sulfonic acid in an NMR tube. The distereo-
meric excess of the two diastereomers, and hence the enantiomeric
excess of amino nitrile 19, was then determined using 1H NMR
spectroscopy.
4.10.2. (S)-(2-Methylphenyl)-trimethylsilanoxy-acetonitrile2c
Obtained as a yellow oil (93% conversion, 66% ee). dH 0.14 (9H,
s), 2.47 (3H, s), 5.61 (1H, s), 7.2–7.4 (4H, m). GC conditions: Initial
temperature 100 °C, hold for 5 min, ramp rate 1 °C/min. tR R enan-
tiomer 35.4 min, tR S enantiomer 35.7 min.
4.10.3. (S)-(3-Methylphenyl)-trimethylsilanoxy-acetonitrile2c
Obtained as a yellow oil (86% conversion, 81% ee). dH 0.24 (9H,
s), 2.39 (3H, s), 5.46 (1H, s), 7.0–7.3 (4H, m). GC conditions: Initial
temperature 100 °C, hold for 5 min, ramp rate 3 °C/min. tR R enan-
tiomer 29.7 min, tR S enantiomer 30.0 min.
4.10.4. (S)-(4-Methylphenyl)-trimethylsilanoxy-acetonitrile2c
Obtained as a yellow oil (90% conversion, 78% ee). dH 0.22 (9H,
s), 2.37 (3H, s), 5.45 (1H, s), 7.0–7.2 (4H, m). GC conditions: Initial
temperature 100 °C, hold for 5 min, ramp rate 5 °C/min. tR R enan-
tiomer 29.7 min, tR S enantiomer 30.0 min.
4.12. Generalprocedurefortheasymmetricsynthesisof
phenylalanine 21
a-methyl
4.10.5. (S)-(3-Methoxyphenyl)-trimethylsilanoxy-acetonitrile2a
Obtained as a yellow oil (98% conversion, 66% ee). dH 0.24 (9H,
s), 3.85 (3H, s), 5.50 (1H, s), 6.9–7.4 (4H, m). GC conditions: Initial
temperature 120 °C, hold for 5 min, ramp rate 20 °C/min. tR R enan-
tiomer 10.9 min, tR S enantiomer 11.1 min.
( )-4-(Chlorobenzylidene)alanine methyl ester 20 (0.237 g,
1.05 mmol), complexes 13a–d or 14a–d (2 mol %, 0.02 mmol) and
powdered sodium hydroxide (excess) were added to dry toluene
(2.5 mL). Benzyl bromide (0.15 mL, 1.26 mmol, 1.2 equiv) was
added, and the reaction mixture was stirred at room temperature
overnight under an argon atmosphere. Methanol (2 mL) and acetyl
chloride (0.5 mL) were then slowly added to the reaction, and the
mixture was left to stir for another 4 h. The solvents were then re-
moved in vacuo, and the residue was purified by column chroma-
tography on silica gel using first EtOAc (300 mL), followed by
EtOAc/EtOH (4:1) as eluent to give amino ester 21. dH 1.32 (3H,
s), 1.54 (2H, br s), 2.71 (1H, d, J 13.2 Hz), 3.04 (1H, d, J 13.2 Hz),
3.63 (3H, s), 7.0–7.3 (5H, m). dc 28.3, 48.6, 53.7, 60.5, 128.6,
129.0, 131.6, 138.2, 179.2. The enantiomeric excess of compound
21 was determined by reaction with (S)-1-phenylethyl isocyanate
in an NMR tube. The diastereomeric excess of the resulting diaste-
reomers, and hence the enantiomeric excess of amino ester 21,
could then be determined by 1H NMR spectroscopy.
4.10.6. (S)-(4-Methoxyphenyl)-trimethylsilanoxy-acetonitrile2c
Obtained as a yellow oil (100% conversion, 45% ee). dH 0.04 (9H,
s), 3.65 (3H, s), 5.23 (1H, s), 6.7–6.8 (2H, m), 7.1–7.2 (2H, m). GC
conditions: Initial temperature 100 °C, hold for 5 min, ramp rate
2 °C/min, final temperature 180 °C, hold for 5 min. tR R enantiomer
42.9 min, tR S enantiomer 43.3 min.
4.10.7. (S)-(4-Trifluoromethylphenyl)-trimethylsilanoxy-acetonitrile2a
Obtained as a yellow oil (100% conversion, 77% ee). dH 0.27 (9H,
s), 5.55 (1H, s), 6.7–6.8 (2H, m), 7.1–7.2 (2H, m). GC conditions: Ini-
tial temperature 100 °C, hold for 5 min, ramp rate 5 °C/min. tR
enantiomer 17.3 min, tR S enantiomer 17.7 min.
R
4.10.8. (S)-2-Trimethylsilanoxy-deconitrile31
Obtained as a yellow oil (93% conversion, 73% ee). dH 0.21 (9H,
s), 0.86 (3H, t, J 6.7 Hz), 1.0–1.1 (10H, m), 1.2–1.3 (2H, m), 1.5–1.6
(2H, m), 4.41 (1H, t, J 6.6 Hz). GC conditions: Initial temperature
100 °C, hold for 5 min, ramp rate 5 °C/min. tR R enantiomer
19.6 min, tR S enantiomer 19.8 min.
