Enantioselective diethylzinc addition to aldehydes using azetidine-derived chiral catalysts

Article abstract of DOI:10.1016/S0040-4039(01)00659-1

High levels of enantioselectivity have been achieved in the diethylzinc addition to both aromatic and aliphatic aldehydes, employing readily available N-substituted-azetidinyl(diphenylmethyl)methanols as chiral catalysts.

Full text of DOI:10.1016/S0040-4039(01)00659-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4243–4245
Enantioselective diethylzinc addition to aldehydes using
azetidine-derived chiral catalysts
P. J. Hermsen, J. G. O. Cremers, L. Thijs and B. Zwanenburg*
Department of Organic Chemistry, NSR Institute for Molecular Structure, Design and Synthesis, University of Nijmegen,
Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received 16 February 2001; accepted 19 April 2001
Abstract—High levels of enantioselectivity have been achieved in the diethylzinc addition to both aromatic and aliphatic
aldehydes, employing readily available N-substituted-azetidinyl(diphenylmethyl)methanols as chiral catalysts. © 2001 Elsevier
Science Ltd. All rights reserved.
One of the most extensively studied methodologies for
asymmetric carbonꢀcarbon formation is the nucleo-
philic addition of organometallic reagents to aldehydes,
catalysed by appropriate chiral ligands. Employing this
methodology for the reaction of aromatic aldehydes
with diethylzinc catalysed by various chiral b-amino
alcohols, 1-aryl-1-ethanols have been obtained in both
excellent chemical yield and enantioselectivity1 (Scheme
1). In contrast, however, the enantioselectivity for
aliphatic aldehydes is usually considerably lower.2
with aldehydes. As these catalysts proved to be very
effective in the diethylzinc reaction, the question arose
as to whether amino carbinols derived from azetidines
would serve the same purpose. One example of such a
ligand, viz. 2, has been prepared from the non-
proteinogenic amino acid azetidine-2-carboxylic acid.9
This ligand showed excellent enantioselectivity for sev-
eral aromatic aldehydes, but gave only moderate induc-
tion in the case of nonanal. Recently, a C2-symmetric
ligand 3 has been reported,10 which showed similar
In the course of our ongoing studies on the synthesis
and application of small-ring functionalised heterocy-
cles,3–7 we recently described the application of N-trityl-
aziridinyl(diphenyl)methanol 18a and its polymer bound
analogue8b as chiral catalysts in the diethylzinc reaction
Scheme 1. Enantioselective addition of diethylzinc to alde-
hydes catalysed by a chiral amino alcohol.
Figure 1. Small-ring heterocyclic amino alcohols used as chiral catalysts for the diethylzinc addition to aldehydes.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00659-1

