Zinc(II) mediated asymmetric aldol condensation catalyzed by chiral aziridine ligands

Article abstract of DOI:10.1016/j.tetlet.2015.10.027

Exploration of chiral aziridine ethers and aziridine alcohols as ligands for the Zn(II) catalyzed enantioselective direct aldol condensations reaction is described. The reaction of acetone with NO₂-substituted aromatic aldehydes in the presence

Full text of DOI:10.1016/j.tetlet.2015.10.027

Tetrahedron Letters 56 (2015) 6506–6507
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Tetrahedron Letters
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Zinc(II) mediated asymmetric aldol condensation catalyzed by chiral
aziridine ligands
⇑
Adam M. Pieczonka, Szymon Jarzy n´ ski, Zuzanna Wujkowska, Stanisław Le s´ niak, Michał Rachwalski
University of Łód ´z , Faculty of Chemistry, Department of Organic and Applied Chemistry, Tamka 12, 91-403 Łód ´z , Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 March 2015
Revised 6 July 2015
Accepted 6 October 2015
Available online 8 October 2015
Exploration of chiral aziridine ethers and aziridine alcohols as ligands for the Zn(II) catalyzed enantios-
elective direct aldol condensations reaction is described. The reaction of acetone with NO -substituted
aromatic aldehydes in the presence of water gave the desired adducts in moderate chemical yields
40–70%) and good to excellent enantiomeric excesses (80–98% ee).
2
(
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Aldol condensation
Asymmetric synthesis
Aziridines
Chiral ligands
Aziridine alcohols and ethers
The aldol condensation reaction is one of the most common
tools in modern organic synthesis for the preparation of
carbon–carbon bonds.1–5 While the aldol condensation reaction is
traditionally carried out using anhydrous solvents it can also be
performed in an aqueous environment. However, this area of
research is underdeveloped and remains the current interest of a
corresponding Weinreb amide and subsequent reaction with vari-
ous Grignard reagents leading to aziridinyl ketones which upon
reduction gave the desired N-trityl aziridine alcohols 1a–e as
2
0
59:41 mixtures of diastereoisomers.
Aziridine ethers were prepared from phenoxyacetyl chloride,
which upon treatment with a series of the corresponding sec-
ondary aziridines and subsequent reduction of the tertiary amide,
6–12
number of different research groups.
organic molecules, for example, amino acid derivatives1
been successfully used as ligands, which can act as previously
On the other hand, small
3,14
21
have
gave optically pure (S)-2a, (S)-2b, (R)-2b (Scheme 1).
Having a series of chiral aziridine catalysts 1a–e and 2a,b in
hand, we examined their catalytic activity in the stereocontrolled
asymmetric aldol condensation of acetone and 4-nitrobenzalde-
1
4
studied enzymatic catalysts (mimicking of type II aldolases ),
and thus promote aldol reactions originally catalyzed by the
enzymes.
2
hyde in the presence of 5 mol % catalyst and 5 mol % Zn(OTf) in
2
4,25
In a series of Letters we have described the application of vari-
ous zinc(II) complexes with aziridine ligands in several stereose-
lective reactions; such as the addition of diethylzinc and
acetone/water (2.9/0.1) (Scheme 2).
The reaction time was optimized for 72 h, after which the reac-
tion products were isolated via column chromatography.
As shown in Table 1, aziridine alcohol ligands 1a–e exhibited
similar catalytic activities leading to the corresponding adduct in
yields ranging from 40% to 54% and enantiomeric excesses in the
range of 90–93%. Chiral aziridine ethers 2a,b also possessed com-
parable catalytic efficacy with (S)-2b (bearing a (S)-2-isopropy-
laziridine moiety) emerging as the best ligand to afford the
corresponding aldol adduct in 60% yield and 93% ee (Table 1,
entry 7).
The most effective ligand (S)-2b was also tested as a chiral cat-
alyst in the aldol condensation of acetone with 2-nitro- and 2,4-
dinitrobenzaldehyde (Table 1, entries 9 and 10). In both cases,
the yields of the corresponding adducts were higher than with 4-
nitrobenzaldehyde (72%), however the values of enantiomeric
1
5–21
22
phenylethynylzinc to aldehydes
and enones. Furthermore,
2
3
chiral aziridine ligands have been successfully applied to the
asymmetric aldol condensation reaction in the presence of Zn(II)
2
4
salts.
As a continuation of our research interests, we decided to
examine the catalytic activity of previously synthesized aziridine
alcohols2 and aziridine ethers in the asymmetric aldol reaction.
0
21
Chiral N-trityl aziridine alcohols 1 and aziridine ethers 2 were
synthesized as previously described.2
0,21
Catalysts of type 1 were
obtained from N-trityl aziridine-2-carboxylic acid ester via the
⇑
Corresponding author. Tel.: +48 426355767.
E-mail address: mrach14@wp.pl (M. Rachwalski).
http://dx.doi.org/10.1016/j.tetlet.2015.10.027
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

