New chiral tetraaza ligands for the efficient enantioselective addition of dialkylzinc to aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2008.07.099

A series of chiral tetraaza ligands were studied for the enantioselective addition of dialkylzinc to aldehydes. These bis(amino amide) ligands show high enantioselectivity in the addition of organozincs to aromatic aldehydes. Different structural elements on the ligands seem to play an important role in determining the observed enantioselectivity. Ligand 4b (N,N′-bis(N-l-valinyl)-1,3-diaminopropane, with an aliphatic spacer with 3C atoms) catalyzed the addition of Et₂Zn to benzaldehyde, 1-naphtaldehyde, 4-methoxybenzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products with excellent conversions and selectivities and with enantioselectivities of 99, 97, 98, and 82%, respectively. DFT calculations provide an understanding of the mechanism of the enantioselection process.

Full text of DOI:10.1016/j.tet.2008.07.099

Tetrahedron 64 (2008) 9717–9724
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New chiral tetraaza ligands for the efficient enantioselective addition
of dialkylzinc to aromatic aldehydes
,
a
a
,
b,
b
M. Isabel Burguete a , Jorge Escorihuela , Santiago V. Luis , Agustı Lledos , Gregori Ujaque
*
*
*
´
´
a
´
´
´
Departamento de Qu´ımica Inorganica y Organica, Unidad Asociada de Materiales Organicos Avanzados (UAMOA), Universitat Jaume I-CSIC,
Avda. Sos Baynat, s/n, 12071 Castello´n, Spain
b
´
´
´
`
Unitat de Quımica Fısica, Departament de Quımica, Edifici Cn, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Catalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2008
Received in revised form 22 July 2008
Accepted 23 July 2008
Available online 29 July 2008
A series of chiral tetraaza ligands were studied for the enantioselective addition of dialkylzinc to alde-
hydes. These bis(amino amide) ligands show high enantioselectivity in the addition of organozincs to
aromatic aldehydes. Different structural elements on the ligands seem to play an important role in de-
termining the observed enantioselectivity. Ligand 4b (N,N0-bis(N-
L-valinyl)-1,3-diaminopropane, with an
aliphatic spacer with 3C atoms) catalyzed the addition of Et2Zn to benzaldehyde, 1-naphtaldehyde, 4-
methoxybenzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products with
excellent conversions and selectivities and with enantioselectivities of 99, 97, 98, and 82%, respectively.
DFT calculations provide an understanding of the mechanism of the enantioselection process.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tetraaza ligands in important biological systems, such as metal-
loporphyrins, clearly illustrates their potential for the development
The search for new ligands in asymmetric catalysis is a field of
continuous interest.1 In this regard, the use of nitrogen-containing
ligands in catalysis has received increasing attention in the last
years.2 For practical applications it is convenient that these ligands
can be easily prepared through simple synthetic pathways from
easily accessible starting materials. Special attention has been given
to the synthesis of C2-symmetric molecules since this kind of
molecules is generally considered advantageous in catalysis be-
cause of the associated reduction in the number of possible tran-
sition states for enantioselective reactions.3 Among the catalytic
C–C bond-forming reactions, the enantioselective addition of dio-
rganozinc reagents to aldehydes represents one of the most im-
portant and fundamental asymmetric reactions.4 Since the first
report by Oguni and Omi,5 different families of chiral ligands
of efficient and selective catalysis.14 Due to their easy accessibility,
bis(amino amides) derived from natural amino acids and having
structure 1 represent an attractive family of C2-symmetric tetra-
dentate tetraaza ligands (see Fig. 1). Cu complexes of simple
a-amino amides 2 have allowed us to develop interesting citrate
sensors.15a Although they do not directly promote the addition of
dialkyl zinc reagents to aldehydes, the corresponding Ni complexes
have shown to be very versatile catalysts for this reaction.15b,c On
the other hand, Polt has studied in detail the use of bis(imino
amides) derivatives 3 containing an aromatic spacer derived from
1,2-diaminobenzene for the same reaction.16 This author could
demonstrate by NMR studies that a tetradentate complex with zinc
is formed by those ligands in the presence of ZnR2 species.
Simple bis(amino amides) 1 containing aliphatic spacers pro-
vide ligands with a higher structural and conformational flexibility.
This kind of compounds have been prepared by our group as pre-
cursors of macrocyclic pseudopeptides being able to display orga-
nogelating properties17a–c or acting as ‘in vivo’ fluorescent pH
have been used for this type of reaction. In this regard, b-amino
alcohols are probably the most used chiral ligands for this kind of
asymmetric reactions.6 Nevertheless, examples of the use of other
C2 ligands include diols,7 such as TADDOLs8 and BINOLs,9
diamines, bis-sulfonamides,10 bis-oxazolines,11 bis(amino alcohol)-
oxalamides,12 etc.
The design, preparation, and study of tetraaza ligands and their
transition metal complexes has been a field of extensive in-
vestigation since the initial report by Ja¨ger.13 The presence of
R
O
O
O
O
NH
HN
O
NH HN
Ph
Ph
H2N
R
R
NH R'
NH2
H2N
N
N
Ph2C
CPh2
2
1
3
* Corresponding authors. Tel.: þ34 964728239; fax: þ34 964728214.
E-mail address: luiss@qio.uji.es (S.V. Luis).
