Novel enantiomer-switching catalysts for asymmetric reductions and Michael reactions

Article abstract of DOI:10.1016/S0040-4039(00)01986-9

The newly developed chiral ligands 1 and 2 show opposite enantioselectivity in prochiral ketone reduction and Michael addition reactions resulting in the production of both enantiomers of the products in good chemical and enantiomeric yield.

Full text of DOI:10.1016/S0040-4039(00)01986-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 719–721
Novel enantiomer-switching catalysts for asymmetric reductions
and Michael reactions
S. Narasimhan,* S. Velmathi, R. Balakumar and V. Radhakrishnan
Centre for Natural Products, SPIC Science Foundation, 111, Mount road, Guindy, Chennai 600 032, India
Received 10 July 2000; revised 16 October 2000; accepted 8 November 2000
Abstract—The newly developed chiral ligands 1 and 2 show opposite enantioselectivity in prochiral ketone reduction and Michael
addition reactions resulting in the production of both enantiomers of the products in good chemical and enantiomeric yield.
©
2001 Elsevier Science Ltd. All rights reserved.
Asymmetric Michael reactions are amongst the mos1t
important methods for creating asymmetric centres.
Earlier we synthesised the new chiral reagents 1 and 2
starting from salicylaldehyde and L-valine methyl ester
2,3
(Scheme 1). We now report the unique behaviour of
‘enantiomeric switching’ in the asymmetric reduction of
Scheme 1.
Scheme 2.
Keywords: Michael reaction; methyl 2-(N-2%-hydroxybenzyl)amino-3-methylbutanoate; 2-[N-2%-hydroxybenzyl]amino-3-methyl-1-butanol; Al-com-
plex; chiral switch.
*
Corresponding author. Fax: (044) 2351504; e-mail: narasimhan s@yahoo.com
–
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01986-9

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S. Narasimhan et al. / Tetrahedron Letters 42 (2001) 719–721
prochiral ketones and Michael additions using ligands 1
and 2. Thus, the bicyclic oxazaborolidines of 2 derived
ratio of 2:1, 4 equivalents of H were liberated instanta-
neously without participation from the ꢀNH group.
2
using BH –THF gave the R-isomer on reduction of
3
ketone 3 in 90% ee, while the Al-complex generated
using LiAlH4 and 2 gave the S-isomer in 60% ee
The Michael reaction of cyclohexenone 8 (n=2) and
diethyl malonate was carried out with 20 mol% of the
Al-complex of 2. A typical work-up procedure gave the
Michael adduct, ee 60% with the R-isomer predominat-
(
Scheme 2, Table 1).
While searching for further applications of these
reagents, we found that Shibasaki and co-workers had
widely studied asymmetric Michael addition using het-
erobimetallic catalysts involving the combination of
monovalent metals like Na or Li with trivalent metals
like La, Gd or Al, achieving excellent enantioselectivity
with BINOL–Al–Li catalysts. This prompted us to
ing, which is similar to the results obtained with cata-
5
lysts having C -symmetry. A similar Michael reaction
2
was carried out with other dialkyl malonates and the
results are presented in Table 2, entries 1–3. Curiously,
the same reaction carried out with the Al-complex of 1
resulted in the S-isomer in 80% ee. In order to study
the efficiency of this catalyst various malonates were
reacted with cyclic enones 8 (n=1 or 2) (Scheme 4), and
the results are presented in Table 2, entries 4–9.
4
form the aluminium complexes of 1 and 2 with LiAlH4
(
Scheme 3) and to study their effect on asymmetric
induction in Michael reactions.
Indeed, the results indicate a high chemical yield and
good enantioselectivity for the S-isomer in short reac-
tion times. The opposite enantioselectivity achieved
with catalysts 1 and 2 may be attributed to the differ-
Ligand 1 when used in a stoichiometric amount reacted
instantaneously with LiAlH liberating two equivalents
4
of hydrogen. However, when ligand 2 was used in a
Table 1. Asymmetric reduction of ketones with boron and aluminium complexes of 2
Substrate
Reagent
Product
Yield (%)
ee% (abs. confg.)
[h]D 23°C c=5, CHCl3
3a
3b
3a
3b
2/1 equiv. LiAlH4
4a
4b
5a
5b
90
90
95
90
60 (S)
55 (R)
90 (R)
85 (S)
−25
−26
+38
+36
¦
2/2 equiv. BH /THF
3
¦
Scheme 3.
Table 2. Asymmetric Michael addition of malonates to cyclic enones with new heterobimetallic catalysts
S.No
Enone 8/9
Malonate (R)
Catalyst
Time (h)
Yield (%)a
ee (%)a
Abs. confg.
[h]D (c=5 in CHCl3)
1
2
3
4
5
6
7
8
9
8, n=2
8, n=2
8, n=2
8, n=1
8, n=1
8, n=1
8, n=2
8, n=2
8, n=2
9
Ethyl
7
7
7
6
6
6
6
6
4
6
5
4
6
5
4
5
4
6
7
5
79
75
80
80 (84)
74
85 (93)
82 (87)
70 (72)
86 (88)
70
60
37
55
73 (91)
–
82 (91)
80 (95)
43 (49)
R
R
R
S
S
S
S
S
S
–
+2
+2
+1
−24
−3
−27
−3
−2
−1
–
Isopropyl
Benzyl
Ethyl
Isopropyl
Benzyl
Ethyl
Isopropyl
Benzyl
Ethyl
Isopropyl
Benzyl
b
6
84 (99)
10
11
12
6 or 7
6 or 7
6 or 7
–
–
–
9
9
65
75
–
–
–
–
a
Values in parentheses indicate the reported yield and ee with (R)-BINOL–Al–Li catalyst (Ref. 4c).
Literature reported ee using L-proline rubidium salt (see Ref. 6).
b