4.13. General procedure for asymmetric Darzens condensations
N,N-Diphenyl-2-halo-acetamide 23 or 24 (0.569 mmol,
1.2 equiv), potassium hydroxide (63 mg, 1.139 mmol, 2.4 equiv.)
and complexes 15a–d (2 mol %) were dissolved in CH2Cl2 (4 mL),
and benzaldehyde (50 mg, 0.474 mmol, 1.0 equiv) was added.
The reaction mixture was stirred at room temperature for 4 h,
and then quenched with 1 M hydrochloric acid (1 mL). The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (3 ꢁ 2 mL). The combined organic phases were washed with
saturated sodium chloride solution (6 mL), dried (Na2SO4), filtered
and the solvent was removed in vacuo. At this stage, the product
was analyzed by 1H NMR spectroscopy to determine the cis/trans
ratio. The product was then purified by column chromatography
on silica gel using hexane/EtOAc (3:1) to give a mixture of cis 25
and trans 26 isomers of product as a yellow oil. HPLC tR cis 10.3
and 12.5 min; tR trans 17.6 and 25.0 min. mmax 3063 (m), 3038
(m), 1689 (s), 1594 (s) and 1492 cmꢀ1 (s). dH(cis) 3.68 (1H, d, J
4.6 Hz), 3.79 (1H, d, J 4.6 Hz), 6.8–7.5 (15H, m). dH(trans) 3.24
(1H, d, J 1.8 Hz), 4.11 (1H, d, J 1.8 Hz), 7.1–7.5 (15H, m). dc(cis)
59.1, 59.4, 126.2, 127.4, 128.3, 128.5, 128.9, 129.6, 129.8, 130.3,
134.2, 135.9, 141.9, 142.2, 165.1. dc(trans) 58.2, 59.0, 126.2,
127.6, 128.3, 128.5, 128.8, 129.6, 129.8, 130.3, 134.2, 135.9,
4.10.9. (S)-2-Trimethylsilanoxy-3-methyl-butanonitrile2a
Obtained as a yellow oil (85% conversion, 73% ee). dH 0.21 (9H,
s), 1.01 (3H, d, J 6.8 Hz), 1.02 (3H, d, J 6.7 Hz), 1.7–1.8 (1H, m), 4.15
(1H, d, J 5.9 Hz). GC conditions: Initial temperature 100 °C, hold for
5 min, ramp rate 5 °C/min. tR R enantiomer 4.5 min, tR S enantio-
mer 4.8 min.
4.10.10. (S)-Cyclohexyl-trimethylsilanoxy-acetonitrile32
Obtained as a yellow oil (91% conversion, 73% ee). dH 0.21 (9H,
s), 0.8–1.1 (6H, m), 1.4–1.7 (5H, m), 4.14 (1H, d, J 6.3 Hz). GC con-
ditions: Initial temperature 100 °C, hold for 5 min, ramp rate 5 °C/
min. tR R enantiomer 17.3 min, tR S enantiomer 17.6 min.
4.10.11. (S)-2-Trimethylsilanoxy-3,3-dimethyl-butanonitrile2c
Obtained as a yellow oil (100% conversion, 45% ee). dH 0.21 (9H,
s), 1.01 (9H, s), 3.99 (1H, s). GC conditions: Initial temperature
100 °C, hold for 5 min, ramp rate 5 °C/min. tR R enantiomer
5.0 min, tR S enantiomer 5.3 min.

Y. N. Belokon0 et al. / Tetrahedron: Asymmetry 19 (2008) 2804–2815
2815
141.9, 142.2, 166.8. Found (ESI) 316.1338 (MH+ C21H18NO2 re-
quires 316.1338).
13. Belokon’, Y. N.; Yashkina, L. V.; Moscalenko, M. A.; Chesnokov, A. A.; Kublitsky,
V. S.; Ikonnikov, N. S.; Orlova, S. A.; Tararov, V. I.; North, M. Russ. Chem. Bull.
1997, 46, 1936–1938.
14. Belokon’, Y. N.; Hunt, J.; North, M. Synlett 2008, 2150–2154.
15. (a) Miller, D. D.; Hsu, F.-L.; Ruffolo, R. R., Jr.; Patil, P. N. J. Med. Chem. 1976, 19,
1382–1384; (b) Laurent, S.; Botteman, F.; Vander Elst, L.; Muller, R. N. Helv.
Chim. Acta 2004, 87, 1077–1089; (c) Corey, E. J.; Grogen, M. J. Org. Lett. 1999, 1,
157–160; (d) Smith, E. L.; Spackman, D. H.; Polglase, W. J. J. Biol. Chem. 1952,
199, 801–817.
Acknowledgements
The authors thank the EPSRC for a studentship (to JH) and the
EPSRC national mass spectrometry service at the University of
Wales, Swansea for low and high resolution mass spectra.
16. (a) Schnell, S.; Karrer, P. Helv. Chim. Acta 1955, 38, 2036–2037; (b) Malkov, A. V.;
ˇ
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17. Compounds 8a–c are known compounds: (a) Kasumov, V. T.; Köksal, F.
Spectrochim. Acta 2005, 61A, 225–231; (b) Kasumov, V. T.; Özalp-Yaman, Sß.;
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