Figure 1. Structures of bis(amino amides) 1, a-amino amide 2, and Polt ligand 3.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.099

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M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
probes.17d On the other hand, homogeneous and supported Cu (II)
complexes of compounds related to 1 have been studied as enan-
tioselective catalysts for the chiral cyclopropanation reaction.17e,f
Here we report on a combined experimental and theoretical study
of those ligands for the catalytic enantioselective alkylation of al-
dehydes with dialkylzinc.
Table 1
Enantioselective addition of Et2Zn to benzaldehyde with ligand 4bc
Entry Solvent
Temp (ꢀC) Time (h) Conversiona (%) Selectivitya eeb (%)
1
2
3
4
5
6
7
8
9
Hexanes
Hexanes
Hexanes
THF
CH3CN
Toluene
CHCl3
0
0
0
0
0
0
0
24
48
72
24
24
24
24
24
24
87
90
99
87
69
65
59
64
91
86
87
87
76
77
82
79
89
65
99 (S)
99 (S)
99 (S)
68 (S)
91 (S)
90 (S)
76 (S)
99 (S)
79 (S)
2. Results and discussion
2.1. Synthesis of ligands
Hexanes ꢁ20
Hexanes þ25
a
Conversions and selectivities were determined by NMR. Selectivity¼(6/
(6þ7))ꢂ100.
Open-chain peptidomimetics 4 derived from L-valine can be
easily prepared starting from the corresponding N-Cbz protected
amino acid through the initial formation of its activated
N-hydroxysuccinimide ester, coupling with a variety of diamines and
final N-deprotection, following previously reported procedures.18
This synthetic procedure is outlined in Scheme 1 and allows an easy
variation of the structural diversity components, i.e., the length of
the aliphatic spacer and the amino acid residue. This is important in
order to improve the optimization, using an iterative process, of the
efficiency of the catalyst, in particular enantioselectivity. Overall
yields for the preparation of compounds 4, after the final depro-
tection step, were in the range 80–90%, being essentially in-
dependent of the nature and length of the aliphatic spacer.
b
Determined by chiral HPLC (Chiralcel OD); the major enantiomer obtained is
indicated in parenthesis.
c
Yield can be calculated as (conversion (%)ꢂselectivity (%))/100.
conditions, but after 72 h, the reaction was essentially complete
(86% yield for 6) (entry 3). When different solvents were consid-
ered, a remarkable effect was found on the enantioselectivity and
the conversion. Non-coordinating solvents such as hexanes and
toluene gave higher enantioselectivities than coordinating solvents
such as THF (entry 4), although differences in selectivity were
lower. When changing the solvent from hexanes to toluene (entry
6), the enantioselectivity decreased from 99 to 90%, but conversion
decreased even more significantly. In the case of THF a good yield
but moderate-low enantioselectivity was obtained after 24 h, in
good agreement with the results reported by Soai with bidentate
ligands.20 It is interesting to note that the opposite effect (en-
hancement of the enantioselectivity) has been found by Dangel and
Polt in the case of tetradentate ligands 3 containing aromatic
spacers and imino groups.16a In the case of CHCl3 and CH3CN,
conversions were low for both solvents after 24 h (entries 5 and 7).
A good enantioselectivity was detected, however, for CH3CN (53%
yield, 91% ee), while it decreased to 76% ee for CHCl3. Since hexanes
gave the best enantioselectivity, this solvent was selected for the
rest of the study.
O
O
O
H
N
H
N
i)
ii)
N
Cbz
O
OH
O
O
Cbz
O
O
O
H
N
H
iii), iv)
N
H2N
NH2
N
N
H
Cbz
Cbz
N
H
N
H
H
n
n
4a-f; n = 0, 1, 2, 3, 4, 6
Scheme 1. Synthesis of chiral bisamide ligands. Reagents: (i) DCC, N-hydroxy-
succinimide, THF, rt; (ii) H2NCH2(CH2)nCH2NH2, DME, rt; (iii) HBr/AcOH; (iv) NaOH aq.
The effect of the temperature was also investigated. Initial ex-
periments were carried out by slow addition of Et2Zn in hexanes
over the solution containing 4b at 0 ꢀC. After 30 min the mixture
was allowed to reach room temperature, benzaldehyde (in hex-
anes) was added, and the reaction was kept at room temperature
for 24 h. Decreasing the reaction temperature to ꢁ20 ꢀC resulted
only in a slight increase of the selectivity, but at the expenses of
much lower reaction rates. On the other hand, when the reaction
(including the addition step) was carried out at room temperature,
the enantioselectivity decreased to 79%. According to the former
results, all subsequent reactions were carried out according to the
initial protocol in hexanes at 0 ꢀC.
In order to determine the optimal amount of the ligand needed
for the addition of diethylzinc to benzaldehyde, initial experiments
using variable quantities of ligand 4b were carried out. In these
studies, the concentrations of benzaldehyde and diethylzinc were
kept constant at 0.3 and 0.6 mM, respectively, and the reaction was
conducted at 0 ꢀC in hexanes. Low conversions (yields lower than
50%) and enantiomeric excesses were observed when using load-
ings of 4b ranging from 0.1 to 0.05 mol % of the catalyst (24 h re-
action time). At 0.5% loading, the ee observed was 87%, with an 87%
conversion (66% yield). Optimum results, in terms of conversion
and enantioselectivity were achieved when 5 mol % of 4b were
used (76% yield, 99% ee). An increase of the quantity of ligand up to
10 mol % only improved slightly the yield, but not enantioselectivity
(83% yield, 99% ee). Thus, for all subsequent reactions loadings of
the chiral ligands were kept at 5 mol % (Fig. 2).