A. M. Pieczonka et al. / Tetrahedron Letters 56 (2015) 6506–6507
6507
OH
R2
an efficient catalytic system for the aldol reaction of acetone with
nitrobenzaldehydes furnishing products with up to 98% ee.
R1
O
R
N
N
Trt
Acknowledgements
1
2
2
Financial support by the National Science Centre (NCN), Grant
No. 2012/05/D/ST5/00505 for M.R. is gratefully acknowledged.
1
R = Me (1a) R = Bn (1d)
R = Ph (1b) R = H (1e)
R = Me, R = H ((S)-2a)
1
2
R = iPr, R = H ((S)-2b)
R = H, R = iPr ((R)-2b)
i
1
2
R = Pr (1c)
References and notes
Scheme 1. Chiral aziridine ligands 1a–e and 2a,b.
1
2
.
.
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O
Ligand 1a-e or 2a,b
OH O
O
Zn(OTf)2
H
H2O
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R
R
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5
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and 2a,b.
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7
8
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1
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Catalyst
R
Yield (%)a
eeb (%)
Abs conf.c
R27
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2b
2c
2b
2b
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
2-NO
2
2
2
2
2
2
2
2
2
50
40
48
52
54
40
60
44
72
72
93
92
91
90
93
88
93
90
47
98
2
2
2
2
2
2
7
7
7
7
7
7
7
R
R
R
R
R
R
1
1
1
2012, 77, 173–187.
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425.
2
S
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2
8
9
R
R
1
0
2,4-DiNO
2
2013, 24, 1336–1340.
a
Reaction conditions: acetone (2.9 mL), H
OTf) (0.025 mmol), aldehyde (1 mmol), 72 h, rt).
Determined by HPLC using a Chiralpak OD-H column.
2
O (0.1 mL), catalyst (0.025 mmol), Zn
18. Le s´ niak, S.; Pieczonka, A. M.; Jarzy n´ ski, S.; Justyna, K.; Rachwalski, E.
(
2
Tetrahedron: Asymmetry 2013, 24, 1341–1344.
b
19. Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219–223.
20. Jarzy n´ ski, S.; Le s´ niak, S.; Pieczonka, A. M.; Rachwalski, M. Tetrahedron:
Asymmetry 2015, 26, 35–40.
c
27–29
Taken from the literature
retention times in HPLC chromatograms).
(on the basis of optical rotations signs and
2
1. Pieczonka, A. M.; Le s´ niak, S.; Jarzy n´ ski, S.; Rachwalski, M. Tetrahedron:
Asymmetry 2015, 26, 148–151.
2
2. Rachwalski, M.; Jarzy n´ ski, S.; Le s´ niak, S. Tetrahedron: Asymmetry 2013, 24,
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excess were variable—47% for the reaction of 2-nitrobenzaldehyde
(
Table 1, entry 9) and 98% for the reaction of 2,4-dinitrobenzalde-
23. Le s´ niak, S.; Rachwalski, M.; Pieczonka, A. M. Curr. Org. Chem. 2014, 18, 3045–
065.
4. Pieczonka, A. M.; Le s´ niak, S.; Rachwalski, M. Tetrahedron Lett. 2014, 55, 2373–
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25. General procedure for the aldol reactions of acetone with aldehydes: Acetone
3
hyde (Table 1, entry 10). The use of aziridine carbinols 1a–e led to
adducts with (R)-absolute configuration. The use of both enan-
tiomers of aziridine ethers (S)-2b and (R)-2b gave the opposite
enantiomers of adducts (entries 7 and 8) which was in accordance
with our previous findings.26
2
2
(
2.9 mL) and
0.025 mmol) and Zn(OTf)
5 min the aldehyde was added, and the resulting mixture stirred at rt and
H
2
O (0.1 mL) were added to
a vial containing the catalyst
(
2
(0.025 mmol). After vigorous stirring at rt for
1
We presume that aziridine ligands 1a–e and 2a,b in combina-
tion with the Zn(II) salt creates an active catalyst which acts as a
Lewis acid through the generation of a zinc enolate (also mimick-
ing the mode of action of type II aldolase).1
monitored by TLC. Following reaction completion, the solvent was evaporated
and the aldol product was purified by flash column chromatography (hexane/
EtOAc). Spectroscopic data of all products were in agreement with published
15
data.
4,29–32
26. Rachwalski, M.; Le s´ niak, S.; Kiełbasi n´ ski, P. Tetrahedron: Asymmetry 2011, 22,
1325–1327.
It is worth mentioning that the application of chiral, small
amine–ether molecules as catalysts, have only been described spo-
radically in the literature.2
2
2
7. Zhou, Y.; Shan, Z. Tetrahedron: Asymmetry 2006, 17, 1671–1677.
8. Subba Reddy, B. V.; Bhavani, K.; Raju, B. V.; Yadav, J. S. Tetrahedron: Asymmetry
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0. Gu, Q.; Wang, X.-F.; Wang, L.; Wu, X.-Y.; Zhou, Q.-L. Tetrahedron: Asymmetry
1,33–36
2
3
The scope of the substrates was limited to nitro-substituted
aldehydes due the fact that such compounds exhibit the highest
2006, 17, 1537–1540.
12,14
activity in this reaction
(especially 2-nitrosubstituted ones as
31. Jankowska, J.; Młynarski, J. J. Org. Chem. 2006, 71, 1317–1321.
32. Jankowska, J.; Paradowska, J.; Rakiel, B.; Młynarski, J. J. Org. Chem. 2007, 72,
explained by Maycock and Ventura37). Previous experiments
conducted in our group using benzaldehydes without the nitro
functional group in the reaction with acetone as well as aliphatic
aldehydes in the reaction with cyclohexanone14 gave no products
or proceeded with low chemical yields and ee values around 10%.
In conclusion we have reported that aziridine-ether ligands in
2
228–2231.
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3
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3
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combination with Zn(OTf)
2
in the presence of water constitutes
37. Maycock, C. D.; Ventura, M. R. Tetrahedron: Asymmetry 2012, 23, 1262–1271.