S. Narasimhan et al. / Tetrahedron Letters 42 (2001) 719–721
721
Scheme 4.
ences in the nature of the complexes involved in the
reactions.
added. The mixture was stirred for 4 h. The reaction
was quenched with 1N HCl and the mixture was
extracted with ethyl acetate. The organic layer was
However, when the reaction was extended to acyclic
a,b-unsaturated ketones (trans-chalcone 9), the Michael
addition was smoother but the expected enantioselectiv-
ity was not achieved (entries 10–12). This may be due
to the loss of rigidity in the acyclic system. Thus, the
newly developed heterobimetallic catalysts can behave
as a chiral switch producing either R or S isomers.
washed successively with saturated NaHCO solution,
3
brine and dried over anhydrous Na SO . Removal of
2
4
the solvent under reduced pressure gave a syrupy mass
which on flash column chromatography gave the
product as a colourless oil (1.1 g, 90% yield), [h] −2.86
D
(c=5 in CHCl3).
General experimental procedure for reduction
Acknowledgements
Reduction of 3a using the Al complex of 2: To 2 (1.45 g,
5
mmol), LiAlH (190 mg, 5 mmol) was added and
4
The authors thank Professor T. R. Govindachari for
his encouragement, Dr. S. Swarnalakshmi for valuable
discussions and S.V. thanks CSIR for financial assis-
tance.
stirred. Acetophenone (0.6 mL, 5 mmol) was added and
the mixture stirred for 1 h at 0°C. The reaction was
then quenched with dil. HCl. The reaction mixture was
extracted with chloroform and washed with water. The
chloroform layer was dried over anhydrous sodium
sulfate and the solvent was removed under reduced
pressure. Purification using column chromatography
with hexane:ethyl acetate (98:2) as eluant gave (S)-(−)-
sec-phenethylalcohol (0.54 g, 90%) with an ee of 60%.
References
1. (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Syntheses; Pergamon Press: 1992. (b) Gawley, R. E.;
Aube, J. Principles of Asymmetric Synthesis, Tetrahedron
Organic Chemistry Series; Pergamon Press: Oxford, 1996;
Vol. 14, p. 161.
2. Narasimhan, S.; Swarnalakshmi, S.; Balakumar, R.; Vel-
mathi, S. Synlett 1998, 12, 1321.
Reduction of 3a using the boron complex of 2: To a
freshly prepared solution of 2 (5 mmol), 1 M borane–
THF solution, (10 mL, 10 mmol) was added and the
mixture stirred at room temperature for 30 min. Ace-
tophenone (0.6 mL, 5 mmol) was added and the mix-
ture stirred for 10 min at room temperature, then
quenched with methanol. The reaction mixture was
worked up and purified as above to give (R)-(+)-sec-
phenethylalcohol (0.56 g, 95%) with an ee of 90%.
3. Narasimhan, S.; Balakumar, R. Synth. Commun. 2000, 30,
accepted for publication.
4. (a) Shibasaki, M.; Sasai, H.; Arai, T. J. Am. Chem. Soc.
1994, 116, 1571. (b) Sasai, H.; Arai, T.; Satow, Y.; Houk,
K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
(c) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.;
Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104.
General experimental procedure for Michael addition
reaction
(
d) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int.
Typically, the chiral ligand 1 (237 mg, 1 mmol) in dry
Ed. Engl. 1997, 36, 1236–1256.
5. Manickam, G.; Sundararajan, G. Tetrahedron 1999, 55,
THF was added to a solution of LiAlH (38 mg, 1
4
mmol) in dry THF. The mixture was stirred for 1 h at
room temperature, then 2-cyclohexenone (490 mg, 5
mmol) and diethyl malonate (800 mg, 5 mmol) were
2721.
6. Yamaguchi, M. et al. Angew. Chem., Int. Ed. Engl. 1993,
32, 1176.
.
.