2.2. Enantioselective additions of diethylzinc to aldehydes
Since benzaldehyde has been the most extensively studied
substrate, we focused our effort on the diethylzinc addition to
benzaldehyde in our initial studies (Scheme 2). The enantiose-
lective addition of diethylzinc to benzaldehyde was evaluated in the
presence of a catalytic amount of the chiral ligand 4b. Ligand 4b,
which is based on L-valine and an aliphatic spacer with 3 carbon
atoms was used to optimize the reaction conditions for the addition
of alkylzinc reagents to aldehydes. For these studies the catalytic Zn
(II) complex was formed in situ from Et2Zn and ligand 4b.19 Com-
plex formation was found to be complete after 1 h at reflux. Dif-
ferent solvents were initially assayed in order to study their effect
and to select the optimal one for the reaction. The reaction was
carried out at 0 ꢀC using 5 mol % of ligand 4b.
O
OH
OH
4a-f
solvent
H
Et2Zn
5
7
6
Scheme 2. Diethylzinc addition to benzaldehyde.
As can be seen from Table 1, the addition of diethylzinc to
benzaldehyde at 0 ꢀC in hexanes afforded, after 24 h, an 87% con-
version with 86% selectivity toward 1-phenyl-1-propanol, pro-
viding a 75% yield for 6 with 99% ee (entry 1). Under the same
The optimized reaction protocol was then used for the enan-
tioselective addition of diethylzinc to benzaldehyde using other

M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
9719
Table 3
Conversion of 5
Selectivity to 6
Yield for 6
Enantioselective addition of Me2Zn to benzaldehyde with ligands 4a–fa
Yielda,b (%)
eec (%)
100
80
60
40
20
0
Entry
Ligand
n
Enantioselectivity for 6
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
0
1
2
3
4
6
71 (99)
83 (99)
82 (99)
74 (99)
72 (99)
75 (99)
89 (S)
90 (S)
92 (S)
90 (S)
89 (S)
85 (S)
a
All reactions were carried out in hexane at 0 ꢀC.
b
Conversions after 24 h, 5% of catalyst was used; conversions were determined by
NMR. Conversions for 48 h are given in parentheses.
c
Determined by GC analysis (capillary column VF-5ms).
para-position (Table 4, entry 5). However, attempts to alkylate ali-
phatic aldehydes, such as hexanal, with diethylzinc or dimethylzinc
in the presence of ligands 4b or 4f were unsuccessful. No conver-
sion was detected after 24 h, neither at 0 ꢀC nor at room tempera-
ture. The lower basicity of the oxygen atom of aliphatic aldehydes
can be, most likely, at the origin of this behavior. As in the case of
benzaldehyde, all the additions to aromatic aldehydes provided the
corresponding S-alcohols as the major isomer with excellent
enantioselectivities (82–98% ee) and in moderate to high yields
(Table 3, entries 1–6). In all cases, again, 4b showed a slightly better
performance than 4f (Table 4).
The relationship between the enantiomeric composition of the
chiral ligand 4b and that of the product arising from the addition of
diethylzinc to benzaldehyde was also investigated. The complete
absence of non-linear effects is in full agreement with the partici-
pation of 1:1 catalytic molecular complexes and allows to rule out
the presence of aggregates species.
0.05
0.1
0.5
1
5
Ligand 4b loading (% mol)
10
20
Figure 2. Effect of ligand loading (4b) on the conversion and ee of the addition of
diethylzinc (0.6 mM) to benzaldehyde (0.3 mM) (24 h).
ligands (4a–f) containing spacers of different lengths. All reactions
were carried out in hexanes at 0 ꢀC. Selectivities ranged for all cases
from 80 to 87%.
As can be seen from Table 2, the addition of diethylzinc to
benzaldehyde at 0 ꢀC afforded (S)-1-phenyl-1-propanol with ex-
cellent enantioselectivities when using those chiral open-chain
pseudopeptides. Although conversions ranged from 72 to 87% after
24 h, almost quantitative conversions (higher than 95%) were
obtained after 48 h. Rather surprisingly, the results show that the
effect of the spacer is not very significant. Only when a very large
spacer derived from 1,8-octanediamine was used (4f) the enan-
tioselectivity decreased to 89% (entry 6). In this regard, modeling
studies suggest that the flexible coordination sphere of Zn(II) al-
lows to easily accommodate those structural changes with only
minor distortions on the tetrahedral coordination of the metal. As
a matter of fact, ESI-MS experiments confirmed the formation of
the corresponding 1:1 complexes for all the ligands.19
The catalytic efficiency of ligands 4 for the addition of Me2Zn to
benzaldehyde was also examined. Reactions were run using 2 equiv
of Me2Zn and 5 mol % of the corresponding bis(amino amide) li-
gand. Results obtained showed similar trends to those found in the
case of Et2Zn. In both cases, ligands 4b and 4c, containing C3 and C4
spacers, seem to provide slightly superior catalytic efficiencies.
Those results encouraged us to apply this reaction to other
2.3. DFT mechanistic analysis
In order to obtain a more detailed understanding of the mech-
anism involved, DFT studies were carried out.
Noyori and co-workers have studied the reaction mechanism
extensively, both experimentally21 and theoretically22 for the ad-
dition of diethylzinc to benzaldehyde mediated by amino alcohols.
