Synthesis of chiral ligands derived from the Betti base and their use in the enantioselective addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)01985-8

A novel procedure for selective direct N,N-alkylation of the chiral Betti base was developed, and a new family of chiral ligands, (S)-1-(α-cycloaminobenzyl)-2-naphthols, were prepared. The ligands with five- and six-membered cyclic amines showed highly efficient asymmetric induction in the addition of diethylzinc to aromatic aldehydes in 93-96% yields and 91-99% ee.

Full text of DOI:10.1016/S0040-4039(02)01985-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8367–8369
Synthesis of chiral ligands derived from the Betti base and their
use in the enantioselective addition of diethylzinc to
aromatic aldehydes
Jun Lu,a Xuenong Xu,a Cunde Wang,a Jiangang He,b Yuefei Hua,* and Hongwen Hua
aDepartment of Chemistry, Nanjing University, Nanjing 210093, People’s Republic of China
bAnalytical Center of China Inspection & Quality Bureau, Nanjing 210001, People’s Republic of China
Received 10 May 2002; revised 2 September 2002; accepted 13 September 2002
Abstract—A novel procedure for selective direct N,N-alkylation of the chiral Betti base was developed, and a new family of chiral
ligands, (S)-1-(a-cycloaminobenzyl)-2-naphthols, were prepared. The ligands with five- and six-membered cyclic amines showed
highly efficient asymmetric induction in the addition of diethylzinc to aromatic aldehydes in 93–96% yields and 91–99% ee.
© 2002 Elsevier Science Ltd. All rights reserved.
Chiral 1,2- and 1,3-amino-hydroxy compounds have
proved to be a very efficient class of ligands in a variety
of asymmetric syntheses catalyzed by metallic ions.
Most have been derived from a few readily available
natural products.1 To increase the understanding of
asymmetric reactions, the design and synthesis of chiral
ligands from non-natural resources is essential research
in the field of synthetic chemistry.2 Therefore, chiral
amino-phenols are gaining increasing importance.3
direct N-alkylation of (S)-1, by which a series of chiral
cycloamine–phenol ligands 4a–c were prepared. In the
asymmetric addition of diethylzinc to aromatic alde-
hydes, these ligands showed highly efficient asymmetric
induction to give the products in up to 96% yield and
99% ee.
All of our initial attempts using published procedures
for selective direct N-alkylation of (S)-1 failed. For
example, pentanediol was obtained quantitatively from
1,5-pentanedial and NaBH4–H2SO4,3a or a mixture of
O-alkylated products was produced using 1,5-
dihalopentane and a variety of bases.6
Racemic 1-(a-aminobenzyl)-2-naphthol (1, the Betti
base) is available in bulk and was resolved into its
enantiomers, (S)-1 and (R)-1, early last century (Chart
1).4 However, they were never employed as chiral lig-
ands in asymmetric catalysis until Cardellicchio’s work
in 1998, in which the asymmetric addition of diethyl-
zinc to benzaldehyde was achieved with ees as high as
99%.3b,c Similar to other reported amino-hydroxy lig-
ands, tertiary amines gave better results than primary
and secondary amines in most cases.3c,f
No suitable method exists for regioselective N-alkyla-
tion of Betti base 1, its chiral N,N-dialkyl derivatives
being prepared by resolving the corresponding racemic
isomers3b,c,5 or by condensation with chiral amines3e–g
rather than directly from (S)-1 or (R)-1. Herein, we
would like to report a novel procedure for selective
Chart 1.
* Corresponding author. Present address: Department of Chemistry,
Tsinghua University, Beijing 100048, P.R. China. Tel.: +86-25-
3592529; fax: +86-25-3317761; e-mail: pyorg@nju.edu.cn
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01985-8

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J. Lu et al. / Tetrahedron Letters 43 (2002) 8367–8369
Scheme 4.
Table 1. Enantioselective addition of ZnEt2 to aromatic
aldehydes catalyzed by ligands 4a–c
Scheme 2.
Entry
Ar
Ligand
Y (%)a
% eeb
1
2
3
4
5
6
7
8
C6H5−
4b
4b
4b
4b
4b
4b
4a
4c
95
95
96
95
96
94
93
93
98 (R)
98 (R)
95 (R)
91 (R)
98 (R)
97 (R)
99 (R)
73 (R)
4-CH3C6H4−
4-CH3OC6H4−
2-ClC6H4−
4-FC6H4−
4-CF3C6H4−
C6H5−
Scheme 3.
C6H5−
a Isolated yields.
b Determined by chiral GC (10% permethylated b-CD).
However, the N-cyclization of a 1,2-amino-alcohols
with bis-aldehydes attracted our attention (Scheme 1).
These procedures usually proceed in the presence of a
−
nucleophilic agent, such as a benzotriazole7 or CN,8 to
applications of these ligands in asymmetric catalysis are
being investigated.
yield substituted piperido[2,1-b]oxazolidine derivatives
2 (Scheme 1). The mechanism strongly suggests that an
unsubstituted product could be obtained by using H− as
a nucleophilic species.
Acknowledgements
We found that the unsubstituted piperido[2,1-b]oxazine
derivative 3b could be obtained in 61% yield when (S)-1
was treated with 1,5-pentanedial in the presence of
NaBH3CN in a buffer solution (aqueous EtOH solution
of Na2HPO4–KH2PO4). Similarly, 3a (59%) and 3c
(51%) were obtained smoothly by using 1,4-butanedial
and 1,6-hexanedial, respectively (Scheme 2).
We are grateful to the National Natural Science Foun-
dation of China for financial support.
References
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The asymmetric addition of ZnEt2 to benzaldehyde was
tested in toluene with 10 mol% of the chiral ligands
4a–c to give the products in 93–96% yields and 73–99%
ee (Scheme 4). As shown in Table 1, the size of the
cyclic amine in ligands 4a–c plays an important role in
the asymmetric induction.
In summary, a novel procedure for selective direct
N,N-alkylation of the chiral Betti base was developed
and
a
new family of chiral ligands (S)-1-(a-
cycloaminobenzyl)-2-naphthols were prepared. Their
asymmetric induction was tested primarily in the addi-
tion of diethylzinc to aromatic aldehydes to give the
products in up to 96% yield and 99% ee. Further

J. Lu et al. / Tetrahedron Letters 43 (2002) 8367–8369
8369
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