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P. J. Hermsen et al. / Tetrahedron Letters 42 (2001) 4243–4245
Table 1. Enantioselective addition of diethylzinc to aromatic aldehydes catalysed by several small-ring heterocyclic amino
alcohols
Entry
Aldehyde
Ligand
Yield (%)
Eea (%)
Conf.b
1
2
3
4
5
6
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
2
3
4
5
6
7
–
98
92
88
35
95
72
S9
S10
R
99
62
75
85
92
S
R
S12
7
8
9
Anisaldehyde
Anisaldehyde
Anisaldehyde
2
4
7
–
91
94
100
\99
79
S9
R
S12
10
11
12
Anisaldehyde
p-Cl-Benzaldehyde
Tolualdehyde
3
4
4
92
80
85
92
96
95
S10
R
R
a Determined by chiral GC (Beta-DEX® 120 fused silica column by Supelco).
b Determined by comparison with the absolute optical rotation given in the literature.
behaviour. Bearing in mind that fine-tuning of the
ligand structure may lead to substantial improvement
of the enantioselectivity, we decided to test the poten-
tial catalysts 4–6 (see Fig. 1).
a better-defined environment around the prochiral
reaction centre.
The best ligand, viz. 6, was also tested with some
aliphatic aldehydes. It was found that this catalyst is
also very effective in the enantioselective addition of
diethylzinc to these aliphatic aldehydes. Enantioselec-
tivities ranging from 77 to 97% were obtained, which
are similar to the ones previously observed with ligand
18 and which can be classified as excellent for these
aldehydes (see Table 2).
These ligands are readily accessible from the corre-
sponding azetidinecarboxylic methyl esters, which are
available in multigram quantities using methodologies
previously developed in our laboratory.11 Thus, treat-
ment of methyl 2,4-dibromobutyrate with benzylamine
in the presence of a co-base yields racemic methyl
N-benzyl azetidine-2-carboxylate. Ammoniolysis using
Candida antarctica lipase selectively converts the (S)
ester into the corresponding amide, from which the
remaining (R) ester can be easily separated. Similarly,
treatment of methyl 2,4-dibromobutyrate with optically
pure (S)-a-methylbenzyl amine, followed by chromato-
graphic separation of the diastereoisomeric esters, gives
the desired (S,R)- and (S,S)-methyl N-methylbenzyl-
azetidine-2-carboxylates in optically pure form. Treat-
ment of the three esters with phenylmagnesiumbromide
leads to the potential catalysts 4, 5 and 6, respectively.
In conclusion, we have developed novel highly effective
ligands for the enantioselective addition of diethylzinc
to aldehydes. The results obtained with these ligands in
the case of aromatic aldehydes are comparable to those
reported for ligands 2 and 3, whereas the effectiveness
of catalyst 6 clearly exceeds that of ligand 2 in the case
of aliphatic aldehydes. It should be noted that ligand 6
is readily available, in contrast to catalyst 2, the syn-
thetic accessibility of which is hampered by the high
price and limited commercial availability of (S)-aze-
tidine-2-carboxylic acid. Currently, we are investigating
the application of the ligands 4–6 in other
organometallic reactions, the results of which will be
reported in due time.
Application of catalyst 4 gave very high enantioselec-
tivities for several substituted benzaldehydes (see Table
1).
Table 2. Enantioselective addition of diethylzinc to
aliphatic aldehydes catalysed by azetidinol 6
We then tested the enantioselectivity of ligands 5 and
6, to establish the influence of a second stereogenic
centre. The enantioselectivity for these ligands is quite
contrasting. For ligand 6, a high ee of 95% was
obtained whilst for the diastereomeric ligand 5, an ee
of only 35% was achieved. Clearly, this is a case of
match/mismatch due to the presence of the second
chiral centre. It should be noted, however, that despite
this extra chiral centre, the absolute configuration of
the secondary alcohols is solely determined by the
configuration of the azetidine ring. It is interesting to
compare the results obtained with these four-mem-
bered ring heterocyclic ligands with those for ligand 7,
derived from proline.12 The more strained ring system
clearly exhibits a better enantioselectivity, possibly due
to the inherent conformational rigidity, which results in
Aldehyde
Ligand
Yield (%)
80
Eea (%)
Conf.b
Cyclohexane–
carboxaldehyde
Isovaleraldehyde
Nonaldehyde
Nonaldehyde
Butyraldehyde
Undecylic
6
97
R
6
6
2
3
6
45
65
–
94
80
90
83
68
65
77c
R
Rc
S
S10
Rc
aldehyde
a Determined by chiral GC (Beta-DEX® 120 fused silica column by
Supelco).
b Determined by comparison with the absolute optical rotation given
in the literature.
c Determined by 19F NMR of Mosher’s ester.13

P. J. Hermsen et al. / Tetrahedron Letters 42 (2001) 4243–4245
4245
The following procedure is representative: Ligand 4 (20
mol%) was dissolved in dry toluene (15 ml) and benz-
aldehyde (5 mmol) was added. The reaction mixture
was cooled to 0°C before addition of diethylzinc (1.0 M
in hexane, 10 mmol, 10 ml) and the resulting solution
was stirred at room temperature overnight. The reac-
tion mixture was quenched by addition of saturated
ammonium chloride solution (5 ml) and the product
was extracted with ether. The organic phase was dried
over MgSO4 and the solvents where removed in vacuo.
The crude product was purified by column chromatog-
raphy (Hex./EtOAc, 4:1 (v/v)).
3. Willems, J. G. H.; Hersmis, M. C.; de Gelder, R.; Smits,
J. M. M.; Hammink, J. B.; Dommerholt, F. J.; Thijs, L.;
Zwanenburg, B. J. Chem. Soc., Perkin Trans. 1 1997, 963.
4. (a) Nayak, S. K.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1999, 40, 981; (b) Nayak, S. K.; Thijs, L.; Zwanen-
burg, B. Synlett 1998, 1187.
5. Willems, J. G. H.; Dommerholt, F. J.; Hammink, J. B.;
Vaarhorst, A. M.; Thijs, L.; Zwanenburg, B. Tetrahedron
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6. (a) Zwanenburg, B.; Thijs, L. Pure Appl. Chem. 1996,
735; (b) Zwanenburg, B. Pure Appl. Chem. 1999, 423.
7. Starmans, W. A. J.; Thijs, L.; Zwanenburg, B. Tetra-
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8. (a) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanen-
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Acknowledgements
NWO/CW is gratefully acknowledged for their finan-
cial support.
10. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10,
1673.
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