In 1995, based on the molecular orbital calculations at the restricted
Hartree–Fock level, Yamakawa and Noyori established the partici-
pation of two 5/4/4-fused tricyclic transition states (the numbers
refer to the size of the rings involved in the process) and one bi-
cyclic TS (see Fig. 3). Among the three possible stereoisomeric TSs,
the tricyclic anti-configuration is the most favored, being 2.9–
3.1 kcal/mol more stable than the tricyclic syn-configuration and
6.9 kcal/mol more stable than the bicyclic TS. In the tricyclic anti-TS,
alkyl migration takes place with retention of configuration,
whereas the high-energy bicyclic pathway would give inversion of
the migrating alkyl group. Similar results were obtained by
aldehydes. Thus, the performance of ligands 4b (N,N0-bis(N-
valinyl)-1,3-diaminopropane) and 4f (N,N0-bis(N-
diaminooctane) were examined for the enantioselective addition
of diethylzinc to a variety of aldehydes under the optimized (see
Table 4). Bulky aromatic aldehydes such as 1-naphthaldehyde also
gave excellent ee values (97%, Table 4, entry 3). The best enantio-
selectivity (98% ee) was obtained for 4-methoxybenzaldehyde,
L-
L
-valinyl)-1,3-
Table 4
a
substrate bearing an electron-donating substituent at the
Enantioselective R2Zn addition to aromatic aldehydes with ligand 4ba
Entry
Ligand
Aryl group
R0
Yieldb (%)
eec (%)
Table 2
1
2
3
4
5
6
7
8
9
10
4b
4f
4b
4f
4b
4f
4b
4f
Phenyl
Phenyl
Et
Et
Et
Et
Et
Et
Et
Et
87
77
80
73
90
83
68
60
83
75
99 (S)
89 (S)
97 (S)
89 (S)
98 (S)
91 (S)
82 (S)
81 (S)
90 (S)
85 (S)
Enantioselective addition of Et2Zn to benzaldehyde with ligands 4a–fa
1-Naphthyl
1-Naphthyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Chlorophenyl
4-Chlorophenyl
Phenyl
Entry
Ligand
n
Yielda,b (%)
eec (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
0
1
2
3
4
6
72 (98)
87 (99)
85 (99)
77 (99)
72 (98)
77 (97)
92 (S)
99 (S)
99 (S)
97 (S)
95 (S)
89 (S)
4b
4f
Me
Me
Phenyl
a
a
All reactions were carried out in hexanes at 0 ꢀC using 5 mol % of 4.
Conversions (after 24 h) were determined by NMR. Conversions for 48 h are
All reactions were carried out in hexanes at 0 ꢀC.
Yields after 24 h, 5% of catalyst was used; yields were determined by NMR.
b
b
given in parentheses.
Quantitative yields were obtained after 48 h.
c
c
Determined by chiral HPLC (Chiralcel OD).
Determined by chiral HPLC (Chiralcel OD).

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M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
H2
N
O
O
H2
N
H2
R
iPr
iPr
R
R
N
Zn
N
Zn
Zn
N
H
3
H
3
2
2
O
O
N
4
N
4
NH2
1
O
O
NH2
1
O
O
O
O
Zn
Zn
NH
5
R
H
Zn
H
Zn
H
Zn R
R
R H
7
9
H
9
O
8
O
NH
CH2
Ph
R
R
Zn
6
Ph
Pri
CH3
Pri
Zn CH2
CH3
8
H
anti tricyclic TS
syn tricyclic TS
bicyclic TS
H3C CH2
CH2
H3C
6
7
Figure 3. Transition states characterized by Yamakawa and Noyori. The terms anti and
syn are used to define the relative disposition of the two terminal rings in the tricyclic
anti-trans TS 10a
syn-trans TS 10b
TSs.
Figure 5. Schematic representation of the anti and syn transition states in the bis(a-
mino amide) promoted addition of diethylzinc to benzaldehyde. Numbering is arbi-
trary and has been used in geometry discussions.
Goldfuss and Houk by means of ONIOM (RHF/LanL2DZ:UFF)
calculations.23
Taking those studies as a starting point, rationalization of the
observed enantioselectivity of enantioselective dialkylzinc addi-
tions to benzaldehyde catalyzed by amino alcohols has been carried
out by different research groups.24 However, the situation can be
very different for the related reaction using tetradentated ligands
such as 4, and theoretical approaches to understand the corre-
sponding mechanism have not been reported up to now. Following
the mechanism described by Yamakawa and Noyori, it can be ra-
tionalized that, the first step must be the coordination of benzal-
dehyde to the catalytic zinc. For this, the oxygen can use either of its
two lone pairs (cis or trans to Ph) giving place to two possible (cis or
trans) complexes. In the case of amino alcohols, coordination to
zinc takes place through displacement of a solvent molecule to
afford tetrahedral zinc complexes like the trans complex 8 (Fig. 4).
This seems unreasonable in the case of Zn-bis(amino amide)
complexes for the stronger coordination ability of amine nitrogen
atoms. Accordingly, the oxygen atom of benzaldehyde is expected
to coordinate to zinc in an apical position to give place to a complex
like 9 (trans complex), taking into consideration that this metal ion,
Zn(II), is able to present bi-, tetra-, and pentacoordination num-
bers.25 In both cases, the chiral ligand favors the approach of
benzaldehyde and the Et2Zn moiety by one of the faces of the mean
plane of the complex. Thus, the configuration shown in 9 with the
Et2Zn fragment located trans to the isopropyl group of the neigh-
boring ring stereogenic center seems the most reasonable.
As in the case of amino alcohols, the anti-trans TS 10a will
provide access to the S enantiomer. The R enantiomer could be
formed via the syn-trans (10b) or anti-cis pathway. The syn-cis TS
would favor the formation of the S enantiomer, but this is always
highly disfavored due to steric crowd (Fig. 5).
In order to check this hypothesis and examine the origin of the
enantioselectivity of the alkylation of benzaldehyde and other al-
dehydes promoted by ligands 4, the reaction mechanism was the-
oretically investigated by means of DFT methods (see Section 4).
The system investigated was the same as the experimental one,
corresponding to complex 9. First of all, calculations confirmed the
hypothesis for the generation of the initial product forming com-
plex 9. When a tetrahedral complex was investigated upon
decoordination of an amine group, a high-energy intermediate was
found (þ25.8 kcal/mol) whereas the benzaldehyde coordination to
form a pentacoordinated complex was found to be much more
favorable (ꢁ13.6 kcal/mol). Upon this coordination, the aldehyde is
electrophilically activated, as suggested by the longer C]O bond of
1.233 Å in 9, compared with 1.216 Å in free benzaldehyde. On the
other hand, diethylzinc becomes significantly more nucleophilic
upon coordination, as suggested by the increase on the Zn–C bonds
in contrast with free diethylzinc (2.105 vs 2.023 Å). Complex 9 is
formed with an exothermicity of 8.1 kcal/mol from ligand 4,
benzaldehyde, and diethylzinc. Among the two possible benzal-
dehyde coordinations, the trans configuration is 0.9 kcal/mol more
stable than the cis one. The trans complex alternative to 9 in which
the benzaldehyde approaches from below the six-membered che-
late ring was calculate to be 0.3 kcal/mol less stable by DFT
calculations.
The stereochemical outcome of the alkylation reaction was ra-
tionalized by transition state modeling. Comparison of the struc-
tures of the diastereomeric transition states 10 provides an
understanding of the mechanism of enantioselection. Each transi-
tion state structure found possesses a single imaginary frequency,
which corresponds to the migration of the suitably oriented ethyl
group to the carbonyl carbon (Fig. 6). As can be seen in Table 5, the
most favored structure is the anti-trans structure. These results are
in agreement with the previous studies by Noyori and co-workers,
despite of the fact that in this case the catalytic Zn(II) is
pentacoordinated.
The anti-cis TS is calculated to be 4.0 kcal/mol higher in energy
relative to the anti-trans TS. The energy difference between these
diastereomeric structures can be provided by several steric in-
teractions, in particular one taking place between the phenyl ring in
benzaldehyde and one isopropyl group from a valine fragment. In
the anti-trans structure, attack of diethylzinc can take place without
a significant deformation in the O1–Zn2–N4–Zn5 ring system with
a dihedral angle of ꢁ3.8ꢀ. On the contrary, in the anti-cis structure,
to reduce the above-mentioned steric interaction, the Zn2–O1–C8
bond angle becomes wider compared to anti-trans structure (anti-
trans, 126ꢀ; anti-cis, 145ꢀ) and the benzaldehyde molecule rotates;
the O1–C8–C7–Zn5 also increases from 27.7ꢀ to 34.5ꢀ. The distor-
tion is also reflected by the increase in the O1–Zn2–N4–Zn5 di-
hedral angle from ꢁ3.8ꢀ to 10.4ꢀ. The C6–C8–Ph angle increases
from 94.9ꢀ to 102.3ꢀ in the anti-cis TS.
The syn-trans transition structure is 3.4 kcal/mol higher in en-
ergy than the anti-trans structure. The syn-cis TS is 4.1 kcal/mol
higher in energy due to a steric interaction between phenyl ring in
benzaldehyde and the propylene spacer. To avoid a high steric in-
teraction, the C6–C8–Ph angle increases significantly from 100.0ꢀ to
110.3ꢀ in the syn-cis TS and the Zn2–O1–C8 bond angle becomes
wider compared to the anti-trans structure as was observed for the
anti transition states (syn-trans, 122ꢀ; syn-cis, 149ꢀ).
O
H
N
H
NH2
N
Zn
CH3
N
NH
An important point is the flexibility of the 5/4/4 ring system core
of the transition states. In agreement with the findings of Noyori
and Yamakawa, the O1–Zn2 distance representing the common
edge of the four-membered rings is shorter in syn transition states
than in anti type ones. A geometrical characteristic that shows this
flexibility is the value of the C9–N4–Zn5 angle. This angle notably
increases from 113.4ꢀ in the anti-trans TS to 122.2ꢀ in the anti-cis
Zn
H
H
O
O
O
O
Ph
Zn
Ph
Zn CH3
Et
H3C
Et
8
9
Figure 4. Initial complexes for amino alcohols, as characterized by Yamakawa and
Noyori (8) and for bis(amino amides) (9).

M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
9721
syn-trans
anti-trans
syn-cis
anti-cis
Figure 6. Transition state structures 10, for anti and syn-models calculated from complex 9. Hydrogen atoms omitted for clarity.
one to avoid unfavorable steric interactions. In both syn TSs, the
C9–N4–Zn5 angle is increased in comparison with the anti-trans
value. In the syn TSs this angle remains essentially constant (119.6ꢀ–
120.4ꢀ) (Fig. 6).
The product forming complex 9 (Fig. 7) is regenerated from the
final complex 11 (Zn-bound alkoxylate) upon reaction with dieth-
ylzinc and benzaldehyde, where the formation of a stable dia-
lkylzinc alkoxide dimer or tetramer is a crucial step for the
completion of the catalytic cycle. The stereochemistry of the
alkoxide product is kinetically determined by the relative energy of
the alternative diastereomeric transition states 10. The energy
difference (3.4 kcal/mol) between the two lowest energy transition
states anti-trans and syn-trans would indicate that this ligand
should induce a high degree of enantioselectivity in the alkylation
reaction. From a qualitative point of view, the predicted enantio-
selectivity assuming a Boltzmann distribution at room temperature
(99%) shows a good concordance with the experimentally observed
one at 0 ꢀC (99%).26
To check the effect of the R group in the bis(amino amide) li-
gands (see Fig. 1), we performed the theoretical analysis for R¼CH3.
This is the smallest R group keeping asymmetry in the ligand and is
based on the alanine residue. Some geometrical parameters and
relative energies of the corresponding anti and syn transition states
are shown in Table 6. The energy difference between the transition
states decreases, which, as expected, reflects the importance of the
steric bulk of the amino acid residue in determining the enantio-
selectivity. The anti-trans and syn-trans transition structures are
again the most stable ones, originating from the aldehyde co-
ordination at the less hindered face of the five-membered chelate
ring. The energy difference between the more stable anti-trans and
syn-trans transition structures accounts in favor of the formation of
(S)-1-phenyl-1-propanol. In the case of the anti-cis TS, the presence
Table 5
Relevant geometrical parameters (Å and ꢀ) for the four possible transition states in
the addition of diethylzinc to benzaldehyde for the
L-valine-based tetraaza ligand 4b
Parameter
anti-trans
anti-cis
syn-trans
syn-cis
Relative energy
O1–Zn2
C6–C8
Zn5–C6
O1–C8
C6–C8–O1
C6–C8–Ph
C9–N4–Zn5
O1–C8–C6–Zn5
O1–Zn2–N4–Zn5
0.0
2.268
2.348
2.329
1.293
114.4
94.9
113.4
27.7
ꢁ3.8
4.0
2.265
2.349
2.278
1.293
115.3
102.3
122.2
34.5
3.4
2.252
2.426
2.284
1.294
115.6
100.0
119.6
ꢁ6.7
4.1
2.245
2.419
2.224
1.293
113.6
110.3
120.4
ꢁ20.1
19.2
10.4
49.6
O
O
N
O
N
N
Zn
NH
Zn
NH2
H
Zn
N
NH2
NH2
Zn
N
N
H
Ph
H
O
NH
Zn
O
O
NH
Zn
O
O
O
Ph
Ph
9
10
11
Figure 7. Mechanism of the ethyl transfer reaction.

9722
M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
Table 6
Table 7
Relevant geometrical parameters (Å and ꢀ) of the four possible transition states in
Effect of the steric bulk of the amino acid residuea
the addition of diethylzinc to benzaldehyde for the alanine-based tetraaza ligand
13b
Entry
Aldehyde
Compound
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Benzaldehyde
4-Methoxybenzaldehyde
Benzaldehyde
Benzaldehyde
4-Methoxybenzaldehyde
Benzaldehyde
4-Methoxybenzaldehyde
Benzaldehyde
4-Methoxybenzaldehyde
4b
4b
4b0
12b
12b
13b
13b
14b
14b
85
90
83
96
91
96
91
87
89
99 (S)
98 (S)
99 (R)
95 (S)
98 (S)
62 (S)
70 (S)
97 (S)
99 (S)
Parameter
anti-trans
anti-cis
syn-trans
syn-cis
Relative energy
O1–Zn2
C6–C8
Zn5–C6
O1–C8
C6–C8–O1
Zn5–C6–C8
C6–C8–Ph
C9–N4–Zn5
O1–C8–C6–Zn5
O1–Zn2–N4–Zn5
0.0
2.294
2.348
2.329
1.293
114.4
66.2
102.5
114.5
27.7
1.8
2.265
2.349
2.278
1.293
115.3
66.1
92.3
116.2
34.5
0.7
2.286
2.422
2.286
1.295
115.7
66.2
1.9
2.281
2.361
2.337
1.292
113.5
65.3
94.1
121.9
ꢁ30.9
12.2
95.1
a
All reactions were carried out in hexanes at 0 ꢀC.
Yields after 24 h, 5% of catalyst was used; yields were determined by NMR.
Determined by chiral HPLC (Chiralcel OD).
120.6
ꢁ2.3
12.3
b
c
ꢁ3.8
10.4
of the unfavorable steric interaction forces a deformation in the
ring system to favor the attack of diethylzinc to benzaldehyde.
The theoretically determined transition state energies reveal
that, for the two ligands studied, the effect of the steric bulk of the
amino acid residue can have a remarkable effect on the enantio-
selectivity of the ethylation process. As can be seen from Tables 5
and 6, a decrease in the steric bulk of the amino acid residue, when
changing from valine to alanine, causes a significant decrease in the
energy difference of the transition state structures. In both cases,
however, the anti-trans configuration is preferred over the syn-
trans one. The energy values were also obtained at MP2 level by
single point calculations on the DFT optimized geometries with no
significant differences.
amino acids in good yields. All ligands were tested for the enan-
tioselective alkylation of dialkylzinc to aromatic aldehydes, show-
ing excellent enantioselectivities (up to 99%). The origin of the
enantioselectivity for bisamides was analyzed using high level
theoretical calculations. The calculations predict that the (S) alcohol
should be the predominant product for these ligands, in agreement
with the experimental results. The proposed transition states can
be compared with those proposed by Noyori and others. Four dif-
ferent 5/4/4-fused tricyclic TSs can be detected and derived from
coordination of Et2Zn to one amino group trans to the side chain
and simultaneous trans coordination of benzaldehyde to an axial
position of the central zinc. From those TSs, the anti-trans is the
most stable one for 4b (
D
E¼ꢁ3.4 kcal/mol relative to syn-trans)
In order to check experimentally the validity of those calcula-
tions, we synthesized three additional chiral ligands related to 4b
and differing on the size and nature of the amino acid side chain.
Thus, a further study was carried out with 12b, 13b, and 14b (de-
rived from alanine, phenylalanine, and isoleucine)17a,18a to evaluate
the efficiency of the catalytic process and the effect of the steric
bulk of the amino acid residue on the enantioselectivity of the
reaction (Fig. 8).
favoring the formation of (S)-1-phenyl-1-propanol, which is in
good agreement with experiments. The nature of the TSs agrees
well with our experimental observations on the influence of the
bulkiness of the substituents on the amino acid residue of bisamide
ligands on the enantioselectivity of the catalytic process. Further
studies are in progress in order to study the scope of this process
and the potential application of these catalytic systems to other
synthetically useful transformations.
As expected, the experimental results confirmed the predictions
from calculations.27 Table 7 gathers some results for the addition of
Et2Zn to benzaldehyde and 4-methoxybenzaldehyde. All catalysts
4. Experimental
except 4b0 (entry 3) were derived from
L
-amino acids and gave the
(S)-secondary alcohol as the major product. Since 4b0 was derived
from -valine, the corresponding product had the (R)-configura-
tion. Furthermore, an additional experiment with an S/R ligand
(derived from -valine and -valine) was carried out to support the
4.1. Addition of diethylzinc to aldehydes. General procedure
D
Ligand 4b (100 mg, 0.37 mmol) was placed in a Schlenk tube,
dissolved in anhydrous hexanes (10 mL), and a 1 M solution of
Et2Zn in hexanes (0.41 mL, 0.41 mmol) was added. The solution was
stirred and heated at 50 ꢀC for 1 h. The reaction mixture was then
cooled and benzaldehyde (0.75 mL, 7.4 mmol) was added at 0 ꢀC.
The mixture was stirred for 30 min, a 1 M solution of the Et2Zn in
hexanes (9.0 mL, 9.0 mmol) was added dropwise, and the reaction
mixture was allowed to warm to rt. The reaction mixture was
stirred at rt for 24 h, quenched by the addition of a 1 M solution of
HCl, and the product was extracted into Et2O (3ꢂ10 mL). The
combined extracts were washed with KHCO3, dried with anhydrous
MgSO4, and the solvent was evaporated in vacuo. The crude product
was purified by column chromatography (silica gel, 9:1 hexanes/
ethyl acetate as the eluent) to give the pure alcohol as a colorless oil.
The yield and the selectivity of the reaction were determined by
NMR and the enantiomeric excess was determined by chiral HPLC.
L
D
mechanistic results. As expected, this complex showed to be active
but not enantioselective in the reaction under study. No significant
differences in ee values were detected for the ligands with bulky
side chains (12b, 13b, 14b). Nevertheless, a sharp decrease in the
enantioselectivity was observed for the ligand derived from L-ala-
nine (13b), therefore confirming the theoretical predictions. In-
terestingly, the predicted enantioselectivity assuming a Boltzmann
distribution at room temperature (65%) shows a good concordance
with the observed one at 0 ꢀC (62%).26
3. Conclusions
Chiral tetradentate ligands 4, 12, 13, and 14 having aliphatic
spacers of different lengths can be easily prepared from simple
4.2. Chiral HPLC analyses of the 1-arylpropan-1-ols
O
R
NH HN
O
R
12 b R = CH2Ph
4.2.1. 1-Phenyl-1-propanol
13 b R = CH3
HPLC analysis (Chiralcel OD column), hexanes/2-prop-
anol¼95:5, 1 mL/min, 254 nm (UV detector), tR¼9.45 min for (R)
and tR¼11.35 min for (S).
NH2 H2N
14 b R = CH(CH3)CH2CH3
Figure 8. Tetraaza ligands prepared using different amino acids.

M.I. Burguete et al. / Tetrahedron 64 (2008) 9717–9724
9723
Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley: Hoboken,
NJ, 2007.
4.2.2. 1-(1-Naphthyl)-1-propanol
HPLC (Chiralcel OD column), hexanes/2-propanol¼90:10,
0.5 mL/min, 254 nm (UV detector), tR¼16.5 min for (R) and tR
27.5 min for (S).
2. (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580; (b)
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4.2.3. 1-(40-Methoxyphenyl)-1-propanol
HPLC analysis (Chiralcel OD column), hexanes/2-prop-
anol¼97:3, 1 mL/min, 254 nm (UV detector), tR¼18.34 min for (R)
and tR¼20.79 min for (S).
4.2.4. 1-(40-Chlorophenyl)-1-propanol
5. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
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Lett. 2002, 4, 3947; (d) Da, C.-s.; Han, Z.-j.; Ni, M.; Yang, F.; Liu, D.-x.; Zhou,
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HPLC analysis (Chiralcel OD column), hexanes/2-propanol¼
99:1, 0.5 mL/min, 254 nm (UV detector), tR¼28.86 min for (R) and
tR¼27.15 min for (S).
4.2.5. 1-(40-Tolyl)-1-propanol
´
Riera, A.; Pericas, M. A. J. Org. Chem. 2003, 68, 3130; (f) Altava, B.; Burguete, M.
I.; Collado, M.; Escorihuela, J.; Garcı´a-Verdugo, E.; Luis, S. V.; Vicent, M. J. Ind.
Eng. Chem. Res. 2003, 42, 5977; (g) Burguete, M. I.; Collado, M.; Garcı´a-Verdugo,
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59, 1797; (h) Dave, R.; Sasaki, N. A. Tetrahedron: Asymmetry 2006, 17, 388; (i)
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95:5, 1 mL/min, 254 nm (UV detector), tR¼7.87 min for (R) and
tR¼11.52 min for (S).
4.2.6. 1-Phenyl-1-ethanol
GC analysis, capillary column VF-5ms; 30mꢂ0.25 mm, 0.25
mm,
15 psi; temperatures: injector 230 ꢀC, detector 300 ꢀC, oven ti¼
60 ꢀC, tf¼130 ꢀC, 10 ꢀC/min, tR¼12.18 min for (R) and tR¼12.51 min
for (S).
4.3. Computational details
8. (a) Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley, R. E.; Kuehnle,
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DFT calculations were performed using the Gaussian 03 soft-
ware package.28 All structures were computed using density
functional theory using the non-local hybrid Becke’s three-pa-
rameter exchange functional (denoted as B3LYP)29 with LanL2DZ
pseudopotential and the associated basis set for Zn30 and the 6-31G
(d)31 basis set for the rest of atoms. Initially, conformers of the
compounds were constructed and computed using the semi-
empirical method PM3 in Spartan.32 The most stable ones were
selected for the full DFTcalculation. Transition state structures were
confirmed by intrinsic reaction coordinate (IRC)33 calculations to
the corresponding reactants and products. All transition states and
local minima were validated through frequency analysis. The single
point energies were also computed using the MP2 method (6-31þG
(d,p) for C, H, O, and N and LanL2DZ for Zn), showing that the po-
tential energy surface at the MP2 level is quite similar to that at the
B3LYP level.
9. (a) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry 1997,
8, 585; (b) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233; (c) Lu, G.; Li, X. S.;
Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172; (d) Balsells, J.; Davis, T. J.;
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2006, 62, 9335; (k) Hara, T.; Ukon, T. Tetrahedron: Asymmetry 2007, 18, 2499.
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Acknowledgements
´
Financial support from the Spanish Ministerio de Educacion y
Ciencia (MEC, projects CTQ2005-08016-C03 and CTQ2005-09000-
12. (a) Pastor, I. M.; Adolfsson, H. Tetrahedron Lett. 2002, 43, 1743; (b) Blay, G.;
Ferna´ndez, I.; Marco-Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005,
16, 1207.
13. Ja¨ger, E.-G. Z. Chem. 1968, 8, 392.
14. Bommarius, A. S.; Riebel-Bommarius, B. R. Biocatalysis: Fundamentals and Ap-
plications; John Willey and Sons: New York, NY, 2004.
´
´
C02-01), Fundacio Caixa Castello-UJI (project P1-1B2004-13),
FEDER and Consolider (Ingenio-2010 CSD2007-00006) is ac-
knowledged. J.E. thanks MEC-CSIC for a predoctoral fellowship. G.U.
acknowledges ‘Ramon y Cajal’ contract funded by Spanish MEC.
15. (a) Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L. Dalton Trans. 2007, 4027; (b)
´
Burguete, M. I.; Collado, M.; Escorihuela, J.; Galindo, F.; Garcıa-Verdugo, E.; Luis,
Supplementary data
S. V.; Vicent, M. J. Tetrahedron Lett. 2003, 44, 6891; (c) Burguete, M. I.; Collado,
M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed. 2007, 46, 9002.
16. (a) Dangel, B.; Clarke, M.; Haley, J.; Sames, D.; Polt, R. J. Am. Chem. Soc. 1997, 119,
10865; (b) Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.099.
17. (a) Becerril, J.; Escuder, B.; Miravet, J. F.; Gavara, R.; Luis, S. V. Eur. J. Org. Chem.
2005, 481; (b) Becerril, J.; Burguete, M. I.; Escuder, B.; Luis, S. V.; Miravet, J. F.;
Querol, M. Chem. Commun. 2002, 738; (c) Becerril, J.; Burguete, M. I.; Escuder, B.;
Galindo, F.; Gavara, R.; Miravet, J. F.; Luis, S. V.; Peris, G. Chem.dEur. J. 2004,
3879; (d) Galindo, F.; Burguete, M. I.; Vigara, L.; Luis, S. V.; Kabir, N.; Gavrilovic,
J.; Russell, D. A. Angew. Chem., Int. Ed. 2005, 44, 6504; (e) Adria´n, F.; Burguete,
M. I.; Fraile, J. M.; Garcı´a, J. I.; Garcı´a-Espan˜a, E.; Luis, S. V.; Mayoral, J. A.; Royo,
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